Small-Molecule-Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death.

High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Passive Monitoring of Mental Health Status in the Criminal Forensic Population.

Current approaches to monitoring patients' mental status rely heavily on self-reported symptomatology, clinician observation, and self-rated symptom scales. The limitations inherent in these methodologies have implications for the accuracy of diagnosis, treatment planning, and prognosis. Certain populations are particularly affected by these limitations because of their unique situations, including criminal forensic patients, who have a history of both criminal behavior and mental disorder, and experience increased stigma and restrictions in their access to mental health care. This population may benefit particularly from recent developments in technology and the growing use of mobile devices and sensors to collect behavioral information via passive monitoring. These technologies offer objective parameters that correlate with mental health status and create an opportunity to use Big Data and machine learning to refine diagnosis and predict behavior in a way that represents a marked shift from current practices. This article reviews the approaches to and limitations of psychiatric assessment and contrasts this with the promise of these new technologies. It then discusses the ethics concerns associated with these technologies and explores their potential relevance to criminal forensic psychiatry and the broader implications they carry for health and criminal justice policy.

The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis.

Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma-specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations. SIGNIFICANCE: This study characterizes a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development.See related commentary by Haines and Huang, p. 4009.

Preoperative frailty is a risk factor for non-home discharge in patients undergoing surgery for endometrial cancer.

OBJECTIVE: Our objective was to examine the association of the modified frailty index (mFI) and non-home discharge in patients undergoing surgery for endometrial cancer (EMCA). METHODS: Patients who underwent surgery for EMCA from 2011 to 2012 were identified from the American College of Surgeons - Nastional Surigical Quality Improvement Project (ACS-NSQIP) database. Current Procedural Terminology (CPT) codes were used to identify surgical characteristics. We excluded patients who were already living in a non-home facility. To determine frailty, we used the NSQIP frailty index. For analysis purposes, patients with an mFI score ≥0.18 were defined as frail. Patients were divided into groups based on discharge destination. Logistic regression were used to identify predictors of post-operative non-home discharge. RESULTS: 1216 patients were identified. 26 (2.1%) were discharged to a non-home facility. On multivariate analysis, patients who were discharged to a non-home facility were older (OR 1.09, 95% CI 1.04-1.14, p < 0.001), had a higher Body Mass Index (BMI) (OR 1.08, 95% CI 1.04-1.12, p < 0.001), were more likely to have disseminated cancer (OR 10.02, 95% CI 2.28-44.1, p = 0.002), and were frail (OR 1.95, 95% CI 1.91-5.01, p = 0.008). Undergoing minimally-invasive surgery was independently associated with discharge to home (OR 0.165, 95% CI 0.059-0.458, p = 0.001). CONCLUSION: Frailty is associated with increased risk of non-home discharge in patients undergoing surgery for EMCA. The mFI can be easily calculated using patient characteristics that are readily available pre-operatively. This information can be used for pre-op counseling and to facilitate appropriate and timely discharge planning.

High-dose chemotherapy and stem-cell rescue for salvage therapy for relapsed malignant mixed ovarian germ cell tumor: A case report.

BACKGROUND: Malignant ovarian germ cell tumors are rare, and often treatable with surgery and chemotherapy. Few data are available for treatment of platinum-resistant tumors. CASE: A 31 year old gravida 0 with a 20 cm pelvic mass was found to have a malignant ovarian germ cell tumor after she underwent debulking surgery. She initially responded to chemotherapy; however her AFP began to rise before all cycles were completed. She underwent additional debulking surgery that was again suboptimal. She was then referred for salvage therapy with high-dose chemotherapy with stem cell transplant, which was successful and she has had no evidence of disease for over two years. CONCLUSION: High-dose chemotherapy with stem cell transplant is a viable salvage therapy for patients with platinum-resistant germ cell tumors.

Longer operative time is associated with increased post-operative complications in patients undergoing minimally-invasive surgery for endometrial cancer.

