Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis.

OBJECTIVE: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers. METHODS: In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival. RESULTS: Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 µg/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001). CONCLUSIONS: Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors.

Prevalence and predictors of HIV screening in invasive cervical cancer: a 10 year cohort study.

BACKGROUND: Invasive cervical carcinoma is associated with a human immunodeficiency virus (HIV) prevalence of >0.1%, and screening is recommended and cost-effective for cancer populations exceeding this threshold. HIV status is also prognostic for cancer-specific survival, but compliance with HIV screening is poor in the USA and abroad. OBJECTIVES: This study aims to describe HIV screening practices in a US comprehensive cancer center. To guide quality improvement, we identify characteristics which may predict compliance with screening. STUDY DESIGN: Women treated for invasive cervical cancer from January 2007 to December 2017 were identified by local cancer registry and billing data. We assessed age, race, ethnicity, insurance status, histology, stage, pregnancy, drug use, and HIV testing status. Univariate logistical regression was performed to assess predictors of completed HIV screening. RESULTS: Of 492 eligible women, the cumulative screening rate was 7.6%. Race, ethnicity, histology, and funding source were not predictive of screening. Every 5 year increase in age was associated with a lower chance of screening (OR 0.86, p=0.015), as was earlier stage at diagnosis (OR 0.43, p=0.017). Pregnancy during, or antecedent to, invasive cervical cancer diagnosis was significantly more predictive of screening compliance (OR 10.57, p=0.0007). Only 8/492 (1.6%) women in the cohort were active or former drug users, but within this group HIV screening was performed more frequently (OR 22.7, p<0.0001). CONCLUSION: Despite US and international recommendations for HIV screening in AIDS-defining cancers, compliance remains low. In our centers, factors including earlier age, advanced stage, active pregnancy at diagnosis, and any drug use history were predictive of greater compliance with screening. These data will inform a tailored intervention to improve compliance with HIV screening in our population.

Preoperative vaginal estrogen and midurethral sling exposure: a retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: We evaluated whether the use of estrogen vaginally prior to synthetic midurethral sling insertion mediates the risk of mesh exposure. A secondary aim was to evaluate other factors that may be associated with mesh exposure. METHODS: We performed a retrospective cohort study of patients undergoing midurethral sling insertion from January to December 2010 within the Southern California Permanente Medical Group. Women who used estrogen vaginally prior to surgery were classified as those who filled a prescription between 1 and 45 days before surgery or whose medical records indicated its use at the time of preoperative evaluation. Logistic regression analysis was used to calculate odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with mesh exposure while controlling for confounding variables. RESULTS: A total of 1544 patients met inclusion criteria, of whom 248 (16.1 %) used estrogen vaginally prior to surgery. Mean age was 53.7 years (range 27-89). Thirty-seven (2.4 %) women were diagnosed with mesh exposure, of whom 19 underwent surgical reoperation. In multivariate logistic regression analysis, preoperative use of estrogen vaginally was not associated with the risk of mesh exposure (OR 0.79, CI 0.26-2.38, p = 0.67). Age, body mass index, menopausal status, use of hormone replacement therapy, smoking status, and diabetes were not associated with risk of mesh exposure. CONCLUSIONS: Preoperative use of estrogen vaginally did not appear to mediate the risk of mesh exposure following midurethral sling placement in this cohort.

A critical assessment of morcellation and its impact on gynecologic surgery and the limitations of the existing literature.

Uterine sarcomas are rare uterine malignancies that are difficult to diagnose preoperatively. Because of cases of disseminated sarcoma after laparoscopic hysterectomy, the role of power morcellators in gynecologic surgery has been questioned. Morcellation is an integral part of making laparoscopic surgery possible for the removal of large uterine leiomyomata, and the development of power morcellation has increased efficiency during these procedures. Minimally invasive surgery has demonstrated benefits that include improved pain control, decreased infection risk, and faster surgical recovery and return to work. In this review, we examine the risk of incidental sarcoma at the time of surgery, the quality of the data, the accuracy of clinical and radiologic predictors of uterine sarcoma, and the impact of morcellation on the prognosis of uterine sarcoma.

