Clinicopathological characteristics and eligibility for adjuvant olaparib of germline BRCA1/2 mutation carriers with HER2-negative early breast cancer.

Following the survival benefit demonstrated in the OlympiA trial, one year of adjuvant olaparib is now recommended for all patients with germline BRCA1/2 pathogenic/likely pathogenic variants (PV) and high-risk, HER2-negative early breast cancer after chemotherapy. However, optimal identification of high-risk patients who may derive benefit from this genomically-directed therapy is debated. In this study, we sought to characterize the real-world proportion of gBRCA1/2 PV carriers eligible for adjuvant olaparib according to the OlympiA criteria, and to compare clinicopathologic characteristics and outcomes between eligible and ineligible patients.

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata.

Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions.

BACKGROUND: High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes. METHODS: We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan-Meier methods to characterize 3-year breast cancer risk in patients without upgrade. RESULTS: Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5-23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8-22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3-26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%). CONCLUSIONS: Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

Prevalence, Dynamics, and Prognostic Role of Clonal Hematopoiesis of Indeterminate Potential in Patients With Breast Cancer.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited. PATIENTS AND METHODS: We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005. RESULTS: CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53-mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC. CONCLUSION: CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53-mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.

Incidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes.

BACKGROUND: The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown. PATIENTS AND METHODS: A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated. RESULTS: Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer. CONCLUSION: Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy.

Impact of Genetic Counseling on Patient-Reported Electronic Cancer Family History Collection.

BACKGROUND: Cancer family history is a vital part of cancer genetic counseling (GC) and genetic testing (GT), but increasing indications for germline cancer GT necessitate less labor-intensive models of collection. We evaluated the impact of GC on patient pedigrees generated by an electronic cancer family history questionnaire (eCFHQ). METHODS: An Institutional Review Board-approved review of pedigrees collected through an eCFHQ was conducted. Paired pre-GC and post-GC pedigrees (n=1,113 each group) were analyzed independently by cancer genetic counselors for changes in patient-reported clinical history and to determine whether the pedigrees met NCCN GT criteria. Discrepancy in meeting NCCN GT criteria between pre-GC and post-GC pedigrees was the outcome variable of logistic regressions, with patient and family history characteristics as covariates. RESULTS: Overall, 780 (70%) patients had cancer (affected), 869 (78%) were female, and the median age was 57 years (interquartile range, 45-66 years; range, 21-91 years). Of the 1,113 pairs of pre-GC and post-GC pedigrees analyzed, 85 (8%) were blank, 933 (84%) were not discrepant, and 95 (9%) were discrepant in meeting any NCCN GT criteria. Of the discrepant pedigrees, n=79 (83%) became eligible for testing by at least one of the NCCN GT criteria after GC. Patients with discrepant pedigrees were more likely to report no or unknown history of GT (odds ratio [OR], 4.54; 95% CI, 1.66-18.70; P=.01, and OR, 18.47; 95% CI, 5.04-88.73; P<.0001, respectively) and belonged to racially and/or ethnically underrepresented groups (OR, 1.91; 95% CI, 1.08-3.25; P=.02). CONCLUSIONS: For most patients (84%), a standalone eCFHQ was sufficient to determine whether NCCN GT criteria were met. More research is needed on the performance of the eCFHQ in diverse patient populations.

Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program.

