cancer

I N D I A S I N G A P O R E M A L AY S I A

ISBN 979-8-88935-537-3

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Author of “My 6 Mothers”

It took me nearly twenty odd years to deeply understand cancer, cancer biology and cancer investigations. The whole journey was very exciting and thrilling. Understanding

“me too” investigations in cancer was a challenge. With each read, knowledge and wisdom expanded. With time, I became more wise. As learning progressed, so did I. In this small manuscript, I have tried to cut long story short in a more lucid way so as to generate interest of the readers as they traverse with me through the journey of cancer biology, choosing investigations wisely. This long odyssey starting from CBC to NGS is rather an interesting saga of endless investigations deluging the minds of medical students, professionals and even many cancers doctors. Lot of learning is still required to conquer cancer. I, with folded hands pray His Almighty to give me strength to help mankind suffering from this menace. I further urge young medical students to choose oncology as a career as they are the future academic athletes. Hopefully, we can checkmate cancer one-day.

Cancer biology.

Choosing investigations wisely.

It comes directly from my heart as it unleashes my thoughts on the process of moving forward in investigating cancer patients in a poor country where financial toxicity far outweighs the scientific data. C for Cancer. C for Chess. C for Checkmate. C for Conquer. Treating cancer is like winning a chess game where we need to checkmate the opponent, the cancer, to conquer it with the best possible strategy. For this, choosing investigations wisely remains the

key to chalk out best possible moves to achieve the goals. A deep understanding of all the investigations cuts time to make an early move to stalemate, if not checkmate. Every investigation is important. Every chess piece on the chess board carries its own significance. CBC might resemble a pawn but is all powerful. PET might look like mighty king but unluckily is allowed only few steps. We as treating physicians, surgeons, gynaecologists and doctors practicing in any speciality, owe a lot to our Alma mater where all of us received formal medical education regarding human diseases and the ways to checkmate them. Sadly, the ugly part of our medical school teaching was a poor focus on oncology chapters at every level of education, may be at a graduation or a post graduation. We, as medical students, were often made to skip chapters on cancers quite smartly saying that these are high order complex ones meant to be learnt in higher classes from some senior doctors teaching in highly reputed medical colleges like AIIMS, The All India Institute of Medical Sciences, New Delhi. Even The Post Graduate Institute of Medical Education and Research, PGIMER Chandigarh, did not have Medical Oncology department during nineties. What to talk of oncology as a clinical subject, even the pharmacology departments of medical colleges just brushed aside the chapters on chemotherapy and anti cancer drugs. What was happening was beyond human imagination. Pharmacology teachers failed to generate interest in anticancer drugs despite the interesting origin of chemotherapy that dates back to World War 1 times when the vesicant properties of nitrogen mustard was a chance medical invention among the war survivors. Classification of anti cancer drugs was another headache for

students. Mugging them was painful. What to talk of others, pathology people laid too much stress on non malignant topics. Oncology was kept untouched. No one taught oncology. No one taught cancer biology. No one taught investigations pertaining to cancer. No one taught how simple blood tests can be viewed through a different lens. No one taught how simple radiography can suspect cancer. No one taught anatomical boundaries of cancers on CT scans and MRI. All these blessings went a long way in dampening the interest of bubbling medical students to study cancer as a disease and pursue oncology as a career. No one taught chemotherapy. No one taught ways to handle cancer patients. No one taught end of life issues. No one taught the ways to play chess. We as medical students were made to cram chemotherapy to vomit on the examination day and to forget the same as early as possible. Write a short note on cyclophosphamide, was the famous question to be asked in pharmacology examination since years. This all looked shallow. We were made targeted doctors to target non cancerous patients. Was the society waiting for such doctors? Where would the ailing cancer patients go? Left to die a miserable end? All of us passed various professionals with flying colours, received big certificates, earned distinctions, won gold medals and ultimately took an honest Hippocrates oath to serve humanity but without an iota of knowledge regarding the most fearful and dreadful disease, the cancer. What to talk of MBBS level, even post graduate doctors have little knowledge regarding cancer, as teaching at postgraduate level is too shallow. Again, benign diseases take away the precious three years of residency period. The whole journey of internal medicine residency starts with

cardiology, neurology, endocrinology, gastroenterology and ends in benign haematology. Likewise, the surgical residency programmes mostly revolves around learning gastrointestinal surgeries with managing polytrauma along with few breast cancer surgeries here and there. Gynaecologists under three years of training period suffer the same story with obstetrics being the main focus of post graduation with a little spice of gynaecological cancers off and on during academic sessions so as to provide a feel good factor to the trainees and to falsely lift the stature of residency programmes. Anyhow, things are definitely changing but at a snails pace. I am happy that at least, we learnt the ways to refer cancer patients to higher centres where some senior level doctor from highly reputed hospital would treat a high level disease. We were finally made doctors. Yes. Good. But were made soft doctors for treating soft curable diseases where happiness prevails all around and where doctors get the whole credit of curing the benign disease in question. We were never made hard doctors. We were never trained for that. We were largely never showed the ugly part of medical science, the incurable diseases, their unending morbidity and mortality. Chronic diseases like cancer and obesity were kept at an arms length. What to talk about investigations regarding cancer patients, I think, even the word cancer used to fear students as if some monster had stuck somewhere in the thoughts of students and teachers. Pages pertaining to oncology in the famous pathology textbook of Robbins were kept nearly untouched even till now as if some curse would fall on if ever we tried to read and decipher those few pages. Furthermore, we were never trained for counselling patients suffering from incurable disease like cancer. What to talk of

patients, counselling attendants to their fullest possible satisfaction was never a part of college ciruclum. Miserable teachings. Need to change the system seriously. It is an underestimated medical politics where the medical industry is like a factory producing fallacious and flawed doctors who seriously are imperfect medical athletes. Training doctors is like training an army to help society to stay away from the bad bugs, bad diseases and to improve the health quality of the country as a whole. Of course, we don’t expect doctors to replace God and destiny but yes, a fully trained doctor can help citizens enjoy a good quality of life. Few handful doctors are still present here and there possessing good qualities to help medical students grow under holistic protocols but are restricted by the sick system and sick framework of red tapism. Anyways, learning never ends. Time passed. Time and teaching unfolded many things and finally with God’s grace, I was able to understand something about cancer biology. Investigations in any cancer patient range from the simplest known test, the complete blood count, the CBC, to the most complex DNA based tumour mutational burden assessment. Mankind since centuries is known to dig deeper and deeper to understand cancer biology to conquer the worst ever hit disease inflicted to humans. With the passage of time, newer and newer modalities of investigating, interrogating, scrutinizing and understanding tumour biology are evolving as if the scientific community is bent upon eradicating cancer totally from the roots and the society. Investigations ranging from detecting tumours early in the course of disease to finding ways to increase the life span of the most advanced incurable cancers are being developed from time to time. The credit

of discovering microcalcifications on simple X ray of the breasts as a harbinger of underlying breast cancer goes to a German surgeon Albert Salomon who performed radiographs of 100 mastectomy specimens and found that microcalcifications were seen behind majority of the cancerous breasts. This gave birth to the concept of screening breasts to detect microcalcifications as an indicator of underlying tumour by a simple but highly effective diagnostic tool called X ray mammography. This was just a start to the present day ways of cutting tumours specimens to the micron level to conduct immunohistochemistry to study molecular signatures of tumours to find ways to increase the life span of even the most advanced incurable cancers. All this was possible due the tireless work of great people, researchers and scientists with intense vision, idealism and scientific skills. Society owes these investigators a debt of gratitude that can never be adequately repaid. Anyhow, as the world progressed, so the medical field and so the cancers tests. They helped us understand cancer in a better way. It becomes extremely difficult to understand the importance of variety of investigations available as of now and the ways to incorporate each test logically and wisely at each step while treating cancer patients given the infinite number and extent of investigations available in the present modern world. Gone are the days when barium swallow was the first investigation of choice for dysphagia. Rat tail appearances so diagnostic of oesophageal cancers on barium swallow are a history in todays time. All these are forgotten radiological pictures. No one gets barium enema done for suspected colonic cancer in present times. Apple core appearances of right sided colonic cancers as seen on barium

enemas are again abandoned radiological pictures. It is sad. Yes indeed. It looks as if we have buried history. I still remember my first professional MBBS examinations where we had to identify the barium swallow findings and the corresponding culprit lesions. Truly enjoyed each and every basic radiological findings. It is this sense of academic satisfaction that gives a professional kick to move further to discover something new everytime. Every radiological investigation, howsoever small it is, carries its own significance in understanding the natural history of a disease process with utmost clarity. Reading about diseases from older editions of medical textbooks helps understanding biology in a better way. No one forgets the famous Sicilian defence. No one forgets the old moves, the old games, the old strategies and the thrill of the great chess grandmasters like Viswanathan Anand. No one forgets the fact that right sided colonic cancers grow towards the lumen as the stool consistency is still liquid and offers least resistance to the ingrowing tumours. This explains the apple core appearances of right sided colonic cancers on barium enema which have almost vanished in all the latest oncology textbooks. Sad part of the story is vanishing away of the popular concept of olden times too, “An Apple a day keeps the doctor away”. As science evolved, so our understanding. Nowadays, molecular intelligence is on the forefront where just a small sample of peripheral blood unleashes the disease, it’s nature, its cause, it’s natural history, it’s naughty behaviour, the ways to tackle it and to predict the final outcome. This small manuscript would definitely help medical students and practicing doctors in almost any specialty in understanding the “when, what and why” of investigations involved in common

malignancies. It would help doctors refining their ways to understand cancer biology in a better way. It would be a ready reckoner for the treating oncologists to freshen their knowledge in a short time. Every investigation is not required in every cancer patient but rather, we need to choose investigations as per the clinical scenario in question. We cannot play chess randomly. Strategic plan is the only trick to checkmate cancer with the best possible moves. Don’t order investigations blindly. Go step by step. We need to understand the relevance of the relevant investigations which are suitable to that particular cancer in question. The investigations ordered should provide maximum true positives keeping in view the financial aspects too. After all, checkmate is the goal!!! Let’s begin the game. The King has all the power but sadly is powerless as regards the first chess move. Poor fellow. Queen, the most powerful chess piece, again has no square to move in the beginning. Poor queen is worth penniless at the start. Similarly the rooks and the bishops are all worthless at the beginning. The least powerful chess piece, the pawn, becomes most powerful and priceless as it has the legitimate right to start the game. Yes, CBC, the pawn, is THE first investigation to start. Complete blood Count is the FIR, The first information report of any cancer patient. Yes. It is. It is perhaps the most powerful chess piece and the first Sicilian defence. It is THE “First Information report” of the patient without modification with which the patient lands into any clinic or any hospital. All subsequent CBC reports get automatically changed as per the doctors treatment and management given to the patient. This must be carefully preserved in the files, hospital record and be handed over to the patient and to the attendants saying and

emphasizing the huge importance of this so called simple blood test. If patients can keep cumbersome big films of MRI scans, why can’t they keep this simple small piece of paper. They would love to do it. Obviously. It is the simplest test any doctor can offer, the cheapest test any clinic can offer and the fastest test any machine can deliver. It is the most widely available test any country can offer, the least cumbersome test any medical industry can offer, the least biased test any institution can offer and the most accurate test any machine can deliver. It has least false positives, false negatives, true positives and of course true negatives. It is bereft of any sensitivities and specificities. It truly is very naive and innocent investigation which is helping doctors across generations to diagnose and treat human diseases. Sadly, with the advent of newer generation and cumbersome investigations like PET scans, it has taken a back seat in the minds of even the most intelligent doctors across the globe. Nowadays CBC is given the least importance and any variation in CBC is often forgiven and forgotten and never rechecked as the findings by the so called big tests like NGS topple the results of poor CBC. In fact, CBC must be very close to the hearts of all doctors whatsoever branch they are practicing despite any number of new kids on the block. It deserves the label of “The Investigation of the Century”. CBC was, is and would continue challenging physicians and doctors in times to come. It had proven its worth when doctors had nothing except a pulse to palpate and a CBC to finalize treatment. CBC is at the helm of everything even today. It would continue to be the heart throb of million doctors in future too. Howsoever small the test may be, it is the “Lionel Messi” of investigations. The King. CBC is a

window to the events happening in the bone marrow. A rise and fall in counts can be physiological as well as pathological. We need an eye to decide the roads. Discussing physiological sine waves of counts is not the present agenda. Taking things in perspective and starting from the basics, CBC often starts with the king of Blood, the haemoglobin levels. Yes. Majority of our citizens are just crazy for haemoglobin levels. Normal haemoglobin ranges somewhere from twelve to fifteen gram per cent with males having slightly higher values. Haemoglobin lives in a house called red cell occupying some space and volume of approximately eighty femtolitres. In order to accommodate haemoglobin in such a tiny space, the red cell sacrifices its nucleus. Once inside the red cell, haemoglobin starts circulating and keeps on doing a tireless job of a zomato boy to pick oxygen from lungs to deliver it to its clients, the cells and tissues across the body and carry back the bad carbon dioxide from tissues to the lungs for removal. A rise of haemoglobin beyond eighteen looks good. Happy. But, is sadly bad. Haematocrit rises with a rise in haemoglobin thereby slowing down the blood flow. At times, blood flow can halt to form serious clots causing blindness, strokes, heart attacks. Patients with very high haemoglobin are unforgettable once seen. Their looks, their red faces, their red conjunctivas, unexplained headaches, unexplained itching are some of the distinctive feature of this disease. This all looks pretty serious. Yes, of course. Rising haemoglobin beyond eighteen gram percent is bad, the underlying cause must be looked into. At times, there are cancers of the bone marrow called primary polycythaemia vera (PV) behind the unexpected rise in haemoglobin levels which needs to be fixed before a

