Comparison of accuracy and reproducibility of colposcopic impression based on a single image versus a two-minute time series of colposcopic images.

OBJECTIVE: Colposcopy is an important part of cervical screening/management programs. Colposcopic appearance is often classified, for teaching and telemedicine, based on static images that do not reveal the dynamics of acetowhitening. We compared the accuracy and reproducibility of colposcopic impression based on a single image at one minute after application of acetic acid versus a time-series of 17 sequential images over two minutes. METHODS: Approximately 5000 colposcopic examinations conducted with the DYSIS colposcopic system were divided into 10 random sets, each assigned to a separate expert colposcopist. Colposcopists first classified single two-dimensional images at one minute and then a time-series of 17 sequential images as 'normal,' 'indeterminate,' 'high grade,' or 'cancer'. Ratings were compared to histologic diagnoses. Additionally, 5 colposcopists reviewed a subset of 200 single images and 200 time series to estimate intra- and inter-rater reliability. RESULTS: Of 4640 patients with adequate images, only 24.4% were correctly categorized by single image visual assessment (11% of 64 cancers; 31% of 605 CIN3; 22.4% of 558 CIN2; 23.9% of 3412 < CIN2). Individual colposcopist accuracy was low; Youden indices (sensitivity plus specificity minus one) ranged from 0.07 to 0.24. Use of the time-series increased the proportion of images classified as normal, regardless of histology. Intra-rater reliability was substantial (weighted kappa = 0.64); inter-rater reliability was fair ( weighted kappa = 0.26). CONCLUSION: Substantial variation exists in visual assessment of colposcopic images, even when a 17-image time series showing the two-minute process of acetowhitening is presented. We are currently evaluating whether deep-learning image evaluation can assist classification.

A demonstration of automated visual evaluation of cervical images taken with a smartphone camera.

We examined whether automated visual evaluation (AVE), a deep learning computer application for cervical cancer screening, can be used on cervix images taken by a contemporary smartphone camera. A large number of cervix images acquired by the commercial MobileODT EVA system were filtered for acceptable visual quality and then 7587 filtered images from 3221 women were annotated by a group of gynecologic oncologists (so the gold standard is an expert impression, not histopathology). We tested and analyzed on multiple random splits of the images using two deep learning, object detection networks. For all the receiver operating characteristics curves, the area under the curve values for the discrimination of the most likely precancer cases from least likely cases (most likely controls) were above 0.90. These results showed that AVE can classify cervix images with confidence scores that are strongly associated with expert evaluations of severity for the same images. The results on a small subset of images that have histopathologic diagnoses further supported the capability of AVE for predicting cervical precancer. We examined the associations of AVE severity score with gynecologic oncologist impression at all regions where we had a sufficient number of cases and controls, and the influence of a woman's age. The method was found generally resilient to regional variation in the appearance of the cervix. This work suggests that using AVE on smartphones could be a useful adjunct to health-worker visual assessment with acetic acid, a cervical cancer screening method commonly used in low- and middle-resource settings.

Risk factors associated with delayed discharge following robotic assisted surgery for gynecologic malignancy.

BACKGROUND: The risk factors for extended length of stay (LOS) have not been examined in a cohort of patients with complex social and medical barriers who undergo robotic assisted (RA) surgery for gynecologic malignancies. We sought to identify those patients with a LOS > 24 h after robotic surgery and the risk factors associated with delayed discharge. Then we aimed to develop a predictive model for clinical care and identify modifiable pre-operative risk factors. METHODS: After IRB approval, data was abstracted from medical records of all patients with a gynecologic malignancy who underwent a RA laparoscopic surgery from 2010 to 2015. Univariable and multivariable logistic regression was performed to identify independent risk factors associated with delayed discharge defined as LOS > 24 h. A multi-variable logistic regression model was performed using a stepwise backward selection for the final prediction model. All testing was two-sided and a p-value < 0.05 was considered statistically significant. RESULTS: Of the 406 eligible and evaluable patients, 194 (48%) had a LOS > 24 h. Age ≥ 60 years, a higher usage of narcotic medication, a longer surgical time, and a larger estimated blood loss were all associated with LOS > 24 h (p < 0.05). Many of these women had a social work consultation and went home with home care services despite no surgical or post-operative complications. Our prediction model has the potential to correctly classified 75% of the patients discharged within 24 h. CONCLUSIONS: The development of a pre-hospitalization risk stratification and anticipating the possible need for home care services pre-operatively shows promise as a strategy to decrease LOS in patients classified as high-risk. These findings warrant prospective validation through the use of this prediction model in our institution.

