The usage of Gellhorn pessary in pelvic organ prolapse and in regards to success, continuity of use and effect on symptoms: a retrospective study of 2 years.

INTRODUCTION: Pelvic organ prolapse (POP) is a condition involving weakened pelvic floor muscles causing organs to protrude. Conservative POP treatment comprises pelvic floor exercises and vaginal pessaries. Besides conservative care, surgery is offered. However, surgery is invasive, risky and unsuitable for those with serious medical conditions. This study aims to assess the acceptance, success and outcomes of the Gellhorn pessary for POP treatment, especially in advanced cases. MATERIALS AND METHODS: The present study is a retrospective cohort study using hospital medical records (patient files) from October 2019 to November 2021 (for 2 years). This study was performed in Malaysian women (n=53) suffering from advanced stages of POP, in which Gellhorn pessaries of diameter (44-76mm) were inserted by trained personnel. Pelvic Floor Distress Inventory-20 (PFDI-20) and Pelvic Floor Impact Questionnaire-7 (PFIQ-7) were used to measure patients' symptoms and quality of life before and after Gellhorn pessary fitting. Patients were reassessed every three months for two years and their satisfaction scores were recorded. RESULTS: We observed a significant difference in pre-test (pre-fitting) and post-test (three months post-fitting) scores on all three subscales and the PFIQ-7 total score. Twentyeight (52.83%) patients continued the use of Gellhorn pessary for at least 24 months, whereas 25 (47.20%) patients discontinued during this period. A retrospective analysis of the patients who discontinued Gellhorn pessary showed that 13 (24.52%) patients gave up the use of pessary for definitive surgery. It is noteworthy to mention here that only one out of the 13 patients who were awaiting surgery, chose surgery and the remaining 12 changed their mind after being fitted with the Gellhorn pessary. Seven (13.20%) patients declined reinsertion due to discomfort and voiding difficulties and refused further intervention, whereas three (5.66%) patients requested a ring pessary. Two (3.77%) patients, requested the removal of pessary due to vesicovaginal fistula and rectovaginal fistula (caused by an impacted pessary). The rate of continued use was 79.24% (42 patients) after 1st year and 52.83% (28 patients) at the end of two years. CONCLUSION: In the current study, the Gellhorn pessary was used to treat stage 3 and 4 POP with significant symptom reduction post-fitting. More than half of the patients continued to use the pessary after 24 months of fitting. Therefore, the Gellhorn pessary can be used as a treatment strategy for stage 3 and 4 POP with reasonable acceptance in the Malaysian population.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma.

The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent "salvage" treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens-Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (p=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti-PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain.

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

A case of mixed connective tissue disease with pseudo-pseudo Meigs' syndrome (PPMS)-like features.

Pseudo-pseudo Meigs' syndrome (PPMS) has been reported to be a rare presentation of patients with systemic lupus erythematosus (SLE). However, such a presentation is not common in other forms of connective tissue disease. We presented a case of gross ascites, pleural effusion, and marked elevation of CA-125 level (PPMS-like features) that led to a diagnosis of MCTD. The patient responded to systemic steroid therapy.

Utilizing twins concordance rates to infer the predisposition to myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder in which patients experience muscular fatigability due to the presence of anti-acetylcholine receptor (AChR) antibodies which inhibit signal transduction across the neuro-muscular junction. Like all complex disorders, disease is caused by an interaction between genetic and environmental factors. Although several genes have been identified which appear to be associated with MG, both classic twin studies and current multi-gene models are insufficient to explain either disease pathogenesis or inheritance. We examined the literature on MG to determine both mono- and dizygotic twin concordance rates, and used this data to (1) estimate the proportion of the population with underlying genetic predisposition to MG and the frequency of the environmental component and (2) derive the number of inherited genetic regions that are required to confer predisposition to MG. Using a MZ twin concordance rate of 35.5%, and a dizygotic rate of approximately 4-5% (based on family data), the probability of encountering environmental components necessary to develop MG in an individual with genetic predisposition is approximately 52.4%, making the frequency of predisposition (1:5240) roughly twice the rate of incidence. Furthermore, the number of genetic regions co-inherited between affected individuals is between two and four, which may be large haplotypes with interacting activity. Determining these haplotypes, by fully sequencing associated regions in cases and controls to identify mutations present, may therefore be a practically step toward the understanding of complex disease.

Effect of ranitidine on the antiplatelet effects of aspirin in healthy human subjects.