permanent damage is caused. Obviously, people staying at higher altitude and athletes have a normal physiological rise in their haemoglobin but yes, serum erythropoietin (Epo) helps to differentiate between the two. In primary polycythaemia, erythropoietin levels are low hinting towards autonomous production of haemoglobin by bone marrow signifying its madness. A raised haemoglobin in a case of primary polycythaemia alerts us towards packed cell volume (PCV) or commonly called the haematocrit (Hct) in CBC. As the haemoglobin rises, so does the haematocrit. A haematocrit of more than fifty percent is quite alarming requiring immediate necessary measures to avoid catastrophic events like stroke, coronary blocks and even blindness. Simple emergency measures such as blood letting are life saving. We hardly require costly gadgets for blood letting and thereby controlling raised haematocrit. Think wisely. Think rationally. Simple investigation helped find out raised haematocrit, intervened and saved life. Choose investigations wisely. An elderly patient with extreme lethargy, weakness, asthenia and pallor is an alarming entity. CBC again remains the first investigation of choice. Here a low haemoglobin (hypochromia) with a low red cell volume (microcytic) suggests microcytic hypochromic anaemia with its usual benign causes like nutritional, iron deficiency and many others. But, from oncology perspective, a simple microcytic hypochromic anaemia in elderly alert us towards hidden gastrointestinal tract malignancies which bleed slowly causing chronic blood loss. Carcinoma stomach and carcinoma colon are the two cancers which befool doctors with this kind of presentation. Understand the moves of the opponent, the cancer. Think logically. The situation is

pretty serious in elderly population warranting further investigations to nip the evil in the bud. Eyes see what the mind knows. Minds needs brushing and hammering of the facts again and again. Forgetting simple tips and tricks cost a lot. Both these malignancies are largely treatable and curable if detected early. Choose investigations wisely. Think wisely. Think rationally. Reading and deciphering CBC is an art. Reasons for microcytic hypochromic anaemias are different in different age groups. Looks like a rainbow phenomenon. It is simple iron deficiency in young menstruating, pregnant and lactating females but spell trouble in elderly population where an underlying GI malignancy must be kept as a key differential. Iron is one of the most common metal in earth’s crust, yet nutritional anaemias are quite common in our country. A low haemoglobin with a high corpuscular volume (MCV) suggest macrocytic hypochromic anaemias. Apart from megaloblastic anaemia as the usual cause, myelodysplastic syndromes (MDS) must be kept in mind which are frequently overlooked and underestimated entity. Myelodysplastic syndromes are a group of disorders where there is total chaos in the bone marrow driven by multiple chromosomal hits at the stem cell level acquired during the lifetime of an individual as a result of multiple aetiologies leading to defective erythropoiesis, defective myelopoesis and defective thrombopoesis. The whole bone marrow environment is completely lawless, turbulent and tumultuous. On one side, the stressed and the defective bone marrow tries to cover up quickly by making more good blood cells but unfortunately ends in making defective cells which are as quickly destroyed as they are produced

giving rise a picture of hypercellular bone marrow but pancytopenia in the peripheral blood. Findings of CBC, peripheral smear combined with bone marrow are almost diagnostic of myelodysplastic syndromes. Each series of blood cells in MDS acquire bizarre features with lots of morphological distortions. Hypolobated neutrophils, hyperlobated neutrophils, hypogranular neutrophils, giant platelets, abnormal erythrocytes are a few to recall. Findings of CBC and PBF carry the hidden diagnosis. Be vigilant while looking at things, howsoever simple that test may be. Think wisely. Think rationally. Analyse moves carefully. Remember, we need to checkmate. The very thought of MDS should knee jerk our minds to obtain a good blood sample for cytogentics for risk stratification of MDS in question. Choose investigations wisely. At times, a part of chromosome 5 is lost (5 q deletion ). 5q deletion is a type of myelodysplastic syndrome where patients get severe anaemia. Genes lost. My God!!! Yes. Need to immediate bring back those lost genes to restore the defective marrow to restart normal haematopoiesis. Only cytogentics with FISH can help us finding the clue to the 5 q story. Choose investigations wisely. Think wisely. Think rationally. Story doesn’t end here. Choose correct vials to send blood for cytogentics for understanding chromosomal deformities. Don’t freeze the sample. Cells damage on freezing. Remember, you are taking the culprit in remand for interrogation. Take him alive to get something out. Choose investigations wisely. Think wisely. Think rationally. Moving forward towards white blood cells. A rise in white cell count in CBC indicates infective process to most of the treating doctors but spell trouble to oncologist. High white

cell counts has little value without a good differential and a good peripheral smear. High profile families have little value without understanding the family tree, the background and the throttle behind. Remember this. Think wisely. High leucocyte counts with majority being neutrophils suggest an infective process as in leukemoid reaction. High leucocyte counts with majority being lymphocytes suggest some lymphoproliferative disorder which further can be pinned down using flow cytometry that can help diagnose the exact lymphoproliferative disorder in question. We have enough circulating lymphocytes to type them quickly with flow cytometry. Yes, with flow cytometry. Choose investigations wisely. Think wisely. Think rationally. Chronic lymphocytic leukaemia CLL, small lymphocytic leukaemia SLL, leukemic phase of follicular lymphoma FL, mantle cell leukaemia MCL, hairy cell leukaemia HCL are some of the common lymphoproliferative disorders that can be segregated by flow cytometry within hours but it was only CBC, the first move which suggested and sensed trouble leading onto the cascade and hence the diagnosis. CBC, the pawn is so very important. No investigation howsoever costly can replace it. Choose investigations wisely. Look at things with an eagles eye. Think wisely and rationally. High leucocyte counts with majority being myelocytes, metamyelocytes, basophils, band forms and neutrophils suggest chronic myeloid leukaemia in chronic phase. Myelocytes, metamyelocytes, band forms are the immature precursors of neutrophils. I call them babies of neutrophils. We never send babies on roads to fight. Circulating babies and basophils with very high leucocyte counts reaching upto hundred thousands or more is highly suggestive of

chronic myeloid leukaemia. A middle aged patient, in reasonably good health, comes walking to our clinic with extremely high leucocyte count with periphery full of myeloid precursors and basophils is highly indicative of chronic myeloid leukaemia which can be confirmed by demonstrating philadelphia chromosome on cytogentics and quantifying philadelphia transcripts, the bcr abl transcripts by polymerase chain reaction along with the examination of the bone marrow. All this looks easy. Practically, it’s not that cakewalk. Hardly any physician would think of CML in any asymptomatic patient who by default is found to have raised TLC. A mechanistic reaction would be to repeat counts. Same values repeat time and again. TLC crossing lacs. Subjecting such patients to n number of antibiotics wouldn’t do any good in decreasing counts. Yes. This is CML. This is THE usual presentation of CML. Yes. This is CML. So, friends, a dreadful but curable malignancy, chronic myeloid leukaemia is simply suspected on CBC combined with a good peripheral smear. Yes. Such a powerful test which helps mankind at large is beyond description and needs a big applaud. Time and again, CBC is proving its worth and winning hearts. Choose investigations wisely. Think wisely and think rationally. High counts with majority being blasts spell a doomsday. Yes. It is acute leukaemia beyond doubt. Needs urgent intervention. Definitely. Needs urgent intervention. Needs a quick flow cytometry to classify acute leukaemia into classical lymphoid or myeloid types. At times, when the periphery is flooded with promyelocytes packed with auer rods, it suggests acute promyelocytic leukaemia, APML beyond doubt. APML patients once seen are again

unforgettable. Sadly, they are very sick and bleed from all the orifices profusely. To everyone’s surprise, worlds top and highly reputed haematology organization, American Society of Haematology (ASH) recommends immediate initiation of chemotherapy in such patients without even waiting for molecular confirmation. This speaks volumes of the significant role of CBC and peripheral smear as an investigation. This is too much. It hardly takes an hour or so for the peripheral smear to be reported so as to start chemotherapy in such a worst but curable leukaemia. Great. No cancer is diagnosed within an hour. No cancer treatment is started within an hour. DIC, so common in such patients get reverse in just 24 hours. Courtesy CBC and PBF. Choose investigations wisely. Think wisely. Think rationally. Pawn wins again. Checkmates!!! No investigation on globe can replace CBC and peripheral smear as far as hematological disease are concerned. Some of the mankind’s worst hit disease, acute leukaemia can be picked by CBC only. In acute leukaemia, the patient in question is devoid of mature neutrophils and the blood is full of non functional blasts which carry no power as regards to the control of infections is concerned. We need to start treatment soon to bring the disease under control (in remission) so that mature functional neutrophils start reappearing again in the blood to protect the patient from bacterial and fungal infections. High counts with majority being eosinophils suggest chronic eosinophilic leukaemia (CEL) which too is treatable but needs further genetic work up. High counts with majority being monocytes steers the diagnosis towards monocytic disorders like chronic myelomonocytic leukaemia (CMML ). Absolute monocyte counts crossing

one thousand is enough to interrogate this uncommon but treatable malignancy. Low white cell counts have many benign cause but from oncology perspective, hairy cell leukaemia, burnt out phase of myelofibrosis, acute promyelocytic leukaemia and acute leukaemia must be ruled out by a good bone marrow biopsy. Primary myelofibrosis is one disease that can be picked by sharp clinical instincts. Primary myelofibrosis is a degenerative disorder of the bone marrow whereby the normal spongy marrow starts hardening by fibrosis thereby compromising healthy marrow spaces. In the initial phases, the marrow reacts to fibrosis by getting irritable, sensing trouble thereby quickly releasing all the available cells into peripheral blood resembling the picture of chronic myeloid leukaemia in chronic phase but the white cell counts hardly cross fifty thousand. Whatever functional marrow is left, it simply squeezes everything out in the peripheral blood. Myelocytes and metamyelocytes start making a guest appearance in CBC along with the classical tear drops as if the marrow is literally in tears asking for someone to help. Bone marrow in such early phases of primary myelofibrosis is highly cellular but with time, the poor marrow gets helpless in stopping irreversible fibrosis which ultimately results in complete destruction of all the available spaces in the marrow, causing a complete shut down of the marrow. The crippled marrow becomes totally dependent on liver and spleen for haematopoiesis. This burnt out phase of myelofibrosis is easily recognized on CBC as pancytopenia. It was hyperleucocytosis with circulating immature cells along with tear drop cells that clinched trouble. Think wisely. Think rationally. Moving forward towards platelets,

both a rise and fall in platelet count is a trouble. High platelet counts beyond ten hundred thousand spell disturbance raising the suspicion of a type of blood cancer called essential thrombocytosis (ET) apart from many other harmless cause of raised platelet counts like simple anaemia and blood loss. ET, as is commonly called, essential thrombocytosis is an uncommon disorder of the marrow where there is uncontrolled production of platelets by megakaryocytes. Obviously the counts need to be reduced by chemotherapy, but, yes, it was again the CBC which helped. Leukaemia undoubtedly needs to be ruled out in cases of low platelet counts by doing a good bone marrow examination and peripheral smear. Again CBC assisted. Not only this, there are some patients in whom all three series of cells are increased or decreased. Such like cases of panmyelosis and pancytopenia need further evaluation to rule out acute and chronic leukaemia. Panmyelosis suggests activation of the marrow as a whole. It looks as if someone has switched the marrow “on”. Yes. JAK 2 is THE switch. JAK 2, The Janus, the Greek God with two faces, majestically regulates the signalling at entry doors. No non sense entry is allowed. Patients with panmyelosis have serious defects at the entry points allowing autonomous proliferation of the marrow as a whole. We need to fix the error smartly by getting JAK 2 tested for mutations. Need to checkmate JAK 2 smartness by JAK 2 blockers. Well, pancytopenia is a broad bone marrow problem, the underlying cause ranging from simple nutrition deficiency to extremely serious acute leukemias with an empty marrow sitting in between the spectrum of pancytopenia. Reticulocyte count do help a lot in choosing further investigations but yes, CBC and PBF

play an instrumental role in picking troubled marrow. Two series of cell lines too can be affected as in bicytopenias which further require intelligent intervention. CBC is the king for detecting blood disorders which is powerfully helped by a good peripheral smear. CBC in addition to good peripheral smear form a Jai Veeru Jodi so famous of Sholay. Cutting long story short, CBC is an invaluable test which has stood the test of time. It helps in diagnosing simple diseases like iron deficiency anaemias to the most complex intricate bone marrow disorders like myelodysplastic syndromes. Moving forward with the next old generation but again highly valued investigation very close to my heart is the measurement of erythrocyte sedimentation rate commonly called the famous ESR. Putting in my own words, it measures how fast red blood cells settle down in a test tube if allowed to fall freely under gravity. Simple physics. The height of clear vertical column in mm above the settled red blood cells is the exact value of ESR. We all are well versed with the apple of Newton. RBC is the apple of doctors. Let it fall freely. The first step in ESR is sticking together of red blood cells one above the other to fall freely under gravity but the surface of each red blood cell bears the same negative charge thereby avoiding piling together of red cells. In multiple myeloma, there is excessive secretion of cathodal proteins, the gamma globulins, which increase the attractions between the red blood cells or decreasing the relative repulsion between the red cells causing a more rapid fall of red cells in the ESR tube thereby increasing the vertical height of plasma above the red cells explaining increased ESR above hundreds in myeloma patients. ESR has nothing to do with myeloma per se but yes, it definitely

acts as a strong surrogate to think of myeloma as an underlying cause for many unexplained chronic low back aches, unexplained anaemias, unexplained hypercalcemia, unexplained renal failures, unexplained proteinuria, unexplained lytic lesions in the bones and unexplained pathological fractures. It acts like a black cloud sensing trouble. ESR is a strong alarm. ESR of more than hundreds definitely speaks of multiple myeloma but yes, has to be taken as a whole. Think wisely. Think rationally. Choose investigations wisely. Presence of excess cathodal proteins in myeloma also cause red cells to stick together to cause rouleax formation seen typically on a good peripheral smear. Rouleax again shouts in silence to investigate for myeloma. Simple. See how simple things are. Think wisely. Think rationally. Simple rouleax is again a strong surrogate for underlying multiple myeloma. Raised fibrinogen is the first line of defence against bacterial invasions in sepsis. The fibrin meshwork entraps the bacteria and try eliminating them. As a defence, in sepsis, fibrinogen is raised. Fibrinogen, again being a cathodal protein, raises ESR. In sepsis, raised ESR functions like a strong whistle-blower hinting as if something is somewhere is wrong. Fibrinogen acts as acute phase reactant in sepsis. Perfect chaperon. Think wisely. Think rationally. Choose investigations wisely. No blood test is complete without assessment of the liver function tests. Jaundice in adults warrant a complete assessment of the liver and associated biliary tree. Conjugated hyperbilirubinemia above fifty years of age is suggestive of malignancy. Ampullary carcinomas, extrahepatic cholangiocarcinomas, biliary tract malignancies and gall bladder cancers are among the few who simply present with

