Citations

Background/aims: Some of the most promising avenues of cancer clinical investigation center on immunotherapeutic approaches. These approaches have provided notable gains in cancer therapeutics with recent Food and Drug Administration approvals of agents of this class in several types of cancers, although gains for ovarian cancer lag behind. This study examined perceptions of therapeutic trials including immunotherapy and virotherapy among ovarian cancer patients and their family members. Methods: A total of 72 semi-structured qualitative interviews were conducted with 33 patients and 39 family members at two National Cancer Institute–designated comprehensive cancer centers. Eligible patients were diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube carcinoma and had experience with clinical trial conversations; family members were nominated by patients and interviewed separately. Applied thematic analysis was used to understand and interpret the data. Results: More participants were aware of vaccine trials than virus trials, although more than half had heard of at least one of them. Initial reactions to vaccine trials were generally favorable. For many, childhood experience with vaccines lent a familiar frame of reference. Virus trials elicited more negative initial reactions, including the use of adjectives such as “scary” and “dreadful.” Viruses seemed contagious or difficult to control. Increased receptivity to these trials occurred in the context of limited therapeutic options and cancer recurrence. Most participants, including those not immediately drawn to these types of trials, indicated openness to learning more. Conclusion: Although vaccine and viral trials are both immunologically based therapeutic approaches, patients who are offered these trials may perceive their potential benefit and safety quite differently. There is a need to consider terminology, solicit and address “gut reactions,” and provide information that enables patients and their family members to better understand the science behind these trials.

Objectives/HypothesisIdiopathic subglottic stenosis (iSGS) is an unexplained obstruction involving the lower laryngeal and upper tracheal airway. Persistent mucosal inflammation is a hallmark of the disease. Epithelial microbiota dysbiosis is found in other chronic inflammatory mucosal diseases; however, the relationship between tracheal microbiota composition and iSGS is unknown.Given the critical role for host defense at mucosal barriers, we analyzed tissue specimens from iSGS patients for the presence of microbial pathogens.MethodsUtilizing 30 human iSGS, 20 intubation‐related tracheal stenosis (iLTS), and 20 healthy control specimens, we applied molecular, immunohistochemical, electron microscopic, immunologic, and Sanger‐sequencing techniques.ResultsWith unbiased culture‐independent nucleic acid, protein, and immunologic approaches, we demonstrate that Mycobacterium species are uniquely associated with iSGS. Phylogenetic analysis of the mycobacterial virulence factor rpoB suggests that, rather than Mycobacterium tuberculosis, a variant member of the Mycobacterium tuberculosis complex or a closely related novel mycobacterium is present in iSGS specimens.ConclusionThese studies identify a novel pathogenic role for established large airway bacteria and provide new targets for future therapeutic intervention.Level of EvidenceNA Laryngoscope, 127:179–185, 2017

Objectives/HypothesisIdiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction. In these studies, we present the initial characterization of the molecular pathogenesis underlying the fibrosing phenotype of iSGS.MethodsUtilizing 20 human iSGS and healthy control specimens, we applied histologic, immunohistochemical, molecular, and immunologic techniques.ResultsWe demonstrate significant activation of the canonical IL‐23/IL‐17A pathway in the tracheal mucosa of iSGS patients, as well as identify γδ T cells as the primary cellular source of IL‐17A.ConclusionOur results suggest that aberrant mucosal immune activation is a component in of the pathogenesis of iSGS. Most critically, our work offers new targets for future therapeutic intervention.Level of EvidenceNA Laryngoscope, 126:E356–E361, 2016

AbstractBackground and AimTumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population‐based CRC utilizing a combination of tumor and germline testing approaches.MethodsColorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR‐deficient tumors and a subset of MMR‐proficient CRCs.ResultsOf the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR‐deficient CRC without MLH1 methylation and a gene mutation were considered Lynch‐like and comprised 41.1% and 25.2% of the MMR‐deficient CRCs for the ACCFR and MCCS, respectively.ConclusionsIdentification of MMR gene mutation carriers in Australian CRC‐affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR‐deficient CRCs will have unknown etiology (Lynch‐like) proving problematic for clinical management.

