Jocelyn S. Chapman

Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity

Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 somatic substitution hotspots in 275 genes. We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position- and mutant allele–specific differences, many of which are likely functional. In total, 243 hotspots were novel and appeared to affect a broad spectrum of molecular function, including hotspots at paralogous residues of Ras-related small GTPases RAC1 and RRAS2. Redefining hotspots at mutant amino acid resolution will help elucidate the allele-specific differences in their function and could have important therapeutic implications.

Neurodevelopmental outcomes of congenital diaphragmatic hernia survivors followed in a multidisciplinary clinic at ages 1 and 3

PURPOSE Infants who survive congenital diaphragmatic hernia (CDH) repair may have ongoing medical and neurodevelopmental morbidity after hospital discharge. We evaluated the relationship between medical and neurodevelopmental outcomes of CDH survivors seen in a multidisciplinary clinic at ages 1 and/or 3. METHODS From January 1997 to December 2004, 69 (61%) of 112 CDH survivors were followed in our CDH clinic at ages 1 and/or 3. Medical issues (cardiac, pulmonary, gastrointestinal) were tabulated at hospital discharge and at follow-up. Neurodevelopmental data were obtained from clinic assessments by a neurodevelopmental pediatrician. Descriptive results were summarized for each cohort. Multivariate analyses were performed to identify predictors of motor problems at age 1. RESULTS Of the 69 study participants, 64% were male, 75% had left-sided CDH, 17% had cardiac anomalies, and 25% had other congenital malformations. Nearly all required ventilator management (99%) with a median ventilator time of 14 days (range, 1-54 days); 30% required extracorporeal membrane oxygenation. While 87% of patients had medical issues at hospital discharge, 61% and 67% had medical issues at ages 1 and 3, respectively. Pulmonary problems were noted in 34% and 33% of the ages 1 and 3 cohorts, respectively. Motor and language problems were detected in 60% and 18% of the age 1 cohort and 73% and 60% of the age 3 cohort, respectively. Multivariate analysis found ventilator time as the only independent predictor of motor problems at age 1 (odds ratio, 1.12 per day; 95% confidence interval, 1.05-1.20; P < .01). CONCLUSIONS Young CDH survivors continue to have ongoing medical problems and a high incidence of motor and language problems. Duration of neonatal ventilatory support was a significant predictor of motor problems at age 1. Prospective studies are needed to confirm these findings.

H1N1 influenza in pregnancy: Cause for concern

CASE 1 A 39-year-old multigravida at 32 weeks of gestation presented to Labor and Delivery triage with a chief complaint of headache for 2 days. Her temperature was 38.6°C, blood pressure 114/61 mm Hg, heart rate 121 beats per minute (bpm), and respiratory rate 22 per minute. Her oxygen saturation was 96% on room air. She reported a sore throat the day prior and, on presentation, a mild cough and fatigue. Past medical history was remarkable for obesity and current tobacco use. On auscultation her chest was clear, and fetal monitoring was reassuring. Laboratory studies were notable for a white blood cell count of 5.8 103/microliters, and rapid antigen tests for influenza A and B were negative. Her fever resolved with acetaminophen, so she was discharged to home. Given her negative rapid influenza testing and mild symptoms, her presentation was felt to be consistent with a viral upper respiratory infection. Recommendations at that time regarding treatment of symptomatic patients with negative test results were vague, and she was managed expectantly. Less than 24 hours later, she presented to triage again with severe worsening of her symptoms, complaining of increased work of breathing and generalized malaise. On initial examination she was febrile to 38.5°C, tachycardic (126 bpm), hypotensive (93/46 mm Hg), and tachypneic (40 per minute), and her oxygen saturation was 74% on room air (Table 1 for additional findings on admission). Initial fetal monitoring was reassuring. She was transferred to the intensive care unit (ICU) where she was intubated within 40 minutes of arriving at the hospital. She required a norepinephrine drip for blood pressure support after intubation. Empiric therapy of ceftriaxone, azithromycin, and oseltamivir (Tamiflu; Roche Pharmaceuticals, Nutley, NJ) was also initiated. Although external fetal monitoring in the ICU was initially reassuring, 15 minutes after intubation a terminal bradycardia to the 80s (bpm) was noted on the fetal heart rate tracing, which was confirmed by ultrasonography. Given this nonreassuring fetal status, she was delivered by emergency cesarean in the ICU. She delivered a female neonate with Apgar scores of 2, 3, and 5 (at 1, 5, and 10 minutes of life, respectively) and a weight of 1,500 g. After delivery, the patient remained acutely ill and was treated with prostacyclin and prone bed positioning for alveolar recruitment. Oxygenation was extremely challenging, with ventilator settings reaching values of 100% FIO2 and positive end expiratory pressure of 37. Her course was complicated by acute renal failure and massive fluid retention requiring a bumetanide drip. On hospital day 13, she developed femoral deep vein thromboses, despite enoxaparin prophylaxis, and a transthoracic echocardiogram revealed right ventricular enlargement, with elevated pulmonary artery pressures consistent with pulmonary embolism. She was too unstable for evaluation with computed tomography, so she was treated empirically with intravenous unfractionated heparin as anticoagulant. She continued to demonstrate profound hypoxia, with arterial oxygen tension ranging from 30–56 mm Hg, despite clot lysis with tissue-type plasminogen activator. On hospital day 19, she beFrom the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, California.

Enhanced Recovery Pathways for Improving Outcomes After Minimally Invasive Gynecologic Oncology Surgery.