obstructive jaundice and conjugated hyperbilirubinemia. Fortunately, ampullary carcinomas are curable to large extent if appropriate whipples surgery be carried at an early stages. Patients with conjugated hyperbilirubinemia look sick with deep jaundice as evident by greenish yellow hue of sclera, extensive yellowish skin pigmentation and generalized itching. All this is a blessing in disguise as early appearance of symptoms forces the jaundiced patient to consult the doctor early rather getting late and ending in having an advanced incurable malignancy. Think wisely. Think rationally. Simple bilirubin values sensed trouble in elderly hence taking wise decisions. Transaminitis is not of much significance in suspecting malignancy because major liver parenchyma needs to undergo substantial necrosis to have a rise in SGOT and SGPT which is not so common in malignancies. Only in advanced cases of malignancies with extensive liver metastasis is transaminitis seen. Significant transaminitis is usually seen in acute states where substantial part of liver parenchyma undergoes necrosis as in acute viral hepatitis and acute alcoholic hepatitis. Rise in conjugated bilirubin is more significant than the rise of liver enzymes to suspect cancer. Raised total proteins with predominantly raised globulins immediately raise the suspicion of multiple myeloma for which further evaluation be carried out accordingly. Serum globulins rise to such significant levels that the famous AG reversal becomes visibly apparent. Think wisely. It is of no surprise that the staging of multiple myeloma still hovers around the values of simple blood tests like serum albumin, serum beta 2 microglobulins and LDH levels. This is too much if deeply understood. Staging myeloma is a simple task. No high end investigations is

required to stage multiple myeloma.!!! Serum beta 2 microglobulin is a protein formed by myeloma cells the values of which are directly proportional to the severity of the cancer. Values of LDH are again directly proportional to the myeloma load. Look how simple things are. We just don’t try to understand and often under rate simple things and simple blood based investigations. Choose investigations wisely. Being observant pays. Being vigilant pays. Look, till now, simple cost effective blood based investigations are helping in diagnosing almost all haematology oncology diseases along with many other common solid tumours. We need to be vigilant in picking up abnormal findings in routine blood tests to pick up cancers fast. Be slow in clinics. Don’t jump. Think. Rethink. See. Observe. Correlate. Slow down. Answers are lying in front. Serum alkaline phosphatase, simply called as SAP, is another enzyme whose values rise in cases of obstructive lesions of the biliary tract. Value of SAP rise in accordance with the rise in conjugated hyperbilirubinemia, though SAP is more slow to rise. In bony metastasis, SAP too rises. Here, we simply have a raised SAP but without hyperbilirubinemia. It helps. In cases of solid tumours suspected of having bony metastasis, SAP helps. Patients with breast cancers having high SAP with normal bilirubin levels are suspected to have bony metastasis which needs confirmation on bone scan. Look how simple things are. Be vigilant. Keep your eyes open. Please don’t underestimate the power of simple blood based tests. Kidney function tests are another group of blood tests which are frequently ordered as a part of initial work up of any cancer patient. Raised creatinine should immediately prompt the treating physicians to think of myeloma. The

renal tubules gets blocked by light chains which are excreted in abundance in myeloma giving rise to raised creatinine. Light chains are proteins formed by plasma cells, the values of which are directly proportional to the tumour load. Light chains get excreted in urine. Unexplained renal failures suggest an underlying multiple myeloma or a light chain disease. Be vigilant. Variations in simple investigations are sometimes a gate to big oncological diagnosis. Think wisely. Lot many myeloma patients simply keep on shuttling between physicians and nephrologists and keep getting unnecessary dialysis. Take care. Not only this, white precipitation occurs on heating small amount of urine in a test tube if light chains are present in urine. Henry Bence Jones, a famous English physician noted this simple but significant observation centuries ago. Remember him whenever you order a urine routine for unexplained proteinuria. Things are simple, but are often forgotten in todays hi technology world. Choose investigations wisely. Think wisely. Hyperkalaemia is another alarming electrolyte abnormality in oncology wards sensing deep trouble. Raised potassium is highly suggestive of tumour lysis. Breaking of tumour cells release lots of potassium beyond the limits to handle, hence the trouble. Spontaneous hyperuricemia with subsequent hyperkalaemia is frequently seen in aggressive lymphomas with high proliferative index as in burkitts lymphoma. Acute lymphoblastic leukaemia with high white cell counts commonly presents with hyperuricemia and hyperkalaemia as a result of spontaneous disintegration of leukemic blasts. Hyperkalaemia is a medical emergency requiring immediate intervention to bring values down. Raised uric acid too is suggestive of tumour lysis. All this

warrants immediate hyperhydration with hyperalkanisation as uric acid dissolves in alkaline ph.. Early use of xanthine oxidase inhibitors helps save the patient from early mortality. Not only this, a single dose of 6 mg rasburicase immediately brings down hyperuricemia. Thanks to rasburicase, which rules in present times. Mortality as a result of tumour lysis is unheard of these days. In multiple myeloma, bone eating cells, the osteoclasts get activated by osteoclast activating factor secreted by myeloma cells stimulating osteoclasts to eat bones thereby releasing lots of calcium in the blood causing hypercalcemia and subsequent trouble. Even lot of solid tumours like advanced breast cancers and head neck squamous cell carcinomas cause hypercalcemia. Hypercalcemia is a serious under recognized electrolyte imbalance. We need to be more observant. Problems are lying in front of us in common blood tests. The eyes see what the mind knows. Think wisely. Think rationally. Hypercalcemia is one of the few life threatening oncological emergencies necessitating emergency measures. Left untreated or unnoticed, patients loose chance of their longevity just because of the shallow knowledge on the part of treating physician in suspecting, diagnosing and treating hypercalcemia. Hypercalcemia demands urgent and aggressive fluid resuscitation, use of bisphosphonates or denosumab in case of concomitant renal dysfunction. No blood test is complete without the assessment of three idiots. Yes, the HBV, HCV and HIV. Serology helps in detecting their presence. Each idiot has its own nuisance. HBV damages the liver causing hepatocellular carcinomas. HCV does the same. In cirrhotics with a positive serology for HBV or HCV, diagnosing hepatocellular cancer in the

presence of classical radiological characteristics become easy and straightforward. HIV subjects are a different kitty of patients suffering from special cancers linked with immunosuppression. HIV knocks off the most powerful defence system, yes, the T cells, allowing a number of HIV related cancers to crop. One such cancer, KS, Kaposi sarcoma was the invention of the world’s greatest Hungarian physician and dermatologist, Dr Moritz Kaposi. He was the pioneer in discovering violet coloured malignant nodules on the skin of HIV patients. With this, he set the ball rolling for discovery of many other cancers specific to HIV population like high grade lymphomas, cervical cancers, cancers of the oral cavity, throat, anus and many more. It is thus a matter of utmost importance to spread awareness among physicians and practicing doctors to check out for the three idiots (HBV, HCV, HIV) before concluding and embarking treatment. Choose investigations wisely. Think wisely. Think rationally. Tumour markers are not much useful in diagnosing cancer at baseline except for a few like PSA, AFP and beta HCG. Raised PSA is highly suggestive of prostate cancer. PSA beyond twenty is almost suggestive of underlying prostatic malignancy. Values below twenty can still be kept under close observation. Raised AFP and beta HCG are quite useful markers in quickly diagnosing germ cell tumours especially the non seminoma in males. Not only this, history and chemistry of choriocarcinoma revolves around HCG which is very close to the hearts of treating gynaecologists and oncologist who as a team are managing these tumours. Pure seminoma are better staged on PET as they are devoid of tumour markers. Plain radiography is another useful modality. Skeletal surveys are

indeed very helpful and save patients from subjecting them to more confusing and costly affairs. X ray skull showing punched out lytic lesions is almost diagnostic of myeloma. Lytic lesions present in any bone is highly suggestive of secondaries. Osteoblastic metastasis are suggestive of prostate cancer if PSA is simultaneously raised. Simple blood tests like complete blood counts, liver function tests, kidney function tests, ESR and simple radiography go a long way in helping pick cancer without the need of so called fancy tests. Mastering over small variations in these tests go a long way in helping patients at low cost. Observant doctors learn and start picking abnormalities soon. It take few months or so to become familiar with abnormal findings in common day to day blood tests. Keep on looking at these simple tests again and again to attain competency. Practice. Yes. Simply practice. Correlate. Try Introspecting. Time is not far when you would start suspecting bony metastasis from a simple rise in serum alkaline phosphatase in liver function test, start diagnosing multiple myeloma from AG reversal, start suspecting myeloma from rouleax formation, start thinking about colonic cancers with a simple fall in haemoglobin, start diagnosing myelofibrosis from tear drop cells in the peripheral blood and so on. Urine examination too is an integral part of investigations. Finding Bence Jones proteins directly suggest multiple myeloma. Urine cytology is often forgotten stuff in cases of suspected urinary bladder cancer. Stool examination too fills the gap in diagnosing cancer from simple tests. Stool for occult blood is suggestive of bleed in the gastrointestinal tract warranting endoscopy, colonoscopy and making us think of gastrointestinal malignancies. In female patients, missing a simple breast

examination along with Pap, HPV testing and colposcopy cost heavily. Things remain hidden at these sites which Indian females try not to disclose. Cancers of breast are leading tumours among females living in urban cities whereas cancers of the cervix is rampant among rural population females. Both these cancers are curable if detected early. Both these organs are easily accessible to simple clinical examination. Sadly females don’t undergo screening. We don’t require costly PET scans to examine and screen breasts and cervix. Both are treatable even if advanced. Bottom line is creation of awareness regarding screening guidelines among doctors who are the torch bearers of society. Public hugely trust medical fraternity. Let’s build more confidence so that more healthy citizens come for screening to detect cancer at a stage when it would largely be curable. Public listens provided we, the doctors and medical professionals educate citizens. I have not seen a single passenger at the airports refusing security check. They very happily and obediently get themselves checked along with their belongings to pass through scanner for security check. Similarly, citizens if counselled sincerely, would definitely get themselves scanned annually or so, as a part of their medical security check up so as to detect cancer at an early stage. After all, we need to checkmate. Compliance would hardly be an issue if things are done sincerely. Moving forwards towards the mighty king of the chessboard. Yes. The all powerful, the king. Yes, the PET Scan. PET was born in Ludhiana somewhere around 2010 in the lap of few wealthy investors who nurtured and cajoled their golden hen. They carried PET in their laps from doctor to doctor, proudly drumbeating regarding the arrival of so called “The

Godfather Test of Cancer” which at that time was seen as a God or Avtaar or Bhagwan in the radiology world. It was extensively marketed as a one stop radiological solution for any cancer patient. It soon turned out to be a big success like a Shah Rukh Khan film. Atmosphere got charged. Everyone was talking about PET PET…and PET. Hashtag “PET”. A strange fear gripped all the radiologists. Giants in the field of radiology started feeling small. Everyone couldn’t invest so much to keep abreast with the latest machines and equipment. Elephants like MRI machines started feeling the heat. They felt ashamed of their all powerful three tesla magnetic strength which was toppled by a new entrant, the PET scan. CT scans too got a big hit. Ultrasound machines looked ancient. Even the technicians felt unemployed. I too cleared dust from my oncology Bibles and started reading again. To me too, a strange quest gripped. I started referring cases for PET scan. To my utter surprise, yes, the tumours started looking brightly coloured. Yes!!! Brightly coloured. Each tumour started looking yellowish orange on PET scan. I got so happy and ecstatic that at times I used to borrow PET films from my patients for a day or so to quietly see them in my retiring room during the night. I simply got fascinated. I could never ever imagine tumours being visually seen as coloured masses. I was used to see tumour masses as black and white on traditional CT films, but the whole gamut changed with PET scans. No more black and white films. All coloured. It looked as if someone has specifically painted tumours and showed them to me. It was a very different and satisfying feeling. My interest in oncology grew more and more with each PET scan. I thought myself as a schoolboy who got coloured crayons in

my clinic to play with. Anyways, time passed. Day and night, I referred patients for PET. Getting PET done after 2 cycles of chemotherapy was pure magic. Yes. The colours disappeared as if someone had erased all the colourful tumour masses. It was captivating. Never ever I had experienced and witnessed such a perfectly enchanting supernatural phenomenon. Yes, my chemotherapy worked, was my immediate conclusion. Yes, chemotherapy works!!!. Yes, CHEMOTHERAPY WORKS. I shouted like a mad but innocent schoolboy as if my teacher had marked my paper and had seconded me my own writings and findings. I already knew that chemotherapy works but observing this magic rekindled my interest in chemotherapy and cancer world. It was a marvellous experience to see tumours vanishing after chemotherapy on PET scans. Not only me, the patients, the attendants and all involved got so much fascinated that they could hardly delay their chemotherapy sessions so as to completely eradicate cancer. I grew. Time passed. PET too grew. Believe me, I totally forgot CBC, PBF, RFT, LFT, ESR, CT Scans, MRI, bone scans and all else. I started doing clinical correlations with PET scan and started following patients longitudinally down the line. I called patients every three month in my clinic to get a follow up PET done. I eagerly waited for the PET reports with the films. In some patient, the colours reappeared. At times, at the previous site and at times, at some distant places. This alarmed of return of the cancer in question. Sad. Yes. Sad. But, I used to take a biopsy or a cytology from the coloured area which had reappeared to confirm its nature histopathologically as my mind was tuned from the very beginning that cytopathology was the surest test of cancer

which I got positive most of the times thereby confirming that reappearance of colour on PET was suggestive of return of the cancer. But, as my experience grew, I was baffled to find that the reappearance of colourful masses never always meant tumour recurrence. Yes, that sounded good for the patient but strange news for me. What was happening? From where did the colour reappear again? If it wasn’t a tumour recurrence, then what was the cause of reappearance of colourful masses? Things started messing up. What looked so easy at the outset baffled me with time. Biopsies that were done on serial follow ups were now showing some sort of inflammatory response to some unknown agents which too was an unanswered question. But, obviously was a good news for both myself and the patients in question. I couldn’t do much to justify inflammatory response but could prescribe some antibiotics for a couple of days and again helplessly follow the patient clinically as repeat PET was costly, cumbersome, worrisome and was adding more of confusions. Out of fear and due to some unanswered questions going in my mind, I called such patients more frequently to my clinic to have some judgement regarding the patient and their disease course but couldn’t really prescribe another PET as I would again stand with the same blank face in front of the patients without giving them a proper explanation to the reappearance of colours on repeat PET. Things moved on. Slowly and slowly, I realized that in majority of the cases I could not answer much to many of the observations and findings which appeared on serial PET scans which I felt totally helpless and too under read oncophysician. I felt as if I have an incomplete knowledge regarding cancer biology. It was shameful indeed. Yes, I was

