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Background/aim: Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced cancers. Most of these treated cancers lack the classical nuclear progesterone receptor (nPR). The hypothesized targets are membrane (m) PRs to inhibit progesterone induced blocking factor (PIBF). To date, there have been no case reports documenting the efficacy of PR antagonists for small cell lung cancer (SCLC) confirmed by pathological analysis. The case reported here demonstrates the efficacy of the single oral agent mifepristone in treating resistant SCLC., Case Report: A 58-year-old man, presenting with a persistent cough, dyspnea on exertion, and marked weakness, was diagnosed with stage IV non-SCLC (NSCLC) that tested positive for the EGFR mutation. He was treated with the single agent osimertinib. When symptoms returned eight months later, along with radiographic evidence of marked cancer progression, a lung biopsy showed SCLC. He failed to respond to pembrolizumab and subsequently to atezolizumab. He was then treated with the single agent mifepristone 200 mg per day orally. He showed marked clinical improvement associated with marked radiographic improvement. Though clinically doing very well, after one year, his dominant lesion increased in size. His oncologist elected to stop mifepristone and treat with camrelizumab with anlototinib. His clinical condition deteriorated on these drugs, and he died five months later., Conclusion: SCLC can be added to the long list of very advanced cancers that are treatment resistant to standard therapy, but respond well to PR antagonists., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The most recent successful advances in lung cancer therapy have directly and increasingly focused on personalized tumor genetic/epigenetic/immunologic profiling, and the identification and development of novel pharmacologic agents aimed at those mutations [e.g., epidermal growth factor receptor (EGFR), Kristen rat sarcoma viral oncogene homolog (KRAS), anaplastic lymphoma kinase (ALK) and immunotherapy against programmed cell death protein 1 (PD-1) and its ligands] which have extended life and provided palliation for lung cancer-patients positive for these mutations. The objective of this study is to provide a review of the large number of drugs and their efficacy as of 2022, for lung cancer, but also introduce a novel treatment that has the potential, based on one controlled murine lung cancer study and 5 anecdotal human cases, that showed marked palliative and longevity benefits in very advanced lung cancer with no other treatment options, i.e., progesterone receptor (PR) antagonists targeting the immunosuppressive protein, the progesterone induced blocking factor (PIBF). Credibility, however, will only be provided when the efficacy can be demonstrated in a large series of lung cancer cases ideally with certain controls. Thus, the ultimate objective of the review is to interest oncologists with a large population of lung cancer patients to perform a well powered study to corroborate or refute the limited experience to date with PR antagonist therapy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR)., Areas Covered: Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells., Expert Opinion: The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Mifepristone treatment for advanced cancer has demonstrated considerable improvement in both length and quality of life in patients who no longer have any other treatment options. The target is the progesterone induced blocking factor (PIBF), which helps the tumor to invade the normal tissue and proliferate and suppress cellular immunity. Most of the benefit has been observed in cancers not associated with the classical nuclear progesterone receptor (nPR). There are data showing that the presence of a nPR may be associated with a better prognosis. Membrane PRs seem to be responsible for PIBF secretion. Mifepristone, possibly fails to block another P associated protein that enables the tumor to proliferate, e.g., the progesterone receptor membrane component-1 (PGRMC-1) protein. One hypothesis is that the nPR helps to inhibit tumor production of PGRMC-1 protein. Thus, mifepristone may inhibit tumor spread by suppressing PIBF, but this may be negated by blocking the nPR, allowing PGRMC-1 levels to increase., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cancer and the fetal-placental semi-allograft share certain characteristics, e.g., rapid proliferation, the capacity to invade normal tissue, and, related to the presence of antigens foreign to the host, the need to evade immune surveillance. Many present-day methods to treat cancer use drugs that can block a key molecule that is important for one or more of these characteristics and thus reduce side effects. The ideal molecule would be one that is essential for both the survival of the fetus and malignant tumor, but not needed for normal cells. There is a potential suitable candidate, the progesterone induced blocking factor (PIBF). The parent 90 kilodalton (kDa) form seems to be required for cell-cycle regulation, required by both the fetal-placental unit and malignant tumors. The parent form may be converted to splice variants that help both the fetus and tumors escape immune surveillance, especially in the fetal and tumor microenvironment. Evidence suggests that membrane progesterone receptors are involved in PIBF production, and indeed there has been anecdotal evidence that progesterone receptor antagonists, e.g., mifepristone, can significantly improve longevity and quality of life, with few side effects.