Although HER2‐positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2‐positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2‐targeted therapies that penetrate the blood‐brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative‐intent surgery during a time period (1980–1997) when no patient received HER2‐targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow‐up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2‐positive (vs ‐negative) primary tumors showed a higher 5‐year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non‐breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2‐positive EACs have a predilection for CNS metastases.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Abstract Rationale The management of severe and refractory hypoxemia in critically ill adult patients is practice based. Variability across individual practitioners and institutions is not well documented. Objectives To conduct a nationwide survey of critical care physicians in the United States regarding accepted definitions and management strategies for severe and refractory hypoxemia. Methods A web-based survey was distributed to a stratified random sample of adult intensivists listed in the American Medical Association Physician Masterfile. The survey was generated by using a mixed-methods approach. Measurements and Main Results: In the survey, 4,865 e-mails were sent and 791 (16.3%) were opened. Among those who opened the e-mail message, 50% (n = 396) responded, representing 8.1% of total surveys sent. Seventy-two percent stated that their institutions lacked a protocol for identification and management of severe or refractory hypoxemia in the setting of acute respiratory failure. While the majority of respondents used low-Vt ventilation (81%), high positive end-expiratory pressure (86%), recruitment maneuvers (89%), and either bolus or infusion neuromuscular blockade (94%), there was marked variability in the use of specific rescue strategies as tier 1 or 2 interventions: prone position (27.8% vs. 47.8%, respectively), extracorporeal membrane oxygenation (2.3% vs. 51.2%, respectively), airway pressure release ventilation (49% vs. 34.5%, respectively), inhaled vasodilators (30.1% vs. 40%, respectively), and high-frequency oscillatory ventilation (7.8% vs. 40%, respectively). The variability was partly explained by providers’ expertise with particular rescue strategies (77.7%), advance directives (70.1%), the training of allied health staff (62.3%), and institutional availability (53.8%). Conclusions U.S. adult critical care physicians predominantly employ lung-protective ventilation for severe hypoxemia. A wide variation in other rescue strategies is noted, which is partly explained by user expertise and availability. Less than 30% institutions have formal protocols for management of refractory hypoxemia.

Nodular fasciitis (NF) is a clonal self‐limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well‐documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6‐USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.

AABB Standards specify that ABO group‐specific whole blood is the only acceptable choice for whole blood transfusions. Although universal donor group O stored whole blood (SWB) was used extensively by the military during the wars of the mid‐twentieth century, its use has fallen out of favor and has never been used to great extent in the civilian trauma population. Interest in the use of whole blood has been renewed, particularly in light of its potential value in far‐forward military and other austere environments. Evidence of preserved platelet function in SWB has heightened enthusiasm for a “one stop shop” resuscitation product providing volume, oxygen carrying capacity, and hemostatic effects. Experience with universal donor group O SWB is required to ascertain whether its use will be an advance in trauma care. Described here is the process of establishing a universal donor group O SWB at a civilian trauma center in the United States.

Recent combat experience reignited interest in transfusing whole blood (WB) for patients with life‐threatening bleeding. US Army data indicate that WB transfusion is associated with improved or comparable survival compared to resuscitation with blood components. These data complement randomized controlled trials that indicate that platelet (PLT)‐containing blood products stored at 4°C have superior hemostatic function, based on reduced bleeding and improved functional measures of hemostasis, compared to PLT‐containing blood products at 22°C. WB is rarely available in civilian hospitals and as a result is rarely transfused for patients with hemorrhagic shock. Recent developments suggest that impediments to WB availability can be overcome, specifically the misconceptions that WB must be ABO specific, that WB cannot be leukoreduced and maintain PLTs, and finally that cold storage causes loss of PLT function. Data indicate that the use of low anti‐A and anti‐B titer group O WB is safe as a universal donor, WB can be leukoreduced with PLT‐sparing filters, and WB stored at 4°C retains PLT function during 15 days of storage. The understanding that these perceived barriers are not insurmountable will improve the availability of WB and facilitate its use. In addition, there are logistic and economic advantages of WB‐based resuscitation compared to component therapy for hemorrhagic shock. The use of low‐titer group O WB stored for up to 15 days at 4°C merits further study to compare its efficacy and safety with current resuscitation approaches for all patients with life‐threatening bleeding.