OBJECTIVE: To examine the impact of operative time on the development of post-operative medical and surgical complications in patients undergoing minimally-invasive surgery for endometrial cancer. METHODS: Patients who underwent laparoscopic surgery for endometrial cancer from 2005 to 2014 were identified from the ACS-NSQIP database. Operative times were initially divided into hour-long intervals and complication rates were determined. Outcomes included development of any complication, medical complication, or surgical complication. Subsequent analysis were based on dividing patients into 2 groups based on operative times <240min and operative times ≥240min. Associations between categorical variables were determined using Chi-Squared and Fisher's exact tests. Differences between means of continuous variables were determined using Student's t-tests. Univariate and multivariate analysis using logistic regression were used to identify predictors of post-operative complications. RESULTS: 9145 patients were included, of which 639 (7%) experienced a complication. As operative time increased, rates of complications also increased. Operative time ≥240min was associated with increased overall complication rate (11.7% vs. 6%, p<0.001), medical complication rate (9.3% vs. 4.2%, p<0.001), and surgical complication rate (3.9% vs. 2.4%, p=0.001). When performing multi-variate logistic regression of factors associated with increased complication rates, increased operative time, COPD, hypertension, diabetes, ASA class ≥3, dependent functional status, and chronic steroid use were found to be independently associated with increased complications. Lymphadenectomy was not associated with increased operative time or increase in complications. CONCLUSION: Increased operative time is independently associated with increased risk of developing complications after laparoscopic surgery for endometrial cancer.

Lynch Syndrome and Endometrial Cancer.

In patients with Lynch syndrome, gynecologic cancer often can be the first presenting malignancy. In this review, we summarize the genetics of Lynch syndrome and review the various modalities of identifying patients at risk for this syndrome. The clinical characteristics of Lynch-associated endometrial cancer and screening and risk-reducing strategies also are described.

The Prognostic Value of Baseline Lymphocyte, Neutrophil, and Monocyte Counts in Locally Advanced Cervical Carcinoma Treated with Radiation.

Background. To determine the prognostic significance of pretreatment levels of circulating lymphocyte (CLC), neutrophil (CNC), and monocyte (CMC) counts in patients with locally advanced cervical carcinoma (CC) treated with definitive radiation. Methods. A retrospective, dual-institution review of patients with Stage IB2-IVA CC from 2005 to 2015. Progression-free (PFS) and Overall Survival (OS) were determined for high and low CLC, CNC, and CMC groups. Multivariate analysis was used to confirm prognostic value of baseline leukocyte counts. Results. 181 patients were included. Median follow-up time was 26 (3-89) months. CNC had no effect on PFS or OS. PFS was similar between CMC groups; however, OS was significantly improved for patients with low CMC (62.5 versus 45.3 months, p = 0.016). High CLC was associated with improved PFS (48.5 versus 27.8 months, p = 0.048) and OS (58.4 versus 34.9 months, p = 0.048). On multivariate analysis, high CNC was associated with increased relapse risk (HR 1.12, p = 0.006) and low CLC was associated with increased mortality risk (HR 0.67, p = 0.027). Conclusion. This study demonstrates that leukocyte values can provide prognostic information in CC. These hypothesis-generating findings warrant further prospective investigations.

Preoperative predictors of delay in initiation of adjuvant chemotherapy in patients undergoing primary debulking surgery for ovarian cancer.

OBJECTIVE: The objective of this study was to identify preoperative characteristics of patients that experience a delay in initiation of adjuvant chemotherapy after primary debulking surgery for ovarian cancer. MATERIALS/METHODS: We performed a retrospective review of patients with Stage II to IV high-grade epithelial ovarian, tubal, and peritoneal carcinoma who underwent primary debulking surgery followed by adjuvant chemotherapy from 2005 to 2013. Patients were divided into 2 groups: Control (those who received their first cycle of chemotherapy within 6weeks of debulking surgery) vs. chemotherapy delay (those who received their first cycle of chemotherapy at an interval >6weeks from primary debulking surgery). Relevant clinical variables and survival outcomes were compared between the 2 groups using standard statistical methods. RESULTS: A total of 221 patients were included in the analyses - 169 (76.5%) were in the control group and 52 (23.5%) were in the chemo delay group. On multi-variate analysis, risk factors that were significantly associated with a delay in initiation in chemotherapy included: age >65, albumin <3.5, and high age-adjusted Charlson Comorbidity Index score. Delay in chemotherapy initiation was associated with a shorter progression-free (p=0.014) but not overall survival (p=0.19). CONCLUSIONS: Delay in initiation of chemotherapy affected 23.5% of patients in our study population. Easily identifiable risk factors for chemotherapy delay exist that can help us pre-operatively identify patients for which neoadjuvant chemotherapy may be a better treatment option. Further study into prospective modeling with these identified risk factors is warranted.

Anticipated regret in shared decision-making: a randomized experimental study.

