Data on the substantial physiological role of the immune system in the organism's ability to manage proper differentiation and function of normal tissues (tissue homeostasis), and detailed causes of the immune system's essential role for the in-vivo stimulation of cancer growth, are severely lacking. This results in a lack of effective cancer immunotherapy without adverse events, and in the lack of long-lasting cancer immune prophylaxes, particularly in ovarian cancers. Elimination of blood auto-antibodies blocking anti-cancer T cell effectors by intermittent moderate doses of cyclophosphamide, facilitation of the immune system reactivity against alloantigens of cancer cells by two subsequent blood transfusions, and augmentation of anticancer immunity by weekly intradermal injections of bacterial toxins, caused during the subsequent treatment-free period, lasting for two to four weeks, regression of inoperable epithelial ovarian cancers and regeneration of the tremendously metastatically altered abdominal tissues into normal healthy conditions without multivisceral cytoreductive surgery, which can result in life-threatening consequences. An otherwise untreated rectal cancer, progressing over 3 years, regressed after severe toxic dermatitis lasting over one week. This was caused by an accidental consumption of a large raw shiitake mushroom. Subsequent daily consumptions of 2 g Metformin ER and honeybee propolis ethanol extract, and weekly single larger raw shiitake mushroom, which all stimulate immune system reactivity against cancer stem cells, prevented malignant recurrence over the next 29 years without recurring dermatitis, and maintained healthy organism's conditions. These observations indicate that regression of advanced inoperable cancers and long-lasting cancer immune prophylaxis can be reached by simple approaches.

Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Vestec Czech Republic

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Andrew W. and Andrew N.V. (1945). Mitotic division and degeneration of lymphocytes within the cells of intestinal epithelium in the mouse. Anat. Rec. 93, 251-277. PubMed

Aral C.A., Kesim S., Greenwell H., Kara M., Cetin A. and Yakan B. (2015). Alveolar bone protective and hypoglycemic effects of systemic propolis treatment in experimental periodontitis and diabetes mellitus. J. Med. Food 18, 195-201. PubMed PMC

Ashraf S., Crowe R., Loizidou M.C., Turmaine M., Taylor I. and Burnstock G. (1996). The absence of autonomic perivascular nerves in human colorectal liver metastases. Br. J. Cancer 73, 349-359. PubMed PMC

Avinash J., Vinay S., Jha K., Das D., Goutham B.S. and Kumar G. (2016). The unexplored anticaries potential of shiitake mushroom. Pharmacogn. Rev. 10, 100-104. PubMed PMC

Baldwin L.A., Huang B., Miller R.W., Tucker T., Goodrich S.T., Podzielinski I., DeSimone C.P., Ueland F.R., van Nagell J.R. and Seamon L.G. (2012). Ten-year relative survival for epithelial ovarian cancer. Obstet. Gynecol. 120, 612-618. PubMed

Barrett T.A., Gajewski T.F., Danielpour D., Chang E.B., Beagley K.W. and Bluestone J.A. (1992). Differential function of intestinal intraepithelial lymphocyte subsets. J. Immunol. 149, 1124-1130. PubMed

Bertrand A., Kostine M., Barnetche T., Truchetet M.E. and Schaeverbeke T. (2015). Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 13, 211. PubMed PMC

Bloch E.M., Jackman R.P., Lee T.H. and Busch M.P. (2013). Transfusion-associated microchimerism: the hybrid within. Transfus. Med. Rev. 27, 10-20. PubMed PMC

Boels D., Landreau A., Bruneau C., Garnier R., Pulce C., Labadie M., de Haro L. and Harry P. (2014). Shiitake dermatitis recorded by French Poison Control Centers - new case series with clinical observations. Clin. Toxicol. (Phila) 52, 625-628. PubMed

Bomford R. and Moreno C. (1977). Mechanism of the anti-tumour effect of glucans and fructosans: a comparison with C. parvum. Br. J. Cancer 36, 41-48. PubMed PMC

Bukovsky A. (1975). Immunological aspects of neoplasia. Cesk. Gynekol. 40, 464-466. (In Czech). PubMed

Bukovsky A. (2011). Immune maintenance of self in morphostasis of distinct tissues, tumor growth, and regenerative medicine. Scand. J. Immunol. 73, 159-189. PubMed

Bukovsky A. (2015). Novel methods of treating ovarian infertility in older and POF women, testicular infertility, and other human functional diseases. Reprod. Biol. Endocrinol. 13, 10. PubMed PMC

