Umut Ozbek

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set (n = 309) and validation set (n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group (P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

The impact of peripheral nerve blocks on perioperative outcome in hip and knee arthroplasty-a population-based study.

Abstract The role of anesthesia techniques on perioperative outcomes on a population level has recently gained widespread interest. Although mainly neuraxial vs general anesthesia has been addressed, population-level data on the impact of peripheral nerve blocks (PNBs) are still lacking. Therefore, we investigated the association between PNB use and outcomes using retrospective data on 1,062,152 recipients of hip and knee arthroplasties (total hip arthroplasty [THA]/total knee arthroplasty [TKA]) from the national Premier Perspective database (2006-2013). Multilevel multivariable logistic regression models measured associations between PNB use and outcomes. Complications included cardiac, pulmonary, gastrointestinal and renal complications, cerebrovascular events, infections, wound complications, thromboembolic complications, inpatient falls, and mortality. Resource utilization variables included blood transfusions, intensive care unit admissions, opioid consumption, cost, and length of stay. Overall, 12.5% of patients received a PNB, with an increase over time particularly among TKAs. Peripheral nerve block use was associated with lower odds for most adverse outcomes mainly among patients with THA. Notable beneficial effects were seen for wound complications (odds ratio 0.60 [95% confidence interval, 0.49-0.74]) among THA recipients and pulmonary complications (odds ratio 0.83 [95% confidence interval, 0.72-0.94]) in patients with TKA. Peripheral nerve block use was significantly (P < 0.0001) associated with a −16.2% and −12.7% reduction in opioid consumption for patients with THA and TKA, respectively. In conclusion, our results indicate that PNBs might be associated with superior perioperative population-level outcomes. In light of the inability to establish a causal relationship and the presence of residual confounding, we strongly advocate for further prospective investigation, ideally in multicenter, randomized trials, to establish the potential impact of PNBs on outcomes on a population level.

MAGIC biomarkers predict long term outcomes for steroid-resistant acute GVHD

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

Adjuvant radiation for salivary gland malignancies is associated with improved survival: A National Cancer Database analysis

Objective There are no randomized data to support the use of postoperative radiation for salivary gland malignancies. This study uses the National Cancer Database (NCDB) to describe the epidemiology of salivary gland cancer patients and to investigate whether treatment with adjuvant radiation improves overall survival. Methods and materials A total of 8243 patients diagnosed with a major salivary gland cancer were identified from the NCDB. All patients received primary surgical resection of their malignancy. Patients were risk-stratified by adverse features, and overall survival rates were determined. Patients were considered high risk if they had extracapsular extension and/or positive margin after resection. Patients were considered intermediate risk if they did not meet the criteria for high risk but had pT3-T4 disease, pN+ disease, lymphovascular space invasion, adenoid cystic histology, or grade 2-3 disease. Patients who did not meet criteria for high or intermediate risk were considered low risk. Overall patient demographics, disease characteristics, treatment factors, and outcomes were summarized with descriptive statistics and analyzed with STATA. Results Median follow-up in this cohort was 42.4 months, with the median age of 58 years. Patients in the high-risk group had greater survival (hazard ratio [HR], 0.76; P = .002; 95% confidence interval [CI], 0.64-0.91) if they received adjuvant radiation therapy. In contrast, patients in the intermediate- (HR, 1.01; P = .904; 95% CI, 0.85-1.20) and low-risk groups (HR, 0.85; P = .427; 95% CI, 0.57-1.26) did not experience a survival benefit with adjuvant radiation therapy. Conclusions This large analysis compared survival outcomes between observation and adjuvant radiation alone in risk-stratified patients after resection of major salivary glands using a national database. The use of adjuvant radiation for high-risk major salivary gland cancers appears to offer a survival benefit. Although an overall survival benefit was not seen in low- and intermediate-risk salivary gland cancers, this study could not address impact on local control because of the limitations of the NCDB.

