Search

There are several parameters that when inadequate, e.g., low serum progesterone (P), low serum estradiol (E2), or a sac size crown-rump length discrepancy with a sac size lagging behind by more than one week, are poor prognostic parameters for the delivery of a healthy baby. Perhaps the most important abnormal prognostic parameter is an inappropriate rise in serial beta human chorionic gonadotropin (hCG) levels. A case is described who had abnormalities in all these parameters including, in addition, issues with both increased and decreased fetal heart rates. She did however deliver a healthy baby just three weeks before her due date. Her treatment consisted of aggressive P supplementation, plus estrogen, antibiotics, and dextroamphetamine sulfate. One cannot say for certainty whether any or all of these treatments were responsible for her good outcome. This case may be, based on the lack of rise of beta hCG levels, to be the case with the worst prognosis to deliver a live baby published to date, based on failure to have an appropriate type of rise of serial beta hCG levels.

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 determine the frequency of ovulation induction, obtaining oocytes leading to embryos, and pregnancy rates per embryo transfer in women with premature menopause. Materials and methods Prospective observational study of women hoping to have in vitro fertilization-embryo transfer (IVF-ET) with their own oocytes despite being in menopause. Ethinyl estradiol was used to lower follicle stimulation hormone (FSH) and restore sensitivity of follicles to mild FSH stimulation. Results Three of five women had a live baby. Only one woman failed to induce ovulation and thus failed to have an embryo to transfer. One woman conceived two times and delivered a live healthy baby twice. The live delivered pregnancy rate per transfer was 20% (4/20) with generally one or occasionally two embryos transferred. The pregnancy rate per retrieval was 9.3% (4/43). Conclusions These data can help other women in this circumstance to decide on IVF with their own eggs or switch to donor eggs.

Human leukemia cancer cell line studies have demonstrated the presence of a 34 kDa intracytoplasmic splice variant of the parent 90 kDa nuclear protein associated with the centrosome that has significant immunosuppressive activity, especially, but not limited to natural killer (NK) cells. One mechanism of suppressing NK cell cytotoxicity is by stabilizing perforin granules. The 34 kDa intracytoplasmic isoform has been shown to be present only in rapidly growing cells, e.g., embryonic, mesenchymal, trophoblast, and cancer cells. During the luteal phase in ovulating women, and throughout pregnancy, there is a rise in the serum level of this immunomodulatory protein. Thus, it is called the progesterone induced blocking factor (PIBF). Interestingly, the abortafacient, mifepristone, has been shown to suppress the 34 kDa intracytoplasmic concentration of PIBF in cancer cell lines, but it does not lower serum PIBF. Based on the demonstration of significant increase in quality and length of life in controlled animal studies, and anecdotal experience in compassionate use treatment of human patients with a variety of advanced cancer types, the FDA has granted an investigator initiated salvage study of 40 patients with advanced non-small cell lung cancer (NSCLC) who have failed a minimum of two rounds of chemo or immunotherapy to be treated with single agent oral mifepristone (www.clinicaltrials.gov). The first 2 patients are doing extremely well (2 years and 1 year so far) with a high quality life without significant disease progression. Sera PIBF levels were obtained on these patients every 2 months using an experimental ELISA assay. For patient 1, a man with stage IV NSCLC with brain metastasis, his PIBF levels (ng/ml) were all in the range of normal males and women in the follicular phase (27, 38, 53, 59, 52, 46, 39, 45, 44, and 49). For patient 2, who is a female positive for the PD-L1 marker, and who progressed despite 3 rounds of chemotherapy and 1 round of nivolumab, her levels were 10, 30, 12, 21, 23, 50, 64, and 30. Thus, these results suggest that measuring serum PIBF levels in patients with very advanced NSCLC has little value in determining which patients will respond to the progesterone receptor modulator mifepristone, or be able to monitor their response to progesterone receptor modulator therapy. Citation Format: Jerome H. Check, Diane Check, Maya Srivastava, Ann DiAntonio. Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 586.

There is evidence that treatment with mifepristone a P receptor antagonist will provide a marked palliative effect for many human and murine spontaneous cancers. One proposed mechanism is that it may work by suppressing the expression of a unique immunomodulatory protein that amongst other things stabilizes perforin granules in natural killer (NK) cells and thus negates their cytolytic activity. In humans exposure to P causes a rapid rise in the serum of this protein called the PIBF. The origin for the circulating PIBF is from gamma/delta T cells and is initiated with P interacting with P receptors on gamma/delta T cells. PIBF exists as a 90 kDa nuclear protein occupying a centrosomal position in near proximity to BRCA-1 and is found in all rapidly growing cells including cancer cells. A 34-36 kDa splice variant is found in the cytoplasm of all cancer cells tested. Mifepristone has been found to provide marked palliation despite the absence of evidence of circulating PIBF in some cancers not known to be positive for P receptors. One possible mechanism is suppression of the formation of the 34-36 kDa intracytoplasmic form from the parent 90 kDa form. The objective of the present study was to determine if tumors known to be P receptor positive may demonstrate circulating PIBF. In a blinded manner, serum PIBF was measured in 21 serum samples of women with breast cancer obtained prior to surgery using a research ELISA assay for PIBF. The PIBF levels were then compared according to estrogen (E) and P receptor status. The mean level of PIBF (ng/mL) for those who were ER positive but P receptor negative in 7 cases was 31.0+49.7 with a range of 2.1 to 142.5. For 7 cases that were ER positive and P receptor positive the mean level +SD was 24.8+37.46 and the range 2.4 to 108.32. For ER negative and P receptor positive for 7 cases, the mean PIBF was 24.6+28.3 and the range 6.0 to 86.9. There were no significant differences by ANOVA. It is not clear as yet if P receptor antagonist therapy will provide better palliative effect for P receptor positive vs. P receptor negative tumors, but if so, the mechanism (if it is immunologic) does not seem to be related to suppressing increased levels of circulating PIBF. Thus, testing serum with this new ELISA assay does not seem to be a helpful method to determine which patients may benefit from P receptor antagonist therapy. Some recent data suggest that the P receptor antagonist may suppress intracellular PIBF but not circulative PIBF. Thus, these data do not exclude the possibility that PIBF may play a vital role in escape of cancer cells from immune surveillance but it is the intracytoplasmic form that provides immune protection. Citation Format: Jerome H. Check, Anne Rosenberg, Ann DiAntonio, Hallgeir Rui, Rachael Cohen, Gabrielle DiAntonio. Serum levels of the immunomodulatory protein, the progesterone induced blocking factor (PIBF) are not higher in women with progesterone (P) receptor (R) positive vs. negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1281. doi:10.1158/1538-7445.AM2015-1281