PURPOSE: Tumor-only genomic testing can uncover somatic and germline pathogenic variants [pathogenic/likely pathogenic (P/LP)] in cancer predisposition genes. We describe the prevalence of P/LPs in BRCA1/2 and PALB2 (B1B2P2) across malignancies and the frequency of clinical germline testing (CGT) in patients with P/LPs in B1B2P2 identified on tumor-only testing. EXPERIMENTAL DESIGN: Among 7,575 patients with cancer tested between 2016 and 2018 with the OncoPanel tumor-only sequencing assay, we characterized P/LP frequencies by tumor type, receipt of CGT prior to or within 12 months after OncoPanel, and factors associated with CGT. RESULTS: 272 (3.6%) patients had OncoPanel-detected P/LPs in B1B2P2: 37.5% of P/LPs were in BRCA-related cancers; the remainder were in non-BRCA tumors. P/LPs were detected in ≥5% of breast, pancreatic, prostate, ovarian, nonmelanoma skin, endometrial, small cell lung, and colorectal cancers. 37.9% of patients with P/LPs received CGT prior to OncoPanel; an additional 10.7% underwent CGT within 12 months of OncoPanel. Among 132 with CGT, 88.6% had ≥1 clinical factor for CGT compared with 47.1% who did not undergo CGT. Patients with BRCA tumors were more likely to have CGT compared with those without (81.4% vs. 29.0%, P < 0.0001). Among patients with CGT, 70.5% (93/132) of P/LPs were germline. CONCLUSIONS: Tumor-only genomic testing identified P/LPs in B1B2P2 in 3.6% of patients. 52.9% of patients with tumor-detected P/LPs and without CGT did not meet personal or family history criteria for CGT. In addition, some patients with tumor-detected P/LPs were not referred for CGT, especially those with non-BRCA tumors. Given implications for treatment selection and familial cancer risk, processes to reliably trigger CGT from tumor-genomic findings are needed.

Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing.

Pathogenic germline variants (PGVs) in cancer susceptibility genes are usually identified through germline testing of DNA from blood or saliva: their detection can affect treatment options and potential risk-reduction strategies for patient relatives. PGV can also be identified in tumor sequencing assays, which, when performed without patient-matched normal specimens, render determination of variants' germline or somatic origin critical. METHODS: Tumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline versus somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity was also determined. Predicted mutational models were compared with clinical germline testing results. Statistical measures were computed to evaluate performance. RESULTS: Tumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. We imputed germline versus somatic status for > 75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with loss of heterozygosity in the tumor specimens (72%) compared with variants of uncertain significance (58%). CONCLUSION: Analyzing tumor-only data in the context of specimens' tumor cell content allows precise, systematic exclusion of somatic variants and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Although technical or systematic errors in measuring variant allele frequency could result in incorrect inference, misestimation of specimen purity could result in inferring somatic variants as germline in somatically mutated tumor suppressor genes. A user-friendly bioinformatics application facilitates objective analysis of tumor-only data in clinical settings.

Evaluation of TP53 Variants Detected on Peripheral Blood or Saliva Testing: Discerning Germline From Somatic TP53 Variants.

PURPOSE: Multigene panel testing (MGPT) identifies TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes, of which only one is classic Li-Fraumeni syndrome. Low variant allelic fraction (VAF) in TP53 found on germline testing may suggest aberrant clonal expansion or constitutional mosaicism. We evaluated TP53-positive probands seen in a cancer genetics program to determine germline versus somatic status. METHODS: We reviewed TP53-positive probands from 2012 to 2019 identified by MGPT on blood or saliva (N = 84). Available VAFs were collected. Probands with a familial variant, who met Li-Fraumeni syndrome testing criteria or who carried a founder variant, were considered germline. For those with uncertain germline status, TP53 variants were further examined using ancillary data of family members and somatic tissue. RESULTS: Of the 84 probands, 54.7% had germline variants with 33.3% meeting criteria for germline status and 21.4% confirmed through ancillary testing. Aberrant clonal expansion comprised 13.1% with clonal hematopoiesis of indeterminate potential and 2.4% with a hematologic malignancy. Constitutional mosaicism was confirmed in 8.3% probands. Definitive status could not be determined in 3.6% despite ancillary assessment, and 17.9% did not have ancillary testing. CONCLUSION: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, approximately half of the patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism require intensified surveillance. A framework of multiple strategies enables discernment of germline from constitutional mosaic and acquired variants, which is essential for appropriate management.

Embedding a genetic counselor into oncology clinics improves testing rates and timeliness for women with ovarian cancer.