BACKGROUND: Explicit consideration of anticipated regret is not part of the standard shared decision-making protocols. This pilot study aimed to compare decisions about a hypothetical surgery for breast cancer and examined whether regret is a consideration in treatment decisions. METHODS: In this randomized experimental study, 184 healthy female volunteers were randomized to receive a standard decision aid (control) or one with information on post-surgical regret (experimental). The main outcome measures were the proportion of subjects choosing lumpectomy vs. mastectomy and the proportion reporting that regret played a role in the decision made. We hypothesized that a greater proportion of the experimental group (regret-incorporated decision aid) would make a surgical treatment preference that favored the less regret-inducing option and that they would be more likely to consider regret in their decision-making process as compared to the control group. RESULTS: A significantly greater proportion of the experimental group subjects reported regret played a role in their decision-making process compared to the control counterparts (78 vs. 65 %; p = 0.039). Recipients of the regret-incorporated experimental decision aid had a threefold increased odds of choosing the less regret-inducing surgery (OR = 2.97; 95 % CI = 1.25, 7.09; p value = 0.014). CONCLUSIONS: In this hypothetical context, the incorporation of regret in a decision aid for preference-sensitive surgery impacted decision-making. This finding suggests that keying in on anticipated regret may be an important element of shared decision-making strategies. Our results make a strong argument for applying this design and pursuing further research in a surgical patient population. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02563808.

Patterns of First Recurrence in African American Patients with High Grade Epithelial Ovarian Carcinoma.

BACKGROUND/AIMS: The aim of this study is to compare the distribution of anatomic sites of first recurrence in African American (AA) patients with ovarian carcinoma compared to Caucasians. METHODS: Patients diagnosed with high-grade epithelial ovarian, fallopian tube or peritoneal carcinoma from 2007 to 2013 were identified. Patterns of recurrence were compared for AA and Caucasian patients. Progression-free survival (PFS) and overall survival (OS) were compared. RESULTS: A total of 238 patients were included - 210 Caucasians and 28 AAs. At a follow-up time of 28 months, AAs were more likely to have multiple anatomic sites of recurrence rather than a single site when compared to Caucasians (63.6 vs. 35.5%, p = 0.01). Time to first recurrence was shorter for AA patients (12 vs. 18 months, p < 0.01). PFS and OS did not differ. AA patients with multiple sites of first recurrence had a significantly shorter OS than Caucasian patients with multiple sites of first recurrence (24 vs. 30 months, p = 0.022). CONCLUSION: Patterns of first recurrence differ between AAs and Caucasians. AAs have shorter times to first recurrence and are more likely to have multiple anatomic sites involved. AA patients with multiple sites of recurrence have a shorter OS than Caucasian patients with multiple sites.

Fertility-sparing management of a stage IB1 small cell neuroendocrine cervical carcinoma with radical abdominal trachelectomy and adjuvant chemotherapy.

•Neuroendocrine (NEC) tumors of the cervix are very rare and aggressive.•We present a case of Stage IB1 disease managed with fertility-sparing surgery.•Further investigation into fertility-sparing surgery is warranted.

Wandering Spleen. A Case of Spontaneous Hemoperitoneum in an HIV-positive Patient with Recurrent Tuboovarian Abscess.

BACKGROUND: Wandering spleen is a rare and potentially devastating condition that can present in a variety of ways. Here we present a case that led to acute abdomen and hemoperitoneum in a young woman. CASE: A 27-year-old woman with a history of human immunodeficiency virus (HIV), pelvic inflammatory disease, and tuboovarian abscess was readmitted to the hospital for intravenous antibiotic treatment. When her clinical picture did not improve, she underwent placement of a pelvic drain for abscess drainage. Overnight she developed an acute abdomen and hemorrhagic shock. She was taken to the operating room for an exploratory laparotomy, which revealed a ruptured spleen with a single, elongated vascular pedicle. CONCLUSION: Wandering spleen is a rare diagnosis, more common in reproductive-aged women, with potentially fatal complications. It is a necessary component of a differential diagnosis for acute abdomen in reproductive-aged women.

Critical role of Wnt/ß-catenin signaling in driving epithelial ovarian cancer platinum resistance.

