Clinical use of PARP inhibitor in recurrent uterine leiomyosarcoma with presence of a somatic BRCA2 mutation.

Uterine leiomyosarcoma (uLMS) is an aggressive mesenchymal tumor associated with a poor prognosis. Research demonstrates that PARP inhibitors (PARPi) improve disease-stable survival in patients with somatic BRCA1/2 mutations through the process of synthetic lethality. Therefore, PARPi's may have a role in treating gynecologic malignancies with deleterious BRCA1/2 mutations. This patient is a 50-year-old female with a history of stage IB uterine leiomyosarcoma, complicated by recurrence along the vaginal cuff and metastases to the lungs. A somatic BRCA2 mutation was identified, and the patient was started on Olaparib for treatment of recurrent disease. The patient has now been disease free for two years. We recommend next generation sequencing be performed to identify functional BRCA1/2 loss in uLMS as PARPi may be a potential targeted therapy for uLMS.

Socially determined cervical cancer care navigation: An effective step toward health care equity and care optimization.

BACKGROUND: Despite being the standard of care for patients with locoregional cervical cancer, many patients do not complete all components of primary chemoradiotherapy (pCRT): external beam radiotherapy, chemosensitization, and brachytherapy. Incomplete or protracted pCRT is associated with worse survival. The authors implemented a socially determined cervical cancer care navigation program at a public safety-net hospital to improve treatment adherence. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IVA cervical cancer who underwent pCRT from 2012 to 2016 were prospectively enrolled into this navigation program spanning the medical, financial, and psychosocial aspects of care. This patient cohort was compared with a similar cohort of consecutive nonnavigated patients who were treated from 1998 to 2008. Patient characteristics, treatment data, and patient outcomes were collected. A database of navigation encounters was maintained prospectively. RESULTS: A total of 46 patients composed the navigated cohort and 85 patients composed the nonnavigated cohort. After implementation of the cervical cancer care navigation program, the percentage of patients receiving ≥5 cycles of weekly cisplatin increased from 74% to 93% (P < .01) and rates of the initiation of brachytherapy during external beam radiotherapy increased from 49% to 78% (P < .01). The median treatment time was reduced from 67 days in the nonnavigated patients to 55 days in the navigated patients (P < .01). Approximately 95% of navigated patients who completed pCRT did so within 63 days, compared with 52% of nonnavigated patients (P < .01). Treatment completion within 63 days was associated with significantly improved overall survival. CONCLUSIONS: Socially informed cervical cancer care navigation can significantly improve the timeliness of guideline-based care, enhance access to resources for underserved minority patients receiving pCRT, and may improve overall patient outcomes.

Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia.

Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.

Tattoo pigment lymphadenopathy mimicking metastasis in vulvar cancer.

BACKGROUND: Approximately 24% of American adults have tattoos. Studies of humans and mice demonstrate that tattoo pigment migrates to lymph nodes and can cause lymphadenopathy. CASE: A 32-year-old woman presented with a 6-cm vulvar mass and extensive bilateral inguinofemoral lymphadenopathy. Bilateral small tattoos were noted in the groins. Vulvar biopsy confirmed squamous cell carcinoma, and fine needle aspiration of the lymph nodes showed no evidence of malignancy. The patient underwent a radical hemivulvectomy and bilateral inguinofemoral lymphadenectomy. Both inguinal and femoral nodes were enlarged because of extracellular tattoo pigment and reactive follicular hyperplasia without any evidence of metastasis. CONCLUSION: This case emphasizes the need to consider tattoo pigment as a cause of lymphadenopathy in any patient with a regional tattoo.

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer.

We examined whether reduced levels of Apolipoprotein A-I (apoA-I) in ovarian cancer patients are causal in ovarian cancer in a mouse model. Mice expressing a human apoA-I transgene had (i) increased survival (P < 0.0001) and (ii) decreased tumor development (P < 0.01), when compared with littermates, following injection of mouse ovarian epithelial papillary serous adenocarcinoma cells (ID-8 cells). ApoA-I mimetic peptides reduced viability and proliferation of ID8 cells and cis-platinum-resistant human ovarian cancer cells, and decreased ID-8 cell-mediated tumor burden in C57BL/6J mice when administered subcutaneously or orally. Serum levels of lysophosphatidic acid, a well-characterized modulator of tumor cell proliferation, were significantly reduced (>50% compared with control mice, P < 0.05) in mice that received apoA-I mimetic peptides (administered either subcutaneously or orally), suggesting that binding and removal of lysophosphatidic acid is a potential mechanism for the inhibition of tumor development by apoA-I mimetic peptides, which may serve as a previously unexplored class of anticancer agents.