Clinical performance of a multivariate index assay for detecting early-stage ovarian cancer.

OBJECTIVE: We sought to analyze the effectiveness of a multivariate index assay (MIA) in identifying early-stage ovarian malignancy compared to clinical assessment, CA 125-II, and modified American Congress of Obstetricians and Gynecologists (ACOG) guidelines among women undergoing surgery for an adnexal mass. STUDY DESIGN: Patients were recruited in 2 related prospective, multi-institutional trials involving 44 sites. All women had preoperative imaging and biomarker analysis. Preoperative biomarker values, physician assessment of ovarian cancer risk, and modified ACOG guideline risk stratification were correlated with surgical pathology. RESULTS: A total of 1016 patients were evaluable for MIA, CA 125-II, and clinical assessment. Overall, 86 patients (8.5%) had primary-stage I/II primary ovarian malignancy, with 70.9% having stage I disease and 29.1% having stage II disease. For all early-stage ovarian malignancies, MIA combined with clinical assessment had significantly higher sensitivity (95.3%; 95% confidence interval [CI], 88.6-98.2) compared to clinical assessment alone (68.6%; 95% CI, 58.2-77.4), CA 125-II (62.8%; 95% CI, 52.2-72.3), and modified ACOG guidelines (76.7%; 95% CI, 66.8-84.4) (P < .0001). Among the 515 premenopausal patients, the sensitivity for early-stage ovarian cancer was 89.3% (95% CI, 72.8-96.3) for MIA combined with clinical assessment, 60.7% (95% CI, 42.4-76.4) for clinical assessment alone, 35.7% (95% CI, 20.7-54.2) for CA 125-II, and 78.6% (95% CI, 60.5-89.8) for modified ACOG guidelines. Early-stage ovarian cancer in postmenopausal patients was correctly detected in 98.3% (95% CI, 90.9-99.7) of cases by MIA combined with clinical assessment, compared to 72.4% (95% CI, 59.8-82.2) for clinical assessment alone, 75.9% (95% CI, 63.5-85.0) for CA 125-II, and 75.9% (95% CI, 63.5-85.0) for modified ACOG guidelines. CONCLUSION: MIA combined with clinical assessment demonstrated higher sensitivity for early-stage ovarian malignancy compared to clinical assessment alone, CA 125-II, and modified ACOG guidelines with consistent performance across menopausal status.

Live unilateral twin ectopic pregnancy in a fallopian tube remnant after previous ipsilateral salpingectomy.

Ectopic pregnancy remains an important cause of morbidity and mortality in women of childbearing age. We report a case of a unilateral twin ectopic pregnancy in a fallopian tube remnant after previous ipsilateral salpingectomy. The pregnancy was conceived spontaneously and included two live gestations. Although the presentation of this ectopic pregnancy was unique, the patient's risk factors were not. As an example of the type of patient who would benefit from ultrasound screening for ectopic pregnancy, our patient renews the debate around this controversial issue.

Pharmacokinetic drug evaluation of niraparib for the treatment of ovarian cancer.

INTRODUCTION: Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes. Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Expert opinion: Following presentation of ENGOT-OV16/NOVA at the European Society for Medical Oncology (ESMO) 2016 Congress, niraparib became the first PARP inhibitor to receive full approval by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of recurrent ovarian cancer, regardless of a patient's germline or somatic mutational status. This approval has had a sweeping impact on treatment strategies, moving the indication for a PARP inhibitor earlier in the treatment course and greatly expanding the population of patients who may benefit from this class of drugs. Active clinical trials suggest that new indications and novel treatment combinations are eagerly sought.

Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report.

