Deep molecular tracking over the 12-yr development of endometrial cancer from hyperplasia in a single patient.

Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.

Program Planning to Develop Infrastructure for Cancer Care in Liberia.

Liberia's health infrastructure was completely devastated after 14 years of back-to-back civil war. Postconflict rebuilding of the country's health workforce and infrastructure has become a priority. Initially, the focus was on the diagnosis and treatment of communicable diseases that caused multigenerational family losses. With the increasing burden of noncommunicable diseases, however, the country has turned its attention to addressing diabetes, cancer, and cardiovascular and respiratory diseases, with the development of the noncommunicable disease unit under the Ministry of Health. Recovering from another setback caused by the Ebola virus outbreak in 2014, the country assembled a diverse group of stakeholders to form Liberia's first National Cancer Committee. To structure a program that would address the increasing burden of cervical and breast cancers, the major cause of mortality among reproductive-aged women in Liberia, input from the International Atomic Energy Agency was critical. This article describes the preplanning activities for developing infrastructure to support cancer care in Liberia that occurred between 2013 and 2020 and is still ongoing. This case study is intended to serve as a planning guide for countries with limited resources as they work toward the goal of eliminating cervical cancer and developing infrastructure to address their country's burden of all cancers.

Community-Institutional Partnerships to Strengthen Maternal Health Care: Case Study of the First Obstetrics and Gynecology Specialty Training Program in Liberia.

Despite major setbacks to its health infrastructure and health workforce capacity, Liberia began its first post-graduate training program for physicians in 2013. Specialty training in Internal Medicine, Pediatrics, General Surgery and Obstetrics and Gynecology were the four inaugural Residency programs that recruited graduates from the country's only medical school, A.M. Dogliotti College of Medicine. The Obstetrics and Gynecology residency program was designed to combat the rising maternal mortality and strengthen health systems to improve maternal care. The program adapted in the face of challenges posed by limited financial support, lack of specialist-faculty and general physician shortages and the Ebola virus outbreak. The manuscript discusses the challenges and successes of the program and demonstrates how the shortage of teaching faculty was addressed by developing a collaboration between local government and educational communities, a United States (US) academic institution and volunteers from the Global Health Service Partnership.

Novel use of fine needle aspiration (FNA) biopsy to diagnose cervical cancer in a low-resource setting: A case series Morovia, Liberia.

The role of pathology in improving cancer in resource-limited countries is essential, yet many barriers exist. FNA is a rapid, low-cost and efficient method for diagnosing cancer, planning treatment, and building a cancer registry.

Cervical cancer risk factors and screening preferences among Muslim women in Monrovia, Liberia.

Cervical cancer is the most common cancer in reproductive aged women in Liberia. Lack of awareness and screening capacity are both major contributors to the prevalence of this disease. The minority Muslim population in this country is largely unscreened. The objective of the study was to assess cervical cancer risk factors and screening preferences among Muslim women living in Monrovia, Liberia and to offer self-screening with HPV testing. A multiple step implementation strategy was devised in order to outreach to the Muslim population with the engagement of community and religious leaders, about an upcoming screening program and informational session at a local clinic. Over 150 Muslim women attended the session, 120 completed the HPV screening, and 55 women completed the questionnaires. Questionnaire data revealed overall low risk factors for cervical cancer, but also low use of family planning as well as low knowledge about cervical cancer and HPV. Participants showed an interest in screening and a majority preferred self-collected tests. These preferences should be incorporated in future programming. To engage minority populations in screening programs, there may be success with targeted messages, involvement of community religious leaders, and eliciting feedback to incorporate preferred strategies and improve participation and programming.

Rapid development and use of patient-specific ctDNA biomarkers to avoid a "rash decision" in an ovarian cancer patient.