Modified frailty index is predictive of wound complications in obese patients undergoing gynecologic surgery via a midline vertical incision.

OBJECTIVES: There are limited methods to identify which obese patients will experience wound complications after undergoing gynecologic surgery. We sought to determine the association between frailty and postoperative wound complications and to develop a prediction model for wound complications in this patient population. METHODS: We reviewed prospectively collected data of obese patients undergoing laparotomy though midline vertical incisions from 7/2013-3/2016. Modified frailty index (mFI) was calculated using 11 comorbidities previously validated. The primary outcome was the composite rate of postoperative wound complication. Data was analyzed using Fisher exact test or Chi-square and t-tests or Kruskal-Wallis tests. Poisson regression models were used to generate relative risks. Prediction models were created with receiver-operator characteristic curve analysis. RESULTS: Of 163 patients included, 56 (34%) were considered frail. Wound complications occurred in 52 patients (31.9%): 28 (50%) frail and 24 (22.4%) non-frail patients (RR 2.23, 95%CI 1.29-3.85). Frail patients had significantly greater frequencies of wound breakdown (37.5% vs 15%, RR 2.51, 95%CI 1.31-4.81). After controlling for BMI, tobacco use, and maximum postoperative glucose, frailty remained an independent predictor of wound complication (aRR 1.88, 95%CI 1.04-3.40). The area under the curve for the predictive model incorporating frailty was 0.73 for wound complications. CONCLUSION: Frailty is associated with wound complications in obese patients undergoing gynecologic surgery via a midline vertical incision and is a useful tool in identifying the most high risk patients. Further prospective research is necessary to incorporate mFI into preoperative planning and counseling.

Utilizing the Patient Reported Outcomes Measurement Information System (PROMIS®) to increase referral to ancillary support services for severely symptomatic patients with gynecologic cancer.

OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS®) Network has developed a comprehensive repository of electronic patient reported outcomes measures (ePROs) of major symptom domains that have been validated in cancer patients. Their use for patients with gynecologic cancer has been understudied. Our objective was to establish feasibility and acceptability of PROMIS ePRO integration in a gynecologic oncology outpatient clinic and assess if it can help identify severely symptomatic patients and increase referral to supportive services. METHODS: English-speaking patients with a confirmed history of gynecologic cancer completed PROMIS ePROs on iPads in the waiting area of an outpatient gynecologic oncology clinic. Symptom scores were calculated for each respondent and grouped using documented severity thresholds. Response data was compared with clinicopathologic characteristics across symptom domains. Severely symptomatic patients were offered referral to ancillary services and asked to complete post-exposure surveys assessing acceptability of the ePRO. RESULTS: Of the 336 patients who completed ePROs, 35% had active disease and 19% had experienced at least one disease recurrence. Sixty-nine percent of the cohort demonstrated moderate to severe physical dysfunction (60%), pain (36%), fatigue (28%), anxiety (9%), depression (8%), and sexual dysfunction (32%). Thirty-nine (12%) severely symptomatic patients were referred to services such as psychiatry, palliative care, pain management, social work or integrative oncology care. Most survey respondents identified the ePROs as helpful (78%) and easy to complete (92%). CONCLUSIONS: Outpatient PROMIS ePRO administration is feasible and acceptable to gynecologic oncology patients and can help identify severely symptomatic patients for referral to ancillary support services.

Comparative Use of Napsin A and Glypican 3 to Distinguish Endometrial Clear Cell from Serous and Endometrioid Carcinomas.

