Disseminated Anaplastic Lymphoma Kinase (ALK)-Positive T-cell Lymphoma Involving the Uterus and Cervix: A Case Report.

Primary or secondary non-Hodgkin lymphomas (NHLs) involving the female gynecologic tract are rare. T-cell subtypes are further rare and portend a worse prognosis. We present a case of a 23-year-old female presenting with a cervical mass accompanied by constitutional symptoms and abnormal vaginal bleeding. Immunohistochemistry studies revealed the presence of disseminated T-cell non-Hodgkin lymphoma that was anaplastic lymphoma kinase (ALK)-positive. The patient demonstrated a complete response to systemic chemotherapy initially and again after the relapse of the disease one year after diagnosis. To our knowledge, this is the first case of an ALK-positive T-cell lymphoma with secondary involvement of the uterus and cervix; all previously published cases of this histologic subtype in the gynecologic tract describe primary disease of the vagina. This case emphasizes the importance of immunohistochemistry studies inclusive of T-cell and B-cell markers when evaluating biopsies from cervical tumors to render the appropriate diagnosis and guide systemic therapy.

Stability Characterization of the Novel Anti-Cancer HM-10/10 HDL-Mimetic Peptide.

Epithelial adenocarcinoma of the ovary and colon are associated with the highest rates of cancer-related deaths in women in the U.S. The literature supports the role of HDL-associated apolipoproteins in the treatment of cancer and other pro-inflammatory diseases. Previously, we developed a novel 20-amino acid mimetic peptide, HM-10/10, which potently inhibits tumor development and growth in colon and ovarian cancer. Here, we report the properties of HM-10/10 relative to its stability in vitro. The results demonstrated that HM-10/10 had the highest half-life in human plasma compared to plasma from other species tested. HM-10/10 demonstrated stability in human plasma and simulated gastric environment, increasing its promise as an oral pharmaceutical. However, under conditions modeling the small intestine, HM-10/10 demonstrated significant degradation, likely due to the peptidases encountered therein. Furthermore, HM-10/10 demonstrated no evidence of time-dependent drug-drug interactions, although it demonstrated CYP450 induction slightly above cutoff. As proteolytic degradation is a common limitation of peptide-based therapeutics, we are pursuing strategies to improve the stability properties of HM-10/10 by extending its bioavailability while retaining its low toxicity profile. HM-10/10 holds promise as a new agent to address the international women's health crisis of epithelial carcinomas of the ovary and colon.

Understanding Health Disparities in Preeclampsia: A Literature Review.

Preeclampsia is a multifactorial pathology with negative outcomes in affected patients in both the peripartum and postpartum period. Black patients in the United States, when compared to their White and Hispanic counterparts, have higher rates of preeclampsia. This article aims to review the current literature to investigate how race, social determinants of health, and genetic profiles influence the prevalence and outcomes of patients with preeclampsia. Published studies utilized in this review were identified through PubMed using authors' topic knowledge and a focused search through a Medline search strategy. These articles were thoroughly reviewed to explore the contributing biosocial factors, genes/biomarkers, as well as negative outcomes associated with disparate rates of preeclampsia. Increased rates of contributing comorbidities, including hypertension and obesity, which are largely associated with low access to care in Black patient populations lead to disparate rates of preeclampsia in this population. Limited research shows an association between increased rate of preeclampsia in Black patients and specific APOL1, HLA-G, and PP13 gene polymorphisms as well as factor V Leiden mutations. Further research is required to understand the use of certain biomarkers in predicting preeclampsia within racial populations. Understanding contributing biosocial factors and identifying genes that may predispose high-risk populations may help to address the disparate rates of preeclampsia in Black patients as described in this review. Further research is required to understand if serum, placental, or urine biomarkers may be used to predict individuals at risk of developing preeclampsia in pregnancy. KEY POINTS: · Prevalence of preeclampsia in the U.S. is higher in Black patients compared to other racial groups.. · Patients with preeclampsia are at risk for poorer health outcomes both during and after delivery.. · Limited research suggests specific biomarkers or gene polymorphisms contribute to this difference; however, explanations for this disparity are multifactorial and further investigation is necessary..

Clinical outcomes in patients with COVID-19 and gynecologic cancer: A society of gynecologic oncology COVID-19 and gynecologic cancer registry study.

OBJECTIVES: Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States. METHODS: The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis. RESULTS: Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis. CONCLUSIONS: Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.

Thirty-day Postoperative Adverse Events in Minimally Invasive versus Open Abdominal Radical Hysterectomy for Early-stage Cervical Cancer.