Aspirin is often taken with H2-receptor antagonists. In vitro data suggest that certain antagonists, such as ranitidine, have inhibitory effects on platelet function. There are no reports on the combined effect of aspirin and H2-receptor antagonists on platelet function in humans. Therefore, this study's aim was to evaluate the effects of aspirin, ranitidine, and their combination on platelet function in humans. Ten healthy men aged 34.7 +/- 2 years received aspirin 325 mg/day for 4 days followed by a 9-day washout period, 3 days of ranitidine treatment (150 mg twice daily), and 4 days of dual-drug treatment. Blood samples were drawn at baseline and on the last days of aspirin monotherapy, the washout period, ranitidine monotherapy, and dual-drug treatment. Platelet aggregation was measured in response to 0.5 mg/ml arachidonic acid, 5 and 10 mumol/L adenosine diphosphate, and 1 micro g/ml collagen. The Platelet Function Analyzer 100 test was performed, and blood salicylate levels were measured in 6 subjects. Aspirin caused a marked reduction in platelet aggregation and prolongation of Platelet Function Analyzer 100 closure time. Ranitidine caused a modest decrease in platelet aggregation. Unexpectedly, the combination of aspirin and ranitidine caused less inhibition of platelet aggregation and prolongation of Platelet Function Analyzer 100 time than aspirin alone (p = 0.02 to 0.07 compared with aspirin alone). Blood salicylate levels were lower when subjects took aspirin with ranitidine than when they took aspirin alone (1 +/- 0.8 vs 1.6 +/- 0.7 mg/dl, p = 0.005). In conclusion, ranitidine appears to attenuate the antiplatelet effects of aspirin in healthy volunteers. The most likely mechanism for these findings is a change in the absorption conditions of aspirin in the presence of ranitidine.

The polyoma virus T antigen interferes with interferon-inducible gene expression.

Murine polyoma virus (MPyV) is a small DNA virus that induces tumors in multiple tissues of infected host. In this investigation, we show that cell lines derived from wild type virus-induced breast tumors are resistant to the growth inhibitory action of interferon beta (IFN-beta). Furthermore, replication of heterologous viruses such as vesicular stomatitis virus and encephalomyocarditis virus was not inhibited by IFN-beta in these cells. This effect was due to inhibition of IFN-stimulated gene expression by viral T antigen. Activation of IFN-stimulated gene factor 3 was inhibited in cells derived from a tumor induced by wild-type MPyV but not those from a mutant that lacks the pRB binding site of the large T antigen. Similarly IFN-gamma-inducible gene expression was also inhibited in cells transformed by wild-type virus. The levels of components of IFN-stimulated gene factor 3 and signal transducing Janus tyrosine kinases were comparable between the cells transformed by the wild-type and mutant viruses. The viral large T antigen bound to Janus tyrosine kinase 1 and inactivated signaling through IFN receptors. Thus, these studies identify a mechanism of viral resistance to IFN action.

In vitro and in vivo secretion of human ISG15, an IFN-induced immunomodulatory cytokine.

ISG15, a 15-kDa protein of unique primary amino acid sequence, functions intracellularly as a ubiquitin homologue and a cytokine that induces production of IFN-gamma and augments NK/lymphokine-activated killer cell proliferation and function. ISG15 is secreted from monocytes and lymphocytes, and in this study we have characterized in vitro and in vivo production of ISG15 in response to IFN-alphabeta. Low levels of ISG15 were present constitutively in PBMCs; dose-dependent ISG15 synthesis was observed in response to IFN-alpha or IFN-beta, but not IFN-gamma. High m.w. conjugates, present in PBMC extracts constitutively, were enhanced after IFN-alpha or IFN-beta treatment. Metabolic labeling experiments demonstrated that IFN-beta-induced ISG15 was released from primary cultures of peripheral blood CD3+ (including both CD4+ and CD8+ subpopulations). Furthermore, ISG15 was released from viable cell lines of monocyte, T lymphocyte, B lymphocyte, and epithelial origins. Since ISG15 was secreted in response to IFN treatment in vitro, its levels in the serum of healthy human volunteers treated with IFN-beta(ser) were quantitated by asymmetric sandwich ELISA. Both single and multiple doses of IFN-beta(ser) increased serum ISG15 levels significantly (p < 0.01) over baseline. A maximum 7.3-fold enhancement of serum ISG15 was obtained after multiple injections of 8 million units of IFN-beta(ser). Significant change was observed at 24 and 48 h of multiple 0.02-million-unit injections, yielding 1.2- and 1.7-fold increases over basal levels, respectively. These studies suggest that ISG15 is a novel member of the cytokine cascade that is synthesized and released in response to IFN-beta both in vitro and in vivo.

Hematologic and immunologic evaluation of recombinant human interleukin-6 in patients with advanced malignant disease: evidence for monocyte activation.