Background/aim: It has been hypothesized that many, or even most cancers, utilize a unique immunomodulatory protein, called the progesterone induced blocking factor (PIBF) to allow spread of the cancer. Support for this concept has been provided by cancer cell line studies showing that PIBF is produced by these cancer cells and mifepristone suppresses this protein and inhibits proliferation of these cells. Furthermore, controlled murine studies with several spontaneous different types of cancer showed a clear beneficial effect of mifepristone over placebo control. Finally, there have been a variety of anecdotal reports showing efficacy of mifepristone in providing increased length and quality of life in patients with different types of advanced cancers., Case Report: Single agent mifepristone was found to provide significant palliative benefit for a 51-year-old male whose metastatic advanced fibroblastic osteosarcoma progressed despite surgery, radiotherapy, multiagent chemotherapy, and targeted therapy., Conclusion: Thus, osteosarcoma can be added to the list of cancers, not necessarily associated with the classic nuclear progesterone receptor, that seem to respond to progesterone receptor antagonist therapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: There is evidence that a unique immunomodulatory protein, known as the progesterone induced blocking factor (PIBF), is utilized by a large variety of cancers to escape immune surveillance. Mifepristone, a progesterone receptor antagonist/modulator, anecdotally, has been found to increase both length and quality of life in many different types of advanced cancers., Case Report: Though there was one previous case of pancreatic cancer that showed a significant reduction in pain for the one month she took mifepristone before changing to an experimental drug, the case presented here provided much greater evidence that this drug can markedly improve both length and quality of life, in at least some patients, with very advanced pancreatic cancer., Conclusion: It is hoped that this case report will influence others to prescribe mifepristone off-label and hopefully substantiate this finding of marked palliative benefit in the majority of a larger series of patients., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Progesterone induced blocking factor (PIBF) is a unique protein that is not present in normal cells, but is found predominantly in rapidly growing cells of the fetal placental unit or cancer cells. There is a larger "parent" form that is a nuclear protein involved in cell to cell regulation, allowing tumor cells to proliferate and invade tissues. The parent compound is cleaved into smaller intracytoplasmic isoforms that can suppress cellular immune response, especially, but not limited to natural killer cells. The progesterone receptor antagonist mifepristone can suppress messenger RNA for PIBF, but can also suppress the intracytoplasmic protein. Treating cancer cell lines, intact animals with a variety of spontaneous cancers, and people with various cancers with mifepristone, has been found to inhibit cancer growth, and provide both palliation of symptoms and longevity possibly by suppressing this unique immunomodulatory protein., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Case Report: Case 1 of an investigator-initiated study using oral single agent mifepristone to halt stage IV non-small cell lung cancer whose tumor was devoid of any targeted markers has remained ECOG zero and in good health for over 3 years. Case 2, reported here, is a 68-year-old woman with stage IV non-small cell lung cancer whose tumor was positive for the programmed death ligand-1 (PD-L1) marker. Her cancer progressed despite treatment with a check-point inhibitor (nivolumab), besides 3 rounds of multi-agent chemotherapy. After 1 ½ years of treatment with single agent mifepristone, her cancer remains stable (even some tumor regression) and her quality of life is only impaired by her pre-existing chronic obstructive lung disease, not her cancer., Conclusion: Mifepristone therapy may provide a method to halt metastatic lung cancer positive for the PD-L1 marker when check-point inhibitors are no longer effective., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: There is an abundance of accumulating data strongly suggesting there is a key role for the progesterone receptor in the molecular events effecting the growth or containment of a variety of cancers. This knowledge should lead to novel new strategies to combat various cancers, including drugs classified as progesterone receptor modulators or monoclonal antibodies against some of the key proteins needed for cancer proliferation by suppressing immune surveillance. Areas covered: The role of the classic nuclear receptor and molecular events needed for proliferation are reviewed including cancers of the breast, endometrium, prostate, thyroid, and leiomyomas and leiomyosarcoma. The potential role of non-genomic membrane progesterone receptors is reviewed. The prognostic role of the presence of progesterone receptors is also discussed. Over 1000 research publications were read after conducting a PubMed search. Expert commentary: Discussion is made about a unique immunomodulatory protein called the progesterone induced blocking factor (PIBF). The role of this protein, that is unique to rapidly growing cells, may hold a key to how the cancer cells escape immune surveillance. Thus, techniques to suppress the intracytoplasmic isoforms of PIBF may play a significant role in the fight against all cancers, not just the ones with the classic nuclear progesterone receptors.