STUDY OBJECTIVE: To identify the incidence, type, and grade of postoperative adverse events in minimally invasive radical hysterectomy vs abdominal radical hysterectomy (ARH) for patients with early-stage cervical cancer and determine risk factors associated with these adverse events. DESIGN: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was queried to identify patients with early-stage cervical cancer undergoing radical hysterectomy. Multivariable logistic regression was used to assess risk factors associated with adverse postoperative outcomes among patients undergoing radical hysterectomy. SETTING: ACS NSQIP participating institutions within the United States. PATIENTS: Patients were collected from the ACS NSQIP databases (2014-2017) undergoing radical hysterectomy for early-stage cervical cancer. INTERVENTIONS: N/A MEASUREMENTS AND MAIN RESULTS: ARH had a significantly increased incidence of any 30-day postoperative adverse event compared with minimally invasive radical hysterectomy (31.2% vs 19.9%, p <.001). There was a higher incidence of surgical site infection, both deep and superficial, and blood transfusions in ARH. On multivariable logistic regression, the abdominal surgical approach was the only risk factor significantly associated with any postoperative adverse event (odds ratio, 1.4; confidence interval, 1.1-1.9; p = .018; 95% CIs). CONCLUSIONS: In this study, the abdominal surgical approach for radical hysterectomy in early-stage cervical cancer was associated with a higher incidence of postoperative adverse events than the minimally invasive approach.

Comparison of vaginal microbiota in gynecologic cancer patients pre- and post-radiation therapy and healthy women.

BACKGROUND: While the importance of commensal microbes in vaginal health is well appreciated, little is known about the effects of gynecological cancer (GynCa) and radiation therapy (RT) on the vaginal microbiome (VM) of postmenopausal women. METHODS: We studied women with GynCa, pre- (N = 65) and post-RT (N = 25) and a group of healthy controls (N = 67) by sequencing the V4 region of the 16S rRNA gene from vaginal swabs and compared the diversity and composition of VMs between the three groups accounting for potential confounding factors in multivariate analysis of variance. RESULTS: Comparisons of cancer vs healthy groups revealed that Lactobacillus and Bifidobacterium have significantly higher relative abundance in the healthy group, while the cancer group was enriched in 16 phylogroups associated with bacterial vaginosis (BV) and inflammation, including Sneathia, Prevotella, Peptoniphilus, Fusobacterium, Anaerococcus, Dialister, Moryella, and Peptostreptococcus. In our sample, RT affected the α-diversity and correlated with higher abundance of typically rare VM species, including several members of the Lacnospiraceae family, a taxon previously linked to vaginal dysbiosis. In addition to cancer and treatment modalities, age and vaginal pH were identified as significant parameters that structure the VM. CONCLUSIONS: This is among the first reports identifying VM changes among postmenopausal women with cancer. RT alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention.

Endometriosis: A Malignant Fingerprint.

BACKGROUND: Endometriosis is complex, but identifying the novel biomarkers, inflammatory molecules, and genetic links holds the key to the enhanced detection, prediction and treatment of both endometriosis and endometriosis related malignant neoplasia. Here we review the literature relating to the specific molecular mechanism(s) mediating tumorigenesis arising within endometriosis. METHODS: Guidance (e.g. Cochrane) and published studies were identified. The Published studies were identified through PubMed using the systematic review methods filter, and the authors' topic knowledge. These data were reviewed to identify key and relevant articles to create a comprehensive review article to explore the molecular fingerprint associated with in endometriosis-driven tumorigenesis. RESULTS: An important focus is the link between C3aR1, PGR, ER1, SOX-17 and other relevant gene expression profiles and endometriosis-driven tumorigenesis. Further studies should also focus on the combined use of CA-125 with HE-4, and the role for OVA1/MIA as clinically relevant diagnostic biomarkers in the prediction of endometriosis-driven tumorigenesis. CONCLUSIONS: Elucidating endometriosis' molecular fingerprint is to understand the molecular mechanisms that drive the endometriosis-associated malignant phenotype. A better understanding of the predictive roles of these genes and the value of the biomarker proteins will allow for the derivation of unique molecular treatment algorithms to better serve our patients.

ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers.

Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

Pre-operative core muscle index in combination with hypoalbuminemia is associated with poor prognosis in advanced ovarian cancer.

BACKGROUND AND OBJECTIVES: Age and frailty have been correlated with poor clinical outcomes in cancer. Core muscle index (CMI) and nutritional status are integral in assessing frailty. We explored the effect of pre-operative serum albumin and body composition on clinical outcomes in patients with epithelial ovarian cancer (EOC). METHODS: We identified stage III-IV EOC patients undergoing primary cytoreductive surgery from 2007 to 2015. Data were abstracted from medical records. Body composition measurements were obtained from pre-operative imaging. Psoas muscle cross-sectional area was normalized to height2 to determine CMI. Sarcopenia was defined as CMI below the population mean. The influence of sarcopenia on short-term morbidity was evaluated. Relationships among body composition measurements and albumin were assessed with Spearman correlations. Patient characteristics and body composition measurements between patients with and without sarcopenia were compared with parametric and non-parametric statistical methods. Kaplan-Meier survival curves were compared using log-rank. RESULTS: 102 women met inclusion criteria. Sarcopenia correlated with albumin (P = 0.0002). Sarcopenia was not associated with short-term morbidity or time to recurrence. Sarcopenia was associated with nearly a fourfold increased risk of death when hypoalbuminemia was present (P = 0.02). CONCLUSIONS: Pre-operative sarcopenia in combination with hypoalbuminemia was associated with significantly worse survival.

