Homologous Recombination Abnormalities Associated With BRCA1/2 Mutations as Predicted by Machine Learning of Targeted Next-Generation Sequencing Data.

Background: Homologous recombination deficiency (HRD) is the hallmark of breast cancer gene 1/2 (BRCA1/2)-mutated tumors and the unique biomarker for predicting response to double-strand break (DSB)-inducing drugs. The demonstration of HRD in tumors with mutations in genes other than BRCA1/2 is considered the best biomarker of potential response to these DSB-inducer drugs. Objectives: We explored the potential of developing a practical approach to predict in any tumor the presence of HRD that is similar to that seen in tumors with BRCA1/2 mutations using next-generation sequencing (NGS) along with machine learning (ML). Design: We use copy number alteration (CNA) generated from routine-targeted NGS data along with a modified naïve Bayesian model for the prediction of the presence of HRD. Methods: The CNA from NGS of 434 targeted genes was analyzed using CNVkit software to calculate the log2 of CNA changes. The log2 values of various sequencing reads (bins) were used in ML to train the system on predicting tumors with BRCA1/2 mutations and tumors with abnormalities similar to those detected in BRCA1/2 mutations. Results: Using 31 breast or ovarian cancers with BRCA1/2 mutations and 84 tumors without mutations in any of 12 homologous recombination repair (HRR) genes, the ML demonstrated high sensitivity (90%, 95% confidence interval [CI] = 73%-97.5%) and specificity (98%, 95% CI = 90%-100%). Testing of 114 tumors with mutations in HRR genes other than BRCA1/2 showed 39% positivity for HRD similar to that seen in BRCA1/2. Testing 213 additional wild-type (WT) cancers showed HRD positivity similar to BRCA1/2 in 32% of cases. Correlation with proportional loss of heterozygosity (LOH) as determined using whole exome sequencing of 51 samples showed 90% (95% CI = 72%-97%) concordance. The approach was also validated in an independent set of 1312 consecutive tumor samples. Conclusions: These data demonstrate that CNA when combined with ML can reliably predict the presence of BRCA1/2 level HRD with high specificity. Using BRCA1/2 mutant cases as gold standard, this ML can be used to predict HRD in cancers with mutations in other HRR genes as well as in WT tumors.

Recurrent granulosa cell tumor of the retroperitoneum during the COVID-19 Pandemic.

Extraovarian granulosa cell tumors are rare with very few cases of isolated retroperitoneal granulosa cell tumors reported in the literature. Granulosa cell tumors are notorious for late recurrences and patients should have long term oncologic follow up. We describe a case of recurrent granulosa cell tumor of the retroperitoneum that originally presented as a renal mass, which has not been described before in the literature. Her management was delayed in part due to the COVID-19 Pandemic. Oncologists must be vigilant regarding the consequences of postponed care during this difficult time.

Clotting events among hospitalized patients infected with COVID-19 in a large multisite cohort in the United States.

INTRODUCTION: COVID-19 infection has been hypothesized to precipitate venous and arterial clotting events more frequently than other illnesses. MATERIALS AND METHODS: We demonstrate this increased risk of blood clots by comparing rates of venous and arterial clotting events in 4400 hospitalized COVID-19 patients in a large multisite clinical network in the United States examined from April through June of 2020, to patients hospitalized for non-COVID illness and influenza during the same time period and in 2019. RESULTS: We demonstrate that COVID-19 increases the risk of venous thrombosis by two-fold compared to the general inpatient population and compared to people with influenza infection. Arterial and venous thrombosis were both common occurrences among patients with COVID-19 infection. Risk factors for thrombosis included male gender, older age, and diabetes. Patients with venous or arterial thrombosis had high rates of admission to the ICU, re-admission to the hospital, and death. CONCLUSION: Given the ongoing scientific discussion about the impact of clotting on COVID-19 disease progression, these results highlight the need to further elucidate the role of anticoagulation in COVID-19 patients, particularly outside the intensive care unit setting. Additionally, concerns regarding clotting and COVID-19 vaccines highlight the importance of addressing the alarmingly high rate of clotting events during actual COVID-19 infection when weighing the risks and benefits of vaccination.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer.

