Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer.

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

Rectal Adenocarcinoma Presenting as a Cervical Mass: A Case Report.

BACKGROUND Invasive cervical tumors are often seen in clinical practice. However, there are multiple structures within the pelvis, and invasion of the cervix from another site must be included in the differential diagnosis. In such cases, a multidisciplinary approach is needed to define the organ of tumor origin. Ensuring proper staging and histologic analysis are critical for optimal management. CASE REPORT We present a case of a 68-year-old woman who presented to her gynecologist with painless post-menopausal vaginal bleeding. She was diagnosed with a locally aggressive cervical adenocarcinoma, which was histologically confirmed by an in-office biopsy. She was referred to the gynecologic oncology service at a tertiary care hospital for definitive management, where a thorough clinical workup was performed. Physical exam revealed that the mass had invaded the anterior rectal wall. Through a multidisciplinary approach and a repeat biopsy, she was correctly diagnosed with an invasive rectal adenocarcinoma. She was treated with neoadjuvant chemoradiotherapy and underwent curative surgery. Had she been incorrectly treated as having a primary cervical adenocarcinoma, there would have been no role for surgery. The change in the organ of primary drastically altered the patient's management and outcome. She is currently undergoing surveillance with cross-sectional imaging. CONCLUSIONS Cervical masses originating from non-gynecologic organs can be difficult to differentiate on physical exam and histologic analysis. When a mass involves the rectum, an invasive primary rectal adenocarcinoma must be included in the differential. This will have a significant impact on patient management and ultimately on patient survival.

Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers.

BACKGROUND: Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. METHODS: Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p < 0.15; Ha: p ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. RESULTS: Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. CONCLUSIONS: The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.

A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women. METHODS: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). RESULTS: 324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia. CONCLUSIONS: Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer. IMPACT: These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

A Not So Perfect Score: Factors Associated with the Rate of Straight Line Scoring in Oncology Training Programs.

Straight line scoring (SLS), defined as trainee assessments with the same score for all evaluation items, is statistically improbable and potentially indicates inaccurate assessment. Factors contributing to higher SLS rates are unknown, and knowledge of SLS prevalence within oncologic training is lacking. SLS frequency was measured for evaluations from all Accreditation Council for Graduate Medical Education (ACGME)-accredited programs at a single cancer care institution between 2014 and 2018. SLS prevalence was estimated using hierarchical linear models (HLM) that considered characteristics of evaluator, trainee, and evaluation potentially related to SLS. Results were compared with national SLS rates. Six thousand one hundred sixty evaluations were included from 476 evaluators. Overall prevalence of SLS was 12.1% (95% CI 4.5-28.8). Residents (vs fellows) were less likely to have SLS evaluations (OR 0.5, 95% CI 0.4-0.8), though for all trainees increasing training year corresponded with increasing SLS frequency (OR 1.5, 95% CI 1.3-1.7). SLS was more common in procedural specialties compared with medical specialties (OR 2.1, 95% CI 1.1-3.8). Formative evaluations had lower SLS rates (OR 0.6, 95% CI 0.5-0.9) than summative evaluations, while milestone-based evaluations had higher rates than those that were not milestone-based (OR 1.5, 95% CI 1.03-2.2). Features of evaluators, such as subspecialty within oncology, and of trainees, such as seniority or trainee type, were related to SLS. Summative intent and milestone-based evaluations were more likely to be straight line scored. Specific evaluation scenarios at higher risk of SLS should be further examined.

Factors associated with response to neoadjuvant chemotherapy in advanced stage ovarian cancer.