Bukovsky A. (2016). Involvement of blood mononuclear cells in the infertility, age-associated diseases and cancer treatment. World J. Stem Cells 8, 399-427. PubMed PMC

Bukovsky A. and Presl J. (1985). Allosensitization in tumor therapy and prophylaxis, and in female contraception--a prospect for clinical use. Med. Hypotheses 16, 241-251. PubMed

Bukovsky A. and Presl J. (1986). How to continue in the finding an effective treatment of cancer?. Cesk. Gynekol. 51, 568-577. (In Czech). PubMed

Bukovsky A., Presl J., Zidovsky J. and Mancal P. (1983). The localization of Thy-1.1, MRC OX 2 and Ia antigens in the rat ovary and fallopian tube. Immunology 48, 587-596. PubMed PMC

Bukovsky A., Michael S.D. and Presl J. (1991). Cell-mediated and neural control of morphostasis. Med. Hypotheses 36, 261-268. PubMed

Bukovsky A., Caudle M.R., Keenan J.A., Upadhyaya N.B., Van Meter S., Wimalasena J. and Elder R.F. (2001a). Association of mesenchymal cells and immunoglobulins with differentiating epithelial cells. BMC Dev. Biol. 1, 11. PubMed PMC

Bukovsky A., Caudle M.R., Wimalasena J., Keenan J.A. and Elder R.F. (2001b). The role of the host-tumor interface and cell hybridization in invasive cancer. Med. Hypotheses 57, 729-735. PubMed

Burgos-Ojeda D., Rueda B.R. and Buckanovich R.J. (2012). Ovarian cancer stem cell markers: prognostic and therapeutic implications. Cancer Lett. 322, 1-7. PubMed PMC

Buttery L.D., McCarthy A., Springall D.R., Sullivan M.H., Elder M.G., Michel T. and Polak J.M. (1994). Endothelial nitric oxide synthase in the human placenta: regional distribution and proposed regulatory role at the feto-maternal interface. Placenta 15, 257-265. PubMed

Chester C., Dorigo O., Berek J.S. and Kohrt H. (2015). Immunotherapeutic approaches to ovarian cancer treatment. J Immunother. Cancer 3, 7. PubMed PMC

Cohen I.R., Globerson A. and Feldman M. (1971). Rejection of tumor allografts by mouse spleen cells sensitized in vitro. J. Exp. Med. 133, 821-833. PubMed PMC

Coleman R.L., Monk B.J., Sood A.K. and Herzog T.J. (2013). Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat. Rev. Clin. Oncol. 10, 211-224. PubMed PMC

Conrad F.J., Rice J.S. and Cambier J.C. (2007). Multiple paths to loss of anergy and gain of autoimmunity. Autoimmunity 40, 418-424. PubMed

Cuk M., Radosevic-Stasic B., Milin C., Kirgin M. and Rukavina D. (1987). Lymphoid system as a regulator of morphostasis and hormonal regulation of these functions. Ann. NY Acad. Sci. 496, 104-107. PubMed

Currie G.A. (1970). Active immunotherapy with Corynebacterium parvum and chemotherapy in murine fibrosarcomas. Br Med. J 1, 541-544. PubMed PMC

Dai X., Stanilka J.M., Rowe C.A., Esteves E.A., Nieves C. Jr, Spaiser S.J., Christman M.C., Langkamp-Henken B. and Percival S.S. (2015). Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: A randomized dietary intervention in healthy young adults. J. Am. Coll. Nutr. 34, 478-487. PubMed

Denekamp J. (1984). Vascular endothelium as the vulnerable element in tumours. Acta Radiol. Oncol. 23, 217-225. PubMed

Drouin V., Viguie F. and Debesse B. (1993). Near-haploid karyotype in a squamous cell lung carcinoma. Genes Chromosomes. Cancer 7, 209-212. PubMed

Editorial (2017). The double edge of cancer immunotherapy. Nat. Med. 23, 137. PubMed

Evans J.M., Donnelly L.A., Emslie-Smith A.M., Alessi D.R. and Morris A.D. (2005). Metformin and reduced risk of cancer in diabetic patients. Br. Med. J. 330, 1304-1305. PubMed PMC

Fan Y., Ma L., Zhang W., Xu Y., Suolangzhaxi, Zhi X., Cui E. and Song X. (2014). Microemulsion can improve the immune-enhancing activity of propolis flavonoid on immunosuppression and immune response. Int. J. Biol. Macromol. 63, 126-132. PubMed