Purpose: To describe another previous unreported manifestation of the sympathetic neural hyperalgesia edema syndrome - autoimmune hearing loss., Materials and Methods: Dextroamphetamine sulfate 30 mg extended release capsules was given to a woman to try to help her conceive since, with her pelvic pain, chronic fatigue syndrome, and diarrhea, it was thought that an inflammatory condition related to permeation of unwanted chemicals into endometrial tissue related to the sympathetic neural hyperalgesia edema syndrome could be inhibiting her failure from conceiving despite three cycles of embryo transfer., Results: Not only did the symptoms mentioned above disappear, but she also noted marked improvement of hearing loss that had been present for several years. The improvement in hearing was documented by audiology tests and had not responded to many months of 15 mg/day prednisone., Conclusions: Autoimmune hearing loss (diagnosis established by her ear nose and throat specialist) should be added to the long list of manifestation of the sympathetic neural hyperalgesia edema syndrome.

Objective: To determine the effect of extremely low sperm morphology on pregnancy rates following intrauterine insemination (IUI) where all other semen parameters were normal., Materials and Methods: Retrospective review of all IUI cycles over a two-year period on infertile women age ≤ 35 where all parameters, but morphology had to be normal. The data were evaluated according to seven levels of percentage of normal morphology (NM): 0, 1, 2, 3, 4, 5, and ≥ 6%., Results: The percent live delivery was 9.5, 16.7, 8.8, 16.1, 11.4, 12.3, and 10.9%., Conclusions: Morphology of 0% or 1% did not seem to impair pregnancy rates following IUI. More studies are needed but should include determining the confounding effect of the type of morphologic abnormality.

Purpose: To demonstrate that it is important to consider all possibilities when confronted with a decision to terminate a pregnancy because it is likely to be chromosomally abnormal., Materials and Methods: A cell free DNA test was performed on a woman with dichorionic diamniotic twins that followed the transfer of a single embryo., Results: The cell free DNA test was consistent with trisomy 21. Two perinatologists favored identical twins and thus suggested termination since both twins would be trisomy 21 and the couple did not want to raise a child with Down's syndrome. Our group suggested the possibility that these were fraternal twins with one occurring from natural conception. We suggested to forego termination by D&E but to undergo an amniocentesis at 16 weeks. One twin had obvious cardiac abnormalities by ultrasound and this one was reduced while amniocentesis with karyotype was performed on fetus 2. The results showed a normal male., Conclusions: One should consider all possibilities before suggesting termination of a very desired pregnancy. This woman had also been advised by other specialists in reproductive endocrinology that conception with her own oocytes (as did occur here) was not possible and she should consider donor oocytes based on her marked diminished oocyte reserve.

Purpose: To determine if dextroamphetamine sulfate could improve symptoms of post-partum depression., Materials and Methods: A woman with severe post-partum depression that was resistant to standard antidepressant therapy and psychotherapy was treated with dextroamphetamine sulfate extended release capsules 15 mg/day., Results: A quick and complete abrogation of the depression ensued along with improvement of migraine headaches, insomnia, and chronic fatigue., Conclusions: Dextr6amphetamine sulfate should be considered as a treatment modality for post-partum depression.

