Citations

While the literature regarding physicians’ childbearing experiences is growing, there are no studies documenting those of anesthesiologists. We surveyed a convenience sample of 72 female anesthesiologists to obtain pilot data. Sixty-six women completed the survey (91.7% response rate), reporting 113 total births from before 1990 to present. Of all birth experiences, proportions of respondents reporting parental leave, lactation facilities, and lactation duration as adequate were 52.3%, 45.2%, and 58.3%, respectively. Most mothers (51.8%) gave birth to their first child while they were trainees. The majority (94.9%) favored an official statement supporting parental leave. These results may serve as groundwork for larger studies.

Nonclonal expansions of immature T cells outside of the thymus, termed indolent T-lymphoblastic proliferation (iT-LBP), have been identified in rare lymphoproliferative disorders. We report that iT-LBP is a frequent finding in cases of follicular dendritic cell sarcoma (FDCS), and shows an association with paraneoplastic autoimmune multiorgan syndrome (PAMS). We studied 31 cases of FDCS by paraffin immunohistochemistry using antibodies to CD21, CD23, CD35, clusterin, CXCL13, podoplanin, CD3, CD4, CD8, CD20, CD1a, and TdT. Chart review was performed to characterize the clinical behavior including evidence of autoimmune disease. FDCS occurred in a wide variety of nodal and extranodal sites. Fourteen of 31 (45%) cases contained immature TdT-positive T cells; in 5 cases these cells were numerous and present throughout the tumor. Four of these 5 patients with numerous immature T cells developed autoimmune disease, clinically categorized as PAMS and/or myasthenia gravis. PAMS persisted after tumor resection, causing severe morbidity and mortality. These findings suggest that the neoplastic follicular dendritic cells can recruit or foster the proliferation of immature T cells and that these cells may play a role in mediating PAMS. Recognition of iT-LBP in FDCS is important to avoid misdiagnosis as thymoma or T-lymphoblastic lymphoma, and may predict serious autoimmune complications in some patients.

TPS3624 Background: To improve survival for patients with mCRC, efforts are needed to identify and treat actionable genomic alterations. HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC. HER2 functions as an oncogenic driver and a mediator of EGFR antibody (Ab) resistance. Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ (HER2 IHC 3+ or HER2 amplified) mCRC, there are no HER2-directed therapies approved for these patients. Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2, currently being developed to treat metastatic breast cancer. In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition. Methods: This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC. Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal Ab. Patients must have HER2+ disease by IHC, FISH, or NGS. Prior treatment with anti-HER2 targeting therapy is excluded. The primary objective is to assess the objective response rate for the combination. Secondary objectives are to evaluate the efficacy (PFS, OS, clinical benefit rate), safety, and tolerability of the combination. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA. Subjects will receive tucatinib at a dose of 300mg by mouth daily, and trastuzumab will be administered every 3 weeks (8 mg/kg IV day 1 of cycle 1, then 6 mg/kg IV Q3 weeks). Response will be assessed every 3 cycles (9 weeks) per RECIST version 1.1. Both agents will be provided by the study. This study was initiated in February 2017. Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United (ACCRU) network. Clinical trial information: NCT03043313.

ObjectivesDevelop multidisciplinary and international consensus on patient, disease, procedural, and perioperative factors, as well as key outcome measures and complications, to be reported for pediatric airway reconstruction studies.MethodsStandard Delphi methods were applied. Participants proposed items in three categories: 1) patient/disease characteristics, 2) procedural/intraoperative/perioperative factors, and 3) outcome measures and complications. Both general and anatomic site‐specific measures were elicited. Participants also suggested specific operations to be encompassed by this project. We then used iterative ranking and review to develop consensus lists via a priori Delphi consensus criteria.ResultsThirty‐three pediatric airway experts from eight countries in North and South America, Europe, and Australia participated, representing otolaryngology (including International Pediatric Otolaryngology Group members), pulmonology, general surgery, and cardiothoracic surgery. Consensus led to inclusion of 19 operations comprising open expansion, resection, and slide procedures of the larynx, trachea, and bronchi as well as three endoscopic procedures. Consensus was achieved on multiple patient/comorbidity (10), disease/stenosis (7), perioperative‐/intraoperative‐/procedure‐related (16) factors. Consensus was reached on multiple outcome and complication measures, both general and site‐specific (8 general, 13 supraglottic, 15 glottic, 17 subglottic, 8 cervical tracheal, 12 thoracic tracheal). The group was able to clarify how each outcome should be measured, with specific instruments defined where applicable.ConclusionThis consensus statement provides a framework to communicate results consistently and reproducibly, facilitating meta‐analyses, quality improvement, transfer of information, and surgeon self‐assessment. It also clarifies expert opinion on which patient, disease, procedural, and outcome measures may be important to consider in any pediatric airway reconstruction patient.Level of Evidence5 Laryngoscope, 129:244–255, 2019

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

AbstractWe aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

Summary Objective Surgery is a stressor that can be categorized by duration and severity and induces a systemic stress response that includes increased adrenal cortisol production. However, the precise impact of surgical stress on the cortisol response remains to be defined. Design We performed a systematic review and meta‐analysis to assess the cortisol stress response induced by surgery and to stratify this response according to different parameters. Methods We conducted a comprehensive search in several databases from 1990 to 2016. Pairs of reviewers independently selected studies, extracted data and evaluated the risk of bias. Cortisol concentrations were standardized, pooled in meta‐analysis and plotted over time. Results We included 71 studies reporting peri‐operative serum cortisol measurements in 2953 patients. The cortisol response differed substantially between moderately/highly invasive and minimally invasive surgical procedures. Minimally invasive procedures did not show a peri‐operative cortisol peak, whereas more invasive surgeries caused a cortisol surge that was more pronounced in older subjects, women and patients undergoing open surgery and general anaesthesia. The duration of the procedure and the use of etomidate for induction of anaesthesia did not affect the cortisol response. Conclusions The peri‐operative cortisol stress response is dynamic and influenced by patient‐specific, surgical and anaesthetic features. However, the available evidence is derived from highly heterogeneous studies, with only two of 71 studies measuring cortisol by mass spectrometry, which currently prevents a precise and reproducible definition of this response.