Febbraro T., Lengyel E., and Romero I.L. (2014). Old drug, new trick: repurposing metformin for gynecologic cancers? Gynecol. Oncol. 135, 614-621. PubMed PMC

Ferrone S., Pellegrino M.A. and Callahan G.N. (1980). Human and murine tumours: changes in cell surface structures coded by the major histocompatibility complex region. J. Immunogenet. 7, 71-79. PubMed

Fujimoto K., Tomonaga M. and Goto S. (2006). A case of recurrent ovarian cancer successfully treated with adoptive immunotherapy and lentinan. Anticancer Res. 26, 4015-4018. PubMed

Gaillard S.L., Secord A.A. and Monk B. (2016). The role of immune checkpoint inhibition in the treatment of ovarian cancer. Gynecol. Oncol. Res. Pract. 3, 11. PubMed PMC

Garson K. and Vanderhyden B.C. (2015). Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm. Reproduction. 149, R59-R70. PubMed

Hazama S., Watanabe S., Ohashi M., Yagi M., Suzuki M., Matsuda K., Yamamoto T., Suga Y., Suga T., Nakazawa S. and Oka M. (2009). Efficacy of orally administered superfine dispersed lentinan (beta- 1,3-glucan) for the treatment of advanced colorectal cancer. Anticancer Res. 29, 2611-2617. PubMed

Hellstrom I., Hellstrom K.E., Sjogren H.O. and Warner G.A. (1971). Serum factors in tumor-free patients cancelling the blocking of cellmediated tumor immunity. Int. J. Cancer 8, 185-191. PubMed

Hirosako S., Goto E., Fujii K., Tsumori K., Hirata N., Tsumura S., Kamohara H. and Kohrogi H. (2009). Human bronchial intraepithelial T cells produce interferon-gamma and stimulate epithelial cells. Clin. Exp. Immunol. 155, 266-274. PubMed PMC

Hirsch H.A., Iliopoulos D., Tsichlis P.N. and Struhl K. (2009). Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507-7511. PubMed PMC

Ina K., Kataoka T. and Ando T. (2013). The use of lentinan for treating gastric cancer. Anticancer Agents Med. Chem. 13, 681-688. PubMed PMC

Kidd P.M. (2000). The use of mushroom glucans and proteoglycans in cancer treatment. Altern. Med. Rev. 5, 4-27. PubMed

Kitamura H., Naoe Y., Kimura S., Miyamoto T., Okamoto S., Toda C., Shimamoto Y., Iwanaga T. and Miyoshi I. (2013). Beneficial effects of Brazilian propolis on type 2 diabetes in ob/ob mice: Possible involvement of immune cells in mesenteric adipose tissue. Adipocyte 2, 227-236. PubMed PMC

Klein J.R. (2006). The immune system as a regulator of thyroid hormone activity. Exp. Biol. Med. (Maywood.) 231, 229-236. PubMed PMC

Komori H.K., Meehan T.F. and Havran W.L. (2006). Epithelial and mucosal gammadelta T cells. Curr. Opin. Immunol. 18, 534-538. PubMed

Kubota Y., Umegaki K., Kobayashi K., Tanaka N., Kagota S., Nakamura K., Kunitomo M. and Shinozuka K. (2004). Anti-hypertensive effects of Brazilian propolis in spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. 31 (Suppl. 2), S29-S30. PubMed

Kveton J. (1972). Bacterinum adnexitidicum SEVAC in the treatment of inflammation of the female genitalia. Cesk. Gynekol. 37, 36-38. (In Czech). PubMed

Ladanyi A., Timar J. and Lapis K. (1993). Effect of lentinan on macrophage cytotoxicity against metastatic tumor cells. Cancer Immunol. Immunother. 36, 123-126. PubMed

Le D.T. and Jaffee E.M. (2012). Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res. 72, 3439-3444. PubMed PMC

Lee T.H., Paglieroni T., Ohto H., Holland P.V. and Busch M.P. (1999). Survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: frequent long-term microchimerism in severe trauma patients. Blood 93, 3127-3139. PubMed

Lee T.H., Paglieroni T., Utter G.H., Chafets D., Gosselin R.C., Reed W., Owings J.T., Holland P.V. and Busch M.P. (2005). High-level longterm white blood cell microchimerism after transfusion of leukoreduced blood components to patients resuscitated after severe traumatic injury. Transfusion 45, 1280-1290. PubMed