Epithelial ovarian cancer (OvCa) is the most lethal female reproductive tract malignancy. A major clinical hurdle in patient management and treatment is that when using current surveillance technologies 80% of patients will be clinically diagnosed as having had a complete clinical response to primary therapy. In fact, the majority of women nonetheless develop disease recurrence within 18 mo. Thus, without more accurate surveillance protocols, the diagnostic question regarding OvCa recurrence remains framed as "when" rather than "if." With this background, we describe the case of a 61-yr-old female who presented with a 3-mo history of unexplained whole-body rash, which unexpectedly led to a diagnosis of and her treatment for OvCa. The rash resolved immediately following debulking surgery. Nearly 1 yr later, however, the rash reappeared, prompting the prospect of tumor recurrence and requirement for additional chemotherapy. To investigate this possibility, we undertook a genomics-based tumor surveillance approach using a targeted 56-gene NGS panel and biobanked tumor samples to develop personalized ctDNA biomarkers. Although tumor-specific TP53 and PTEN mutations were detectable in all originally collected tumor samples, pelvic washes, and blood samples, they were not detectable in any biosample collected beyond the first month of treatment. No additional chemotherapy was given. The rash spontaneously resolved. Now, 2 yr beyond the patient's original surgery, and in the face of continued negative ctDNA findings, the patient remains with no evidence of disease. As this single case report suggests, we believe for the first time that ctDNA can provide an additional layer of information to avoid overtreatment.

Use of a multi-drug regimen gemcitabine, 5-fluorouracil, irinotecan, cisplatin, bevacizumab, docetaxel, and cyclophosphamide (GFIP/BDC) for heavily pretreated relapsed epithelial ovarian, fallopian tube and primary peritoneal cancer.

BACKGROUND: Epithelial ovarian cancer has the highest fatality rate of all gynecologic malignancies. Although the majority of patients achieve complete clinical response after initial cytoreductive surgery and platinum-based chemotherapy, most recur and almost all will eventually acquire platinum-resistance for which treatment options become limited. The objective of the study was to describe response and tolerability of metronomic chemotherapy regimen GFIP/BDC, a modification of the G-FLIP regimen, in patients with persistent or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. METHODS: A retrospective descriptive analysis of 20 patients from a single academic institution who received combination GFIP/BDC therapy from January 1, 2011 to August 31, 2016 for persistent or recurrent EOC/FT/PP. Treatment consisted of a 2-day combination of gemcitabine 300 mg, 5-fluorouracil 500 mg/m2, irinotecan 20-30 mg/m2, cisplatin 20 mg/m2, bevacizumab 4 mg/kg, docetaxel 20 mg/m2, and cyclophosphamide 200 mg/m2 administered every 14 days. Toxicities were retrospectively graded using CTCAE v4.0. RESULTS: Twenty patients were identified with a median age 57.5 years (range 32-71). A total of 85% of patients were non-Hispanic white, 90% had cancer of high-grade serous histology, and all had a GOG performance status of 0-1. Patients had received a median of 3 prior regimens and 95% were platinum-resistant. Median number of cycles of GFIP/BDC administered was 9 (range 3-48) and patients remained on treatment for a median of 5.1 months (range 1.5-24). Eleven patients (55%) experienced a partial clinical response with a median duration of 6 months (range 1.5-20). Six patients (30%) survived progression free for at least 6 months. Ten patients (50%) experienced at least one grade 3/4 adverse event. Grade 3 adverse events were hematologic (n = 5), constitutional (n = 3), gastrointestinal (n = 3), neurologic (n = 2), and vascular (n = 1). There was only one grade 4 adverse event which was severe neutropenia. Patients discontinued treatment due to disease progression 65% (n = 13), toxicity 20% (n = 4), patient preference 10% (n = 2), and 5% (n = 1) is currently on treatment. CONCLUSIONS: Selected patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have failed multiple lines of conventional cytotoxic treatment may benefit from GFIP/BDC. Toxicity might be a limiting factor for administration.

Cervical Cancer Screening in HIV-Positive Farmers in South Africa: Mixed-Method Assessment.

