Mote:
(a)
(i) The patient at issue was 马进仓 (50岁, 青海, 胃癌晚期 (can not be operated), who died of gastric cancer. He had been treated by 陆巍 of 上海交通大学医学院附属新华医院 普外科 副主任医师.
But I do not know why 张煜 used theterm 二线治疗 (second-line)? What is the first-line treatment for Mr 马?
(ii)
AFP alpha-fetoprotein (a serum protein that is found in fetus but not after delivery. "It is thought to be the fetal analog of serum albumin [白蛋白]." en.wikipedia.org for "alpha fetoprotein." It is always indicative of a malignancy when a human has elevated serum alpha fetoprotein.)
NGS 测序
"高通量测序技术（High-throughput sequencing）又称 '下一代' 测序技术（'Next-generation' sequencing technology）": from the Web.
培美曲塞 pemetrexed which FDA in 2004 approved metastatic non-squamous, non-small cell lung cancer (NSCLC).
安罗替尼 anlotinib (not approved by FDA)
奥沙利铂 oxaliplatin which FDA in 2002 approved for advanced colorectal cancer
卡培他滨 capecitabine which FDA in 1998 approved to treat advanced colorectal or breast cancers
他莫昔芬 tamoxifen
紫杉类 紫杉醇（英文：paclitaxel, PTX)
日达仙 zadaxin whose United States Adopted Name is Thymalfasin and which FDA in 2006 approved to treat advanced melanoma
(iii)
(A) About NGS sequencing of tumor cells. I think Dr Zhang is WRONG. Using blood to detect cancer (or circulating fetal cells in pregnant women) is quite common.
At pages 82-83 (online: pages 3-4 of 10): "Choice of clinical samples [which is septional heading:] * * * There has been great progress in altering DNA extraction methods such that FFPE [fixed in formalin (4 % formaldehyde) and embedded in paraffin] specimens are just as useful for NGS as fresh frozen samples. * * * For most cancers, the standard pathological diagnosis will require a direct sample of tissue for biopsy. However, many research groups are exploring the diagnostic and therapeutic utility of 'liquid biopsies.' One such source of genetic material for disease monitoring are circulating tumor cells (CTCs). These suffer from a low frequency (approximately 1 cell in 106–108 total circulating cells) and must, therefore, go through an enrichment step")
(B) paclitaxel https://en.wikipedia.org/wiki/Paclitaxel
(brand name: taxol; is given by injection into a vein; section 3 Mechanism of action: Unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly)
Paclitaxel is United States Adopted Name.
(iv) Regarding chemotherapy options, I do not know who is right or wrong, in part because 陆巍 (who publicly defended himself days later) cited any research.
(b)
(i) PubMed https://en.wikipedia.org/wiki/PubMed
(The United States National Library of Medicine (NLM) at the National Institutes of Health maintain the database)
The database is easy to maintain. When authors submit a draft for publication, the draft must include abstract (summary). After publication, the abstract automatically go to PubMed without payment in either direction (publisher or PubMed).
(ii) Searching PubMed with (gastric cancer AFP) shows moderate returns (because this kind of stomach cancer is rare), most of which are reported by doctors in China, some from Japan, and none from Europeans or Americans. This is not surprising. See next.
(iii) For simplicity, I will use gastric cancer, though the term stomach cancer is also used (interchangeably) in medicine.
(iv) incidence rate of gastric cancer, compared with colorectal cancer:
(A) GBD 2017 Stomach Cancer Collaborators, The Global, Regional, and National Burden of Stomach Cancer in 195 Countries, 1990–2017: a Systematic Analysis for the Global Burden of Disease study 2017. The Lancet (Gastroenterology & Hepatology), 5: 42 (Jan 1, 2020) https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30328-0/fulltext
("The epidemiology of stomach cancer has substantial geographical heterogeneity, and its incidence can vary 5-fold to 10-fold between high-risk and low-risk countries. Part of this geographical variation correlates with H pylori infection rates across populations; however, a number of environmental factors also contribute to the risk of stomach cancer. Cigarette smoking has been shown to be a risk factor for both cardia and non-cardia stomach cancers. Evidence suggests that salt and salt-preserved foods might increase the risk of stomach cancer. Both types of stomach cancer are more common among males, which might be due to the higher prevalence of risk factors, such as smoking, or hormonal factors contributing to this difference. * * * H pylori infection is the most important established risk factor for stomach cancer") (citations omitted)
• Besides the quotation above, view only Figure 2 Age-standardised incidence rate of stomach cancer per 100 000 population in 2017, for 195 countries and territories.