honestly accepting my trivial command on the subject. A strange feeling of emptiness gripped me about my superficial knowledge concerning PET scan and its clinico radiological correlations for cancer patients. I started getting scary in prescribing PET scans to my patients. I very well knew I will not be able to answer to much of their queries. An investigation nearing twenty thousand rupees is a huge money in low income country like ours. It was a shameful act on my part. It was absolutely not justified. Yes. Not justified. I started thinking before I prescribed PET. With whatever experience I had gathered, I felt, leaving aside lymphomas and a few more cancers, I could hardly figure out any cancer in which I could fully justify such a huge payment on a single radiological investigation. Let me explain in simple words. Going back to my good old knowledge of investigating cancers, simple X ray of pelvis or lumbosacral spine costing just few hundred rupees could stage my prostate cancer. Yes. Sounds strange. But yes. It is true. Prostate cancer is notorious for its typical osteoblastic bony metastasis that are easily visible on plain radiography of the pelvis or of the lumbosarcal spine as dense whitish spots indicative of bony metastasis. Stage 4 prostate cancer proven!!! Simple. What else we want…? Remember good old medical school days when our worthy teachers would often repeat and make sure that these kind of radiology pictures get fixed in our brains. Why should we forget the simple wisdom imparted to us when we were innocent and naive medical kids? Why should I get PET scan done in such prostate cancer patients? Why??? Any good reason? So, dear readers, choose investigations wisely. Think wisely. Think rationally. If we can checkmate cancer with a single

easy step, why try complicated strategies? Moreover, baseline PSA levels and histopathological grading provides a better information regarding the way forward than just blindly ordering PET or PSMA PET. Go slow if baseline PSA levels are less than 10 ng per ml. Rule out prostatitis. Chances of finding a malignancy with PSA less than 10 is quite low. What to talk of PET, we can safely avoid biopsy and further investigations. Wait and watch. Think wisely. Conduct a prostatic biopsy if PSA is more 10. High chances of finding a prostatic malignancy when PSA is beyond 20. But again, go slow with extensive investigations if PSA is still less than 20. Chances of finding distant metastasis are extremely low with a PSA of less than 20. PSA kinetics matter a lot in prostate cancer. How fast is prostate cancer growing is reflected directly by the speed of rise in PSA. Lot of prostate cancer biology can easily be read by PSA doubling time. PSA trajectory is a powerful weapon in deciding treatments. PSA less than 20 speaks of a localized disease more often for which a good quality 3 tesla MRI pelvis is much better to evaluate the primary prostatic malignancy and its local extent rather PET scans. Choose investigations wisely. Think wisely. Think rationally. Baseline risk stratification for clinically localized prostate cancer depends upon grading as seen on histopathology, PSA levels, T and N staging. T staging and N staging for prostate cancer is accurately done by contrast MRI of pelvis. It clearly show the extent of primary prostatic tumour, capsular breach, involvement of seminal vesicles, neurovascular bundle and infiltration into adjacent organs. Why should I get PET or for that matter PSMA based PET done? If we are suspecting bony metastasis clinically, we can simply order a plain radiography of the

painful area in question or get bone scan. Bone scan is a conventional technetium 99 m based scanning in which technetium is taken up by bone having high turn over. It helps detecting osteoblastic bony metastasis. Not only this, bone scan helps in response assessments and in detecting newer lesions. PSMA PET sounds great. It is prostate specific membrane antigen PET. But, hold on. I agree PSMA detects small bony metastasis which cannot be picked by radiography, but don’t forget age old bone scan. Too powerful. It along with CT / MR picks up almost same amount of metastasis what PSMA PET can do. PSMA PET however is not able to change treatment protocols. Yes!!! By and large, PSMA PET is not going to add any good. Moreover, interpretation becomes quite difficult due to high variability among PET CT and PET MRI equipments and protocols among institutions. FDG PET should not be routinely used for staging prostate cancer. Prostate cancer is a hormone (testosterone) dependent malignancy which is produced primarily from the testis. Why can’t we subject advanced stage prostate cancer patients to bilateral orchiectomy immediately after due consent? Why do we wait for PET scans or PSMA PET? Honestly speaking, I don’t understand the logic and rational behind all this. This is sheer harassment. Undoubtedly. Once surgically castrated, patients PSA starts declining exponentially. Clinical improvement is dramatic post bilateral orchiectomy. Not only this, even bed ridden patients with extensive bony metastasis start walking and enjoy a good quality of life for years. Choose investigations wisely. Following these patients with monthly PSA levels is simple, cheap and practical. I have yet to come across a patient of adenocarcinoma

prostatic with extensive bony metastasis with normal PSA levels. PSA would undoubtedly rise either in case of tumour recurrence or if patient in question becomes refractory to castration. PSA is a simple but highly reliable tumour marker which is THE deciding factor for almost all the clinical decisions to be carried out in the best interest of the patient. Patients keep their records of PSA reports meticulously and feel a pride in doing so. At times, they put us to shame the way the record is kept. Try making things simple and uncomplicated. Choose investigations wisely. Think wisely. Think rationally. Similarly for urinary bladder cancers which are limited to mucosa or submucosa without muscle involvement, PET remains questionable as chances of distant metastasis is quite low. Only in muscle invasive high grade urothelial cancers can PET be helpful to find out distant metastasis. Well, don’t panic if you don’t have an access to PET scan. Stay cool. A good quality contrast CT which is available everywhere is good enough for detecting urinary bladder metastasis to a larger extent. Preoperative evaluation of renal cell carcinomas too don’t have much dependence on PET. This is because of normal physiological excretion of FDG via kidneys thereby decreasing the contrast between tumour and normal renal parenchyma. Good quality contrast CT is enough to see renal cell carcinomas including the renal vein tumour thrombosis. Ultrasound abdomen can help finding secondaries in the liver in malignancies as hypoechoic target lesions. Choose investigations wisely. Literature is deluged with canon ball secondaries to be seen purely on simple X Ray chest. Why should I get PET done in already known primaries? Choriocarcinoma is known for lung metastasis which are

clearly visible on plain X ray. PET stands questionable. Simple. Choose investigations wisely. Think wisely. Think rationally. Fifty percent of times, the primary gastric cancers are not picked by PET. We need to have good number of GLUT receptors on the tumour cells to pick up the radioactive dye otherwise tumour would not brighten up on PET. Sadly, half of the primary gastric tumours are PET non avid. As a primary modality to pick up gastric cancers, role of PET stands questionable. Of course, primary gastric lymphomas do brighten up nicely on PET, but are uncommon. Upper GI endoscopy is THE investigation of choice for picking up early gastric cancers. In this procedure, multiple biopsies too can be taken in the same sitting. Searching for a primary in a case of Krukenbergs is again a very challenging task. Upper GI endoscopy stands quite helpful in picking up small pyloric tumours which are a frequent cause of Krukenbergs. Palpable stony hard left supraclavicular lymph node, the Virchow’s node (Troisiers sign) in a known case of stomach cancer automatically speaks of stage 4 disease. Why should I get PET done? I will not. Choose investigations wisely. Use PET judiously. A palpable left axillary lymph node (Irish lymph node) in a known case of stomach cancer makes it directly stage 4. Why should I get PET done? I will not. Choose investigations wisely. Use PET judiously. Palpable nodules around umbilicus (Sister Mary Joseph lymph node) in a known case of stomach cancer and in pelvis malignancies makes it stage 4 without doubts. Why should I get PET done? I will not. Use PET judiously. Choose investigations wisely. Hard growth felt per rectum (Blumers shelf) in a known case of stomach cancer makes it advanced cancer signifying

involvement of pouch of douglas beyond cure. Why should I get PET done.? I will not. Use PET judiously. Choose investigations wisely. Blumer was a proliferic writer who authored three volumes on bedside diagnosis. Yes, dear. On bedside diagnosis. History speaks. Learned scholars of the past were far more observant and sharp. Not only doctors, even the staff was trained, had an eagles eye and were more vigilant. Sister Mary Joseph who was a surgical assistant to Sir William James Mayo drew attention of the operating surgeons towards the presence of a hard umbilical nodules before surgery. She was the first person who noticed the relation between periumblical nodules and advanced pelvic malignancies. Are we forgetting our hero’s? Are we torturing their souls by blindly ordering PET scans or unnecessary irrational investigations? Are we playing with scientific data …? Are we better well read? Great personalities like Troisier, Rudolf Ludwig Karl Virchow and many others spent years and years in clinical practice helping patients. They had already made us wise with their simple but robust observations regarding the clinical signs and skills which we simply ignore, side track and push aside, and forget them in the present high technology world full of complicated investigations. Choose investigations wisely. Gall bladder malignancy is quite common in the region where I practice. These cancers often invade and infiltrate the underlying liver bed which of course is clearly delineated by a good quality contrast CT scan. PET again stands questionable in assessment of local invasions. Gall bladder cancers are locally invasive tumours which are notorious for invading adjacent structures like duodenum or transverse colon causing fistulous connections. All this can easily be picked

by contrast CT scans. PET again takes a back seat in such clinical situations. Choose investigations wisely. As a matter of fact, we as clinicians have simply forgotten to get up from our royal chairs to examine patients clinically in our day to day practice. What to talk of pulse and blood pressure, we hardly ever examine testis and rarely ever do a per rectum examination. Try introspecting. There are innumerable books on hard core clinical methods spanning every specialty and subspecialty. To quote a few, Hutchinson book on clinical methods is so very popular among budding medical students that it is loved by all, read by all, but sadly, the clinical wisdom provided by that manuscript has totally been forgotten in the present days as radiology tries to dominate into clinical practice. The moment doctors start practicing, monetary gains outweigh simple logical evidence based science. It is tragic and disheartening. I take this opportunity to highlight the forgotten importance of examining testis in a case of carcinoma of unknown primary. It is a blunder on the part of treating physicians for not doing this. Undescended testis is another clinical sign that cuts long stories short in the flick of the wrist while looking out for the primary in a cases of unknown primary. Big unsolved clinical dilemmas and diagnostic challenges like unexplained retroperitoneal lymphadenopathy in young adults, unexplained bulky mediastinal masses in young adults, unexplained metastatic lung nodules and unexplained left supraclavicular lymph nodes get quickly solved by simple testicular examination and by ordering a simple blood test measuring serum levels of AFP and beta HCG solving the hidden mystery in no time. Testicular malignancies should definitely be kept alive in our minds.

Detecting testicular masses, especially the undescended testis are often forgotten stuff in clinical practice leading to treatment delays, controversies, unnecessary medical politics and unnecessary tumour boards. Yes. This is true. We have forgotten a simple wisdom that a left sided varicocele is a hint towards left sided renal cell carcinoma. Yes. It is not that we don’t know. We know, but have become lazy to examine testis. On the other hand, to everyone’s surprise, I have come across cases in whom a trans scrotal fine needle aspiration cytology has been carried out. This is too much. We probably can never checkmate these cancers where such callous steps have been taken. Scrotal skin has an entirely different lymphatic drainage. Lymphatics from scrotal skin drain into superficial inguinal lymph nodes. Testicular lymphatics drain into para aortic lymph nodes. By doing a trans scrotal fine needle aspiration cytology, we give the opponent an alternative route to escape, spread and defeat us. Take care!!! Big NO to such a blunder. High inguinal orchiectomy is THE method to diagnose undiagnosed painless testicular masses. Choose investigations wisely. Think wisely. Think rationally. Think anatomically. A simple clinical breast examination can help stage breast cancer. Even a doctor sitting in the remote area can stage breast cancer accurately. Why should the doctor get PET done? Obviously, will not. Right from T 1 to T4 d and from N1 to N 3, breast cancer is clinically staged. Lethal breast cancers like Inflammatory breast cancers are a simple clinical diagnosis. Simple ultrasound abdomen detects liver metastasis in no time, no risk of radio activity of FDG, at much lesser costs and is more patient friendly. Grading of tumour, assessments regarding proliferative index Ki67,

knowledge regarding the receptor status of breast cancer are far more important and go a long way in treatment planning and replanning than ordering fancy investigations. Ring enhancing lesion in the cerebellum or anywhere else in the brain in a known case of breast cancer on a contrast MRI is enough to label the patient as having brain metastasis. Why should I get PET done? I will not. PET is of no use for detecting brain metastasis. Choose investigations wisely. Inability to abduct an eye ball is indicative of abducent nerve involvement, better scanned on contrast MRI. Why should I get PET done? Choose investigations wisely. A simple fine needle aspiration cytology by an expert pathologists is good enough to start neoadjuvant chemotherapy in clinically advanced breast cancers or stage 4 breast cancers with liver metastasis as evident on simple ultrasound liver or lung nodules as seen on plain chest radiographs. I would rather go for a trucut biopsy, send the valuable tissue for molecular genotyping and push first cycle of chemotherapy on that very day rather ordering unnecessary PETs which would hardly change my treatment protocols. By next chemotherapy session, receptor studies get ready, modifying treatment accordingly if needed. Choose investigations wisely. Think wisely. Think rationally. Think scientifically. Here subjecting a biopsy for receptor studies far outweigh than ordering unnecessary PET scans. Important part is the tissue preservation techniques. Pathologists must be kept in loop for preserving unstained slides, stained slides, preserving tissues adequately and preparing good quality cell blocks for molecular studies. Getting an echocardiography or a MUGA scan done is far more logical for pushing an anthracyclines rather adding to

the financial toxicity of the patient by ordering unnecessary PETs in breast cancer patients. Not only this, breast cancer patients during routine follow up usually don’t require PET. Yearly mammography of the healthy breast with symptoms directed investigations carry more weightage. CA 15.3, a simple tumour marker helps in detecting early breast recurrence in many cases. Head Neck cancers form a good chunk of our day to day clinical practice. Starting right from the lip, buccal mucosa, the gingivobuccal sulcus, soft palate, hard palate, tongue, base of tongue, tonsils and almost all the structures are clearly visible to human eye and that too to an eye of experienced clinicians who can easily do a clinical T staging by simple inspection and can do a clinical N staging by simple palpation of the neck nodes and M staging by a simple non contrast CT scan chest. Finished. Yes, staging done. Simple. Staging of head neck cancers done. At the most, good quality contrast CT helps in providing local tumour extent, involvement of bony structures, involvement of soft tissue and understanding the relationship with airways. Pan endoscopy provides additional help in taking the necessary biopsy from the viable tissue. PET again stands questionable to a large extent in head neck cancers as a staging modality. The inability to protrude tongue automatically makes a tongue cancer at an advanced stage. Why should I get fancy tests done? Choose investigations wisely. Hard fixed regional neck nodes in a known case of head neck cancer directly makes it locally advanced. Simple. Presence of malignant ascites, malignant pleural effusion and malignant pericardial effusions in known cases of primary automatically makes cancers advanced. Simple. I would rather tap the malignant