OBJECTIVE: Diagnosis of endometrial clear cell carcinomas is difficult owing to the low reproducibility of histological cell type in high-grade endometrial cancers. Recently, immunoreactivity for napsin A and glypican 3 has been reported in clear cell cancers. We sought to evaluate the use of napsin A and glypican 3 staining to distinguish clear cell carcinoma from other high-grade endometrial cancers. METHODS/MATERIALS: Twenty cases of pure and mixed endometrial clear cell carcinoma were extracted from the 2000-2014 archival material in the Departments of Obstetrics & Gynecology and Pathology at Montefiore Medical Center and compared to serous and grade 3 endometrioid controls. Representative sections were stained with monoclonal antibodies to napsin A and glypican 3. Immunostains were independently reviewed by 2 pathologists to assess frequency and pattern of staining. Charts were reviewed for clinicopathologic and treatment data. RESULTS: Granular cytoplasmic positivity for napsin A was observed in 70% of endometrial clear cell carcinomas; only 25% showed cytoplasmic or membranous glypican 3 positivity. No serous or high-grade endometrioid tumors stained for either marker. No cases of clear cell carcinoma that stained negative for napsin A stained positive for glypican 3. No difference in the immunohistochemical profile was found between pure and mixed clear cell carcinomas and between early- and advanced-stage clear cell carcinomas. CONCLUSIONS: Napsin A is a more sensitive marker for endometrial clear cell carcinoma than glypican 3. In histologically ambiguous cases, napsin A and glypican 3 may help distinguish clear cell carcinoma from other high-grade histologies. Further investigation of endometrial clear cell carcinoma is needed to identify additional diagnostic tools for this rare histology. Correlation of a unique immunohistochemical profile and clinical outcomes is necessary.

Systematic Review of International Colposcopy Quality Improvement Guidelines.

OBJECTIVES: The American Society for Colposcopy and Cervical Pathology Colposcopy Standards Committee organized multiple working groups to draft colposcopy standards for the United States. As part of this project, international quality assurance and improvement measures were examined. MATERIALS AND METHODS: The quality improvement working group performed a systematic review of the literature to collate international guidelines related to quality improvement. Source guidelines were collected using searches in Medline, Google Scholar, the International Federation of Cervical Pathology and Colposcopy Web site, other regional colposcopy group's Web sites, and communications with International Federation of Cervical Pathology and Colposcopy board of directors' members and other expert members of various national groups. Once identified, the sources were reviewed by multiple workgroup members for potential guideline materials. RESULTS: Fifty-six unique documents were identified, of which 18 met inclusion criteria and contributed data to the analysis. Information was abstracted and grouped by related subject. CONCLUSIONS: Wide variation exists in colposcopy guidance and quality indicators from regional and national colposcopy societies. Abstracted international guidelines are presented.

ASCCP Colposcopy Standards: Colposcopy Quality Improvement Recommendations for the United States.

OBJECTIVES: The American Society for Colposcopy and Cervical Pathology (ASCCP) Colposcopy Standards recommendations address the role of and approach to colposcopy and biopsy for cervical cancer prevention in the United States. The recommendations were developed by an expert working group appointed by ASCCP's Board of Directors. The ASCCP Quality Improvement Working Group developed evidence-based guidelines to promote best practices and reduce errors in colposcopy and recommended indicators to measure colposcopy quality. MATERIALS AND METHODS: The working group performed a systematic review of existing major society and national guidelines and quality indicators. An initial list of potential quality indicators was developed and refined through successive iterative discussions, and draft quality indicators were proposed. The draft recommendations were then reviewed and commented on by the entire Colposcopy Standards Committee, posted online for public comment, and presented at the International Federation for Cervical Pathology and Colposcopy 2017 World Congress for further comment. All comments were considered, additional adjustments made, and the final recommendations approved by the entire Task Force. RESULTS: Eleven quality indicators were selected spanning documentation, biopsy protocols, and time intervals between index screening tests and completion of diagnostic evaluation. CONCLUSIONS: The proposed quality indicators are intended to serve as a starting point for quality improvement in colposcopy at a time when colposcopy volume is decreasing and individual procedures are becoming technically more difficult to perform.

Evidence-Based Consensus Recommendations for Colposcopy Practice for Cervical Cancer Prevention in the United States.

The American Society for Colposcopy and Cervical Pathology (ASCCP) Colposcopy Standards recommendations address the role of colposcopy and directed biopsy for cervical cancer prevention in the United States (US). The recommendations were developed by an expert working group appointed by ASCCP's Board of Directors. An extensive literature review was conducted and supplemented by a systematic review and meta-analysis of unpublished data. In addition, a survey of practicing colposcopists was conducted to assess current colposcopy practice in the US. Recommendations were approved by the working group members, and the final revisions were made based on comments received from the public. The recommendations cover terminology, risk-based colposcopy, colposcopy procedures, and colposcopy adjuncts. The ASCCP Colposcopy Standards recommendations are an important step toward raising the standard of colposcopy services delivered to women in the US. Because cervical cancer screening programs are currently undergoing important changes that may affect colposcopy performance, updates to some of the current recommendations may be necessary in the future.