The prognostic impact of human papillomavirus status following treatment failure in oropharyngeal cancer

Introduction Despite the human papillomavirus conferring a better prognosis in the primary treatment setting, the prognostic impact of viral status after treatment failure in oropharyngeal squamous cell carcinoma patients is poorly understood. Methods We retrospectively identified 33 oropharyngeal squamous cell carcinoma (OPC) patients with local and/or distant disease recurrence post-treatment, and looked at metastatic patterns, time to failure and survival patterns by HPV status. Results Median overall survival following local failure was not significantly different by HPV status (17 months for HPV+ vs. 14 months for HPV-, p = 0.23). However, following distant failures, HPV+ patients lived significantly longer than HPV- patients (median 42 months vs. 11 months, p = 0.004). HPV- patients were more likely to have locoregional failures as compared to HPV+ patients (p = 0.005), but the difference in distant failure between both groups was not significant (p = 0.09). HPV+ patients were more likely to develop metastases to sites other than the lung and bones. Conclusion HPV positivity predicts a favorable prognosis with the potential for long-term survival following distant, not locoregional, failures. These results have important implications for the aggressiveness of treatment and type of surveillance imaging performed.

Patient Safety and Comparative Effectiveness of Anesthetic Technique in Open Lung Resections

BACKGROUND Despite literature suggesting benefits of using regional anesthesia, the impact of neuraxial anesthesia on perioperative outcomes in patients undergoing lung surgery remains unstudied. We studied the effect of combined neuraxial/general anesthesia (vs general anesthesia) on perioperative outcome in a large national sample of patients who underwent open lung resection. METHODS We extracted data from the Premier Perspective database on patients who underwent open lung resection. The main effect of interest was anesthesia type: general and combined neuraxial/general anesthesia. Patient and health-care variables, complications, and resource use were compared between groups. Multivariable analyses assessed the independent impact of choice of anesthetic technique on outcomes. RESULTS For 18,943 patients, anesthesia type was known: 79% (n = 14,912) were administered general anesthesia, and 21% (n = 4,031) received neuraxial/general anesthesia. Comparing general vs neuraxial/general anesthesia, unadjusted incidences for the latter were lower for acute myocardial infarction (1.09% vs 0.67%, P = .018), pulmonary complications (20.96% vs 18.98%, P = .006), blood transfusion (14.15% vs 9.80%, P < .0001), and mechanical ventilation (11.60% vs 8.81%, P < .0001). Neuraxial/general anesthesia was associated with lower adjusted odds of blood transfusion (OR, 0.82; 95% CI, 0.69-0.98) and mechanical ventilation (OR, 0.81; 95% CI , 0.67-0.98), while higher odds were seen for DVT (OR, 1.50; 95% CI, 1.01-2.23) and pulmonary embolism (OR, 1.56; 95% CI, 1.02-2.38). CONCLUSIONS This study illustrates the association between adding neuraxial to general anesthesia in open lung resections among patients with cancer and perioperative outcomes. Neuraxial anesthesia use was associated with decreased risk for blood transfusion but increased thromboembolic risks. Additional studies are needed to elucidate mechanisms by which neuraxial anesthesia may affect these outcomes.

Effect of Helicobacter pylori infection on outcomes in resected gastric and gastroesophageal junction cancer