BACKGROUND: In 2015, a See and Treat cervical cancer screening program was implemented at a local HIV clinic in Limpopo, South Africa, where infrastructure limited adequate Pap smear usability. OBJECTIVE: The purpose of this evaluation was to determine the quality and sustainability of the implemented program. METHODS: A mixed-methods program analysis was conducted at 18-months post implementation. Data collection techniques included in-depth interviews of staff and patients, observation of healthcare workers delivering screening, and review of charts and patient logs. FINDINGS: Eighteen in-depth interviews revealed improved cervical cancer screening understanding and awareness. Privacy concerns and negative perceptions of medical care were barriers to screening. Informal observations revealed continued clinical competence among healthcare workers who had been previously trained. Review of charts demonstrated positive correlation between VIA and Pap smear results. In evaluating loss to attrition, about half of the first cohort of patients were lost to follow-up. VIAs and Pap smears were offered on an ongoing basis, and month-over-month change for overlapping four months of programming between 2015 and 2016 showed a 4.4% negative change in number of Pap smears and a 57% negative change in VIAs. CONCLUSION: Our evaluation reveals successful integration of See and Treat into current clinic services in rural South Africa and increased awareness of cervical cancer among health workers and participants. Program sustainability was challenging to assess as many patients were lost to follow-up, given the migrant and transient population attending this clinic. Acceptance by health workers and patients alike is vital for the long-term impact on cervical cancer incidence in this region.

Elimination of cervical cancer: challenges for developing countries.

Cervical cancer is one of the most preventable cancers today, yet over 500,000 new cases are diagnosed globally each year and every 2 minutes a woman dies from cervical cancer. The burden of this disease and the highest mortality from cervical cancer occur in developing countries. High-income countries are poised to eliminate cervical cancer in the 21st century, but despite a global call to eliminate this disease, low- and middle-income countries face many challenges as they strive to answer that call.

Human Papillomavirus Knowledge, Attitudes, Practices, and Prevalence Among Men Who Have Sex With Men in Monrovia, Liberia.

OBJECTIVE: The aim of this study was to assess human papillomavirus (HPV) prevalence, knowledge, attitudes, and practices, among men who have sex with men (MSM) in Monrovia, Liberia. MATERIALS AND METHOD: This cross-sectional study was conducted with 107 MSM, aged 18 to 58 years, completing questionnaires and anal HPV screenings. Using peer-educators and direct community involvement, demographics, risk factors, and HPV knowledge data were collected. RESULTS: Forty-eight participants (45%) were HPV positive and 21 participants (19.6%) self-identified as HIV positive. When examining HPV risk factors, 22 participants reported first sexual experience before the age of 15 years. Approximately half of participants (n = 58, 54.2%) have receptive anal sex and 40 (37.4%) reported more than 20 lifetime sexual partners. Eight participants (7.5%) had no formal education and 80 (74.8%) were not formally employed. Two-thirds of participants (64%) had never heard of HPV. Education was not significantly correlated with HPV knowledge. χ tests of independence were performed, and the relation between oral and anal sex and HPV knowledge was significant (χ (1) = 5.08, p < .05; χ (1) = 4.18, p < .05), respectively, such that those who engaged in oral and anal sex had lower levels of HPV knowledge. CONCLUSIONS: Among the MSM population, HPV prevalence is high, as are high-risk practices. Participants lack HPV knowledge, independent of educational achievement, and are eager to receive educational information. Future studies should focus on identifying additional risk factors and implementing public health educational interventions.

Laparoscopic Assessment to Determine the Likelihood of Achieving Optimal Cytoreduction in Patients Undergoing Primary Debulking Surgery for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of laparoscopic assessment to determine the likelihood of achieving optimal cytoreduction (OC) in patients undergoing primary debulking surgery (PDS) for ovarian cancer. METHODS: All patients who underwent diagnostic laparoscopy and PDS at our institution from January 2008 to December 2013 were identified. We determined the likelihood of achieving optimal cytoreduction by laparoscopic assessment based on tumor site, pattern of spread, and disease burden. Sensitivity was defined as the number of patients who achieved optimal cytoreduction after laparoscopic assessment divided by the number of patients with disease deemed resectable by laparoscopy. RESULTS: We identified 55 patients during study period. Twenty-one of the 55 patients (38%) were early stage disease. Six (10.9%) patients had disease deemed unresectable and 49 (89.1%) had disease deemed resectable at the time of laparoscopy. OC was achieved in 48 of 49 (97.9%) patients. The sensitivity of laparoscopy in predicting OC was 98% (95% confidence interval, 89.3%-99.9%). The operation was completed laparoscopically in 23 of 49 patients (47%); in 26 of 49 (53%), PDS was performed by laparotomy. There were no port site metastases reported. The rate of postoperative complications was 16%. With a median follow-up of 30 months, the median overall survival was not reached and the 75th percentile for overall survival was 37 months. CONCLUSIONS: Laparoscopy was shown to have a high sensitivity in predicting OC and is a feasible tool in triaging patients with ovarian cancer. Laparoscopy is not associated with adverse surgical outcomes.