OBJECTIVE: Germline genetic testing is crucial to the care of ovarian cancer patients, and as part of the guideline-based care for ovarian cancer patient's adherence to this recommendation has been low. We sought to determine whether embedding a genetic counselor (GC) within a medical and gynecologic oncology clinic would increase testing rates and improve the timeliness of testing. METHODS: Prospective cohort study of 358 ovarian cancer patients seen by medical and gynecologic oncologists between 2013 and 2015. Rates of referrals, completion of counseling, and genetic testing and timeliness of counseling were abstracted before and after a GC was embedded in the clinic in 2014. An additional year of data (2015) was collected to evaluate sustainability of the intervention. RESULTS: Between 2013 and 2015, 88-92% of women were referred for genetic testing, but in 2013 only 66% completed counseling and 61% were tested. After a GC was embedded in the clinic in 2014, more than 80% of referred women completed counseling and germline genetic testing. Time to genetic counseling also decreased from a median of 107 to 40 days, irrespective of age and cancer family history (p < 0.01). CONCLUSIONS: Embedding a GC into the workflow for ovarian cancer patients is an effective way of improving access to genetic counseling, testing rates, and the timeliness of testing.

Histopathologic features of breast cancer in Li-Fraumeni syndrome.

Breast cancer is the most common malignancy in female patients with Li-Fraumeni syndrome (LFS), a rare autosomal dominant hereditary syndrome characterized by germline TP53 mutations. Recent studies have shown that the majority of these tumors are estrogen receptor (ER) positive with frequent HER2 co-expression. However, the morphologic features of these tumors have not been as well studied as other germline-associated breast cancers. We evaluated the pathologic features of 27 invasive and in situ carcinomas from patients with known germline TP53 mutations collected through the Li-Fraumeni Consortium. Overall, 60% of cases were HER2 positive and 44% showed ER co-expression. Most DCIS was high nuclear grade with central necrosis and associated periductal fibrosis and lymphocytic response. Invasive carcinomas were mostly of ductal type (NOS), modified Scarff-Bloom-Richardson (mSBR) high grade, with marked nuclear atypia and high mitotic rate. Prominent tumor infiltrating lymphocytes, syncytial growth pattern, or pushing borders were not seen in these tumors. High p53 IHC expression was seen in tumors from individuals with germline TP53 missense mutations whereas little or no protein expression (<1% nuclear expression, null pattern) was seen in tumors from carriers of non-missense mutations. In this study, we report in detail the morphologic features of invasive and in situ carcinomas in LFS. We found that these tumors share features with cancers harboring somatic TP53 mutations but are distinct from BRCA-associated breast cancers.

Unexpected Pathogenic RET p.V804M Variant Leads to the Clinical Diagnosis and Management of Medullary Thyroid Carcinoma.

BACKGROUND RET p.V804M is a known activating oncogenic variant that confers an increased risk for medullary thyroid carcinoma (MTC). Based on age-specific penetrance, the American Thyroid Association (ATA) categorizes this variant as posing moderate risk. Therefore, ATA guidelines endorse prophylactic thyroidectomy for carriers in childhood (by age 5-10 years) or adulthood, or when the serum calcitonin level becomes elevated. The recommendation for thyroidectomy is increasingly controversial due to the recently reported low penetrance of the RET p.V804M variant in a large unbiased ascertainment cohort. CASE REPORT We describe the unexpected identification of this variant in a 62-year-old woman undergoing broad, multigene cancer panel testing for her personal and family history of breast cancer. There was no known family history of MTC. Biochemical screening prompted by the RET p.V804M result revealed a mildly elevated serum calcitonin. Pathology examination of her thyroidectomy specimen revealed multifocal medullary thyroid microcarcinoma; her sibling's prophylactic thyroidectomy after a RET p.V840M-positive result similarly revealed early-stage MTC. CONCLUSIONS This report demonstrates the value of genetic counseling, shared decision-making, cascade testing, and timely thyroidectomy in the management of a patient with an unexpected RET p.V804M result.

Prevalence of cardiovascular and respiratory complications following trauma in patients with obesity.