• Global Burden of Disease Study https://en.wikipedia.org/wiki/Global_Burden_of_Disease_Study
(GBD; is based out of the Institute for Health Metrics and Evaluation (IHME) at the University of Washington [at Washington state] and funded by the Bill and Melinda Gates Foundation. * * * began in 1990 as a single World Bank-commissioned[3] study [but later that year] was was 'institutionalized' at the World Health Organization (WHO) [and remains with WHO]")
• incidence (epidemiology) https://en.wikipedia.org/wiki/Incidence_(epidemiology)
(section 3 Incidence v prevalence)
• Helicobacter pylori https://en.wikipedia.org/wiki/Helicobacter_pylori
("The bacterium was first identified in 1982 by Australian doctors Barry Marshall and Robin Warren. * * * H. pylori infection usually has no symptoms but sometimes causes * * * ulcers of the stomach or first part of the small intestine" besides gastric cancer)
• The Helico in the genus name Helicobacter shares the same root as
helicopter (n; late 19th century from French hélicoptère, from [Ancient] Greek [noun feminine] helix spiral + [noun neuter] pteron wing) https://www.lexico.com/definition/helicopter
• stomach https://en.wikipedia.org/wiki/Stomach
(section 1 Structure, section 1.1 Sections)
The fundus is the part of stomach that is higher (upper) than the cardia.
The cardia is from Ancient Greek kardia heart. The English noun heart is from Old English.
pylorus (n; etymology) https://www.lexico.com/definition/pylorus
(definition and pronunciation)
(B) Western countries have high incidence of colorectal cancer and low incidence rate of stomach cancer, whereas Chinese and Japanese in their countries are opposite. I add "in their countries" because it was found early on that when these people immigrated to the United States, their incidence rate of stomach cancer reduced to the same level of other Americans.
Xie Y et al, Gastrointestinal cancers in China, the USA, and Europe. Gastroenterology Report, _: _ (online publication: Mar 29, 2021; not found in PubMed, suggesting this article is not yet published in a physical copy of the journal) https://academic.oup.com/gastro/ ... tro/goab010/6199178
View only Fig 1 (caption: Time trends of incidence rates of colorectal cancer in men and women across China, the USA, and Europe), Table 1 (The estimated incidence and mortality (per 100,000) of gastrointestinal cancers by age groups in GLOBOCAN 2020), and Fig 2 (Time trends of incidence rates of gastric cancer in men and women across China, the USA, and Europe).
The significance of Table 1 is its inclusion of esophageal cancer, which is high in China but low in Europe or the United States. So far, no bacterium or virus is found to be consistently associated with esophageal cancer.
(C) There are regional differences among Chinese (in China), in terms of gastric cancer risk.
(c) Harada M et al, A Case of a Long-Term Survival Achieved by Surgical Treatment and Chemotherapy for Late Recurrence of AFP-Producing Gastric Cancer. Surgical Case Reports, 5: 106 (2019) https://pubmed.ncbi.nlm.nih.gov/31264022/
("Alpha-fetoprotein-producing gastric cancer (AFP-GC) is a relatively rare disease, accounting for 1.3–15% cases of gastric cancer. AFP-GC is associated with poor prognosis because of high rates of liver and lymph node metastases. * * * Herein, we present a case of a patient with long-term survival after successful treatment with radical surgery for the solitary [a mass with the size of 75 × 70-mm] metastasis of the mesentery and chemotherapy for the multiple liver metastases of AFP-GC at 22 years after the first gastrectomy. * * * Consequently, we diagnosed the tumor to have metastasized from the AFP-GC resected 15 years previously. The preoperative serum AFP levels, which were postoperatively examined, were 17,447 ng/mL [the high level indicated tumor load, though hidden at the time] (normal range < 10 ng/mL). [Fig 2 shows HE stain and immunohistochemical examination with anti-AFP antibody to detect AFP.] Two months after the second surgery, CE-CT scan revealed multiple liver metastases (Fig 3) and serum AFP level increased to 94,838 ng/mL (Fig 4). Therefore, chemotherapy with S-1+CDDP [SP therapy] was initiated [to treat liver metastasis]. However, after two courses of therapy, the patient refused any further treatment owing to severe adverse effects (ie, appetite loss and general fatigue). A CE-CT scan performed after two courses of chemotherapy revealed that all liver metastatic lesions disappeared. Additionally, serum AFP levels declined to normal range (1.0 ng/mL). Seven years after the second surgery, and without any chemotherapy, the patient is alive and well, without any recurrence. In a study by Liu et al, the authors reported that the 1-, 3-, and 5-year survival rates of AFP-GC were 53%, 35%, and 28%, respectively. However, Kripp et al described a long-term survival case of unresectable AFP-GC of the esophago-gastric junction with several liver metastases, which was successfully treated with capecitabine- and oxaliplatin-based combination therapy * * * Gastric cancer usually recurs within the first 2 years of gastrectomy. Late recurrences are rare, with approximately < 1% cases recurring after 10 years. * * * [It is suspected, without proof anywhere in the world, that] the second surgery reactivated the tumor cells which were [had been] dormant [in patient's liver, without multiplication] for 15 years. * * * In Japan, SP therapy for unresectable and recurrent gastric cancers has been recognized as the standard therapy. * * * Surprisingly, the patient is alive without any sign of recurrence at 7 years after the second surgery. With the development of chemotherapy strategies, there are increasing cases who achieved complete response by only several courses of chemotherapy in unresectable gastric cancer") (citations omitted).