Generation and Characterization of Recombinant Antibody-like ADP-Ribose Binding Proteins.

ADP-ribosylation is an enzyme-catalyzed post-translational modification of proteins in which the ADP-ribose (ADPR) moiety of NAD+ is transferred to a specific amino acid in a substrate protein. The biological functions of ADP-ribosylation are numerous and diverse, ranging from normal physiology to pathological conditions. Biochemical and cellular studies of the diverse forms and functions of ADPR require immunological reagents that can be used for detection and enrichment. The lack of a complete set of tools that recognize all forms of ADPR [i.e., mono-, oligo-, and poly(ADP-ribose)] has hampered progress. Herein, we describe the generation and characterization of a set of recombinant antibody-like ADP-ribose binding proteins, in which naturally occurring ADPR binding domains, including macrodomains and WWE domains, have been functionalized by fusion to the Fc region of rabbit immunoglobulin. These reagents, which collectively recognize all forms of ADPR with different specificities, are useful in a broad array of antibody-based assays, such as immunoblotting, immunofluorescent staining of cells, and immunoprecipitation. Observations from these assays suggest that the biology of ADPR is more diverse, rich, and complex than previously thought. The ARBD-Fc fusion proteins described herein will be useful tools for future exploration of the chemistry, biochemistry, and biology of ADP-ribose.

Factors influencing primary treatment of midline vulvar cancers.

OBJECTIVES: Advanced vulvar cancers involving midline structures pose a therapeutic challenge. Our objectives were to review the management and outcomes, and identify factors influencing primary treatment modality. METHODS: Patients with midline vulvar cancers diagnosed from 1985 to 2012 were included in the analysis. Medical records were abstracted for demographics, clinico-pathological findings, treatment, and outcomes. Groin node status was defined by clinical findings or pathology. Survival was analyzed by Kaplan-Meier method and differences by log-rank test and Cox proportional hazards model. Factors influencing treatment modality were evaluated using stepwise logistic regression. RESULTS: Forty-two patients were identified. Twenty-one underwent primary radical vulvectomy and 21 underwent primary radiation. Median tumor diameter was 3.4cm (range 2-9cm) for primary radical vulvectomy and 5cm (range 2.3-15cm) for primary radiation. Primary radiation was significantly associated with a tumor diameter ≥5cm (p=0.02), or when 2 or more midline (p=0.008) or 1 or more mucosal structures (p=0.03) were involved. On multivariate analysis, age and tumor diameter were predictors of progression-free survival (PFS) (p=0.02 and p=0.0004, respectively) and overall survival (OS) (p=0.03 and p=0.0005, respectively). Thirty-month OS for primary surgery and primary radiation was 74% and 71% (p=0.78), respectively. There were no differences in PFS or recurrence rates between the two treatment groups. CONCLUSIONS: Clinical tumor diameter and the number of midline or mucosal structures involved influence selection of primary treatment modality. Survival outcomes and recurrence rates did not differ between treatment groups. Age and tumor diameter are important prognostic factors for survival.

Make New Friends But Keep the Old: Minimally Invasive Surgery Training in Gynecologic Oncology Fellowship Programs.

OBJECTIVES: To evaluate the role of minimally invasive surgery (MIS) in gynecologic oncology fellowship training and fellows' predictions of their use of MIS in their future practice. METHODS: All fellows-in-training in American Board of Obstetrics and Gynecology-approved training programs were surveyed in 2012 through an online or mailed-paper survey. Data were analyzed and compared to results of a similar 2007 survey. RESULTS: Of 172 fellows, 69 (40%) responded. Ninety-nine percent of respondents (n = 68) indicated that MIS was either very important or important in gynecologic oncology, a proportion essentially unchanged from 2007 (100%). Compared to 2007, greater proportions of fellows considered laparoscopic radical hysterectomy and node dissection for cervical cancer (87% vs 54%; P < 0.0001) and trachelectomy and staging for cervical cancer (83% vs 32%; P < 0.0001) appropriate for MIS. Of the respondents, 92% believed that maximum or some emphasis should be placed on robotic-assisted surgery and 89% on traditional laparoscopy during fellowship training. Ten percent rated their fellowship training in laparoendoscopic single-site surgery as very poor; 44% said that the question was not applicable. Most respondents (60%) in 2012 performed at least 11 procedures per month, whereas most respondents (45%) in 2007 performed 6 to 10 procedures per month (P = 0.005). All respondents at institutions where robotic surgery was used were allowed to operate at the robotic console, and 63% of respondents reported that in robotic-assisted surgery cases when a fellow sat at the robot, the fellow performed more than 50% of the case at the console. CONCLUSIONS: These findings indicate that MIS in gynecologic oncology is here to stay. Fellowship programs should develop a systematic approach to training in MIS and in individual MIS platforms as they become more prevalent. Fellowship programs should also develop and apply an objective assessment of minimum proficiency in MIS to ensure that programs are adequately preparing trainees.