In vitro inhibition of human papillomavirus following use of a carrageenan-containing vaginal gel.

OBJECTIVE: To assess in vitro efficacy of Divine 9, a carrageenan-based vaginal lubricant that is being studied as a microbicide to inhibit HPV16 pseudovirus (PsV) infection. METHODS: Sexually active US women between 19 and 35years without prior HPV vaccination or cervical intraepithelial neoplasia were instructed to use Divine 9 vaginally with an applicator either before sex only or before and after intercourse. Women who applied a single dose of gel returned for cervicovaginal lavage (CVL) collection 1, 4 or 8-12h after intercourse versus those who applied gel before and after intercourse returned 1, 4 or 8-12h after the second gel dose. Carrageenan concentrations were assessed using an ELISA assay and the inhibitory activity was assessed using a PsV-based neutralization assay against HPV16 infection. Carrageenan concentrations and the percentage of PsV16 inhibition were compared using the Wilcoxon rank sum test. RESULTS: Thirteen women were enrolled and thirty specimens from different time-points were assessed. 87% of CVL samples had detectable carrageenans with levels decreasing over time from intercourse. 93% of CVL samples had detectable PsV16 inhibition with median inhibition of 97.5%. PsV16 inhibition decreased over time, but remained high, with median inhibition of 98.1%, 97.4% and 83.4% at 1, 4 and 8-12h, respectively. Higher carrageenan concentrations were associated with higher levels of PsV16 inhibition (rho=0.69). CONCLUSIONS: This is the first report of a human study investigating in vitro HPV inhibition of a carrageenan-based vaginal lubricant with CVL collected after sexual intercourse. We demonstrate excellent efficacy in preventing PsV16 infection.

A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients.

OBJECTIVES: Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. METHODS: Women with a body mass index (BMI) ≥30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Camper's fascia, closure of Camper's fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway. RESULTS: 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). CONCLUSION: This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2).

Etiology and workup of fevers in gynecologic oncology patients.

OBJECTIVES: The objectives of this study are to identify the characteristics of febrile gynecologic oncology patients and to evaluate the utility of common diagnostic procedures used to assess the etiologies of their fevers. METHODS/MATERIALS: Retrospective data were collected for 200 consecutive patients admitted to the gynecologic oncology service at 1 institution between January 2008 and December 2012 for a diagnosis of fever. Data were collected using contingency tables, and the χ test was used as appropriate. RESULTS: Of the patients admitted for evaluation of fever, 142 (71%) of 200 had a documented fever during hospitalization. The most common etiologies of fever in this population were urinary tract infections (28%) and bloodstream infections (27%), whereas 24% of those admitted for fever did not have a source identified. Abdominal/pelvic computed tomography (CT) scans established the etiology of fever in 53 (60%) of the 89 patients tested, whereas chest x-ray and chest CT were diagnostic for 6% and 21%, respectively. Blood and urine cultures were diagnostic in 29% and 32% of cases, respectively. Patients admitted within 30 days of surgery had a higher percentage of wound infections (38% vs 10%, P < 0.001) as compared with those admitted for more than 30 days after surgery. CONCLUSIONS: The initial evaluation of the febrile gynecologic oncology patient without obvious source by history and examination should include urinalysis with reflex culture and blood cultures. Abdominopelvic and chest CT may be useful when fever persists and initial assessment is unrevealing. Chest x-ray is commonly done but infrequently diagnostic. Wound exploration may be important in patients with fevers for more than 30 days after surgery.

Design of the HPV-automated visual evaluation (PAVE) study: Validating a novel cervical screening strategy.