BACKGROUND: Nivolumab is an immune checkpoint inhibitor specific for the programmed death 1 (PD-1) receptor that has led to clinical responses in many cancer types. Identifying biomarkers predictive of response to PD-1 blockade is an area of active investigation. CASE PRESENTATION: We present a patient with recurrent, metastatic, PD-L1-negative small cell neuroendocrine carcinoma of the cervix (SCNEC) who experienced a complete response to nivolumab. Though nivolumab was discontinued over 4 months ago due to treatment-related adverse events, she continues to have no evidence of disease. CONCLUSIONS: Immune checkpoint inhibitors may be active in neuroendocrine cervical cancer, with potential for dramatic responses in a modest subset of patients.

Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma.

INTRODUCTION: Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors. AREAS COVERED: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of unresectable or metastatic melanoma. EXPERT OPINION: Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities.

Erratum to: Immunotherapy in endometrial cancer - an evolving therapeutic paradigm.

[This corrects the article DOI: 10.1186/s40661-015-0020-3.].

Immunotherapy in endometrial cancer - an evolving therapeutic paradigm.

Endometrial cancer is the only gynecologic malignancy with a rising incidence and mortality. While cure is routinely achieved with surgery alone or in combination with adjuvant pelvic radiotherapy when disease is confined to the uterus, patients with metastatic or recurrent disease exhibit limited response rates to cytotoxic chemotherapy, targeted agents, or hormonal therapy. Given the unmet clinical need in this patient population, exploration of novel therapeutic approaches is warranted, and attention is turning to immunomodulation of the tumor microenvironment. Existing evidence suggests that endometrial cancer is sufficiently immunogenic to be a reasonable candidate for active and/or passive immunotherapy. In this review, we critically examine what is known about the microenvironment in endometrial cancer and what has been learned from preliminary immunotherapy trials that enrolled endometrial cancer patients, encouraging further attempts at immunomodulation in the treatment of aggressive forms of this disease.

Pharmacologic management of advanced cervical cancer: antiangiogenesis therapy and immunotherapeutic considerations.

As a consequence of disparities in access to and utilization of preventative healthcare, the incidence and death rates from cervical cancer remain substantial in the face of indisputable evidence that screening saves lives. While disparities persist, there will be an urgent need for research into the treatment of advanced forms of this disease. In this review, we explore the evolution of the treatment of metastatic, recurrent, and persistent cervical cancer from cytotoxic agents to targeted therapy. We discuss why targeted therapies are unlikely to produce sustained responses alone but may be more successful in combination with immunotherapies. We also provide a rationale for the potential next phase in treatment of this challenging disease-combined therapy with antiangiogenic agents and immune checkpoint inhibitors. In doing so, we highlight recent paradigm shifts within cancer therapeutics, including the shift in focus from the tumor cell itself to the tumor microenvironment, and from stimulating the immune system to inhibiting the inhibitors of an adequate immune response.

Immune checkpoint inhibition: therapeutic implications in epithelial ovarian cancer.

Ovarian cancer accounts for more deaths than any other gynecologic malignancy. According to the Ovarian Cancer National Alliance, overall mortality rates due to ovarian cancer have not significantly improved in 40 years, a statistic that highlights the need for innovative treatment strategies. Immune checkpoint inhibitors are part of an emerging immunotherapeutic model that seeks to "inhibit the inhibitors" of adequate cancer immunosurveillance. Immune checkpoints encompass a variety of inhibitory pathways that downregulate an immune response, which allows them to assume an important physiologic role in maintaining homeostasis. While cancer cells are adept at utilizing these pathways to their advantage, basic scientists, translational researchers, and clinical trialists are making great strides in this area of investigation. This review article will focus on the development of anti-CTLA-4 and anti-PD1 monoclonal antibodies, their current role in the treatment of advanced stage EOC, and recently published patents that incorporate the use of immune checkpoint inhibition in the treatment of cancer.