Notes from "Cancer: The Emperor of All Maladies" - Part I

• In US, 1 in 3 women and 1 in 2 men will develop cancer in their lifetime
• Sidney Farber, father of modern Chemotherapy
• Leukemia is cancer of WBC
• Cancer is disease caused by uncontrolled growth of a single cell. This growth is unleashed by mutations in DNA. In cancer cell, the circuits to regulate cell division and cell death is broken.
• Malignant growth and normal cell growth is so intertwined that its a modern day medicine challenge to distinguish between the two.
• Mutations in cancer genes accumulate with age, therefore cancer is intrinsically related with age.
• Virchow discovered Leukemia in 1847. Initially he called it Weisses Blut (white blood) but later changed it to Leukemia, from Leukos (greek word for white).
• Hypertrophy: Getting bigger by increasing in size. Hyperplasia: Getting bigger by increasing in number. In animals, fat and muscle grow by hypertrophy and liver, gut, skin etc grow by hyperplasia
• Normal WBC can be divided into 2 categories: Myeloid or Lymphoid cells. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are cancer of respective cells. ALL is cancer of immature lymphoid cells. Cancer of mature lymphoid cells is called Lymphomas
• Leukemia can be measured, by drawing sample of blood and just counting the WBCs. Therefore drugs can be given and potency can be assessed.
• In 1949 winter, an antibiotic Streptomycin was purified out of a clod of mold from a chicken farmer’s barnyard.
• William Halsted was pioneer of radical mastectomy in the 1890s.
• Neglect in the field of cancer research was also a factor of its slow prominence in society.
• Cancer was present in 19th century but it was overshadowed by more common illnesses like TB, influenza etc.
• In 1926, cancer became 2nd most deadly in US, after heart disease.
• Anemia is caused by lack of iron but there are variants of anemia that are caused by lack of other molecules. Pernicious Anemia is caused by lack of vitamin B12.
• Folic acid is crucial building block for DNA and therefore for cell division. Blood cells are produced by most fearsome rate of cell division - more than 300 billion cells a day - genesis of blood is dependent on FA. In absence of FA, production of new blood will cease, like what was observed men and women in Bombay due to lack of vegetables in diet. If FA accelarates leukemia, an antifolate will block it therefore stopping leukemia. Basis of Sidney Farber’s chemotherapy.
• Subbaroa’s team could create slight variants of FA, which possessed counter intuitive properties. Such decoy molecules bind to the enzymes and block its action like a false key jamming the lock.
• Antifolate could stop leukemia but remission was inevitable.
• Metastasis: migration of cancer cells from one site to another. Meta-stasis I.e ‘beyond stillness’ in latin.
• Every generation of cancer cells creates a small number of genetically different cells. When a chemotherapeutic drug or immune system attacks cancer, mutant clones that can resist the attack, grow out. Fittest cancer cell survives and cycle continues.
• In 1862, Edwin Smith found the 2500BC papyrus in Egypt which had mention of a tumor in breast.
• Atossa, queen of Persia, was struck by breast cancer in 440BC.
• Also 1000 yr old mummy was found to have spicules in bone, without question, sign of bone tumor, osteosarcoma. Likewise there were other ancient artifacts showing signs of cancer presence.
• Still historically, less mention of cancer. Cancer is age related disease but human lifespan was very less in ancient societies.
• Civilizations did not cause cancer, but by improving human lifespan, it has unveiled it. Longevity is not the only factor. Our capacity to detect cancer earlier and earlier and attributing deaths accurately to it has also dramatically increased its prevalence in modern society.
• Due to modern life culture, some cancers have increased and some have decreased. Stomach cancer was very common in early 19th century because of carcinogens found in pickling reagents and preservatives but modern refrigerators and hygiene policies have reduced it. In contrast, lung cancer has increased because of smoking.
• In the time of Hippocrates, around 400BC, a word for cancer first appeared in medical literature: karkinos (greek for crab). The tumor with its clutch of blood vessels reminded Hippocrates of a crab dug in sand with its leg spread in circle.