OBJECTIVES: To evaluate the factors associated with response to neoadjuvant chemotherapy (NACT) and the ability to undergo interval tumor reductive surgery (iTRS) in patients with advanced ovarian cancer. METHODS: We performed a retrospective review from April 2013 to March 2019 of patients with advanced stage ovarian cancer triaged to NACT based on our standard triage algorithm. Clinicopathologic and treatment data were analyzed for factors associated with response to NACT, outcomes at iTRS, and their impact on progression-free survival (PFS). RESULTS: 562 patients met inclusion criteria and triaged to NACT following laparoscopy (n = 132) or without laparoscopy (n = 430). 413 patients underwent iTRS (74%). Factors that correlated with a patient reaching iTRS included increasing age (p < 0.001), higher Charlson comorbidity index (p < 0.001), ECOG status 2 or 3 (<0.001), and laparoscopic assessment (<0.001). Patients with CA-125 ≤ 35 U/mL at iTRS had higher rates of complete gross resection (88% vs. 65%, p < 0.001) and improved PFS (16.8 vs. 12.7 months, p < 0.001). Patients receiving dose-dense paclitaxel (76% vs. 60%, p = 0.004) and CA-125 ≤ 35 U/mL at iTRS (85% vs. 66%, p < 0.001) had higher rates of complete radiographic response. On multivariate analysis, germline BRCA 1/2 mutation (p = 0.001), iTRS vs. no surgery (R0, p < 0.001; ≤1 cm, p < 0.001; >1 cm, p < 0.001), dose-dense chemotherapy (p = 0.01), and CA-125 ≤ 35 U/mL at iTRS (p = 0.001) were independent significant factors affecting PFS. CONCLUSIONS: Normalization of CA-125 at the time of iTRS following NACT may serve as a surrogate marker for prognosis in this high-risk population. Our NACT cohort experienced improved response rates and PFS with dose-dense therapy compared to conventional dosing.

Post-operative gastroparesis following carbohydrate loading in a diabetic patient.

Gastroparesis is a syndrome of delayed gastric emptying associated with nausea, vomiting, and postprandial fullness. Despite multiple etiologies, diabetes is one of the principal causes of gastroparesis. This case report examines a 57 year-old woman with poorly controlled diabetes type II (HbA1c 8.3%) complicated by diabetic nephropathy who was readmitted for gastroparesis after two days following uncomplicated robotic surgical staging for endometrial cancer. Prior to the procedure, the patient had received carbohydrate loading in accordance with our center's enhanced recovery pathway; this resulted in severe acute hyperglycemia, a recognized cause of gastroparesis in women with diabetes. During her readmission, she improved with bowel rest and optimization of glycemic control. This case suggests that routine pre-operative carbohydrate loading should be used with caution in poorly controlled diabetic patients.

Correlation of surgeon radiology assessment with laparoscopic disease site scoring in patients with advanced ovarian cancer.

BACKGROUND: Radiographic triage measures in patients with new advanced ovarian cancer have yielded inconsistent results. OBJECTIVE: To determine the correlation between surgeon radiology assessment and laparoscopic scoring by disease sites in patients with newly diagnosed advanced stage ovarian cancer. METHODS: Fourteen gynecologic oncology surgeons from a single institution performed a blinded review of pre-operative contrast-enhanced CT imaging from patients with advanced stage ovarian cancer. Each of the patients had also undergone laparoscopic scoring assessment, between April 2013 and December 2017, to determine primary resectability using the validated Fagotti scoring method, and assigned a predictive index value score. Surgeons were asked to provide expected predictive index value scores based on their blinded review of the antecedent CT imaging. Linear mixed models were conducted to calculate the correlation between radiologic and laparoscopic score for surgeons individually, and as a group. Once the model was fit, the inter-class correlation and 95% CI were calculated. RESULTS: Radiology review was performed on 20 patients with advanced stage ovarian cancer who underwent laparoscopic scoring assessment. Surgeon faculty rank included assistant professor (n=5), associate professor (p=4), and professor (n=5). The kappa inter-rater agreement was -0.017 (95% CI -0.023 to -0.005), indicating low inter-rater agreement between radiology review and actual laparoscopic score. The inter-class correlation in this model was 0.06 (0.02-0.21), indicating that surgeons do not score the same across all the images. When using a clinical cut-off point for the predictive index value of 8, the probability of agreement between radiology and actual laparoscopic score was 0.56 (95% CI 0.49 to 0.73). Examination of disease site sub-scales showed that the probability of agreement was as follows: peritoneum 0.57 (95% CI 0.51 to 0.62), diaphragm 0.54 (95% CI 0.48 to 0.60), mesentery 0.51 (95% CI 0.45 to 0.57), omentum 0.61 (95% CI 0.55 to 0.67), bowel 0.54 (95% CI 0.44 to 0.64), stomach 0.71 (95% CI 0.65 to 0.76), and liver 0.36 (95% CI 0.31 to 0.42). The number of laparoscopic scoring cases, tumor reductive surgery cases, or faculty rank was not significantly associated with overall or sub-scale agreement. CONCLUSIONS: Surgeon radiology review did not correlate highly with actual laparoscopic scoring assessment findings in patients with advanced stage ovarian cancer. Our study highlights the limited accuracy of surgeon radiographic assessment to determine resectability.