Lindahl K.F. (1979). Anomalous H-2 antigens on tumour cells. Nature 280, 105-106. PubMed

Littman D.R. (2015). Releasing the brakes on cancer immunotherapy. Cell 162, 1186-1190. PubMed

Lotfi-Jam K., Carey M., Jefford M., Schofield P., Charleson C. and Aranda S. (2008). Nonpharmacologic strategies for managing common chemotherapy adverse effects: a systematic review. J. Clin. Oncol. 26, 5618-5629. PubMed

Lupia M. and Cavallaro U. (2017). Ovarian cancer stem cells: still an elusive entity? Mol. Cancer 16, 64. PubMed PMC

Macleod A.S. and Havran W.L. (2011). Functions of skin-resident gammadelta T cells. Cell Mol. Life Sci. 68, 2399-2408. PubMed PMC

Mantha S., Sarasohn D., Ma W., Devlin S.M., Chi D.S., Roche K.L., Suidan R.S., Woo K. and Soff G.A. (2015). Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance. Am. J. Obstet. Gynecol. 213, 208-204. PubMed PMC

Mathe G. (1997). Immunity aging. I. The chronic perduration of the thymus acute involution at puberty? Or the participation of the lymphoid organs and cells in fatal physiologic decline? Biomed. Pharmacother. 51, 49-57. PubMed

McCarthy E.F. (2006). The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J. 26, 154-158. PubMed PMC

McWhinney S.R., Goldberg R.M. and McLeod H.L. (2009). Platinum neurotoxicity pharmacogenetics. Mol. Cancer Ther. 8, 10-16. PubMed PMC

Mendonca C.N., Silva P.M., Avelleira J.C., Nishimori F.S. and Cassia F.F. (2015). Shiitake dermatitis. An. Bras. Dermatol. 90, 276-278. PubMed PMC

Milek T., Wozniak W., Porzycki P., Habib A., Timorek A., Ciostek P., Sawicki W. and Cendrowski K. (2016). Evaluation of urgent multivisceral resections due to complications resulting from an advanced ovarian cancer. Ginekol. Pol. 87, 685-689. PubMed PMC

Missima F. and Sforcin J.M. (2008). Green brazilian propolis action on macrophages and lymphoid organs of chronically stressed mice. J. Evidence-based Complementary Alt. Med. 5, 71-75. PubMed PMC

Morrison S.J. and Kimble J. (2006). Asymmetric and symmetric stemcell divisions in development and cancer. Nature 441, 1068-1074. PubMed

Mueller D.L. (2010). Mechanisms maintaining peripheral tolerance. Nat. Immunol. 11, 21-27. PubMed

Nakamoto N., Cho H., Shaked A., Olthoff K., Valiga M.E., Kaminski M., Gostick E., Price D.A., Freeman G.J., Wherry E.J. and Chang K.M. (2009). Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS. Pathog. 5, e1000313. PubMed PMC

Pagliarone A.C., Orsatti C.L., Bufalo M.C., Missima F., Bachiega T.F., Junior J.P. and Sforcin J.M. (2009). Propolis effects on proinflammatory cytokine production and Toll-like receptor 2 and 4 expression in stressed mice. Int. Immunopharmacol. 9, 1352-1356. PubMed

Papa A., Caruso D., Strudel M., Tomao S. and Tomao F. (2016). Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment. J. Transl. Med. 14, 267. PubMed PMC

Pisano C., Bruni G.S., Facchini G., Marchetti C. and Pignata S. (2009). Treatment of recurrent epithelial ovarian cancer. Ther. Clin. Risk Manag. 5, 421-426. PubMed PMC

Richardson M.A., Ramirez T., Russell N.C. and Moye L.A. (1999). Coley toxins immunotherapy: a retrospective review. Altern. Ther. Health Med. 5, 42-47. PubMed

Rifa'i M. and Widodo N. (2014). Significance of propolis administration for homeostasis of CD4(+) CD25(+) immunoregulatory T cells controlling hyperglycemia. Springerplus 3, 526. PubMed PMC

Rihova B. and Stastny M. (2015). History of immuno-therapy - from coley toxins to check-points of the immune reaction. Klin. Onkol. 28 Suppl 4, 4S8-14. PubMed