Purpose: To determine if serum levels of the immunomodulatory protein, the progesterone induced blocking factor (PIBF), which is present in high levels during normal pregnancy, is present in higher levels in women with breast cancer positive for progesterone receptors. The study would also determine whether the presence or absence of the estrogen receptor in any way modifies PIBF expression., Materials and Methods: PIBF using a research ELISA was evaluated in the follicular phase in 21 women with receptor status as follows: seven with estrogen receptor (ER)+ and progesterone receptor (PR)+, seven with ER- and PR+, and seven with ER+ and PR., Results: The results showed no differences in serum PIBF in the three groups. The serum PIBF levels were no different than historical controls in the follicular phase., Conclusions: Measurement of serum PIBF does not seem to be an important marker to use to either detect women with breast cancer or to help determine tumor virulence or potential specific therapies. If PIBF plays a role in helping cancer cells to escape immune surveillance, it seems that the intracytoplasmic PIBF would be the form most likely operative.

Purpose: To compare pregnancy rates following ovulation induction in anovulatory women with clomiphene citrate vs. letrozole and to determine the relative confounding effect of inducing menses or not. The study also evaluated whether starting these anti-estrogen drugs later in the menstrual cycle has-less adverse effect on endometrial thickness., Materials and Methods: Prospective series with choice by physician of inducing menses or not or choosing clomiphene citrate or letrozole for ovulation induction. Peak endometrial thickness was compared between drugs and between those conceiving or not., Results: There were 21 first cycles using letrozole and 42 using clomiphene. Menses were not induced in 18/21 (86%) letrozole cycles and 24/42 (57%) clomiphene cycles. Clinical pregnancies occurred in four (22.2%) letrozole cycles without induced menses with one miscarriage vs. 4/24 (16.6%) clomiphene cycles, no mis- carriage. One of three (33.3%) letrozole cycles with menses induced achieved a clinical pregnancy vs. only 1/18 (5.5%) of clomiphene cycles. There were no miscarriages., Conclusions: Though the endometrial thickness was higher with clomiphene without induced menses vs. menses induced (11 mm vs. 9.5 mm), one cannot explain the trend for lower pregnancy rates in women with induced menses because of thinner endometria since the thickness was 10.3 mm for clomiphene and 10.0 with letrozole.

Case Report: We show long-term high-quality survival following single-agent treatment with a progesterone receptor antagonist in two cases of advanced metastatic cancer. Because no biopsy was performed (patient refused) the exact type of lung cancer was not determined but the majority of oncologists who evaluated the patient thought that the rapid onset and syndrome of inappropriate anti-diuretic hormone was more consistent with small-cell lung cancer. The US Food and Drug Association granted a compassionate-use investigational new drug approval for use of single-agent 200 mg mifepristone orally/day to a moribund woman with never-treated metastatic lung cancer and a male with bilateral renal cell carcinoma who had undergone only a unilateral hemi-nephrectomy. Both had long-term high-quality survival (5 years for the patient with lung cancer with complete remission of all lung lesions, and 12 years for the male patient with kidney cancer). Neither patient had any side-effects from mifepristone therapy., Conclusion: These cases helped influence the US Food and Drug Association in granting an investigator-initiated investigational new drug study on advanced non-small cell lung cancer., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Recurrent aphthous stomatitis is a common disorder of the oral mucosa. The symptoms can range from a minor nuisance to severe forms that can be extremely debilitating. Two cases of chronic aphthous stomatitis are described. The patients sought help to ameliorate vasomotor symptoms. A diagnosis of sympathetic nervous system hypofunction was established. Treatment was aimed at restoring normal sympathetic function by the administration of dextroamphetamine sulfate. Since the patients have been on the amphetamine salts, neither their vasomotor symptoms nor their aphthous lesions have returned. Hypofunction of the sympathetic nervous system should be considered as a possible etiologic factor in patients with recurrent oral ulcers when not associated with known systemic diseases.