Cancer Surgery Scheduling During and After the COVID-19 First Wave: The MD Anderson Cancer Center Experience.

OBJECTIVE: To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. SUMMARY OF BACKGROUND DATA: The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. METHODS: The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. RESULTS: We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. CONCLUSIONS: Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

Clinical Updates in Women's Health Care Summary: Surgical Considerations: Primary and Preventive Care Review.

Obstetrician-gynecologists often incorporate surgical procedures in the care of women. Each phase of a woman's life cycle presents different challenges regarding preoperative, intraoperative, and postoperative management. Appropriate workup and preparation of patients for surgery are key to a successful surgical outcome. As women age, their risk of medical comorbidities, such as coronary artery disease, diabetes mellitus, or obesity, increases, as does the need for surgical procedures. Correctly identifying medical conditions and related surgical risks will help obstetrician-gynecologists provide safe, appropriate, and evidence-based care to women. Increasingly, obstetrician-gynecologists work in the setting of multidisciplinary teams, and many have access to preoperative assessment clinics and hospitalists to assist in the management of preoperative and perioperative patients. It is the responsibility of the referring physician to understand the services these clinics and hospitalists provide. An appropriate and cost-effective evidence-based preliminary workup, such as laboratory and imaging tests, also is important. The purpose of this monograph is to help guide obstetrician-gynecologists through the appropriate preoperative assessment of women who require surgery and identify intraoperative and postoperative management strategies that will help decrease avoidable morbidity and mortality of these patients.

A practical guide for the safe implementation of early phase drug development and immunotherapy program in gynecologic oncology practice.

The success of targeted and immune therapies in other malignancies has led to an exponential increase in the number of active and pending clinical trials using these therapeutic approaches in patients with gynecologic cancers. These novel investigational agents are associated with unique and potentially life-threatening toxicities and many require special multidisciplinary logistical considerations. The objective of this review is to describe a practical approach for the safe implementation of targeted and immune therapies in academic gynecologic oncology practices based on our experience at M.D. Anderson Cancer Center.

Complete Resection Is Essential in the Surgical Treatment of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to determine the utility of surgery in patients with gestational trophoblastic neoplasia (GTN). MATERIALS AND METHODS: We performed a retrospective institutional review board-approved analysis of all patients with GTN at a single institution from 1985 to 2015 and compared all patients who underwent surgery as definitive management for their disease to a matched cohort of those who did not. Kaplan-Meier curves were used to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-nine patients underwent a total of 94 surgeries as definitive treatment for GTN. Nineteen patients had multiple surgeries. Progression-free survival and OS were improved in patients with complete macroscopic surgical resection (n = 61) compared with patients with gross residual disease (n = 33) (median PFS 91.2 months vs 3.3 months, and median OS not reached at 108.8 months vs 66.3 months, respectively; P < 0.05). The nature of the surgery (emergent vs planned) and site of metastatic disease did not influence PFS or OS. Of the 61 patients with no visible residual disease, 17 received adjuvant chemotherapy and 44 did not; there were no observed differences in PFS or OS. Patients who underwent surgery as part of definitive treatment (n = 69 patients) were compared with patients with GTN over the same period who received chemotherapy alone (n = 33 patients). Median PFS was improved in the surgical group (5.9 vs 5.1 months, P < 0.01), but OS was not significantly different (P = 0.37). CONCLUSIONS: Complete resection results in improved outcomes in patients who undergo surgery for GTN, whether emergent or planned, independent of disease site, and should be considered as an important component of treatment in some situations.

A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma.

Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441-9. ©2017 AACR.

Gynecologic Cancer InterGroup (GCIG) consensus review for mucinous ovarian carcinoma.

Mucinous carcinomas of the ovary can be primary or metastatic in origin. Improvements in the pathological diagnosis have increased the ability to distinguish between primary and metastatic ovarian cancers and shown that primary mucinous carcinomas are a rare subtype of ovarian cancer. Most tumors are diagnosed at an early stage, and the prognosis after surgery is good. Advanced or recurrent mucinous carcinoma of the ovary responds poorly to current cytotoxic treatments, and the prognosis is poor. Here, we review the guidelines for surgery and the results of treatment of advanced and recurrent disease. Chemotherapy with platinum and paclitaxel is currently used to treat advanced disease, but the effect of these drugs is modest, and new treatments are needed.

Attempted conservative management of a placental site trophoblastic tumor: a case report.