(i) Click in upper right corner for free access.
(ii) H&E stain https://en.wikipedia.org/wiki/H%26E_stain
("The hematoxylin stains cell nuclei blue, and eosin stains the extracellular matrix and cytoplasm pink")
(iii) CE-CT stands for contrast-enhanced computed tomography. See CT scan https://en.wikipedia.org/wiki/CT_scan
(section 7 Mechanism, section 7.1 Contrast)
To enhance the image (tumor and normal tissue are not the same), a bolus of contrast media is injected into an artery or a vein (depending on the design of the investigation). Contrast media is usually iodide-based and looks radiopaque (white) in x-ray (which is usually black except for bones). Contrast media reaches the organ under study (vessels in cancers and normal tissues look different, the former tortuous and leaky), to capillaries and diffuse into the organ and tumor (at different rates).
(iv) TeysunoTM (S-1) Receives CHIMP Positive Opinion for Approval as First-Line Therapy or Advanced Gastric Cancer. Taiho Pharmaceutical Co, Ltd, Dec 20, 2010 https://www.taiho.co.jp/en/release/2010/20101220.html
("Taiho Pharmaceutical Co, Ltd, and its parent company, Otsuka Holdings Co, Ltd, announced today that the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), has issued an opinion recommending approval of Teysuno™ (S-1), a novel oral anti-cancer agent, for treatment in adults with advanced gastric cancer when given in combination with cisplatin")
(A) Taihō Pharmaceutical Co, Ltd 岡山大鵬薬品株式会社 (located in 岡山県)
• The hō is Chinese pronunciation of kanji 鵬, which has the same meaning as in China.
• Japanese-English dictionary:
* 鵬 【ほう】 (n): "(arch[chaic]) (See 鯤) [Chinese pronunciation:] peng (in Chinese mythology, giant bird said to transform from a fish)"
* kon 鯤 【こん】 (n): "(arch) (See 鵬) kun (in Chinese mythology, giant fish said to be able to turn into a bird)"
(B) Ōtsuka Holdings Co, Ltd 大塚ホールディングス株式会社 (ホールディングス = holdings; based in Tokyo)
(C) FDA has not approved its use in US. See
Search Orphan Drug Designations and Approvals. FDA, undated https://www.accessdata.fda.gov/s ... fm?cfgridkey=225006
(v) tegafur/gimeracil/oteracil https://en.wikipedia.org/wiki/Tegafur/gimeracil/oteracil
(table: Other names; S-1; section 3 Mechanism of action: "Tegafur is converted to the medicine fluorouracil in the body [what part of body?] * * * Fluorouracil is very similar to pyrimidine [but which pyrimidine?]")
(vi) pyrimidine https://en.wikipedia.org/wiki/Pyrimidine
, whose section 7 Derivatives shows you ring numbering and substitutions for cytosine, thymine, and uracil (three pyrimidine found in nucleotides, the last, uracil, in RNA and the first two in DNA). The synthetic (5-)fluorouracil is close to thymine (in that Fluoride ion is similar in size to methyl group). So thymine is a candidate to compete with fluorouracil, I gather. And indeed it is.