The impact of nativity on cervical cancer survival in the public hospital system of Queens, New York.

OBJECTIVE: We studied cervical cancer patients who presented to the Public Hospital System in ethnically-diverse Queens, New York from 2000 to 2010 with the purpose of examining the relationship between nativity (birthplace) and survival. METHODS: A retrospective review of tumor registries was used to identify patients diagnosed with cervical cancer between January 1, 2000 and December 31, 2010. Using electronic medical records, data from 317 patients were available for this analysis. RESULTS: The majority of patients were born outside the United States (US) (85.5% versus 14.5%). One hundred patients (31.5%) were born in Latin America, 105 in the Caribbean Islands (33.1%), 48 in Asia (15.1%), 8 in the South Asia (2.5%), 10 in Russia/Eastern Europe (3.2%) and 46 (14.5%) in the United States. Patients presented at varying stages of disease: 51.4% at stage I, 19.6% at stage II, 19.6% at stage III, and 8.5% at stage IV. Kaplan-Meier estimated survival curves stratified by birthplace demonstrated significant differences in survival distributions among the groups using the log-rank test (P<0.0001). The most favorable survival curves were observed among patients born in Latin America and Asia whereas the least favorable was demonstrated in US-born patients. Time to death was analyzed using the Cox proportional hazards model. Adjusting for age at diagnosis, insurance status, stage and treatment modality, nodal metastases and hydronephrosis, birthplace was significantly associated with survival time (P<0.0001). CONCLUSION: An immigrant health paradox was defined for foreign-born Latino and Asian patients presenting with cervical cancer to the Public Hospital System of Queens, New York as patients born in Latin America and Asia were less likely to die at any given time compared to those born in the United States.

Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a "Molecular Second Look".

OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this "molecular second look" with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1-8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.

Cervical cancer screening in rural South Africa among HIV-infected migrant farm workers and sex workers.

At an HIV clinic in the Limpopo province of South Africa, chart reviews revealed long delays in addressing abnormal Pap smears, difficulty in referrals, poor quality and lost results, and increasing cases of cervical cancer. To address these barriers, a "see and treat" approach to screening was proposed. The objective was to integrate this method into current HIV care offered by local providers and to obtain demographic and risk factor data for use in future educational and intervention programs in the region. A cross sectional study of HIV farm workers and at-risk sex workers attending an HIV clinic was performed with visual inspection with acetic acid (VIA). Those with positive screens were offered cryotherapy. Clinic charts were reviewed retrospectively for Pap smear results for the previous year at the time of program initiation and at 12 and 18 months post-program. A total of 403 participants consented and underwent screening with VIA (306 Farm workers and 97 sex workers participated). 83.9% of participants (32.9% sex workers and 100% farm workers) were HIV +. VIA was positive in 30.5% of participants, necessitating cryotherapy. There was no significant difference in VIA positivity between HIV + farm workers and sex workers. There was a positive correlation between Pap smears and VIAs results. We demonstrate successful integration of cervical cancer screening using VIA for HIV + farm workers and sex workers into an existing HIV treatment and prevention clinic in rural South Africa, addressing and treating abnormal results promptly.

Challenges to development of cervical and breast cancer program development in post conflict Liberia: Presentation prepared for African First Ladies' Conference, 10th SCCA Conference, Addis Ababa, Ethiopia 2016.

•Integrating cancer care in post-conflict settings.•Building health worker and infrastructure for cancer care in low resource setting.•Foreword by Her Excellency President Sirleaf, Republic of Liberia.

Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers.

BACKGROUND: High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools. METHODS AND FINDINGS: Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival. CONCLUSIONS: Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection point in precision medicine. This study suggests that the use of personalized ctDNA biomarkers in gynecologic cancers can identify the presence of residual tumor while also more dynamically predicting response to treatment relative to currently used serum and imaging studies. Of particular interest, ctDNA was an independent predictor of survival in patients with ovarian and endometrial cancers. Earlier recognition of disease persistence and/or recurrence and the ability to stratify into better and worse outcome groups through ctDNA surveillance may open the window for improved survival and quality and life in these cancers.