BACKGROUND: Placental site trophoblastic tumors (PSTTs) are rare malignant forms of gestational trophoblastic neoplasia (GTN). Controversy exists regarding the most important pathologic or radiologic predictors of extent of disease. Consequently, there is limited information as to the best candidates for conservative surgery. CASE: A 28-year-old female presented 18 months after a term delivery with a biopsy confirmed PSTT. She declined hysterectomy. Imaging revealed a locally limited lesion without myometrial invasion, and no evidence of metastatic disease. She was given two cycles of neoadjuvant etoposide, methrotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO) chemotherapy followed by an attempt at laparoscopically guided hysteroscopic resection. Pathology showed extensive myometrial invasion with positive surgical margin, and our recommendation for hysterectomy with pelvic lymph node dissection was accepted. Postoperatively, she was given two cycles ofpaclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE) chemotherapy. CONCLUSION: Fertility sparing options are desirable and should be considered. However, as our case and much of the literature demonstrates, hysterectomy remains the most successful treatment.

Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi-agent chemotherapy for epithelial ovarian cancer.

OBJECTIVE: There is limited information concerning the role of relative dose intensity (RDI) on clinical outcomes in solid tumors. The objectives of our study were to evaluate the prognostic significance of RDI and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian carcinoma (EOC) treated with platinum-based chemotherapy. METHODS: A multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy between 1995 and 2009 was conducted. Data were obtained to include the first four chemotherapy cycles administered. Outcomes included: (1) planned and delivered relative dose intensity (RDI), (2) progression-free (PFS) and overall (OS) survival. Survival estimates were based on Kaplan and Meier method, and multivariate analyses were based on logistic regression and Cox proportional hazards regression. RESULTS: Evaluable subjects included 325 women. With median follow-up of 34 months (range, 0.4-170), progression or recurrence was recorded in 241 (73.9%) and death in 179 (54.9%). In multivariate analysis, predictors of reduced planned RDI were: treatment off research protocols (odds ratio [OR]=4.3; P<0.001) and BSA >2m(2) (OR=6.14; P<0.001); predictors of reduced delivered RDI were: BMI over 30 kg/m(2) (OR=2.35; P=0.008) and use of carboplatin (OR=2.71; P=0.008). In multivariate analysis, the following factors were independently associated with OS: delivered RDI <85% (hazard ratio [HR]=1.71; P=0.003) and elevated CA-125 at cycle 1 (HR=2.29; P=0.017). CONCLUSION: In this retrospective analysis, reduced chemotherapy RDI for ovarian cancer was associated with lower OS, but not PFS, despite adjustment for established prognostic factors.

A surveillance conundrum: a case of 4 distinct primary malignancies in a BRCA-1 mutation carrier.

Women with HBOC syndrome present a unique challenge to the oncology community, as will many genetic cancer syndromes yet to be discovered as genetic testing increases in availability. Issues of management and, most importantly, implication are yet to be elucidated. After a diagnosis of epithelial ovarian carcinoma lifelong follow-up is recommended. Given the high recurrence rate and dismal long term prognosis of advanced epithelial ovarian carcinoma this recommendation is more often than not moot. There are no clear guidelines or recommendations for surveillance designed for women with disease free survival greater than five years. This case presents a unique scenario of a woman with predictable disease that remains unpreventable.

Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development.

Expression of the T-cell receptor (TCR):CD3 complex is tightly regulated during T-cell development. The mechanism and physiological role of this regulation are unclear. Here, we show that the TCR:CD3 complex is constitutively ubiquitylated in immature double positive (DP) thymocytes, but not mature single positive (SP) thymocytes or splenic T cells. This steady state, tonic CD3 monoubiquitylation is mediated by the CD3varepsilon proline-rich sequence, Lck, c-Cbl, and SLAP, which collectively trigger the dynamin-dependent downmodulation, lysosomal sequestration and degradation of surface TCR:CD3 complexes. Blocking this tonic ubiquitylation by mutating all the lysines in the CD3 cytoplasmic tails significantly upregulates TCR levels on DP thymocytes. Mimicking monoubiquitylation by expression of a CD3zeta-monoubiquitin (monoUb) fusion molecule significantly reduces TCR levels on immature thymocytes. Moreover, modulating CD3 ubiquitylation alters immunological synapse (IS) formation and Erk phosphorylation, thereby shifting the signalling threshold for positive and negative selection, and regulatory T-cell development. Thus, tonic TCR:CD3 ubiquitylation results in precise regulation of TCR expression on immature T cells, which is required to maintain the fidelity of T-cell development.