FGFR-TACC fusions, including FGFR3-TACC3, have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol. We report the identification of an FGFR3-TACC3 fusion in a case of metastatic endometrioid endometrial cancer. Other potentially actionable alterations detected in this specimen included PIK3CA T1025S and an uncharacterized rearrangement involving TSC2 The patient initially received an FGFR inhibitor as an investigational agent and experienced stable disease with complete resolution of a pelvic nodule; however, treatment had to be discontinued because of intolerable side effects. A PET/CT scan nearly 3 mo after discontinuation showed disease progression. She subsequently received the mTOR inhibitor, temsirolimus, later accompanied by letrozole, and achieved stable disease. Clinical benefit was attributed to the mTOR inhibitor as tumor stained negative for estrogen receptor. Temsirolimus was discontinued after >17 mo because of disease progression. FGFR inhibitors may have clinical benefit in the treatment of endometrial carcinoma with FGFR3-TACC3 fusions. Additionally, clinical benefit from an mTOR inhibitor may reflect a response to targeting the alteration in PIK3CA or TSC2 More research is needed to understand the activity of FGFR3-TACC3 fusions on tumors and to discover additional therapeutic options for endometrial carcinoma patients with this gene fusion.

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers.

OBJECTIVE: To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy. METHODS: A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed. RESULTS: Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median=4; range, 1-26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Sixty-four percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease. CONCLUSION: These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.

Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.

OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Dysplastic endocervical curettings: a predictor of cervical squamous cell carcinoma.

OBJECTIVE: To identify parameters associated with the presence or development of invasive cervical cancer among patients who underwent cold knife conization (CKC) following loop electrocautery excision procedure (LEEP) revealing positive endocervical curettings for stage 3 cervical intraepithelial neoplasia (CIN III). STUDY DESIGN: Patients who underwent CKC following LEEP with endocervical curettings indicating CIN III were observed retrospectively. RESULTS: Of 146 patients identified, 133 (91.1%) had residual CIN on their cone biopsy; 23 (15.8%) had invasive cervical carcinoma. Patients with residual CIN III, ectocervical and endocervical margins with CIN, and positive endocervical curettings on cone biopsy were more likely to harbor or develop invasive cervical carcinoma. CONCLUSION: Patients with CIN III on endocervical curettage at the time of LEEP procedure are at high risk for harboring residual cervical dysplasia or micros-invasive carcinoma, or developing carcinoma in the future. Residual CIN III, ectocervical or endocervical margins positive for CIN, and/or positive endocervical curettings on CKC subsequent to LEEP with positive endocervical curettings for CIN III all indicate a higher likelihood of harboring or developing cervical carcinoma.

Primary spindle cell sarcoma of the vagina treated with neoadjuvant radiation and pelvic exenteration.

OBJECTIVE: Malignant neoplasms of the vagina are rare gynecologic tumors. Primary vaginal sarcomas are even more unusual lesions, representing fewer than 2% of malignant vaginal lesions. CASE: We present a case of a primary vaginal spindle cell sarcoma, treated with neoadjuvant radiation followed by total pelvic exenteration. The patient remains without evidence of disease 2 years after surgery. CONCLUSIONS: The mainstay of treatment of vaginal sarcomas is surgical. Neoadjuvant radiation treatment may decrease surgical morbidity and lead to long-term cure.

Is body mass index an independent risk factor of survival among patients with endometrial cancer?

OBJECTIVE: To evaluate whether body mass index (BMI) is an independent risk factor for survival in patients with endometrial adenocarcinoma. METHODS: Women treated for endometrial cancer at the State University of New York (SUNY), Downstate and Kings County Hospital between January 1982 and September 2003 were eligible. Patients were divided into groups based upon their histology at the time of diagnosis. The first included patients with low-grade endometrioid adenocarcinoma (FIGO grades 1 and 2); the second included grade 3 endometrioid adenocarcinoma; and the third contained papillary serous and clear cell carcinomas. Data regarding BMI, patient age, race, grade, and stage of disease and overall survival, were assessed by survival analysis, with P < 0.05 considered significant throughout. RESULTS: The analysis included 442 patients. Mean BMI was 32.6 +/- 8.2. There were 312 patients (70%) treated for low-grade endometrial adenocarcinoma; 64 patients (14%) for grade 3 endometrioid adenocarcinoma; and 71 patients (16%) for papillary serous and clear cell adenocarcinoma. Increased BMI was associated with improved overall survival (P = 0.003). BMI was also correlated to tumor grade, stage at diagnosis, age, and race. Tumor grade, stage, age, and race were correlated to survival. Statistical analyses revealed the majority of the association between BMI and survival can be attributed to the association between BMI and these other risk factors for survival in endometrial cancer. CONCLUSIONS: Increased BMI is associated with survival advantage among patients with endometrial cancer. Because of the relationship between obesity and other confounding variables obesity alone is not an independent predictor of survival.