BACKGROUND Helicobacter pylori (H pylori) infection is a known risk factor for gastric cancer (GC) and has been linked with gastroesophageal junction (GEJ) cancer. Studies examining the relationship between H. pylori infection, GC characteristics and prognosis are limited and have yielded conflicting results. We report on the clinicopathologic characteristics and oncologic outcomes of gastric and GEJ cancer patients with and without a history of H. pylori treated at our institution. METHODS We retrospectively reviewed the medical records of patients over the age of 18 years who underwent curative resection for GEJ and GC at Mount Sinai Hospital between 2007 and 2012 who had histopathologic documentation of the presence or absence of H pylori infection. Demographic, clinical, pathologic, treatment characteristics and outcomes including recurrence-free survival (RFS) and overall survival (OS) were compared. RESULTS Ninety-five patients were identified. The majority of patients were male (61%), white (36%) or Asian (34%), with median age at diagnosis 64. Tumors were stage I (51%), stage II (23%), stage III (25%), and stage IV (1%). H pylori infection status was documented at the time of cancer diagnosis in 89 (94%) patients, and following cancer diagnosis and treatment in 6 (6%) patients. Younger age at diagnosis, Asian race and Lauren histologic classification were associated with H Pylori infection. H pylori positive patients exhibited higher 5-year OS and 5-year RFS compared to H pylori negative patients, though the difference was not statistically significant in either univariate or multivariate analyses. CONCLUSIONS In this retrospective series of predominantly early stage GC and GEJ cancers, H. pylori positive patients were significantly younger at cancer diagnosis and were more frequently Asian compared to H. pylori negative patients. Other demographic and histologic classifications except for Lauren histologic classification were similar between the two groups. H pylori positive patients appeared to have improved outcomes compared to H. pylori negative patients.

Survival signal REG3-α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3&agr; (REG3&agr;) is a biomarker specific for GI GVHD. REG3&agr; serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3&ggr; (the mouse homolog of human REG3&agr;), and the absence of REG3&ggr; in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3&ggr; production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g−/− mice. In vitro, addition of REG3&agr; reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3&agr;/&ggr; to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.

Statistics for X-chromosome associations

In a genome‐wide association study (GWAS), association between genotype and phenotype at autosomal loci is generally tested by regression models. However, X‐chromosome data are often excluded from published analyses of autosomes because of the difference between males and females in number of X chromosomes. Failure to analyze X‐chromosome data at all is obviously less than ideal, and can lead to missed discoveries. Even when X‐chromosome data are included, they are often analyzed with suboptimal statistics. Several mathematically sensible statistics for X‐chromosome association have been proposed. The optimality of these statistics, however, is based on very specific simple genetic models. In addition, while previous simulation studies of these statistics have been informative, they have focused on single‐marker tests and have not considered the types of error that occur even under the null hypothesis when the entire X chromosome is scanned. In this study, we comprehensively tested several X‐chromosome association statistics using simulation studies that include the entire chromosome. We also considered a wide range of trait models for sex differences and phenotypic effects of X inactivation. We found that models that do not incorporate a sex effect can have large type I error in some cases. We also found that many of the best statistics perform well even when there are modest deviations, such as trait variance differences between the sexes or small sex differences in allele frequencies, from assumptions.

Ex vivo human HSC expansion requires coordination of cellular reprogramming with mitochondrial remodeling and p53 activation

The limited number of hematopoietic stem cells (HSCs) in umbilical cord blood (UCB) units restricts their use for stem cell transplantation. Ex vivo treatment of UCB-CD34+ cells with valproic acid (VPA) increases the number of transplantable HSCs. In this study, we demonstrate that HSC expansion is not merely a result of proliferation of the existing stem cells but, rather, a result of a rapid reprogramming of CD34+CD90- cells into CD34+CD90+ cells, which is accompanied by limited numbers of cell divisions. Beyond this phenotypic switch, the treated cells acquire and retain a transcriptomic and mitochondrial profile, reminiscent of primary HSCs. Single and bulk RNA-seq revealed a signature highly enriched for transcripts characteristic of primary HSCs. The acquisition of this HSC signature is linked to mitochondrial remodeling accompanied by a reduced activity and enhanced glycolytic potential. These events act in concert with a modest upregulation of p53 activity to limit the levels of reactive oxygen species (ROS). Inhibition of either glycolysis or p53 activity impairs HSC expansion. This study indicates that a complex interplay of events is required for effective ex vivo expansion of UCB-HSCs.