(vii)
(A) fluorouracil. In Highlights of Prescribing Information. FDA, undated https://www.accessdata.fda.gov/d ... 6/012209s040lbl.pdf
("Initial US Approval: 1962"/ "INDICATIONS[:] (colorectal cancer and gastric cancer, among others: my words: this page uses 'adenocarcinoma' in lieu of 'cancer') / "Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion")
Fluorouracil is on the World Health Organization's List of Essential Medicines. Charles Heidelberger (PhD from Harvard in organic chemistry) was credited with discovery of fluorouracil at University of Wisconsin.
There is no corresponding page in "Highlights of Prescribing Information" for tegafur, because FDA has not approved it.
(B) But fluorouracil has severe side effects. Thus tegafur was invented (by attaching a five-membered furan ring to fluorouracil) to sidestep side effects of fluorouracil.
tegafur. PubChem, US National Library of Medicine, undated https://pubchem.ncbi.nlm.nih.gov/compound/Tegafur
• In this Web page, first look at the chemical structure. The fluorine atom at the 10 o'clock position of the top six-membered ring (containing two blue nitrogen atoms) is colored purple. The lower five-membered ring will be lost when tegafur is converted to fluorouracil (the top ring).
• Also in this Web page, you will find "USAN:INN:BAN:JAN." In a word, that says that tegafur is the name of the drug in United, WHO, Britain, and Japan. The acronyms stand for United States Adopted Name, nternational nonproprietary name, British Approved Name, and Japanese Accepted Name.
• Taken orally, tegafur is converted by enzyme "cytochrome 450 2A6" (CYP2A6 for short) in liver to fluorouracil. Neither tegafur nor fluorouracil is bioactive (though the latter causes side effects).
• Fluorouracil then converted to 5-FdUMP. See
V Craig Jordan, A Retrospective: On Clinical Studies with 5-Fluorouracil. Cancer Research, 76: 767 (2016; under the heading: Cancer Research 75th Anniversary Commentaries) https://pubmed.ncbi.nlm.nih.gov/26880809/
("The target for 5-fluorouracil (5FU) is thymidylate synthetase, and the goal of the targeted therapy is to create a thymine-less state. Without available thymine to be incorporated into DNA, this would be toxic to rapidly dividing cancer cells. However, 5FU is not active itself and must first be activated by conversion to the nucleotide deoxyuridine monophosphate (5-FdUMP), which now allows appropriate targeting to thymidylate synthease. In addition, a reduced folate cofactor is required for tight binding of the inhibitor to thymidylate synthetase. The natural substrate is N5,10- methylenetetrahydrofolic acid, which binds covalently to 5-FdUMP. As a result, the enzyme is neutralized. The clinical development program for 5FU, combining the McArdle Laboratory, the Clinical Oncology Group [headed by Charles Heidelberger] at the University of Wisconsin Hospital, and Hoffman-LaRoche, was, on the face of it, traditional")
FdUMP (where F stands for fluorine atom and d, deoxyribose (the five-membered ring in DNA, in contrast to ribose in RNA). See ribose https://en.wikipedia.org/wiki/Ribose
Take notice that in section 2 Structure, the 2' has -OH attached to it, which would be -H in deoxyribose. Why 2'? More generally, why the five carbons in ribose are numbered with a prime (')?
prime (symbol) https://en.wikipedia.org/wiki/Prime_(symbol) ("differ little in appearance from those of the apostrophe (or the single or double quotation mark)" )
This is because by convention, the purine or pyrimidine ring uses 1, 2, 3 etc (without a prime).
dUMP has a full name of either "deoxyuridine monophosphate" or "deoxyuridylic acid or deoxyuridylate." https://en.wikipedia.org/wiki/Deoxyuridine_monophosphate
Note one phosphate ion covalently linked to carbon 5', which is not marked but shown as a right angle with two arms point to left and down.
"Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP)" by adding a methyl group (-CH3) to No 5 of the 6-membered pyrimidine ring. en.wikipedia.org for "thymidylate synthase."
However, once FdUMP (the bioactive molecule) binds to thymidylate synthase (which mistakes FdUMP for dUMP), dTMP (also known as thymidylate) can not be synthesized.
• It sounds too good to be true. In reality, cancers will counteract by producing a lot of thymidylate synthase so that fluorouracil or tegafur become less and less effective (against these cancers).