OBJECTIVE: To estimate whether an enhanced recovery after surgery pathway facilitates early recovery and discharge in gynecologic oncology patients undergoing minimally invasive surgery. METHODS: This was a retrospective case–control study. Consecutive gynecologic oncology patients undergoing laparoscopic or robotic surgery between July 1 and November 5, 2014, were treated on an enhanced recovery pathway. Enhanced recovery pathway components included patient education, multimodal analgesia, opioid minimization, nausea prophylaxis as well as early catheter removal, ambulation, and feeding. Cases were matched in a one-to-two ratio with historical control patients on the basis of surgery type and age. Primary endpoints were length of hospital stay, rates of discharge by noon, 30-day hospital readmission rates, and hospital costs. RESULTS: There were 165 patients included in the final cohort, 55 of whom were enhanced recovery pathway patients. Enhanced recovery patients were more likely to be discharged on postoperative day 1 compared with patients in the control group (91% compared with 60%, P<.001, odds ratio 6.7, 95% confidence interval 2.46–18.04). Fifteen percent of enhanced recovery patients achieved discharge by noon compared with 4% of historical control patients (P=.03). Postoperative pain scores decreased (2.6 compared with 3.12, P=.03) despite a 30% reduction in opioid use. Average total hospital costs were decreased by 12% in the enhanced recovery group (

Post-operative enteral immunonutrition for gynecologic oncology patients undergoing laparotomy decreases wound complications

13,771 compared with

Managing symptoms and maximizing quality of life after preventive interventions for cancer risk reduction.

15,649, P=.01). Readmission rates, mortality, and reoperation rates did not differ between the two groups. CONCLUSION: An enhanced recovery pathway in patients undergoing gynecologic oncology minimally invasive surgery is associated with significant improvements in recovery time, decreased pain despite reduced opioid use, and overall lower hospital costs.

PET/MR Imaging in Gynecologic Oncology

OBJECTIVES The aim of this study is to determine if peri-operative immune modulating dietary supplements decrease wound complications in gynecologic oncology patients undergoing laparotomy. METHODS In July 2013 we instituted a practice change and recommended pre- and post-operative oral immune modulating diets (IMDs) to patients undergoing laparotomy. We retrospectively compared patients who received IMDs to those who did not for the study period July 2012 to June 2014. Our outcome of interest was the frequency of Centers for Disease Control surgical site infections (CDC SSIs). RESULTS Of the 338 patients who underwent laparotomy during the study period, 112 (33%) received IMDs post-operatively. There were 89 (26%) wound complications, including 69 (78%) CDC SSI class 1, 7(8%) class 2 and 13(15%) class 3. Patients receiving IMDs had fewer wound complications than those who did not (19.6% vs. 33%, p=0.049). After controlling for variables significantly associated with the development of a wound complication (ASA classification, body mass index (BMI), history of diabetes mellitus or pelvic radiation, length of surgery and blood loss) consumption of IMDs remained protective against wound complications (OR 0.45, CI 0.25-0.84, p=0.013) and was associated with a 78% reduction in the incidence of CDC SSI class 2 and 3 infections (OR=0.22, CI 0.05-0.95, p=0.044). CONCLUSIONS Post-operative IMDs are associated with fewer wound complications in patients undergoing laparotomy for gynecologic malignancy and may reduce the incidence of CDC SSI class 2 and 3 infections.

Genomic insights in gynecologic cancer

Purpose of review The prevention of breast, ovarian and endometrial cancer frequently involves hormonal or surgical interventions. Each of these may have noncancerous sequelae and can affect quality of life in women with hereditary cancer syndromes. The purpose of this review is to discuss the medical management of hormonal suppression and surgical menopause in hereditary breast and ovarian cancer syndromes and in Lynch syndrome. Recent findings As we gain a better understanding of genetic cancer risk, we are able to reduce the development of cancer with risk-reducing surgery. Understanding the significance of noncancer outcomes helps improve surveillance and treatment strategies and improves our understanding of the interaction between our interventions and their effects on quality of life. Summary Advances in our understanding of the pathogenesis of hereditary breast and ovarian cancer, as well as the difference in ovarian ageing in these high-risk women, allow us to improve our counselling and interventions for family planning and risk-reducing surgery. Studies are ongoing regarding the optimal surveillance of cardiovascular and bone health after risk-reducing salpingo-oophorectomy, although more studies are needed regarding the optimal management of sexual health and other quality of life measures.

Primary Non-Hodgkin Lymphoma of the Ovary

MR imaging and PET using 2-Deoxy-2-[18F]fluoroglucose (FDG) are both useful in the evaluation of gynecologic malignancies. MR imaging is superior for local staging of disease whereas fludeoxyglucose FDG PET is superior for detecting distant metastases. Integrated PET/MR imaging scanners have great promise for gynecologic malignancies by combining the advantages of each modality into a single scan. This article reviews the technology behind PET/MR imaging acquisitions and technical challenges relevant to imaging the pelvis. A dedicated PET/MR imaging protocol; the roles of PET and MR imaging in cervical, endometrial, and ovarian cancers; and future directions for PET/MR imaging are discussed.

Abstract LB-316: The landscape of actionable genomic lesions in small cell bladder cancer

Recent technological advances in DNA sequencing have enabled a remarkably detailed understanding of the molecular changes that define gynecologic and other cancers. Several groups have carried out large-scale genomic analyses of ovarian, uterine, and most recently, cervical cancer. These analyses have led to new insights into the molecular changes characterizing these cancers, which provide insight into clinical outcomes. These molecular characterizations have similarly led to new genomic-based classification schemas, which may better stratify clinical outcomes, help prognosticate and guide treatments. Discovery of characteristic mutations may also provide potential new targets for molecularly targeted chemotherapies, as has been already described with poly-ADP ribose polymerase inhibitors and ovarian cancer. The purpose of this article is to provide an overview of the defining molecular abnormalities and markers in gynecologic cancer, to discuss the clinical implications, and to provide a comprehensive view of the current state of genomic knowledge in gynecologic cancer.