• Another greek word, onkos: meaning mass or burden, reminding of tumor especially, which gave birth to field of oncology
• Disease of Depression or melancholia (medieval name for depression) was attributed to be cause of imbalance of black (melas) bile (khole). Only other disease resulting from black bile is cancer.
• Autopsy: (greek) to see for oneself
• Early 19th century cancer surgeons were hesitant to perform surgery but between 1846-1867, two discoveries made surgery viable options for curing cancer. 1 anesthesia in 1846 and antiseptics in 1867.
• Early 20th century, many locally restricted cancers (primary tumors without metastatic lesions) could be removed by surgery. Uterine, ovarian, breast, prostate, colon and lung. If they were removed before they invaded other organs, surgeries produced cures in significant fraction of patients.
• Post surgery recurrences had accumulated precisely around the margins of original surgery, as if minute remnants of surgery had been left behind. This led to the rise of Radical surgery
• Women with metastatic cancer is not going to be cured by radical mastectomy. Women with small confined cancer does benefit from local mastectomy
• Of the 76 breast cancer treated the radical way, only 40 survived more than 3 years.
• X-rays can shatter strands of DNA or generate toxic chemicals that corrode DNA. Cells either die or cease to divide.
• X-rays were ineffective for cancer that had metastasized. X-rays could be used for local tumors. Leading to growth of radiation oncology. 
• Radium was infused with gold wires and stitched directly into local tumors to produce higher levels of X-rays. Surgeons implanted radium pellets into abdominal tumors. By 1930s and 40s, America had a surplus of radium.
• Radiation oncology had 2 limitations: X-rays could only be targeted for local tumors and X-rays themselves were causing cancer. Evidenced by “radium girls”, watch factory workers who developed cancer of jawline, leukemias, bone, tongue, neck etc.
• The dye chemical, Aniline and Aniline derivatives was used to dye animal tissue and it was found out that the dye was selectively coloring some parts of cells, leaving others untouched, binding to some, sparing others. This raised the question. What if some chemical can be found that’d only kill bacterial cells, sparing normal human cells.
• The survivors of mustard gas attack in 1919 were found to have dried up bone marrow, almost zero WBCs. Men were anemic.
• In early 1950s Joseph Burchenal and Mary Lois Murphy tried 6-MP on children with ALL. Cure was temporary, lasting only few weeks.
• National Fundraising effort was started to tackle Polio. Roosevelt, radio personalities, Hollywood starts all collaborated. Within few weeks, 2680000 dimes had poured into White House by citizens. By late 1940s, John Enders nearly succeeded in culturing polio virus in his lab and Sabin and Salk, building on Enders’s work, were ready with first polio vaccine.
• Mary Lasker was called fairy godmother of medical research because of her work to elevate cancer and corr. Research into public limelight.
• Goal directed strategies, like the Manhattan project, is useful during wartime but is of limited use during peacetime.
• A focused drug -discovery unit for anti cancer drugs was instituted in 1954 after much lobbying by Laskerites. Cancer Chemotherapy National Service Center (CCNSC) between 1954-64 would test 82700 synthetic chemicals, 115000 fermentation products and 17200 plant based derivatives.
• Like penicillin mold, which produces penicillin, bacteria also produce antibiotics to wage chemical warfare on other microbes. Once such antibiotic came from rod-shaped microbe called Actinomyces. Waksman called it Actinomyces-D
• Actinomyces D, combined with X-rays, was effective for Wilms’ tumor metastasis, a rare form of kidney cancer. WIlms’ tumor was first metastatic solid tumor to respond to chemotherapy.
• Mycobacteria, germs that cause TB, would become resistant to antibiotics if the drugs were used singly. Same was found to be true for cancer. Therefore a combination of 2-3 cytotoxic drug combination was sought for chemotherapy.
• Choriocarcinoma - cancer of placenta, in pregnant women.
• Li used chemotherapy to treat choriocarcinoma and used the level of Hcg hormone as a tracker of cancer level. He administered chemo until hcg level went to zero. It was found out that patients who had stopped the drug early inevitably relapsed but patient on Li’s protocol remained free of disease. A fundamental principle of oncology emerged. Cancer needed to be treated long after every visible sign of it had vanished.