Role of Minimally Invasive Surgery in Gynecologic Oncology: An Updated Survey of Members of the Society of Gynecologic Oncology.

OBJECTIVES: To evaluate the current patterns of use of minimally invasive surgical procedures, including traditional, robotic-assisted, and single-port laparoscopy, by Society of Gynecologic Oncology (SGO) members and to compare the results to those of our 2004 and 2007 surveys. METHODS: The Society of Gynecologic Oncology members were surveyed through an online or mailed-paper survey. Data were analyzed and compared with results of our prior surveys. RESULTS: Four hundred six (32%) of 1279 SGO members responded. Eighty-three percent of respondents (n = 337) performed traditional laparoscopic surgery (compared with 84% in 2004 and 91% in 2007). Ninety-seven percent of respondents performed robotic surgery (compared with 27% in 2007). When respondents were asked to indicate procedures that they performed with the robot but not with traditional laparoscopy, 75% indicated radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Overall, 70% of respondents indicated that hysterectomy and staging for uterine cancer was the procedure they most commonly performed with a minimally invasive approach. Only 17% of respondents who performed minimally invasive surgery performed single-port laparoscopy, and only 5% of respondents indicated that single-port laparoscopy has an important or very important role in the field. CONCLUSIONS: Since our prior surveys, we found a significant increase in the overall use and indications for robotic surgery. Radical hysterectomy or trachelectomy and pelvic lymphadenectomy for cervical cancer and total hysterectomy and staging for endometrial cancer were procedures found to be significantly more appropriate for the robotic platform in comparison to traditional laparoscopy. The indications for laparoscopy have expanded beyond endometrial cancer staging to include surgical management of early-stage cervical and ovarian cancers, but the use of single-port laparoscopy remains limited.

Management of Persistent Postpartum Hemorrhage Caused by Inner Myometrial Lacerations.

BACKGROUND: Postpartum hemorrhage management must involve rapid recognition of the source of bleeding. Inner myometrial laceration is an uncommonly recognized cause; most cases are demonstrated only by evaluation of peripartum hysterectomy specimens. The exact cause of this laceration is unknown; however, it can be identified by uterine cavity exploration and managed with conservative surgery that preserves fertility. CASE: Postpartum hemorrhage caused by inner myometrial lacerations is presented. We explored the uterine cavity through laparotomy and uterine hysterotomy to identify and repair the source of bleeding. CONCLUSION: In persistent hemorrhage that fails initial interventions, inner myometrial laceration should be considered. Uterine cavity exploration with laparotomy incision and hysterotomy to directly visualize the source are essential steps to manage postpartum hemorrhage while avoiding maternal morbidity, peripartum hysterectomy, and potential mortality.

Use of a visual aid to improve counseling at the threshold of viability.

OBJECTIVES: To pilot-test a visual aid developed to help counsel pregnant women. METHODS: After agreeing to participate, pregnant women at >28 weeks of gestation were assigned randomly to counseling with or without a visual aid. The visual aid contained pictures, graphics, and short messages about delivery room resuscitation, chances of survival, anticipated neonatal course, and long-term neurodevelopmental disabilities. A neonatal fellow performed counseling with a standardized script for an anticipated delivery at 23 weeks of gestation. In precounseling and postcounseling sessions, women were given a structured interview to assess their knowledge of chances of survival and disability and attitudes toward resuscitation. RESULTS: Of the 89 women who participated, 76% were black and 59% read below a 9th-grade level. Compared with the no-visual aid group, women in the visual aid group recalled more disabilities and predicted longer neonatal stays (P = .01). For both groups, mothers' perceptions of the chances of survival were lower after counseling; the decrease was greater in the visual aid group (P = .03). The majority of women in each group opted for resuscitation, which was not affected by counseling. In multivariate analyses, use of the visual aid was a significant independent factor in explaining before/after differences in survival chances and recall of a long NICU stay and number of disabilities; higher literacy levels also were significant for recalling the number of disabilities. CONCLUSIONS: Use of a visual aid improved mothers' knowledge and showed promise as a decision aid for counseling at the threshold of viability.