BACKGROUND: It is generally accepted that obesity puts patients at an increased risk for cardiovascular and respiratory complications after surgical procedures. However, in the setting of trauma, there have been mixed findings in regards to whether obesity increases the risk for additional complications. OBJECTIVE: The aim of this study was to identify whether obese patients suffer an increased risk of cardiac and respiratory complications following traumatic injury. METHODS: A retrospective analysis of 275,393 patients was conducted using the 2012 National Trauma Data Bank. Hierarchical regression modeling was performed to determine the probability of experiencing a cardiac or respiratory complication. RESULTS: Patients with obesity were at a significantly higher risk of cardiac and respiratory complications compared to patients without obesity [OR: 1.81; CI: 1.72-1.91]. Prevalence of cardiovascular and respiratory complications for patients with obesity was 12.6% compared to 5.2% for non-obese patients. CONCLUSIONS: Obesity is predictive of an increased risk for cardiovascular and respiratory complications following trauma.

Development of a Multidisciplinary Program to Expedite Care of Esophageal Emergencies.

BACKGROUND: Level 1 programs have improved outcomes by expediting the multidisciplinary care of critically ill patients. We established a novel level 1 program for the management of esophageal emergencies. METHODS: After institutional review board approval, we performed a retrospective analysis of patients referred to our level 1 esophageal emergency program from April 2013 through November 2015. A historical comparison group of patients treated for the same diagnosis in the previous 2 years was used. RESULTS: Eighty patients were referred and transported an average distance of 56 miles (range, 1-163 miles). Median time from referral to arrival was 2.4 hours (range, 0.4-12.9 hours). Referrals included 6 (7%) patients with esophageal obstruction and 71 (89%) patients with suspected esophageal perforation. Of the patients with suspected esophageal perforation, causes included iatrogenic (n = 26), Boerhaave's syndrome (n = 32), and other (n = 13). Forty-six percent (n = 33) of patients were referred because of pneumomediastinum, but perforation could not be subsequently demonstrated. Initial management of patients with documented esophageal perforation included operative treatment (n = 25), endoscopic intervention (n = 8), and supportive care (n = 5). Retrospective analysis demonstrated a statistically significant difference in mean Pittsburgh severity index score (PSS) between esophageal perforation treatment groups (p < 0.01). In patients with confirmed perforations, there were 3 (8%) mortalities within 30 days. More patients in the esophageal level 1 program were transferred to our institution in less than 24 hours after diagnosis than in the historical comparison group (p < 0.01). CONCLUSIONS: Development of an esophageal emergency referral program has facilitated multidisciplinary care at a high-volume institution, and early outcomes appear favorable.

Clinical indicators of hemorrhagic shock in pregnancy.

BACKGROUND: Several hemodynamic parameters have been promoted to help establish a rapid diagnosis of hemorrhagic shock, but they have not been well validated in the pregnant population. In this study, we examined the association between three measures of shock and early blood transfusion requirements among pregnant trauma patients. METHODS: This study included 81 pregnant trauma patients admitted to a level 1 trauma center (2010-2015). In separate logistic regression models, we tested the relationship between exposure variables-initial systolic blood pressure (SBP), shock index (SI), and rate over pressure evaluation (ROPE)-and the outcome of transfusion of blood products within 24 hours of admission. To test the predictive ability of each measure, we used receiver operating characteristic (ROC) curves. RESULTS: A total of 10% of patients received blood products in the patient cohort. No patients had an initial SBP≤90, so the SBP measure was excluded from analysis. We found that patients with SI>1 were significantly more likely to receive blood transfusions compared with patients with SI<1 (OR 10.35; 95% CI 1.80 to 59.62), whereas ROPE>3 was not associated with blood transfusion compared with ROPE≤3 (OR 2.92; 95% CI 0.28 to 30.42). Furthermore, comparison of area under the ROC curve for SI (0.68) and ROPE (0.54) suggested that SI was more predictive than ROPE of blood transfusion. CONCLUSION: We found that an elevated SI was more closely associated with early blood product transfusion than SBP and ROPE in injured pregnant patients. LEVEL OF EVIDENCE: Prognostic, level III.

A randomized trial to assess advancement of enteral feedings following surgery for hypertrophic pyloric stenosis.