• Leukemia children treated with VAMP showed great recovery and showed no sigh of cancer cells in blood. But after few months, children came back to hospital with complaints of headache, dizziness, numbness, seizures etc. Bone marrow biopsies were clean but turned out leukemia cells had invaded the nervous system causing quick and unexpected death. Brain and spinal cord are insulated by a tight cellular seal called blood-brain barrier. This is body’s mechanism to keep poisons away from brain. But this defense mechanism also kept VAMP out of nervous system, therefore cancer cells grew uninhibited in nervous system while it was getting cleaned up from rest of body. A very small percentage of patient survived with VAMP, possible because the cancer was treated well before it could invade nervous system.
• Hodgkin’s disease is cancer of lymph glands- a lymphoma. It infiltrates lymph nodes locally, one by one. Other cancers are unpredictable for e.g Lung cancer may start as a spicular nodule in lung and then suddenly ambulate in brain, pancreatic cancer goes faraway to bones and liver. But Hodgkin’s moved more orderly, affecting one node to another, gland to gland, region to region.
• Hidgkin’s could be treated with radiation, but it’d always relapse with affected lymph node immediately contiguous to original radiated area. This gave rise to assigning staging of cancer. Further the stage if faraway lymph node was affected, thereby also reducing chances of cure and recovery. And subsequently, treatment was adjusted as per staging of cancer.
• One side effect of chemotherapy emerged. Several patients cured of Hidgkin’s would relapse with a second cancer - typically an aggressive drug resistant leukemia. 
• In 1961, Pinkel and his team developed 4 innovations to checmotherapy.
• Combinations of drugs is better than single drug but sometimes we need combinations of combinations I.e 6, 7, or even 8 different chemical poisons combined. 
• If needed, inject chemotherapy directly into nervous system to get over the blood brain barrier.
• Add high dose radiation to skulls if needed, to clear last remnants of residual cancer cells.
• Continue chemo even months or years after cancer is cured.
• With above regimens, results were impressive. Even some patients (30%) never relapsed at all. 
• Cancer of scrotum was prevalent among chimney sweeps, Marie curie, radium girls etc, these observations led to Theory of somatic mutations of cancer I. Environmental carcinogens induce permanent cell structure change thereby causing cancer.
• Experimenting with spindle cell sarcoma, Rous found that injecting tumor from one chicken into another causes cancer to transmit. He kept on filtering the cells through finer and finer sieves before transmitting but still was able to transmit cancer. He found that not only environmental carcinogen, but even viruses (which are very very minuscule and therefore can skip through the sieve of the filter) can cause cancer. His virus was later named Rous Sarcoma Virus (RSV).
• First cancer causing virus found  in humans was Epstein-Barr virus (EBV), which causes mono.
• Religious movements or cult are founded on tetrad of elements: Prophet, prophecy, book and revelation.
• National Cancer act, signed Dec 23 1971 by Nixon. Flood of money authorized for cancer research, $400mil for 1972, $500m for 73, $600m for 74, was a monumental achievement.
• Cancer’s spread is erratic and unpredictable. 
• A major trial across US and Canada with 1765 patients confirmed that rates of breast cancer recurrence, relapse, death and distant metastasis were identical for 3 groups of treatments: radical mastectomy, simple mastectomy, surgery followed by radiation.
• Variants of thyroid cancer continued to make thyroid hormone. Even though cancerous these cells remembered their former selves. 
• Normal prostate cells require testosterone therefore malignant prostate cells require testosterone too. When Huggins removed testicles of prostate cancer bearing dogs, the tumors involuted within days. Therefore Huggins proposed that cancer can be controlled by controlling hormones. Huggins developed hormone therapy: injecting synthetic estrogen into males to stop the production of testosterone to cure prostate cancer. This was called chemical castration. Hormone therapy patients also relapsed once they developed immunity to hormone. Only about 2/3rds of all women with breast cancer responded to when their ovaries were removed.