Transperineal sonography of a large vulvar hematoma following blunt perineal trauma.

Vulvar hematomas may result from puerperal or nonpuerperal-related trauma. These perineal injuries, especially the puerperal type, may be life-threatening and require surgical exploration, evacuation, and hemostasis. In the absence of acute hematoma expansion, expectant management may suffice. Experience with transperineal sonography in the assessment of female perineal trauma has been limited to a single case report pertaining to a puerperal vulvar hematoma. We present an unusual case in which the transperineal sonographic appearance of a large vulvar hematoma following a straddle injury to the perineum assisted in the expectant management of this condition.

Acute onset of severe hemolysis, elevated liver enzymes, and low platelet count syndrome in a patient with a partial hydatidiform mole at 17 weeks gestation.

Preeclampsia is uncommon prior to 24 weeks gestation and has been associated with partial and complete hydatidiform moles. We present an unusual case in which a patient was diagnosed with preeclampsia at 17 weeks gestation. Ultrasound findings were consistent with a partial hydatidiform mole. Within 24 hours of the onset of symptoms, the patient developed severe hemolysis, elevated liver enzymes, and low platelet count syndrome, with a platelet count of 20 x 10 (9) cells/L. Termination of pregnancy was performed with rapid resolution of signs, symptoms, and laboratory abnormalities. Triploid 69,XXY was confirmed at karyotype analysis. This case demonstrates the acuteness in which life-threatening maternal conditions can arise with this uncommon complication of pregnancy, and the importance of correct identification of the characteristic ultrasonographic findings associated with a partial hydatidiform mole.

Do serum beta-human chorionic gonadotropin levels on day 4 following methotrexate treatment of patients with ectopic pregnancy predict successful single-dose therapy?

The purpose of this study is to assess whether serum beta-human chorionic gonadotropin (beta-hCG) levels on day 4 following methotrexate (MTX) treatment in patients with ectopic pregnancy predict successful single-dose therapy or the need for subsequent surgical intervention. Retrospective analysis of patients with ectopic pregnancies treated with MTX (50 mg/m (2)) was conducted. Inclusion criteria for MTX management were serum beta-hCG < 15,000 mU/mL, absent fetal cardiac activity, ultrasonographic gestational sac < 3.5 cm, normal liver function tests, hemodynamically stable patient with no evidence of hemoperitoneum, and informed consent. Day 1, 4, and 7 serum beta-hCG levels were obtained. Outcome parameters included successful single-dose MTX management, the requirement for multiple treatments, and whether subsequent surgery was required. Receiver operator characteristic (ROC) curves were used. P < 0.05 was considered significant throughout. Eighty-three patients were studied. Of these, 60 patients were treated successfully with single doses, 16 patients required two doses, and two patients required three doses of MTX, and five underwent surgical management. Mean day 1 serum beta-hCG levels of patients successfully treated with single-dose MTX was 3938.5 (+/- 589.2 [standard deviation]) versus 1767.65 (+/- 1237.8) mU/mL in patients requiring multiple doses of MTX therapy, ( P < 0.0001). ROC curves for serum beta-hCG levels on days 1, 4, and 7 were 0.449, 0.592, and 0.754, respectively, indicating that only day 7 serum beta-hCG levels were associated with successful single-dose MTX therapy. Serum beta-hCG levels on day 4 of MTX in patients with ectopic pregnancy do not predict successful single-dose therapy or the need for surgery.