Background: The HPV-automated visual evaluation (PAVE) Study is an extensive, multinational initiative designed to advance cervical cancer prevention in resource-constrained regions. Cervical cancer disproportionally affects regions with limited access to preventive measures. PAVE aims to assess a novel screening-triage-treatment strategy integrating self-sampled HPV testing, deep-learning-based automated visual evaluation (AVE), and targeted therapies. Methods: Phase 1 efficacy involves screening up to 100,000 women aged 25-49 across nine countries, using self-collected vaginal samples for hierarchical HPV evaluation: HPV16, else HPV18/45, else HPV31/33/35/52/58, else HPV39/51/56/59/68 else negative. HPV-positive individuals undergo further evaluation, including pelvic exams, cervical imaging, and biopsies. AVE algorithms analyze images, assigning risk scores for precancer, validated against histologic high-grade precancer. Phase 1, however, does not integrate AVE results into patient management, contrasting them with local standard care.Phase 2 effectiveness focuses on deploying AVE software and HPV genotype data in real-time clinical decision-making, evaluating feasibility, acceptability, cost-effectiveness, and health communication of the PAVE strategy in practice. Results: Currently, sites have commenced fieldwork, and conclusive results are pending. Conclusions: The study aspires to validate a screen-triage-treat protocol utilizing innovative biomarkers to deliver an accurate, feasible, and cost-effective strategy for cervical cancer prevention in resource-limited areas. Should the study validate PAVE, its broader implementation could be recommended, potentially expanding cervical cancer prevention worldwide. Funding: The consortial sites are responsible for their own study costs. Research equipment and supplies, and the NCI-affiliated staff are funded by the National Cancer Institute Intramural Research Program including supplemental funding from the Cancer Cures Moonshot Initiative. No commercial support was obtained. Brian Befano was supported by NCI/ NIH under Grant T32CA09168.

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.

BACKGROUND: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed. RESULTS: Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. CONCLUSIONS: Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.

Management of sarcomas of the uterus.

PURPOSE OF REVIEW: Uterine sarcomas are rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognosis. Management of uterine sarcomas including leiomyosarcoma (LMS), endometrial stromal sarcoma, high-grade undifferentiated sarcoma and adenosarcoma is reviewed. RECENT FINDINGS: Uterine carcinosarcomas are staged and treated similarly to high-grade epithelial endometrial carcinomas and are no longer considered uterine sarcomas. Gemcitabine/docetaxel with doxorubicin holds promise for the treatment of LMS. A recently developed nomogram was demonstrated to predict disease recurrence in patients with LMS which may allow us to identify a subset of patients who are likely to recur and target this population for adjuvant systemic therapy. Cytogenetic abnormalities have been identified that allow differentiation of endometrial stromal sarcomas from high-grade undifferentiated uterine sarcomas which may be useful in pathologically difficult cases. SUMMARY: Uterine sarcomas are a heterogeneous group of tumors. To date, limited advancements have been made in discovering targeted therapies to these tumors. Chemotherapy with gemcitabine/docetaxel followed by doxorubicin holds promise in the treatment of LMS. Given the rarity of these tumors and the lack of clinical trials to guide management, patients with uterine sarcomas should be encouraged to enroll on clinical trials.

Frequent mutations in the RPL22 gene and its clinical and functional implications.

OBJECTIVE: To determine the frequency and spectrum of mutations in RPL22 a gene identified by The Cancer Genome Atlas (TCGA) as mutated in endometrioid endometrial cancer, and determine the relationship between RPL22 defects and clinicopathologic features. METHODS: Direct sequencing of the entire coding region of the RPL22 cDNA and exons 2/4 was performed in tumors with/without microsatellite instability (MSI). RPL22 expression was assessed by immunofluorescence microscopy in the KLE, RL952 and AN3CA cell lines, wildtype, heterozygous and homozygous mutants, respectively. Relationships between RPL22 mutation and clinicopathological features were assessed using Chi-squared analysis and Student's t test. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of recurrence. RESULTS: A single nucleotide deletion in an A8 coding repeat was identified in exon 2 of the RPL22 gene in 116/226 (52%) of MSI-high tumors. No mutations were identified in MSI-stable tumors. Only 2% of the tumors expressed a homozygous A deletion. RPL22 mutation was not associated with stage, grade, race and lymphovascular space invasion. Women whose tumors harbored RPL22 mutations were significantly older (67 vs. 63years, p=0.005). There was no difference in PFS between patients with the wildtype and mutant genotypes. CONCLUSIONS: RPL22 is frequently mutated in MSI-high endometrioid endometrial cancers. The A8 mutation identified was not reported in the whole exome sequences analyzed by the TCGA. The demonstration of frequent mutation in RPL22 may point to a limitation of the exome capture and next generation sequencing analysis methods for some mononucleotide string mutations. Functional assessment of the RPL22 knockdown may be warranted.