Eighteen advanced cancer patients received weekday subcutaneous injections of recombinant interleukin-6 (rIL-6) for 4 weeks at escalating doses. Patients were evaluated for hematologic and immune system effects. Hematologic monitoring included WBC, differential, Hgb and Hct, platelet counts, and assessment of marrow and peripheral blood progenitors. Immunologic monitoring included evaluation of acute-phase reactants (APRs), immunophenotyping, serum cytokine levels, cytokine-induced proteins, and cytokine messenger RNA (mRNA). The maximal tolerated dose (MTD) was 8.0 micrograms/kg/day, with neurocortical toxicity as the major limiting factor. All patients became anemic, and most had fever and chills. APRs were increased throughout treatment. WBCs increased transiently on day 2; granulocytes and monocytes increased again through day 26, whereas lymphocytes decreased to baseline or lower levels. Platelets responded by day 12 and increased through day 26 at the MTD with no effect on colony-forming unit-megakaryocyte (CFU-Mk). Peripheral WBC and RBC progenitors were not affected but decreased in the marrow. T-cell percentages declined with little effect on absolute numbers; T-cell activation was seen. CD45RO+ T cells decreased, but there was no significant effect on CD8+ CD28+ T cells. Neither B cells nor natural killer (NK) cells were affected. However, evidence of monocyte effects included upregulation of CD71, induction of the cytokine-induced proteins 2-5A synthetase and neopterin, and increases in tumor necrosis factor-alpha (TNF-alpha) mRNA. Serum cytokines were undetected, and mRNA for IL-1 beta, IL-2, and interferon-gamma (IFN-gamma) was not induced; however, mRNA for IL-4 and IL-10 did increase suggesting activation of Th2-like T cells. One mixed tumor response was seen. We conclude that IL-6 alone has systemic activity on the immune system, as well as the hematopoietic system, which at the MTD, primarily involves induction of APR, activation and expansion of monocytes, and activation of Th2-like T cells.

Amrita Bindu--a salt-spice-herbal health food supplement for the prevention of nitrosamine induced depletion of antioxidants.

Ayurveda, practised in India, identified a large number of plant components to be used in the diet for the prevention or the delayed development of degenerative disorders. They include some of the commonly used spices, namely pepper and ginger. The Materia Medica includes both naturally occurring and artificially produced salts, as a partial substitute for common salt. Health promoting herbs and spices which are classified pharmacologically as rejuvenating, nourishing, invigorating, cleansing, wound-healing, etc., are used as food additives. Amrita Bindu is a salt-spice-herbal mixture based on these principles and was tested for its effect in maintaining antioxidant defense systems in blood and liver when exposed to a carcinogenic nitrosamine, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Amrita Bindu supplementation prevented MNNG induced depletion of the antioxidant enzymes and the scavenger antioxidants glutathione and vitamins A, C and E. Amrita Bindu provides protection against free radical and reactive oxygen species induced tissue lipid peroxidation and the resultant tissue degeneration.

Mechanism of clastogenic and co-clastogenic activity of cremophore with benzene in mice.

Cremophore E1 (CR), a frequently used solubilizer and emulsifier in the pharmaceutical, cosmetic and animal-raising industries, is made up of ethylene oxide and castor oil. Since ethylene oxide has been shown to be a potent genotoxic agent, we have studied the clastogenic activity of CR and its co-clastogenic activity with benzene (BZ) in mice. Male CD1 mice were divided into untreated, vehicle control and experimental groups. Mice in the experimental groups were treated orally with 0.03, 0.3 or 3% CR in water, 440 mg/kg BZ in olive oil, BZ plus the three different doses of CR (1 h apart) or BZ plus 3% CR separated by 1, 3 and 5 h intervals. Mice were killed at 30 h after the treatment for the single-treatment groups and after the first treatment for the combined treatment groups. Bone marrow cells were harvested for determination of micronuclei (MN) frequencies in polychromatic erythrocytes (PCE). The presence of known genotoxic metabolites of benzene (phenol and trans,trans muconic acid) was quantitated in collected urine. The effect on hepatic cytochrome P450 isoenzyme expression in livers of treated mice were also analyzed. We found that CR did not induce any significant or dose-dependent increase in MN. However, CR enhanced the clastogenic activity of BZ in a dose-dependent manner (from 41.6 to 47.3, 60.5 and 67.1 MN/1000 PCE respectively; P less than 0.05). The combined treatment showed an inverse time-dependent change in MN frequencies when CR was administered at 1, 3 and 5 h after BZ (41.6 to 67.1, 43.4 and 42.0 MN/1000 PCE respectively). The enhancement effect of CR is apparently due to its ability to induce significantly the cytochrome P450I family when CR was administered 1 h after treatment with BZ. However, no positive synergistic effect was observed when the combined treatment intervals were extended to 3 and 5 h. Enhanced induction of these isoenzymes is correlated with increased metabolic activation of BZ to excrete increased amounts of trans,trans muconic acid, the putative active metabolite of BZ, in urine. Our integrated study demonstrates that an apparently innocuous agent that is consumed by the general population can enhance the genotoxic activity of a ubiquitous environmental carcinogen. The potential existence of this type of interaction in our daily lives is frequently overlooked and should be investigated.