Resistance to platinum-based chemotherapy is the major barrier to treating epithelial ovarian cancer. To improve patient outcomes, it is critical to identify the underlying mechanisms that promote platinum resistance. Emerging evidence supports the concept that platinum-based therapies are able to eliminate the bulk of differentiated cancer cells, but are unable to eliminate cancer initiating cells (CIC). To date, the relevant pathways that regulate ovarian CICs remain elusive. Several correlative studies have shown that Wnt/ß-catenin pathway activation is associated with poor outcomes in patients with high-grade serous ovarian cancer (HGSOC). However, the functional relevance of these findings remain to be delineated. We have uncovered that Wnt/ß-catenin pathway activation is a critical driver of HGSOC chemotherapy resistance, and targeted inhibition of this pathway, which eliminates CICs, represents a novel and effective treatment for chemoresistant HGSOC. Here we show that Wnt/ß-catenin signaling is activated in ovarian CICs, and targeted inhibition of ß-catenin potently sensitized cells to cisplatin and decreased CIC tumor sphere formation. Furthermore, the Wnt/ß-catenin specific inhibitor iCG-001 potently sensitized cells to cisplatin and decreased stem-cell frequency in platinum resistant cells. Taken together, our data is the first report providing evidence that the Wnt/ß-catenin signaling pathway maintains stem-like properties and drug resistance of primary HGSOC PDX derived platinum resistant models, and therapeutic targeting of this pathway with iCG-001/PRI-724, which has been shown to be well tolerated in Phase I trials, may be an effective treatment option.

An unusual presentation of a urethral diverticulum as a vaginal wall mass: a case report.

INTRODUCTION: The diagnosis of urethral diverticulum can be challenging given the vague or absent presenting symptoms. In addition, vaginal cancer can present with elusive symptoms--some parallel to urethral diverticula. A case of a bleeding ulcerated mass anticipated to be a vaginal cancer was instead identified as a benign urethral diverticulum. To the best of our knowledge, this is the first case report of a benign urethral diverticulum presenting as a bleeding, necrotic ulcerated mass. CASE PRESENTATION: A 52 year-old multiparous African-American woman presented with a 2-day history of heavy vaginal bleeding passing large clots and suprapubic pain. A pelvic examination revealed blood clots in the vagina along with a friable, fibrous ulcerated lesion on the anterior suburethral vagina, just left of the midline measuring 4 × 2cm. Initially, this mass was considered to be a vaginal cancer. Intraoperative diagnosis of a benign urethral diverticulum was made. CONCLUSIONS: The diagnosis of urethral diverticula based on the vast array of presenting symptoms, is difficult. This original case report may benefit both gynecologic oncologists and female pelvic surgeons and reconstructive surgeons to keep urethral diverticulum in the differential diagnosis when faced with a bleeding midline anterior vaginal mass. This unusual presentation of a urethral diverticulum demonstrates how similarly it may present to a vaginal cancerous mass.

Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers.

OBJECTIVE: Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. METHODS: We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. RESULTS: 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. CONCLUSIONS: The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.

Assessment of FANCD2 nuclear foci formation in paraffin-embedded tumors: a potential patient-enrichment strategy for treatment with DNA interstrand crosslinking agents.

A major mechanism of DNA repair related to homologous recombination is the Fanconi anemia (FA) pathway. FA genes collaborate with BRCA genes to form foci of DNA repair on chromatin after DNA damage or during the S phase of the cell cycle. Our goal was to develop a method capable of evaluating the functional status of the pathway in patients' tumor tissue, which could also be practically incorporated into large-scale screening. To develop this method, we first used Western immunoblot to detect FANCD2 protein monoubiquitination in fresh tumor specimens of patients with ovarian cancer undergoing surgery and stained formalin-fixed paraffin-embedded tumor tissue simultaneously with 4',6-diamidino-2-phenylindole, FANCD2, and Ki67 antibodies, eventually extending this method to other solid tumors. This triple stain permitted evaluation of the presence, or lack thereof, of FANCD2 subnuclear repair foci in proliferating cells by immunofluorescence microscopy. Overall, we evaluated 156 formalin-fixed paraffin-embedded tumor samples using the FA triple-staining immunofluorescence method. The ratios of FANCD2 foci-negative tumors in ovarian, lung, and breast tumor samples were 21%, 20%, and 29.4%, respectively. Our studies have led to the development of a suitable method for screening, capable of identifying tumors with somatic functional defects in the FA pathway. The use of paraffin-embedded tissues renders the reported method suitable for large-scale screening to select patients for treatment with DNA interstrand crosslinking agents, poly ADP-ribose polymerase inhibitors, or their combination.