PURPOSE: The rate of feeding advancement following surgery for hypertrophic pyloric stenosis (HPS) affects length of stay. We hypothesized that: 1) a relaxed feeding regimen following pyloromyotomy would allow infants to achieve feeding goals more quickly without affecting postoperative emesis, and 2) preoperative metabolic derangements would impair the ability to advance feedings following pyloromyotomy. METHODS: A prospective, randomized trial compared two postoperative feeding methods. The primary outcome was length of time to tolerate two consecutive goal feeds (GFs). Infants were randomized into the Incremental-arm (N=74), in which infants were gradually advanced on enteral formula, or the Relaxed-arm (N=69), in which infants were allowed to consume up to GF immediately. Preoperative variables, time to GF, preoperative laboratory values, and postoperative emesis were recorded. A p-value less than 0.05 was significant. RESULTS: Patient demographics, pyloric ultrasound measurements, and episodes of postoperative emesis were similar between groups. Infants in the Relaxed-arm reached GF more quickly than those in the Incremental-arm and had a shorter length of stay (p<0.001). Infants with preoperative serum chloride less than 100mmol/L reached GF more slowly than those with normal labs (p<0.03). CONCLUSION: Following surgery for HPS, surgeons can safely utilize a relaxed, nonstructured feeding regimen, which may allow infants to reach feeding goals more quickly without untoward vomiting. LEVEL OF EVIDENCE: Level 1-therapeutic.

Infectious complications in obese patients after trauma.

BACKGROUND: Obesity is a public health concern in the United States due to its increasing prevalence, especially in younger age groups. Trauma is the most common cause of death for people under aged 40 y. The purpose of this study is to determine the association between obesity and specific infectious complications after traumatic injury. MATERIALS AND METHODS: A retrospective analysis was conducted using data from the 2012 National Trauma Data Bank. The National Trauma Data Bank defined obesity as having a body mass index of 30 or greater. Descriptive statistics were calculated and stratified by obesity status. A hierarchical regression model was used to determine the odds of experiencing an infectious complication in patients with obesity while controlling for age, gender, diabetes, number of comorbidities, injury severity, injury mechanism, head injury, and surgical procedure. RESULTS: Patients with a body mass index of 30 or greater compared with nonobese patients had increased odds of having an infectious complication (Odds Ratio, 1.59; 1.49-1.69). In addition to obesity, injury severity score greater than 29, age 40 y or older, diabetes, comorbid conditions, and having a surgical procedure were also predictive of an infectious complication. CONCLUSIONS: Our results indicate that trauma patients with obesity are nearly 60% more likely to develop an infectious complication in the hospital. Infection prevention and control measures should be implemented soon after hospital arrival for patients with obesity, particularly those with operative trauma.

Human Adipose Stromal Cells Increase Survival and Mesenteric Perfusion Following Intestinal Ischemia and Reperfusion Injury.

OBJECTIVE: Intestinal ischemia can quickly escalate to bowel necrosis and perforation. Transplantation of stem cells presents a novel treatment modality for this problem. We hypothesized that: human adipose-derived stromal cells (hASCs) would increase survival and mesenteric perfusion to a greater degree compared with differentiated cellular controls following ischemic intestinal injury, and improved outcomes with hASC therapy would be associated with preservation of intestinal histological and tight junction architecture, and lower levels of systemic inflammation following intestinal injury. METHODS: hASCs and keratinocytes (differentiated cellular control) were cultured on polystyrene flasks at 37°C in 5% CO2 in air. Adult male C57Bl6J mice were anesthetized and a midline laparotomy performed. The intestines were eviscerated, the small bowel mesenteric root identified, and intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 min with a noncrushing vascular clamp. Following ischemia, the clamp was removed, and the intestines were returned to the abdominal cavity. Before abdominal closure, 2 million hASCs or keratinocytes in 250 µL of phosphate-buffered saline (carrier for cells and control solution) were infused into the peritoneum. Animals were allowed to recover for 12 or 24 h (perfusion, histology, cytokine, and immunofluoresence studies), or 7 days (survival studies). Intestinal perfusion was assessed by laser Doppler imaging. Intestinal tissue segments were stained with hematoxylin and eosin, as well as antibodies for the tight junction protein claudin-1. Separate aliquots of intestine, liver, and lung tissue were homogenized and assessed for inflammatory cytokines via multiplex beaded assay. RESULTS: Animals administered hASCs following intestinal ischemia and reperfusion (I/R) injury had significantly greater 7-day survival and better postischemic recovery of mesenteric perfusion compared with vehicle or keratinocyte therapy. hASCs also abated intestinal mucosal destruction, facilitated preservation of intestinal tight junctions, and decreased the systemic inflammatory response to injury. CONCLUSIONS: Human adipose-derived stromal cells improved survival and mesenteric perfusion and attenuated the mucosal damage associated with intestinal I/R injury. hASCs should be considered as a plausible cell source for novel cellular treatment plans following intestinal ischemia.