effusions, make cell blocks, test for drivers to search for treatment options rather adopting a different route. Choose investigations wisely. There are innumerable examples quoting hundreds and thousands of clinical situations in cancers where we can strongly declare that the cancer in question is at an advanced stage by simple clinical observation and simple cost effective tests. Why should I get complicated investigations in such cases? I will not. I live in a poor country. Choose investigations wisely. Why should I be responsible for increasing the cost of the patient and adding to the financial toxicity? I have no right to burden humanity at large. A simple X ray chest helps finding pleural effusion in lung cancer patient. Even simple clinical examination reveals effusion. Choose investigations wisely. Hoarseness of voice, Horner’s syndrome or clinical signs of superior venae cava obstruction speak volumes of advanced nature of bronchogenic carcinoma. Anatomical localisations of such clinical situations are better defined by contrast CT. Choose investigations wisely. Unilateral leg pain resembling sciatica in a known case of carcinoma cervix itself speaks of involvement of sciatic nerve which can be better delineated by contrast MRI rather an unjustified PET. Choose investigations wisely. My soul is not allowing me to get patients spend huge costs. Things started looking seriously full of flaws. Not only this, PET is not available in every city across states. Patients need to travel to far off places for getting PET done, adding financial burden, botheration and exhaustion. For what? Just for adding more confusion to their already bundle of uncertainties pertaining to the outcome of their disease. Poor fellows. I got more deeper into the way the PET was conducted. Patient need to go

empty stomach, keep sugars under control, be at the PET centre at about eight in the morning, and get injection of radioactive dye called fluourodeoxyglucose (FDG) via intravenous route. Patient is made to sit in a box like compact closed room with his or her hand protruding out of small window through which this radioactive dye is injected by a trained staff nurse. The moment the radioactive dye is injected, the patient becomes a moving source of radioactivity for at least six odd hours. He or she is emitting harmful radiation to everyone around, though at a very low level. Even then, it’s scary!!!! Anyhow, I moved forward to study more on PET scans with lots of heightened interest. Patients after getting their PET scans were advised to stay away from children or pregnant ladies for at least six hours from the time the test was conducted. It again was scary. Yes. In a country where there is so much of population explosion, who is going to adhere to such extremely relevant instructions? Perhaps very few. A country full of illiteracy and divided opinions hardly stick to instructions. Rather, the public feel proud in crossing boundaries. The outcome is extremely worrisome. I don’t know. You don’t know. Know one knows. How can a patient stay away from a pregnant lady? Is he or she going to ask every lady coming close by? Looks weird. How can a patient stay away from children? It should be mandatory for PET centres to provide adequate counselling regarding post PET isolation of the patients for at least for six hours. These are significant but practical issues. The frequency with which PET scans are being conducted with poor counselling regarding post PET care is worrisome. Moving forward, the radioactive dye is not made on spot. We need a big cyclotron to make FDG.

It usually is made at a single government approved site catering to many adjacent states and then distributed to several PET centre early morning. There is high probability that many PET centres may not get the dye on time and patients are then sent back home without their test being conducted. This wastes their time adding to their woes and harassments. It’s very easy for cancer doctors to prescribe PET scan but is practically very taxing, bothersome and inconvenient. As technology is improving, newer set of PET scans are being flooded in the markets which are further additional headaches for patients to decide. Let me put things in perspective. I again request my fellow colleagues to please take out time to listen to patients history. History in short means his story. Yes. It is the patients story in his own words. Listen to it carefully. Don’t interrupt. Let the patient say whatever he wants to say. Give him full ten minutes to unfold his mind and misery so that we can easily understand his chemistry. This automatically lead us to some logical conclusion and the way forward. After listening, please do a detailed clinical examination pertaining to his complaints. I am sure you would be able to stage his cancer to a larger extent with the help of clinical findings and the radiological modalities available in almost all hospitals. You don’t have to search for hospitals having elephants. Occurrence of a cancer is somewhat simulating a murder or a crime scene. We need to interrogate public, persons in question, for which lots of questioning is needed. We need to round off prime suspects, question and counter question to reach to some logical conclusion. Not only this, we need to take photographs, collect samples from the crime scene, send them to a forensic laboratory for final reports which would

help nabbing criminals. Read again. Collect samples from the crime scene to send them to the forensic lab for final reports. Yes. Similarly in cancer, history taking, clinical examination and handling of samples constitute an important part of investigation. Everything is not PET. Yes. Collect samples carefully. Handle samples carefully. Send samples carefully. Follow guidelines in collecting and transferring samples. This practical wisdom outweighs the confusing conclusions of PET in many cancers. Blood and bone marrow samples be drawn into anticoagulated levander coloured tubes containg EDTA as an anticoagulant for haematology assessments. Then shift at ambient temperature. Blood should never be frozen before reaching the appropriate laboratory. Yes, PET definitely forms a part of the whole story somewhere, but whenever justified. I find no logic in getting PET scans done during follow up visits in the era of tumour markers in many cancers. Testing tumour markers and following them serially is a scientific, logical and an easy way of keeping a watch on cancers at length. Tumours markers are patient friendly, acceptable and easy to do investigation to help detect recurrences. It helps in maintaining good patient compliance. Patients take them easy and friendly. They are cost effective ways to keep things in control. Patients hardly miss their visits for getting them done or at times get them done at their native place and can keep a watch on their own too. All what is needed is a good quality counselling sessions at length with patients and the attendants. Once proper education is imparted regarding the cut off levels of tumour markers, patients hardly make mistakes in not reporting at the right time. In colonic cancer patients, 80 percent of recurrences are picked

by serial CEA levels, rest 20 percent by history and physical examination. It makes 100 percent. PET stands questionable in detecting colon cancer recurrences. CEA is an extremely valuable test. It is the king of colonic cancer. Three monthly CEA for first three years from diagnosis is good enough to keep a watch on tumour behaviour. Once CEA starts rising, don’t panic. Stick to basics. Listen to history. Yes. His story. Inspect the crime scene. Yes. Do a thorough clinical examination. I am pretty sure to find the culprit lesion. As far as radiology is concerned, a simple X ray chest and an ultrasound abdomen is sure to give an answer in majority as initial investigation. Majority of colonic cancer recurrences happen in the liver, at the anastomotic sites, as malignant ascites, as pulmonary nodules and uncommonly in bones. I don’t feel that PET is the only available modality for detecting recurrences at these sites. But yes, it definitely helps in establishing an oligo metastatic disease if surgical resections of metastasis is being planned. Yes, I do agree that a rising CEA with no evidence of disease found anywhere after an exhaustive work up would scare any treating doctor and automatically at subconscious level order an immediate PET, but that too would not be able to provide any good information further. Visual inspection of the entire colon by colonoscopy does a good job for picking a recurrence at the anastomotic site in addition to detecting metachronous lesion or a second primary or a precancerous polyp anywhere else in the field. Resecting precancerous polyps there and then during surveillance colonoscopy again would do a lot good to the patient adding years to his life. Why should I get PET done? PET doesn’t pick precancerous lesions. PET doesn’t pick polys. Practically speaking, it’s a a mixture of

history, clinical findings, CEA levels, colonoscopy observations, CT impressions combined with PET if required, helps clinicians by and large in day to day clinics to help colon cancer patients. We need an eye as to what we are looking at. Choose investigations wisely. Think rationally. Think logically. Understanding tumour biology is THE key to order investigations. I would prefer counselling patients regarding molecular signatures or the molecular genotyping or DNA sequencing of the tumour DNA to offer the best possible evidence based chemotherapy on the forefront to get best possible results. Molecular genotyping is a DNA based test where we extract DNA from the tumour tissue, study it and try finding any mutation that is driving the cancer. If the mutation in question is druggable, we try to stop its signalling by the best possible drugs available so as to increase longevity. With treatment, goal again should be to bring CEA levels back to normal suggesting happy days again. We did stalemate, if not checkmate. PET probably has a less role in the era of CEA based follow up in colon cancers. Same is the story with rectal cancers. Choose investigations wisely. Think rationally. In undiagnosed pelvic masses suspected to be of ovarian origin, the first investigation of choice is a transvaginal ultrasonography (TVS ). Conditions raising the concern of possible ovarian malignancy include bilateral disease, complex masses with TVS evidence of solid areas, thick septations, mural nodules, complex masses of any size in postmenopausal patients, masses associated with elevated tumour markers and finally symptomatic masses. All these can be evaluated using a single, simple, easily available and cost effective investigation, the one and the only one, the

powerful transvaginal ultrasonography (TVS ). CT or MR further helps in demonstration of omental disease, peritoneal carcinomatosis, liver surface and liver parenchymal deposits. With each breath, the ascitic fluid circulates in the peritoneal cavity, laying a perfect platform for spread of disease extensively onto the peritoneal surface including subdiaghragmatic surface, for which contrast CT is good enough to pick up widespread deposits. PET has limited role in initial work up of suspected ovarian malignancy. Choose investigations wisely. CA 125 is an invaluable asset in the hands of the patients, gynaecologists and oncologists. This too is a simple, cost effective, easily available blood test across states and very easily understandable. Patients are counselled regarding three monthly follow up visit with CA 125 levels done a day before their visit to the clinic or the patient is advised to report to the clinic in case of any unexpected rise in CA 125 levels. Once increased, again don’t panic. Stick to basics. Listen to history. It is her history. Do a good thorough clinical examination. Get an ultrasound abdomen, X ray chest and a good quality contrast CT abdomen done. In majority, culprit lesions will be picked and treated by appropriate second or subsequent lines of salvage chemotherapy with or without surgical resections as per clinical scenario. In germ cell tumours of the ovary, PET again has a limited significance attached. Blood levels of HCG and AFP are good enough to detect an early recurrence. Disease sites can easily be evaluated using a contrast CT. Salvage chemotherapy again bring disease under control as evident by decreasing tumour markers followed by complete excision of the residual masses if left as evident on CT Scans. With the availability of such high

sensitive tumour markers which have a pretty long history in the cancer world, the utility of PET stands controversial. CA125, HCG and AFP are easily available, cheap and easily reproducible. Inhibin A and B, too are easily available blood tests in predicting recurrences in case of granulosa cell tumours. Yes, in cervical cancer, PET does help pick regional nodal disease for radiotherapy planning. Besides this, testicular tumours are another success stories in the history of cancer treatment. Handful of patients do get rid of their disease, but in others, disease does recurs. The beauty of testicular tumours is high cure rates despite recurrence, but remember the bottom line. We need to detect recurrences at an early stage. We can’t get PET done every month for detecting testicular tumour recurrences. What a foolish idea!!! Here comes the role of a single blood test to help detect recurrence. Yes, a single prick can help the treating doctor know about the disease status. Viable non seminoma testicular tumours produce beta HCG and AFP s whose rising values signal that the tumour in question is back. Cancer markers are so robust and significant that even at baseline the role of histopathology to confirm the diagnosis of germ cell tumours stand questionable. Yes, PET is important in planning treatment once chemotherapy has stabilized and normalized the tumour markers so that the left over residual masses can be surgically removed. Even in such cases a contrast CT would suffice in financially weak patients. In patients with unknown primary suspected to have germ cell tumours, tumour markers not only play an important diagnostic role but makes the patient at a considerable ease as they are the fastest way of reaching to the diagnosis. Patients are saved from undergoing exhaustive

battery of tests passing through which is another nightmare for the them and family as a whole. Aim and fame are two different sides of the same coin. In cancer, aim must be and should be simple cost effective diagnostic tools which help pick cancer, stage it and help move forward without much confusion. Rather, the quality of investigations performed be so authentic that it should give the treating doctor a different level of confidence and surety that whatsoever happen down the line in the course of treatment, the treating doctor should never ever think of revisiting the baseline diagnosis. Cancer biology is so very surprising that unexpected happenings, unexpected twists, unexpected tragic endings do happen in the course of treatment to the extent that patients, the care providers, the treating oncologists and other team members in the loop are taken aback. The treating oncologist once again come under scanner and scrutiny. We must stick to our baseline diagnosis so very confidently that no second opinions on earth could change the diagnosis. This can happen only if basics are embraced very lovingly in every patient. Spend time. A good detailed history, good personal history, lifestyle history, good family history, good physical examination forms the backbone of any problem solving skill. Why should I get PET done at baseline as the first test in cancer patient? I find no logic. I cannot move the king on chessboard to start the game. Medical books since times immemorial have been working up patients without PET. Yes, I do agree that we need to change with time. Agreed. Embrace PET where scientifically required. Embrace PET if justified. Don’t add PET as an investigation to complete the list of do’s and don’t in cancer treatment. Don’t get PET to buy time to

understand the patient. Don’t get PET out of scare. Don’t get PET done out of fear, that yes, PET might provide some different information as if we human beings have hidden niches which are accessible to PET only. We don’t have lockers inside us. PET is not a key for hidden lockers. Use PET judiously. Modern investigations like PET are fraught with confusions and dilemmas. PET definitely has a limited but significant role in cancer treatment. If used carefully, it can be an asset to our armamentarium. It is extremely helpful in staging patients with lymphomas. Once the patient is histopathologically proven to be a case of lymphoma, irrespective of whether it is a Hodgkin’s or a Non Hodgkin’s, PET is THE investigation of choice for staging these cancers. Gone are the days of cumbersome lymphangiography to stage such tumours. So much so that bilateral bone marrow biopsies too have taken a back seat for detecting bone marrow infiltration in staging lymphomas. It was a frightening experience for patients to undergo bilateral bone marrow biopsies which were painful and inconclusive a number of times. Not only this, marrow involvement by lymphoma cells is patchy. The pathologists nearly had to hunt for lymphoma cells in a limited amount of 1 cm of marrow. Subcortical marrow biopsy was another fear. It was a challenging and a daunting task for the pathologists. Yes, there are spaces or niches in marrow where the lymphoma cells go, hide, live and proliferate. Same is the case with metastatic cells. Bone marrow provides a perfect atmosphere and a rich milieu for lymphoma cells to hide and play tricks to proliferate. Pathologists performing bone marrow biopsies are unaware of these spaces pre hand ending in frustration. PET has turned tables in detecting