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer.

OBJECTIVE: We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC). METHODS: Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m(2) IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS). RESULTS: Thirty-four patients received a median of 7 treatment cycles (range, 2-26). Median follow-up was 25.7 months (range, 3.0-47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38-71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25-59), 18 stable disease (53%; 35-70) and 2 progressive disease (6%; 1-20). Median PFS was 7.9 months (95% CI, 4.6-10.9), with a median OS of 25.7 months (95% CI, 15.4-29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of >6 months prior to enrollment. Grade 3-4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3-4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment. CONCLUSIONS: Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.

Lithium chloride and inhibition of glycogen synthase kinase 3ß as a potential therapy for serous ovarian cancer.

OBJECTIVE: Lithium chloride (LiCl) has been shown to demonstrate anticancer properties at supratherapeutic doses. This study was designed to determine whether LiCl, as a single agent or in combination with cytotoxic agents, reduces ovarian cancer cell growth and metabolic activity at clinically achievable levels. METHODS: We studied the effects of LiCl on 2 high-grade serous ovarian cancer cell lines, SKOV3 and OVCA 433, and primary cultures developed from ascitic fluid collected from patients with metastatic high-grade serous ovarian cancer. We assessed proliferation and metabolism using cell cycle analysis, MTT assays, and cellular proliferation and clonogenic potential assays. RESULTS: Treatment with 1 mM LiCl had no effect on the cell cycle distribution or metabolic activity of the SKOV3 and OVCA 433 cell lines. Combination treatment with cisplatin or paclitaxel led to statistically significant decreases in metabolic activity in the OVCA 433 cell line and 50% of cultures investigated. The decreased metabolic activity was not, however, associated with decreased cell growth or clonogenic potential. CONCLUSIONS: Combination treatment with LiCl and cytotoxic agents at physiologically achievable drug concentrations reduces ovarian cancer cell metabolism but does not appear to affect cellular proliferation. The potential for combined lithium/cytoxic therapies appears to be limited based on our analysis of both established cell lines and short-term ovarian cancer cultures.

Timing of referral for genetic counseling and genetic testing in patients with ovarian, fallopian tube, or primary peritoneal carcinoma.

OBJECTIVE: The objective of this study was to assess patients' preferences of the timing of referral for genetic counseling and testing in relation to the diagnosis, treatment, and recurrence of ovarian, tubal, or primary peritoneal cancers. METHODS: Ninety-two patients who underwent counseling and testing by 1 certified genetic counselor were identified. An introductory letter, consent form, and questionnaire were mailed to gather information regarding factors influencing the decision to undergo genetic counseling and testing and opinions regarding optimal timing. Medical records were reviewed for demographic and clinical data. RESULTS: Of 47 consenting women, 45 underwent testing. Eight (18%) were found to have a genetic mutation. Women lacked consensus about the optimal time for referral for and to undergo genetic testing, although women with stage I disease preferred testing after completion of chemotherapy. Most women were comfortable receiving the results by phone, but one third preferred an office visit. CONCLUSIONS: Patients' views regarding the best time to be referred for and undergo counseling and testing varied greatly. Because of the high mortality of this disease, clinicians should discuss referral early and personalize the timing to each patient. The subset of patients who prefer results disclosure during an office visit should be identified at the time of their initial counseling.

Use of risk-based cervical screening programs in resource-limited settings.

Cervical cancer screening and management in the U.S. has adopted a risk-based approach. However, the majority of cervical cancer cases and deaths occur in resource-limited settings, where screening and management are not widely available. We describe a conceptual model that optimizes cervical cancer screening and management in resource-limited settings by utilizing a risk-based approach. The principles of risk-based screening and management in resource limited settings include (1) ensure that the screening method effectively separates low-risk from high-risk patients; (2) directing resources to populations at the highest cancer risk; (3) screen using HPV testing via self-sampling; (4) utilize HPV genotyping to improve risk stratification and better determine who will benefit from treatment, and (5) automated visual evaluation with artificial intelligence may further improve risk stratification. Risk-based screening and management in resource limited settings can optimize prevention by focusing triage and treatment resources on the highest risk patients while minimizing interventions in lower risk patients.