PIBF is a unique protein that is secreted by gamma/delta T cells and precipitously rises in the sera following progesterone (P) exposure. The 34 kDa protein protects the fetal semi-allograft from immune surveillance by reducing cytoxicity of natural killer (NK) cells by stabilizing perforin granules. The parent 90 kDa form occupies a centrosomal position close to BRCA-1. PIBF can be found in most rapidly dividing cells. One study found an over-expression of the mRNA for the PIBF protein in all 29 leukemia cell lines tested. The P receptor antagonist mifepristone was found to down-regulate PIBF protein. Mifepristone provided significant palliative benefit to a large variety of spontaneous murine and human cancers. P could also be responsible for converting the 90 kDa parent form to a 34-36 kDa split variant in the cytoplasm which may be the immunosuppressive form in cancer cells. Alternatively, some P-like secretion by the tumor could influence gamma/delta T cells in the tumor microenvironment to secrete PIBF and possibly spill over to the sera. The aim of this study was to determine if there is any increase in serum PIBF in women with gynecologic cancer as opposed to controls. Serum was obtained from women about to have surgery for gynecologic problems including malignant and benign disorders. The samples would then be measured for PIBF using a new non-commercial enzyme linked immunoabsorbent assay (ELISA) for PIBF and serum progesterone. The PIBF levels (ng/mL) from lowest to highest in women with various gynecologic cancers (in all cases serum progesterone (P) 800ng/mL. Citation Format: Jerome H. Check, Mojirayo Sarumi, Ann DiAntonio, Krystal Hunter, Gunda Simpkins, Marie Duroseau. A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2014-4096

Recently a sensitive ELISA assay been created to detect serum levels of the immunomodulatory protein, the PIBF. One of the 34 kDa forms of PIBF increases markedly after exposure to progesterone (P) and inhibits natural killer (NK) cytolytic activity by stabilizing perforin granules and causes of shift from thymic helper (TH)1 to TH2 dominance thus diminishing the activity of the cellular immune system. The 34 kDa form is secreted by gamma/delta T cells and is considered a vital step in preventing immune destruction of the fetal semi-allograft. Evaluation of mRNA for PIBF and PIBF protein found that 29 of 29 human leukemia cell lines over-expressed mRNA for PIBF but only 3 of the lines expressed the PIBF protein. Adding P to the culture up-regulated PIBF protein expression whereas adding the P receptor antagonist mifepristone caused down-regulation of PIBF expression. Mifepristone treatment has been demonstrated to show significant palliative effects on a wide variety of murine and human cancers many of which are not known to be P receptor positive. The hypothesized mechanism is that these tumors either secrete PIBF or direct secretion by gamma/delta T cells in the tumor microenvironment and thus inhibit NK cell cytolytic activity. The inhibition is abrogated by inhibiting P receptors and thus a local form of P secretion by the tumor is hypothesized. The objective of this study was to determine if mifepristone will only help inhibit cancer growth in those individuals who have an increased PIBF level present in their serum. An 81 year old woman with chronic lymphocytic leukemia (CLL) started more rapid advancement and became very symptomatic. She refused chemotherapy when she almost had a lethal complication to oral chlorambucil. She requested mifepristone. Her serum PIBF level of 34.9 ng/mL was in the same range as controls without cancer. However within a month of taking 200mg daily of mifepristone orally she showed a dramatic improvement in her CLL with her white blood cell count dropping from 28,000 to 8,000. Her platelet count increased from 40,000 to 240,000 and 2 lung nodules thought to represent possible primary lung cancer (but possibly nodules from her CLL) completely disappeared on repeat CT scan. Also her energy markedly improved and her persistent cough stopped. The serum PIBF did not decrease with mifepristone therapy - 48.3 ng/mL one month later. These data demonstrated that failure to see a marked increase in serum PIBF in a patient with cancer does not predict failure to respond to mifepristone. Though mifepristone has ameliorated murine leukemia in AKR mice this is the first case report of this drug improving human leukemia. The 34-36 kDa PIBF found in cytoplasm of cancer cells may either not be secreted in the serum or may be immunologically different from serum PIBF found after P exposure. Citation Format: Jerome H. Check, Ann DiAntonio, Diane Check, Alex Jaffe, Rachael Cohen, Mojirayo Sarumi, Maya Srivastava. Clinical improvement of symptomatic advancing chronic lymphocytic leukemia following mifepristone therapy despite normal serum levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 490. doi:10.1158/1538-7445.AM2013-490