bone marrow infiltration quite accurately. Pathologists across the globe definitely heaved a sigh of relief as they were always fired and fingered by the treating oncologists regarding the validity of bone marrow biopsy reports. Not only this, blocks were retrieved a number of times, sent to another pathologist for a second opinion. At times, mess was created if the reviewed report was not in sync with the previous marrow report as the number of chemotherapy sessions would decrease or even increase if marrow involvement was proven by another pathologist. This whole pandora box came to an end with the advent of PET in identifying marrow infiltration quite reliably. The beauty of PET goes beyond saying that it definitely is a one stop radiological investigation to exactly stage lymphomas. I salute PET for helping lymphoma patients. PET is a mandatory investigation at the baseline for all lymphoma patients as a part of staging work up. No investigation till date can surpass PET in such a clinical scenario. Choose investigations wisely. Think wisely. Think rationally. Moving forward, it not only helps in staging, but is a perfect test to asses the response to chemotherapy for lymphoma patients. There never ever existed a reliable investigation to test whether chemotherapy worked or not. Responses to chemotherapy were confirmed clinically and radiologically by contrast CT scans. The patients were taken into remission if they were clinically improving and radiologically stabilizing. The lymphoma masses never melt or disappear completely after chemotherapy cycles. It was extremely difficult to be sure of complete eradication of lymphoma at the end of treatment. We, the treating oncologists across the globe had no option except to move forward. PET changed

the world in lymphomas. It redefined everything. I felt as if I can talk with lymphoma masses and be an eye witness to the disappearing lymphomas after chemotherapy. All the colourful lymphoma masses disappear after two cycles of chemotherapy. Yes!!!. Chemotherapy worked!!! Yes, ABVD, the age old chemotherapy worked in Hodgkin’s. ABVD is the gold standard chemotherapy for Hodgkin’s since ages developed by Vincent T DaVita and George Caneloss at the famous National Cancer Institute, The NCI, USA. But, what we are observing after the arrival of PET is just amazing and exciting. All colourful masses disappeared suggesting complete metabolic responses. Yes, we could talk with tumours on metabolic front. Courtesy PET. I again salute PET for helping medical oncologists the way forward. All lymphoma disappeared. PET is mandatory after two cycles of chemotherapy in lymphoma patients to asses response to chemotherapy. No investigation till date could surpass PET in such a clinical scenario. Choose investigations wisely. Think wisely. Think rationally. Such a complete metabolic response as seen on PET after two cycles of chemotherapy triggered Hodgkin’s trialists across the globe to decrease the chemotherapy cycles to minimize toxicity caused by multiple chemotherapy drugs. Minimizing chemotherapy sessions!!! What??? Yes. Wow.!!! Time had arrived to think on such issues. Courtesy PET. We did decrease number of cycles and the patients could get away with lesser number of chemotherapy sessions with the SAME outcome. This wasn’t possible pre PET era. There was no possible way to confirm the last cell kill. PET changed the whole landscape. It helped prove and justify treatment success, treatment alterations and even confidently labelling the patient as

disease free. This was a huge success for lymphomas. Huge success!!!. Yes, courtesy PET. YES, COURTSEY, PET. Suddenly, things changed. Trials changed. Trialists ideas changed. Hodgkin’s specialists across the globe got more charged, rejuvenated, innovative, more refined and always kept an eye on PET during chemotherapy sessions to help get directions and the way forward. ABVD is the best chemotherapy regimen for Hodgkin’s lymphomas. ABVD consists of four anticancer drugs namely Adriamycin, Bleomycin, Vinblastine and Dacarabazine. They are as tough as their names. Needless to say, they are very good antilymphoma drugs for Hodgkin’s but have good number of side effects which can give patients a considerable morbidity if appropriate check is not kept on them. PET further helped reducing the toxicity as de escalation policy got possible in the present PET era. Patients achieving complete disappearance of lymphoma masses as evident by negative PET after two cycles of ABVD can continue chemotherapy cycles with omission of Bleomycin, the most toxic drug in ABVD causing no harm down the line as far as the outcome and survival of patients is concerned. This is too much. I stand and give a big applaud to PET in helping Hodgkin’s patients achieve a good disease control keeping an eye on all possible aspects. Never before, the treating oncologist could ever think of fiddling with ABVD. Taking Bleomycin out from ABVD had never been possible without the help of PET. PET needs thunderous applauses for this. Bleomycin is toxic to lungs, skin and heart. It causes fibrosis of lungs, makes skin dark and injures the coronaries. Patients get saved from such a torture. This is possible because of interim PET, done after two cycles of chemotherapy

sessions. Patients achieving a complete metabolic response after 2 cycles of ABVD can continue further with AVD saying goodbye to Bleomycin. This was never possible in the pre PET era. It further strengthens the need for PET scan after 2 cycles of ABVD. Choose investigations wisely. Think wisely. Think rationally. Story doesn’t finish here. Ninety percent of Hodgkin patients are cured successfully by ABVD. Ten percent Hodgkin’s are bad. They don’t respond to ABVD. But, we had no way of identifying those ten percent cases in the pre PET era. There was no hope for such primary refractory Hodgkin’s cases. PET opened another success door for identifying and treating such hard nuts at an early stage. Poor responders to ABVD as identified on PET after two cycles of chemotherapy notoriously had a bad outcome. After the advent of PET, it got possible for the treating oncologists to identify such poor responders and act accordingly. Chemotherapy in such primary refractory Hodgkin’s was immediately changed to a more aggressive chemotherapy called escalated BAECOPP. The very name suggests more aggressive treatment for such aggressive Hodgkin’s. PET helped to change chemotherapy for such patients. This never happened before. History was re written. PET turned out to be a huge mountain support for Hodgkin patients. Thanks again to PET in helping modifying treatment. Huge success. Choose investigations wisely. The success story of PET in Hodgkin’s doesn’t finish here. Hodgkin’s once treated are usually called for follow up visits every three monthly and are subjected to clinical examination, proper history taking and getting ESR done if the same was raised at the baseline. PET is never a part in the follow up of such cases. But, if the history or the clinical

examination or a raised ESR does suggest a recurrence, PET is immediately done to see for any reappearance of colourful lymphoma masses. In the pre PET era, it was extremely tough to establish an early recurrence. Yes, such cases who are detected early respond more favourably as the load of disease in early recurrence is low as compared to others. Almost similar trend is followed in patients of Non Hodgkin’s lymphomas. The same story repeats in Non Hodgkin’s lymphomas. PET is very helpful in staging, assessing responses to chemotherapy and detection of early recurrences in Non Hodgkin’s lymphoma patients. PET has a special place in the world of bone marrow transplants. PET is mandatory before taking lymphoma patients for transplant as it is good to have a lymphoma free state before taking and subjecting the patient for such a toxic procedure. Primary CNS lymphoma is another nightmare story. PET is important to rule out systemic lymphoma only. Primary brain lesions are taken care by good quality 3 D contrast MRI. For ocular involvement, slit lamp stands like a good friend to help. Carcinoma of unknown primary is another interesting, gripping and fascinating entity. Here the patient in question does have a malignancy but the primary site of origin is not evident. Crime done. Culprits fled. No hints. No suggestions. In the pre PET era, exhaustive clinical and radiological work up would be done before embarking treatment. We definitely took the help of exhaustive history, baseline blood tests, X ray mammography, whole body contrast CT scans, pan endoscopies, upper GI endoscopies, colonoscopies, multiple biopsies and all other possible radiological modalities available from time to time. Not only this, there was a time when blind biopsies were taken

from fossa of rossenmullar in cases of unexplained malignant cervical lymphadenopathy. It was hard to establish the primary. It was a daunting task with complete confusion. PET changed the whole scenario. It helps finding primaries quite easily. Pan endoscopy of head neck area are unknown nowadays. Blind biopsies are in deep slumber in present times. Finding a primary has become a cake walk. I again salute PET for helping mankind at large in such situations. Choose investigations wisely. PET has a special place in assessing responses to imatinib in gastrointestinal stromal tumours. Well, PET definitely is not helpful in assessing brain metastasis or in evaluating primary brain tumours. MRI is a perfect radiological modality for such lesions. Normal brain cells are heavily dependent on glucose as their primary food. Tumour cells too are notorious for their dependency on glucose. It becomes extremely difficult to wipe out the background FDG activity to asses the lesion in brain. Gastrointestinal tumours too are a tough nut to crack on PET scans. With the advent of high end flexible endoscopy and colonoscopy, the whole gastrointestinal tract is visible in a short time. It’s a big success. The journey of the tumours, from mucosa to serosa, is clearly visible with the help of endoscopic ultrasound. Choose investigations wisely. Detecting early mucosal tumours is another success story of interventional gastroenterology. T staging and N staging of oesophageal tumours are best completed on endoscopic ultrasound. M staging can easily be picked by simple ultrasound liver for hunting secondaries in the liver and by doing a bone scan for skeletal metastasis or a simple radiography of the symptomatic region. Contrast CT completes the rest. Tumours of the bile ducts are visible and

biopsied on endoscopic cannulation, commonly called endoscopic retrograde cholangiopancreatography, the famous ERCP. Imaging is completed by multiphasic contrast enhanced CT and magnetic resonance cholangiopancreatography, the MRCP. PET, as an imaging modality is not much useful in staging biliary tract tumours. Choose investigations wisely. Think wisely. Think rationally. Same is the case with ampullary tumours. Good quality contrast CT or MRI is enough to stage them. Imaging should preferably be performed before stent placement or biopsy to avoid the effects of potential post procedure inflammation interfering with staging assessments. Hilar tumours, the famous Klatskins tumours, their anatomical localisations, their oncological types, their anatomical spread, their relationship to the beautiful biliary tree is best assessed by a contrast MRI. How enthusiastically and meticulously Dr Gerald Klatskin worked on hilar cholangiocarcinomas to provide a lucid account of these malignancies is beyond words. Great personalities. The life and work of Klatskin documents a pioneering hepatologist and a devoted teacher. How can we forget? Endo sonography guided fine needle cytology of hilar masses and regional nodes is the most useful tool for their diagnosis and staging. Choose investigations wisely. Think rationally. Think wisely. Pancreatic tumours are best localized by contrast CT scans using pancreatic protocols. In case of renal dysfunction or in case of allergies to intravenous contrast, non contrast MRI stands superior to non contrast CT because of better soft tissue demarcation. How successfully a surgeon is able to resect pancreatic tumour is highly dependent on its relation with surrounding arterial and venous network that

can be planned with the help of contrast CT scan and not by PET. PET again takes a back seat in assessing the surgical resectability of pancreatic tumours. Choose investigations wisely. Yes, if the primary pancreatic tumour is invading adjacent vasculature, we ought to rule out distant metastasis by PET scan as micro metastasis develop at a cellular level in which metabolic tumour assessment is more sensitive in picking distant metastasis. The job of finding secondaries in pancreatic cancer is again done equally well with a good contrast CT in financially hit population. Assessment of CA 19.9 helps in hinting towards malignancy. High levels of CA 19.9 in a proven case of pancreatic malignancy with a no evidence of distant metastasis on PET is even scary. In such like cases, further assessments by a diagnostic laparoscopy is important in assessing peritoneal surfaces which too are very clever to play hide and seek on PET. Things aren’t easy the way we expect. Choose investigations wisely. Primary hepatic tumours are best assessed by triple phase contrast CT scans performed with hepatic arterial, portal venous and delayed venous phases. Hepatocellular carcinomas rarely develop on a normal liver. They arise on the background of an already injured cirrhotic liver which is better picked on ultrasound scanning combined with fibro scan. Incorporating age old Child Pugh criteria for the assessment of underlying cirrhosis completes the story in fully prognosticating the patient. Child Pugh scoring is simple amalgamation of clinical findings and a few liver function tests. Simple. Don’t underestimate the power of simple clinical examination and few simple liver function tests. The scoring is far more important in deciding treatment routes. Success of chemotherapy for hepatocellular

carcinomas need a fully functional background liver for which CP score stands like a handy calculator. CP is all powerful. Oncology community is deeply grateful to the great surgeon and portal hypertension expert, Charles Gardner Child who along with Pugh devised this all time favourite “The Child Pugh Score”. Choose investigations wisely. Think wisely. Everything in cancer is not CT. Everything in cancer is not MRI. Everything in cancer is not PET. Choose investigations wisely. Assess the situation and act likewise. We seriously need to think logically, rationally and finally investigate to checkmate. PET is not of much help in delineating these tumours for which a triple phase CT stands much ahead. Hepatocellular carcinomas are smart enough to high jack arterial supply of the host to grow and flourish. This is very evident as seen by the arterial peripheral enhancements seen in the earlier arterial phase. This speaks volumes of its rich blood supply. Triple phase CT nicely portrays the tumour extent along with the portal vein status which is of utmost importance for treatment planning. The picture of early arterial peripheral enhancement with a delayed venous wash out is classically observed in time tested triple phase CT scan. PET stands far inferior to assess all these classical tumour related characteristics. Hepatocellular tumours are dependent on hepatic artery for their arterial supply and food. They are flooded with blood from hepatic artery which if blocked can cause tumours to shrink and wither away. The demonstration of these classical radiological characteristics of HCC is not everyone’s cup of tea, what to talk of PET. It took years and years for CT scans to improve their sensitivities to finally reach to the present day level of triple

phase CT scans. How can a triple phase CT easily give away its skill to PET. Probably would never. I doubt. Anyways, PET is a smart modality. It tries to fit somewhere. Localized hepatocellular carcinomas with no evidence of extrahepatic spread with patent portal vein can be burnt or destroyed by blocking hepatic artery and by installation of chemotherapy into the tumour bed by a time tested famous procedure called trans arterial chemoembolization (TACE ). TACE burns small hepatocellular carcinomas providing a good disease control. Following TACE, hepatic artery gets blocked. Triple phase CT relied heavily on patent hepatic artery to give its characteristics early arterial enhancements so typical of hepatocellular carcinomas. Now, the problems arise. How would triple phase CT now work? Hepatic artery is blocked intentionally and therapeutically. At this point of time, PET comes in as a rescue modality to help the treating oncologist to give an idea of residual tumour in the interventional bed as PET has no dependence on patent hepatic artery. Great. It simply relies on the viable tumour cells to assess the response to TACE. Smart PET. After all, it is the king of the chess board. It definitely makes its presence feel everytime somewhere. Smart man. FDG enhancements in the centre of the interventional bed signify residual tumour but an uptake at the peripheral signify inflammatory response to TACE. PET of course is helpful in assessing the response but not as a diagnostic modality in hepatocellular carcinomas where triple phase CT is the first and the foremost investigation of choice. Logical thinking is important in choosing investigations. Think wisely. Choose wisely. Understand the underlying disease. We need to understand the tricks the diseases play to choose