Validation of serum biomarkers for detection of early-stage ovarian cancer.

OBJECTIVE: Ovarian cancer has the highest mortality of all the gynecologic malignancies with most patients diagnosed at late stages. Serum CA-125 is elevated in only half of patients with stages I-II. We identified 3 serum proteins (apolipoprotein A-1, transthyretin, and transferrin) for the detection of ovarian cancer and reported them combined with CA-125 to effectively detect early-stage mucinous tumors. The objectives of this study were to assess the effectiveness of the panel in detection of early-stage serous and endometrioid ovarian cancers. STUDY DESIGN: In all, 358 serum samples (control, benign adnexal masses, and early-stage and late-stage ovarian cancer) were obtained from the National Cancer Institute. The level of each marker was measured. Multiple logistic regression models were built to calculate sensitivity and specificity. RESULTS: When combined with CA-125, the panel detected early-stage cancer with a sensitivity of 96%. The highest sensitivity was seen for detection of endometrioid subtype of early-stage carcinomas (98%). CONCLUSION: A panel of 4 serum biomarkers effectively detected early-stage ovarian cancers with the highest reported overall sensitivity of 96%. Endometrioid tumors were detected at early stages with a sensitivity of 98%. Prospective clinical analysis of the panel is needed to validate it as an effective screening tool for early-stage ovarian cancer.

The early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125?

Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. More than 80% of patients present with advanced disease, with 5 year survival rates between 15% and 45%. In contrast, the survival rate for stage I disease, with malignancy confined to the ovary, is approximately 95%. Given the discrepancy in survival outcomes between early- and late-stage disease, strategies that would allow for the detection of ovarian cancer in its early stages would hold promise to significantly improve the mortality rate from ovarian cancer. Unfortunately, current screening methods for the detection of early stage ovarian cancer are inadequate. However, several recent proteomics-based biomarker discovery projects show promise for the development of highly sensitive and specific markers for gynecological malignancies, including ovarian cancer. In this review, we hope to provide an overview of the early detection ovarian cancer from traditional methods to recent promises in the proteomics pipeline.

Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: potential use in diagnosis and prognosis.

One hundred eighty-four serum samples from patients with ovarian cancer (n = 109), patients with benign tumors (n = 19), and healthy donors (n = 56) were analyzed on strong anion-exchange surfaces using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry technology. Univariate and multivariate statistical analyses applied to protein-profiling data obtained from 140 training serum samples identified three biomarker protein panels. The first panel of five candidate protein biomarkers, termed the screening biomarker panel, effectively diagnosed benign and malignant ovarian neoplasia [95.7% sensitivity, 82.6% specificity, 89.2% accuracy, and receiver operating characteristic (ROC) area under the curve of 0.94]. The other two panels, consisting of five and four candidate protein biomarkers each, effectively distinguished between benign and malignant ovarian neoplasia and were therefore referred to as validation biomarker panel I (81.5% sensitivity, 94.9% specificity, 88.2% accuracy, and ROC = 0.94) and validation biomarker panel II (72.8% sensitivity, 94.9% specificity, 83.9% accuracy, and ROC = 0.90). The three ovarian cancer biomarker protein panels correctly diagnosed 41 of the 44 blinded test samples: 21 of 22 malignant ovarian neoplasias [10 of 11 early-stage ovarian cancer (I/II) and 11 of 11 advanced-stage ovarian cancer (III/IV)], 6 of 6 low malignant potential, 5 of the 6 benign tumors, and 9 of 10 normal patient samples. In conclusion, we have discovered three ovarian cancer biomarker protein panels that, when used together, effectively distinguished serum samples from healthy controls and patients with either benign or malignant ovarian neoplasia.