Sforcin J.M. (2007). Propolis and the immune system: a review. J. Ethnopharmacol. 113, 1-14. PubMed

Shabo I. and Svanvik J. (2011). Expression of macrophage antigens by tumor cells. Adv. Exp Med. Biol 714, 141-150. PubMed

Shah M.M. and Landen C.N. (2014). Ovarian cancer stem cells: are they real and why are they important? Gynecol. Oncol. 132, 483- 489. PubMed PMC

Shanklin W.M. (1951). Lymphocytes and lymphoid tissue in the human pituitary. Anat. Rec. 111, 177-191. PubMed

Simova J. and Bubenik J. (1975). Effect of prophylactic and therapeutic administration of BCG vaccine on growth of experimental sarcoma. Folia Biol. (Praha) 21, 329-333. PubMed

Sinkovics J.G., DiSaia P.J. and Rutledge F.N. (1970). Tumour immunology and evolution of the placenta. Lancet 2, 1190-1191. PubMed

Steele G. Jr, Sjogren H.O. and Ankerst J. (1974). The effects of cyclophosphamide on in vitro correlates of tumor immunity. Int. J. Cancer 14, 743-752. PubMed

Suzuki M., Takatsuki F., Maeda Y.Y., Hamuro J. and Chihara G. (1994). Antitumor and immunological activity of lentinan in comparison with LPS. Int. J. Immunopharmacol. 16, 463-468. PubMed

Tao Y., Wang D., Hu Y., Huang Y., Yu Y. and Wang D. (2014). The immunological enhancement activity of propolis flavonoids liposome in vitro and in vivo. Evid. Based. Complement Alternat. Med. 2014, 483-513. PubMed PMC

Terada T. and Matsunaga Y. (2001). S-100-positive nerve fibers in hepatocellular carcinoma and intrahepatic cholangiocarcinoma: an immunohistochemical study. Pathol. Int. 51, 89-93. PubMed

Tureci O., Sahin U., Zwick C., Koslowski M., Seitz G. and Pfreundschuh M. (1998). Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens. Proc. Natl. Acad. Sci. USA 95, 5211-5216. PubMed PMC

van de Wetering M., Sancho E., Verweij C., de Lau W., Oving I., Hurlstone A., van der Horn K., Batlle E., Coudreuse D., Haramis A.P., Tjon-Pon-Fong M., Moerer P., van den Born M., Soete G., Pals S., Eilers M., Medema R. and Clevers H. (2002). The betacatenin/ TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241-250. PubMed

Vetvicka V. and Vetvickova J. (2014). Immune-enhancing effects of Maitake (Grifola frondosa) and Shiitake (Lentinula edodes) extracts. Ann. Transl. Med. 2, 14. PubMed PMC

Weiderpass E. and Tyczynski J.E. (2015). Epidemiology of patients with ovarian cancer with and without a BRCA1/2 mutation. Mol. Diagn. Ther. 19, 351-364. PubMed

Winnock M., Garcia B.M., Lukomska B., Huet S., Saric J., Balabaud C. and Bioulac-Sage P. (1995). Human liver-associated lymphocytes: an overview. J. Gastroenterol. Hepatol. 10 (Suppl. 1), S43- S46. PubMed

Yuan J., Zhang D., Wang L., Liu M., Mao J., Yin Y., Ye X., Liu N., Han J., Gao Y., Cheng T., Keefe D.L. and Liu L. (2013). No evidence for neo-oogenesis may link to ovarian senescence in adult monkey. Stem Cells 31, 2538-2550. PubMed

Zhan Q., Wang C. and Ngai S. (2013). Ovarian cancer stem cells: a new target for cancer therapy. Biomed. Res. Int. 2013, 916819. PubMed PMC

Zhang S., Balch C., Chan M.W., Lai H.C., Matei D., Schilder J.M., Yan P.S., Huang T.H. and Nephew K.P. (2008). Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 68, 4311-4320. PubMed PMC

Zhang R., Zhang P., Wang H., Hou D., Li W., Xiao G. and Li C. (2015). Inhibitory effects of metformin at low concentration on epithelialmesenchymal transition of CD44(+)CD117(+) ovarian cancer stem cells. Stem Cell Res. Ther. 6, 262. PubMed PMC

Ziccheddu G., Proietti E. and Moschella F. (2013). The Janus face of cyclophosphamide: A sterile inflammatory response that potentiates cancer immunotherapy. Oncoimmunology 2, e25789. PubMed PMC