investigations wisely. Rising AFP following TACE too needs PET to asses the residual lesion in the intervention bed or to know the source of viable tumour in the body. Cutting long story short, triple phase CT scan, PET scan, ultrasound of the liver, fibro scan liver and the serial measurements of AFP go hand in hand during the course of the management of these tumours. We simply need to be aware of the correct time tags to use the correct modalities in the best interest of the patient. During the follow up of these patients, three monthly AFP, three monthly ultrasound with six monthly triple phase CT with PET when needed as per clinical judgement or by rising AFP following TACE is a good logical plan. Choose investigations wisely. Think wisely. Think rationally. Remember that background liver is diseased in hepatocellular carcinoma patients. The liver may be diseased due to alcohol, virus, obesity or as a part of metabolic syndrome or due to non alcoholic steao hepatitis (NASH ). The diseased liver acts as a perfect ground for oncogenesis for the development of new dysplastic nodules elsewhere in the liver at any point of time. We need to crush these dysplastic nodules before they become big and worrisome tumours. Local ablative therapies form the cornerstone for long survival of hepatocellular carcinoma patients. Ultrasound is an excellent modality for picking up new dysplastic lesions. CT and MR too pick up new dysplastic lesions but sadly PET fails again. Taken together, each modality is important at a particular stage and at particular phase in the natural history of disease. We simply need to be vigilant and move forward with all the positivity, opening the door of success as time pass by. Moving down, colonic cancers are surgically staged. T and N staging is

done surgically. M is staged with a simple ultrasound abdomen to see for liver metastasis. A contrast CT is enough to detect liver metastasis if in doubt during ultrasonography. A non contrast CT chest can help detecting lung nodules. Simple. Full length colonoscopy evaluates whole colon ruling out synchronous lesions which too can be taken care of surgically. Why should I get PET done as a staging modality in colon cancers? PET fails in detecting mucosal polyps, early mucosal tumours and off course synchronous lesions. During follow up visits, CEA is good enough as a surveillance strategy. Three monthly contrast CT Abdomen would fill the gap for first two years. Why should I get PET done? CEA rules the show in colon cancers. Rectal cancer is a totally different ball game. Rectal tumours are mostly localized or locally advanced for which PET has nothing much more to offer as far as assessment of local disease is concerned. Contrast MRI of the pelvis is THE investigation of choice in evaluating the local disease extent, assessing the involvement of levators, studying the relation with the sphincter, the borders, the mesorectum and adjoining structures. Non contrast CT chest helps rule out lung metastasis. Choose investigations wisely. During follow up visits too, a thorough history, clinical evaluation and CEA is helpful in detecting early recurrence. CEA is often an under estimated tumour marker. It is a very robust marker which starts rising once the tumour recurs. Why should I get PET done? Yes, once CEA is rising, we can take the help of PET to locate secondaries in addition to colonoscopy. Choose investigations wisely. PET has a special place in assessing responses in gastrointestinal stromal tumours as responses to imatinib in such tumours are even taken as one of the

methods for diagnosis. I strongly advocate PET after two months of imatinib in such tumours to asses response and to modify treatment accordingly. Moving towards the common cancers of females, breast Cancer is the most common cancer among females in urban cities of Punjab. Breast Cancer is clinically and pathologically staged tumour. The tumour is visible to naked eye. Simple. Right from T 1 to T 4d, it is clinically staged. The tumour can be seen and felt. Simple. Axillary nodes too can be seen and palpated. Simple. Right from N0 to N 3, it is clinically staged. Simple. Clinical T and N staging completed in few minutes. Simple. Obviously, we as treating doctors are sensible enough to get an ultrasound abdomen to rule out liver metastasis once clinical T staging increases or if nodal staging is felt to be advanced. X Ray chest is good enough for lung lesions or at the most can be picked by a non contrast CT chest. I don’t feel PET adds any good information in the management of breast cancer at large. Rise in serum alkaline phosphatase in liver function tests points towards bony metastasis for which a technetium bone scan with a gamma camera helps in imaging bony metastasis. Contralateral breast can be subjected to simple X ray mammography to asses any hidden malignancy and microcalcifications. Ascites in breast cancer can easily be tapped and submitted for cytological evaluation. Demonstration of malignant cells in ascitic fluid is enough to call it a stage 4 advanced malignancy in a known case of breast cancer. Why PET? I will not. Use PET judiously. Rather would immediately request my pathologist colleagues to prepare cell blocks to assess receptor status to select the right chemotherapy to help increase survival. Similarly, pleural effusion in a case of

breast cancer can be detected clinically by classical stony dull note and further proven cytologically with simple pleural fluid cytological examination. For evaluation of brain in suspected brain metastasis, PET is of no use. Contrast 3D MR is the modality of choice for brain metastasis. I personally do not subject patients of breast cancer to PET. Bone Scan is a good modality for evaluating skeletal metastasis. What are we doing? Where are we heading? Need serious introspection. It pains when breast cancer patient are subjected to repeat PET scans for disease evaluation and response assessments. Breast cancer patients are often seen carrying bundles of PET reports with them as if some hot cake is served free of cost at cancer centres. It is not fair. Wake up. Use PET judiously. Use ultrasounds for liver metastasis. Use bone scan for bone forming bone metastasis. Use non contrast or HRCT chest for lung metastasis. Use clinical judgement. Satellite nodules on the chest wall on the site of previous mastectomy scars spell trouble. Get a biopsy done. Use PET when justified. Use clinical judgement and clinical evaluation. Listen more. Listen more. History is far more important. Cancer screening is a subject which is often overlooked and set aside. PET scan has no place in cancer screening. Why aren’t we people giving more attention to screening guidelines rather focusing our attention on getting unnecessary scans done. Have we ever screened patients for other cancers, leaving aside the primary tumour in question. Perhaps not. Have we ever screened relatives of patients accompanying them? Perhaps not. Things aren’t fair the way they are going. We need to introspect again and again to change our goals, our thought process and our vision. Screening is mandatory.

Screening is everyone’s right. Screening is must. Our souls will not rest if we don’t screen public and treat early stage curable cancers. X ray mammography is a radiological gift to every woman. It is a simple cost effective method of detecting breast cancer at a stage when there is no palpable lump. This is the beauty of X ray mammography. It detects cancer far before the development of a clinically palpable breast lump. Detection of microcalcifications on X ray mammography are a harbinger of breast cancer which needs to be fixed as per detailed discussion with the patient in question. Yearly mammography after forty helps detecting breast cancer at an early stage. Be naughty at forty. Cost of mammography is peanuts in comparison to other costly investigations but saves more lives. Gift mammography to your wife for her long life, is my personal request to all the readers out there, may be on her birthday!!! October, the pink month, is celebrated as breast cancer awareness month across the globe to spread awareness among doctors and public regarding the huge potential of X ray mammography as a test to detect early stage breast cancer and to lay emphasis on breast self examination as a method to detect early breast lumps. To maintain the pink of her life, please take your wife to the nearest radiology centre to get her mammography done. Choose birthday gifts wisely. May be a Mammography!!! Not only this, have you ever taken your wife to the nearest gynaecologist to get a simple pap and HPV to screen for cervical cancer. Perhaps not. Do it. Try investing on simple things. Choose investigations wisely. Have you ever vaccinated your children against HPV? Perhaps not. Do it. Try investing on simple things. Did you ever take your parents for colonoscopy for screening for colorectal cancer.

Perhaps not. Do it. Try investing on simple things. Choose investigations wisely. Did you ever got your father tested for PSA levels? Perhaps not. Do it. Choose investigations wisely. Obviously there is no a single investigational modality which is complete in itself. We definitely have to select radiological investigations as per the cancer in question keeping in view the stage and the clinical scenario at which the investigation is required. Patients need treatment. Patients need solutions. Patients need remission of their malignancy. Patients are least bothered about medical politics, medical intricacies and medical advances. It is only we people who become more involved with the latest happenings and develop a strong attachment to fancy futuristic tests forgetting age old simple solutions to a complex problem like cancer. Well, we need to sit with the patient, attendants and their nears and dears to explain our plan which might not include PET, might not include CT, might not include MRI or for that matter might not include NGS. We might just solve the problem with a simple CBC, enlightening us the way forward. Patients take discussions very comfortably provided we are able to fully justify during our counselling sessions. No patient comes for PET. No patient comes for CT. No patient comes for MRI. No patient comes for ultrasound. Patients come for easy evidence based solutions. An intelligent physician who is well versed with the natural history of disease can stage tumours with minimum investigation. Would rather make patients spend finances on relevant treatment to provide reasonably good survival with good quality of life. I was taken aback to see PET being endorsed by one of the reputed cancer organization in the world for myeloma work

up. This is enough. Let’s rise to the occasion and take some solid measures. Oncology community has been treating myeloma since years with unbelievable results. A simple X ray skull showing punched out lytic lesions is good enough an evidence to prove bony involvement in patients of multiple myeloma. This is so very easy. Yes. X ray machines are available in the remotest area of our poor country. Not only this, in no time can plain radiography of the whole skeleton be done as a part of skeletal survey knowing the bony involvement in multiple myeloma. Keep things simple. Patients prefer simplicity. Whole body low dose CT scan, available almost everywhere is THE preferred method to detect bone disease in myeloma. For cord compression evaluation, MRI is a preferred radiological modality. Why PET? How many PET centre’s do we have? Who is going to pay for PET? How complicated is the method of appointments? Try building indigenous guidelines. We live in India. Majority of our patients are poor. Sadly, we copy west blindly. Getting PET done to asses skeleton involvement in myeloma is stretching things beyond borders. Multiple myeloma is a mathematical disease with a proper quantification and well established blood based tests for diagnosis and response assessments. Making things simple both for the patient and the treating doctor go a long way in better compliance, mutual understanding and trust building. Complex intricate tests with their subsequent discussions going off the heads makes things worse. Even the best of the cancer organizations must stand to the cause that cancer is a poor man’s disease and things be kept under control keeping the perspective of the public at large rather adding unnecessary burdens which make things loose its

original shine. People have treated large number of myeloma patients with simple investigations like bone marrow biopsy, serum protein electrophoresis, serum free light chain assay and then repeating them as desired on case to case basis every three months to asses response is a reasonably good strategy. Patients remained in complete remission or at least in very good partial remission for long time. Some of them underwent autologous stem cell transplant too as per the availability and finances. Not only this, serum free light chain assay is a very sensitive and a reliable method which pick up early recurrences that mandates the change of the existing chemotherapy protocols. Honestly speaking, myeloma per se hardly requires PET scan. This investigation definitely is a rich man’s kitty. What to talk of PET, poor myeloma patients cannot even afford immunomodulatry drugs which form the backbone of myeloma treatment. We need to be more logical in our approach towards our Indian cancer patients. Try embracing investigation revealing maximum information with minimum cost involved. Try saving patients finances for future to avoid financial toxicity. The day is not far when western countries would be proud of Indian work providing same survival benefits with abbreviated investigations. This manuscript is not a personal attack on anyone but a true outpour of an oncologist who keeps abreast with the latest. As a practicing oncologist, I feel certain things are far more important than PET itself in certain cancers. Understanding tumour biology has far reaching consequences. It perhaps is the most valuable information regarding the final outcome of any cancer patient. Every coin has two sides. Likewise, every cancer has two sides. Same cancer behaves differently in different

individuals. Some cancers are good. Some are bad. I mean, some cancers behave in a less malignant manner, while the same cancer behaves worst in others, killing the patient in question in short span. Such clinical observations need explanations at cellular level. Obviously, its the nucleus in the cell which stores all the information and guide the cell regarding its behaviour. Simple investigations like complete blood counts, liver function tests, renal functions tests, ESR, radiological investigations would probably offer no explanation for such diverse and erratic behaviour of cancers. Helicoptering cellular level and trying to get logical scientific explanations need time, resources and passion. Starting from birds eyes view, the nucleus of the cell is the information centre. Complete information is stored in forty six chromosomes which are beautifully paired and seen during the mitotic phase of cell division. Conventional karyotyping and cytogentics help see the classical collection of army of forty six chromosomes arranged in twenty three pairs. Deletions, duplications and reciprocal translocations amongst chromosomes are clearly visible genetic hits explaining the possible outcomes in cancers. Some CMLs are good. Some CMLs are bad. Some breast cancers are good. Some breast cancers are bad. Some CLLs are good. Some CLLs are bad. The list is never ending. Chromosomes have the answers. Yes. Answers are buried deep down somewhere in the chromosomes, the DNAs, the RNAs and the proteins. Some chronic myeloid leukaemia patients live long, do well with imatinib and enjoy a good quality of life. On the other hand, some CMLs are bad having multiple additional chromosomal abnormalities conferring bad prognosis and bad outcome. Imatinib fails miserably in

these cases. We need more strong tyrosine kinase inhibitors for such bad CML s. At times, ponatinib, the strongest tyrosine kinase inhibitor fails miserably requiring an allogenic stem cell transplant to control things. Trisomy 8, double philadelphia chromosome and iso chromosome 17 are some additional chromosomal abnormalities giving CML a bad outcome. A single philadelphia chromosome gives birth to chronic myeloid leukaemia. Double philadelphia chromosome would double the disease impact. No investigation can detect double philadelphia chromosome except conventional karyotyping and cytogentics. Choose investigations wisely. Think wisely. Think rationally. Patients need to be aware of the fact that they are harbouring double philadelphia chromosome negating survival. It is his disease. Patients have the right to know about things. As chronic myeloid leukaemia patients progress from chronic phase to blast crisis through accelerated phase, so do the gain of additional cytogenetic abnormalities. Only cytogentics is the window to see all this. Choose investigations wisely. Diagnosis and risk stratification of many cancers have been developed on the basis of visible chromosome pattern only. Hematological malignancies including acute leukemias, chronic leukemias, multiple myeloma are some to recall. It speaks volumes of tumour biology and getting them done right at the beginning of treatment throws light on the final outcome of the cancer in question. Prognosticating patients become easy. Choose investigations wisely. Not only in haematology, visible chromosomal changes are seen in solid tumours too. When certain parts of chromosomes get amplified, their function too get amplified giving rise to more bad and more