NF-κB signaling is increased in HD3 cells following exposure to 1,4-benzoquinone: role of reactive oxygen species and p38-MAPK.

In utero exposure to benzene, a known environmental contaminant, is associated with increased risk of leukemia. We have previously shown that in utero benzene exposure can alter the redox-sensitive transcription factor NF-κB, and we hypothesize that this is through benzene-induced reactive oxygen species (ROS) production interfering with the signaling pathway involving NF-κB and p38-Mitogen Activated Protein Kinase (MAPK). As benzoquinone (BQ) is one of benzene's most toxic metabolites, the objectives of this study were to determine whether ROS and p38-MAPK-mediated BQ-induced increased NF-κB activity. HD3 chicken erythroblast cells were transfected with an NF-κB luciferase-linked reporter plasmid and exposed to BQ (25 µM) for 2-24 h. NF-κB activities were determined through luciferase assays; Western blotting was conducted to assess changes in protein levels in nontransfected cells; and the presence of ROS was determined via 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) flow cytometric assays. Results demonstrated that NF-κB activity was significantly increased following exposure to BQ for 16 and 24 h and DCFDA assays and pretreatment with antioxidants indicated that BQ-mediated ROS production was responsible for this increase. Furthermore, decreased inhibitor of kappaB-alpha (IκB-α) expression suggests that nuclear factor-kappaB (NF-κB) translocates into the nucleus and that p38-MAPK activation through a ROS-dependent pathway mediates BQ-mediated increases in NF-κB activity. Future studies investigating the role of p38-MAPK in this pathway are warranted. Evaluating the effects of toxicant exposure on cell signaling pathways is vital for understanding mechanisms of xenobiotic-induced toxicity.

Disclosing medical errors to patients: it's not what you say, it's what they hear.

BACKGROUND: There is consensus that patients should be told if they are injured by medical care. However, there is little information on how they react to different methods of disclosure. OBJECTIVE: To determine if volunteers' reactions to videos of physicians disclosing adverse events are related to the physician apologizing and accepting responsibility. DESIGN: Survey of viewers randomized to watch videos of disclosures of three adverse events (missed mammogram, chemotherapy overdose, delay in surgical therapy) with designed variations in extent of apology (full, non-specific, none) and acceptance of responsibility (full, none). PARTICIPANTS: Adult volunteer sample from the general community in Baltimore. MEASUREMENTS: Viewer evaluations of physicians in the videos using standardized scales. RESULTS: Of 200 volunteers, 50% were <40 years, 25% were female, 80% were African American, and 50% had completed high school. For designed variations, scores were non-significantly higher for full apology/responsibility, and lower for no apology/no responsibility. Perceived apology or responsibility was related to significantly higher ratings (chi-square, 81% vs. 38% trusted; 56% vs. 27% would refer, p < 0.05), but inclination to sue was unchanged (43% vs. 47%). In logistic regression analyses adjusting for age, gender, race and education, perceived apology and perceived responsibility were independently related to higher ratings for all measures. Inclination to sue was reduced non-significantly. CONCLUSIONS: Patients will probably respond more favorably to physicians who apologize and accept responsibility for medical errors than those who do not apologize or give ambiguous responses. Patient perceptions of what is said may be more important than what is actually said. Desire to sue may not be affected despite a full apology and acceptance of responsibility.