(C)
• ter Veer E et al (from the Netherlands), The efficacy and safety of S-1-Based Regimens in the First-Line Treatment of Advanced Gastric Cancer: a Systematic Review and Meta-analysis. Gastric Cancer, 19: 696 (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906062/
("Discussion: Previous meta-analyses have suggested that 5-FU may be replaced by S-1 in first-line therapy for advanced gastric cancer because of a survival benefit in favour of S-1. Our updated meta-analysis does not confirm this finding. * * * However, in Western patients S-1-based therapy did have clear clinically relevant advantages in terms of the toxicity profile over 5-FU-based therapy—namely," less side effects) (citations omitted)’
meta-analysis https://en.wikipedia.org/wiki/Meta-analysis
• Ilson DH, Advances in the treatment of gastric cancer. Current Opinion in Gastroenterology, 34: 465 (2018) https://pubmed.ncbi.nlm.nih.gov/30303856/
(Abstract: "Addition of postoperative radiation therapy to perioperative chemotherapy offers no survival benefit. Fluoropyrimidines, in particular 5-fluorouracil (5-FU), are the backbone for gastric cancer chemotherapy. S-1, an oral prodrug of 5-FU, has become the mainstay for gastric cancer chemotherapy in Japan")
(vi) The Harada paper at the beginning of Note (c) also mentioned CDDP, which is cisplatin.
(A) Dasari S and Tchounwou PB, Cisplatin in Cancer Therapy: Molecular Mechanisms of Action. European Journal of Pharmacology, 740: 364 (2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146684/
(Introduction: "Cisplatin * * * also called cis-diamminedichloroplatinum (II), is a metallic (platinum) coordination compound with a square planar geometry. It is a white or deep yellow to yellow-orange crystalline powder at room temperature. It is slightly soluble in water and soluble in dimethylprimanide and N,N-dimethylformamide. * * * the compound did not gain scientific investigations until the 1960's when the initial observations of Rosenberg (Rosenberg, Vancamp [the first two of the three authors] et al, 1965 [published in Nature]) at Michigan State University pointed out that certain electrolysis products of platinum mesh electrodes were capable of inhibiting cell division in Escherichia coli created much interest in the possible use of these products in cancer chemotherapy. Since the identification of cis-dichlorodiammineplatinum (II) * * * as the agent responsible for this activity, much interest has been generated in the use of coordination complexes of platinum, palladium, and other noble metals in the treatment of cancer")
• cis-diamminedichloroplatinum (II) -- hence the acronym CDDP, for two ammines and two chlorine atoms.
• Continue on this Web page is Fig 1, where oxaliplatin is mislabeled as Fig 1(C), while in fact it is Fig 1(D).
(B)
• oxaliplatin. PubChem, National Library of Medicine, undated https://pubchem.ncbi.nlm.nih.gov/compound/Oxaliplatin
("Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with an oxalate ligand * * * alkylate macromolecules, forming both inter- and intra-strand platinum-DNA crosslinks, which result in inhibition of DNA replication")
• oxaliplatin https://en.wikipedia.org/wiki/Oxaliplatin
Pay attention to chemical structure ONLY. This Wiki page tells you what "1,2-diaminocyclohexane" looks like. As for oxalic acid, it is HOOC-COOH (composed of two carboxyl group.
The English oxalic is from Latin, and then Ancient Greek, nouns of the same spelling: oxalis https://en.wiktionary.org/wiki/oxalis
, that means sorrel. https://en.wikipedia.org/wiki/Sorrel
Hence in Taiwan, oxalic acid is 草酸.
(C) "Cisplatin is the prototype platinum coordination complex classified as an alkylating agent and used intravenously in the treatment of several forms of cancer." PubChem.
(D) cisplatin https://en.wikipedia.org/wiki/Cisplatin
section 3 Pharmacology, section 3,1 Molecular structure: " * * * The prefix cis indicates the cis isomer in which two similar ligands are in adjacent positions. The systematic chemical name of this molecule is cis–diamminedichloroplatinum, where ammine with two m's indicates an ammonia (NH3) ligand, as opposed to an organic amine with one m."
Section 4 History: " * * * a soluble platinum complex which inhibited binary fission in Escherichia coli (E. coli) bacteria [which normally is rod-shaped]. Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length. * * * [cis] but not the trans isomer, was found to be effective at forcing filamentous growth of E. coli cells."
Recall that all German nouns have the first letter capitalized.
(v) Rather than "二线治疗" (张煜's words about Dr Lu), I think S-1 + CDDP might be 一线治疗. So Dr Zhang is Wrong in this point also.
But he is probably right in saying tumor sequencing was unnecessary, because sequencing may be very quick (days), but it takes a lot of efforts to find out which mutations (there are many, many) in a cancer that fuel cancer growth, from simply copy mistakes of the cancer (which is prone to replication mistakes).