malignant tumours. HER 2 is a bad gene with big bad stories. HER 2 gene located on chromosome 17, is responsible for controlling the proliferation of breast cancer. In twenty five percent breast cancer patients, HER 2 gene gets amplified giving rise to a fast growing HER 2 positive breast cancers. They proliferate so fast that incidence of brain metastasis is quite high in HER 2 positive breast cancers. Patients must be aware of the natural course of such bad tumours which can only be possible if chromosomal studies are performed at the baseline. Immunohistochemistry and FISH techniques help detecting HER 2 amplifications. Yes. Choosing investigations wisely makes a difference. Time and again, a different set of investigations are needed to move forward as per the clinical scenario. Cancer biology. Choose investigations wisely is a small window to a big ocean. We face similar tragic outcomes of HER 2 amplifications in gastric cancers, colon cancers, lung cancers, biliary tract cancers and many others. HER 2 amplified tumours are bad, grow fast and kill early. Lots of anti HER 2 drugs are available but are costly, unaffordable to a big number and develop resistance fast. Gone are the days of simple histopathology. Gone are the days of simple classification of lung cancer into small cell and non small cell carcinoma. Gone are the days of simple adenocarcinoma for colon cancer as a pathological diagnosis. Gone are the days of adenocarcinoma endometrium. Nowadays, the pathologists, the oncopathologists, the immunohistochemistry experts, the cytogentists, the pcr experts, the FISH experts, the NGS people leave no stone unturned to completely identify the tumour in question right upto the cellular and sub cellular level. They are able

to identify the molecular drivers of the tumour in question. Lung cancer is no longer a one disease. EGFR driven lung cancers have a different story. ALK translocated lung cancers sing different tunes. ROS mutated lung cancers choose alternative paths. The story is unending. Colon cancer too has gone a sea change in management as per the genetic profile of patients. To give readers the final thrust regarding onco genetics, some of the worst hit paediatric cancer is finally druggable. Yes. Diffuse intrapontine gliomas (DIPG) have finally been tamed. Driver mutation found and drugged. Yes!!! With ONC201. YES!!!!! The story is unending. In this way, choosing investigations wisely go a long way in helping cancer patients enjoy good unimaginable survival. In the present fast moving times, oncology books too get a hit. Authors are unable to make up with the editions. Research is happening at such a brisk pace, that recommendations are changing fast. Some new set of unbelievable investigations are flooded in the market. Time has come of liquid biopsies where circulating DNA shed from tumour tissue into the peripheral blood is picked and subjected to next generation sequencing to study the necessary molecular signatures of the tumour. Recurrences too get picked up early, much before the clinical manifestation of the cancer due to reappearance of circulating DNA. Significant decrease in circulating tumour DNA gives a perfect platform for studying molecular response assessments in addition to metabolic responses as evident by PET scans. Obviously, this is way too costly and carriers its own weak points but this definitely avoid biopsies from inaccessible sites thereby shortening the time to treatment. I know, as a service provider, it is a big challenge

for all of us to incorporate all the vital investigations wisely as per patients financial status. With NGS, we are able to go beyond borders to understand and sequence tumour genetic codes to help mankind at large. Sequencing is not something new. Students of class tenth who opt for advanced mathematics study series and sequencing in the shape of arithmetic progression, geometric progression and harmonic progression as a part of series and sequencing. To make things simple, they are given some sequence of numbers having a definite fixed pattern. In arithmetic progression, the numbers are sequenced in such a way that the difference between two consecutive numbers is fixed. Similarly, in geometric progression, the numbers are arranged in such a sequence that the ratio between two consecutive numbers is fixed. Likewise in our human cells, we have a nucleus that has forty six chromosomes which contain approximately twenty five thousand functional genes in total. Each gene consists of numerous base pairs arranged in a particular sequence. There are about three billion base pairs in a human genome. There are four bases in human DNA namely adenine (A ), guanine (G ), thymine (T) and cytosine (C ). Adenine pairs with thymine with a double bond. Guanine pairs with cytosine with a triple bond. Each gene consists of a definite and a fixed arrangement of base pairs arranged in a fixed sequence like ATTCCGCT …This very fixed sequence of bases contain the crucial information regarding the production of the final proteins which ultimately carry out all human biological activities essential for the day to day activities of an individual. Any variation (mutation) in this sequence is detrimental. Even a single change in a base pair is enough to cause a disease. The

corresponding proteins so formed as a result of any change in the sequence of base pairs contain errors resulting in disruption of the normal working of the human machinery resulting in malignancies at times. To keep a check on the occurrence of breast cancer, we have two powerful guards genes, BRCA 1 and BRCA 2 commonly addressed as tumour suppressor genes. Perfect German shepherds, faithful to the master. With the help of modern techniques of NGS, we are able to fully sequence the BRCA gene to help finding error in its sequence. The product of BRCA gene is a protein which helps fixing errors during cell division to maintain fidelity. Normal healthy progeny is ensured. Unhealthy cancerous cells are formed once the guard genes get defective or mutated. Any mutation or change in the base pairs of BRCA gene makes patients vulnerable to get breast, ovary, uterus and prostate cancer. Aggressive screening in BRCA mutated families be carried out to help detect cancers at an early treatable stage or adequate prophylaxis be ensured to nip the evil in the bud. A big round of applause to the famous American actress and a filmmaker, Angelina Jolie for getting bilateral mastectomy done as a preventive measure against breast cancer as she possessed a faulty protective gene, the BRCA 1. Risk drops by whooping 90 percent in women who accept bilateral mastectomies. A number of females followed the suit, the so called Angelina Jolie effect. Multi gene assay are now available for sequencing and analysing other guard genes. Next generation sequencing commonly called NGS is one such type of high end investigation which detects large number of variations in the given tumour sample in short time. Not all such variations are disease causing but yes, it

definitely helps in throwing lights into the causation of cancers. Not everyone is benefitted from next generation sequencing as it creates lot of confusion when non pathogenic variants which are clinically insignificant come to surface. They might contain hidden answers to many unsolved mysteries of human body. We still are in a learning curve as regards NGS is concerned. Probably time would unfold things. As of now, the dictum is to choose investigations wisely. Not everyone requires NGS. Yes. Not everyone requires NGS. Next generation sequencing is definitely important in rare cancers where the data is too scarce, where we need to understand disease better and to offer some evidence based treatment to the patient. No organization across the globe has addressed working protocols for rare cancers as it is too tough to conduct trials due to paucity of rare patients. NGS is helpful in patients who have exhausted treatment options but are still in good shape to tolerate further therapy. Why should I get NGS done in cancers who already have well established treatment protocols? Why should I get NGS done in near dying patients. Obviously a big NO. Choose investigations wisely. Another big milestone in the history of cancer was achieved in 2018 with the announcement of Nobel prize in Medicine. 2018 Nobel prize in Medicine and physiology was awarded to Sir James P Allison and Tasuku Honjo for launching an effective new way to attack cancer cells by treating immune system rather than the cancer cells itself. Till recently, there were only three pillars of cancer treatment namely surgery, chemotherapy and radiotherapy. With the advent of the seminal discovery by these two great scientists, immunotherapy has emerged as the fourth and the greatest

pillar of cancer treatment. Since long, the scientists were struggling with the question as to why our human bodies who possess the most powerful immune system fails to kill the cancer cells. Our immune system is very effective in killing any foreign bacteria, virus and other biological dangers. T lymphocytes are chief players involved in this killing. Obviously, T cells are intelligent in distinguishing from a self and a nonself thereby causing controlled killing. Looking at the lymph node biopsy of Hodgkin’s lymphoma, for instance, it is clear that malignant Reed Sternberg cells of Hodgkin’s lymphoma constitute just 1 percentage of the total lymph node population. The classical cancerous Reed Sternberg cells are surrounded by a hypercellular environment rich in lymphocytes, plasma cells, macrophage and neutrophils but are unable to kill few malignant cells. It was quite surprising. Yes. Surrounded by incompetent T cells??? Incompetent macrophage??? Well, this is not acceptable. True. Not acceptable. Looks very surprising. Who made them incompetent??? On one hand, we are so very proud of our immune system and on the other hand it fails miserably to kill just few cancerous Reed Sternberg cells. Heights of indiscipline on the part of T cells. Something somewhere went wrong. Definitely. Similar observations were seen in many other tumours where the attacking immune T cells were definitely present but were unable to kill the tumour cells. It looked as if the surrounding T cells are unable to kill the cancerous cells or are sedated by something secreted by cancerous cells. Yes. They are sedated. They are made non functional. Yes, they are made non competent. Yes, they are not able to kill the tumour cells. These very questions troubled both the Nobel prize winners

since years. After years of commitment towards research, it was finally found that many receptors were found on the surface of T cells, the activation of which would dampen the killing activities of T cells. One such receptor is the programmed cell death receptor (PD 1 ), present on the surface of immunocompetent T cells, the activation of which was responsible for applying brakes on the functioning of T Cells rendering them non functional. Another receptor called CTLA4 was found on the surface of surrounding T Cells again responsible for dampening the activity of T cells. Cancer cells are smart. No doubt in it. They secrete a protein called programmed cell death protein (PDL 1) that acts as a ligand which interacts with the programmed cell death receptor PD 1 or with CTLA 4 receptor on the surface of surrounding T cells rendering them crippled thereby high jacking the most powerful immune system of the body to their advantage. PD 1 acts like a simple switch, which when turned “on” makes T cells non functional. Simple. PD L1 switches it “on” making T cells incompetent. Simple. The moment biopsy of the tumour is done, it should immediately be subjected to conventional histopathology along with immunohistochemistry to detect percentage surrounding T cells or tumour cells expressing PDL1 to select patients for immunotherapy. Choose investigations wisely. Think rationally. Think wisely. In tumours expressing more than 1 percent of these markers, immunotherapy worked and killed tumours to a significant extent. Immunotherapy stops the interaction between the programmed cell death ligand and programmed cell death protein on T cells thereby setting T cells free from brakes and making them fully functional again to check out for cancer cells to kill them.

Monoclonal antibodies against PD1 or PDL1 have been developed, used successfully and approved worldwide for the use in day to day clinics to kill cancer cells. This is just the beginning of the success story of immunotherapy. So much so, in tumours expressing more than 50 percent programmed cell death receptor or its ligand, single agent immunotherapy worked wonders, melting tumours away, that too without chemotherapy. Use of chemotherapy took a back seat in these hot tumours. Pembrolizumab and nivolumab are some of the immunotherapies being extensively used in clinics with amazing results. Not only this, once the immune system starts attacking cancer cells, it retains its memory for future use too. Such a huge advancement in cancer treatment with the use of immunotherapy makes it mandatory to get immunohistochemistry done for assessment of programmed cell death receptor ligand on the blocks to select patients for immunotherapy. Choose investigations wisely. Think wisely. Think out of the box. Yes, again this is not required in every case. Choose investigations wisely. Renal cell carcinoma is a highly immunogenic tumour, not requiring assessments of PD 1 or PDL 1 by immunohistochemistry to move forward with immunotherapy. Melanomas and Hodgkin’s being richly immunogenic, it is understandable to use immunotherapy as a part of the treatment in these tumours too. Responses to immunotherapy are dramatic and game changers. Primary refractory Hodgkin’s is another big success story. Nivolumab works wonders in such difficult to treat tumour. So much so, nivolumab has taken a front seat as a first line therapy along with chemotherapy in unfavourable Hodgkin’s. Huge success. Great Grandmaster.

Assessments of our guards like mismatch repair proteins (MMR) by immunohistochemistry too identify patients requiring immunotherapy. Replication errors arising during cell division get immediately fixed by intact mismatch repair protein system. In patients with deficient mismatch repair proteins (d MMR tumours ), cells are unable to make exact replica of their own resulting in variations down the progeny. As a result, lots of defective cells are formed expressing lots of neo antigens making them highly immunogenic, predicting good responses to immunotherapy. Of late, dostarlimab hit the headlines as the “Miracle Drug” across the globe sending ripples with its 100 percent response in colorectal cancers in patients with deficient mismatch repair proteins. All this is enough to trigger the treating oncologists to pick up cancers having deficient mismatch repair proteins to give them the chance of being selected for immunotherapy. Choose investigations wisely. Think wisely. Think rationally. Choose patients having deficient in mismatch repair proteins so as to open another path for success and longevity. Offering such patients immunotherapy go a long way in helping patients suffering from advanced incurable cancers. In patients with intact mismatch repair proteins or having proficient mismatch repair proteins, p MMR tumours, we hardly observe any replication defects. Such tumours are cold, non immunogenic as no neoantigens are formed. Hence will not be benefitted from immunotherapy. Choose investigations wisely. Immunotherapy is costly affair. Right patient selection is mandatory for success of immunotherapy. Remember, everything is not immunotherapy in cancer. Solution to every cancer is not immunotherapy. Right patient selection is mandatory for the success of

immunotherapy. Assessments of tumour mutation burden (TMB) is another way to find out patients that would benefit from immunotherapy. TMB is a good way for looking at the number of neo antigens expressed on tumour cell surface. TMB is a simple test whereby 1 cm of the tumour DNA is extracted from cell blocks or from circulating tumour DNA, studied for mutations (changes) in the base sequences contained in that 1 cm of tumour DNA. 1 cm of tumour DNA contains an approximately of 10 lakh (1 mega base) base pairs. More than 10 mutations (changes) in 1 mega base of DNA make the tumour as having high mutational burden, a high TMB tumour (TMB – H ). More the TMB, more are the mutations, more is the formation of neoantigens, more hot the tumour, more immunogenic the tumour would be, more it gets surrounded by T cells to kill neoantigens hence more benefits from immunotherapy. PDL 1, MMR proteins and TMB testing are good predictors available in clinics to help clinicians pick and choose the right patients for immunotherapy. Choose investigations wisely. Think wisely. Think rationally. As of now, if any one of these markers are suggestive of immunogenicity, role of immunotherapy stand justified. Again, choose investigations wisely. Not all tumours require assessments of all three. PDL1 and MMR protein assessments form the first line investigations for immunotherapy keeping TMB as a reserve as it takes approximately 30 days for reading and reporting 10 lac base pairs. Report of PDL 1 and MMR is available in about 3 to 4 working days. Choose investigations wisely. Think wisely. Think rationally. The list of futuristic investigations is endless keeping in view the pace of research. This small

journey of cancer investigations from a small pawn to the all powerful king hopefully made us realize the significance of each chess piece. Each investigation carries a tremendous power to help checkmate cancer. I know, in a financially weak country like India, we still need to move forward with all the positivity and vigour to help cancer patients achieve the best possible longevity with best possible investigations. We, the learned clinicians, are wise enough to choose investigations meticulously from a never ending basket of “me too” investigations. Hopefully, one day, we can say, Good bye cancer!!!

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