Search

Rhabdomyosarcoma (RMS) arises from abnormal muscle development. We reported previously that Fragile-X-Related 1 (FXR1), essential to normal myogenesis, was highly expressed in RMS relative to other embryonal tumors. This current study explored FXR1 expression across RMS disease characteristics and treatment response. RMS patients ≤18 years (1980–2019; n = 152) were categorized according to tumor histology, PAX/FOXO1 translocation, and vital status. FXR1 protein expression was compared before and after chemotherapy. Impact of FXR1 expression on relapse-free (RFS) and overall survival (OS) was analyzed. FXR1 was most intensely expressed in the cytosol of undifferentiated rhabdomyoblasts. At diagnosis, FXR1 expression was ubiquitous and strong across all disease characteristics and foremost associated with worse RFS in translocation-positive patients (p = 0.0411). Among embryonal and translocation-negative RMS, survivors showed a significantly greater decrease in FXR1 expression after chemotherapy (p < 0.001) compared to decedents (p = 0.8). In contrast, alveolar and translocation-positive RMS specimens showed insignificant changes in FXR1 expression across therapy. As expected, alveolar histology, translocation presence, stage, and clinical group associated with worse survival. FXR1 was expressed strongly across RMS specimens at diagnosis regardless of disease or patient characteristics, and particularly in undifferentiated cells. Reduction in FXR1 expression after chemotherapy associated with improved survival for embryonal and translocation-negative RMS patients. [ABSTRACT FROM AUTHOR]

Wilms tumor (WT) poses a cancer health disparity to black children globally, which has not been evaluated thoroughly for other pediatric renal cancers. We aimed to characterize health disparities among Tennessee children treated for any renal cancer. The Tennessee Cancer Registry (TCR) was queried for patients ≤ 18 years having any renal cancer (n = 160). To clarify treatment and outcomes, we performed a retrospective cohort study of pediatric renal cancer patients in our institutional cancer registry (ICR; n = 121). Diagnoses in both registries included WT, Sarcoma/Other, and Renal Cell Carcinoma. Wilcoxon/Pearson, Kaplan–Meier, and logistic regression were completed. In both registries, WT comprised the most common renal cancer and youngest median age. Sarcoma was intermediate in frequency and age, and RCC was least common, having the oldest age (p < 0.001). In the TCR, black patients comprised 26% of all patients, presented more commonly with distant disease than white patients (37% v. 16%; p = 0.021), and showed worse overall survival (73% v. 89%; p = 0.018), while the ICR showed similar survival between race groups (92% v. 93%, p = 0.868). Sarcoma and metastases were independent predictors of death in both registries (p ≤ 0.002). Black children in Tennessee presented with more advanced disease and experienced worse survival when combining all renal cancer types, particularly RCC and Sarcoma. When treated at a comprehensive pediatric cancer center, these survival disparities appear diminished. Prognostic study. Level II (retrospective cohort). [ABSTRACT FROM AUTHOR]

The current neuroblastoma (NBL) staging system employs image-defined risk factors (IDRFs) to assess numerous anatomic features, but the impact of IDRFs on surgical and oncologic outcomes is unclear. The Vanderbilt Cancer Registry identified children treated for NBL from 2002 to 2017. Tumor volume (TV) and IDRFs were measured radiographically at diagnosis and before resection. Perioperative and oncologic outcomes were evaluated. At diagnosis of 106 NBL, 61% were IDRF positive. MYCN-amplified and undifferentiated NBL had more IDRFs than nonamplified and more differentiated tumors (p = 0.001 and p = 0.01). Of 86 NBLs resected, 43% were IDRF positive, which associated with higher stage, risk, and TV (each p < 0.001). The presence of IDRF at resection was also associated with increased blood loss (p < 0.001), longer operating times (p < 0.001), greater incidence of intraoperative complications (p = 0.03), more frequent ICU admissions postoperatively (p < 0.001), and longer hospital stays (p < 0.001). IDRF negative and positive tumors did not have significantly different rates of gross total resection (p = 0.2). Five-year relapse-free and overall survival was similar for IDRF negative and positive NBL (p = 0.9 and p = 0.8). IDRFs at diagnosis were associated with larger, less differentiated, advanced stage, and higher risk NBL and at resection with increased operative difficulty and perioperative morbidity. However, the frequency of gross total resection and patient survival after resection were not associated with the presence of IDRFs. Retrospective cohort study. Level III. [ABSTRACT FROM AUTHOR]

Indeterminate pulmonary nodules (IPNs) represent a significant diagnostic burden in health care. We aimed to compare a combination clinical prediction model (Mayo Clinic model), fungal (histoplasmosis serology), imaging (computed tomography [CT] radiomics), and cancer (high-sensitivity cytokeratin fraction 21; hsCYFRA 21-1) biomarker approach to a validated prediction model in diagnosing lung cancer. A prospective specimen collection, retrospective blinded evaluation study was performed in 3 independent cohorts with 6- to 30-mm IPNs (n = 281). Serum histoplasmosis immunoglobulin G and immunoglobulin M antibodies and hsCYFRA 21-1 levels were measured and a validated CT radiomic score was calculated. Multivariable logistic regression models were estimated with Mayo Clinic model variables, histoplasmosis antibody levels, CT radiomic score, and hsCYFRA 21-1. Diagnostic performance of the combination model was compared with that of the Mayo Clinic model. Bias-corrected clinical net reclassification index (cNRI) was used to estimate the clinical utility of a combination biomarker approach. A total of 281 patients were included (111 from a histoplasmosis-endemic region). The combination biomarker model including the Mayo Clinic model score, histoplasmosis antibody levels, radiomics, and hsCYFRA 21-1 level showed improved diagnostic accuracy for IPNs compared with the Mayo Clinic model alone with an area under the receiver operating characteristics curve of 0.80 (95% CI, 0.76-0.84) versus 0.72 (95% CI, 0.66-0.78). Use of this combination model correctly reclassified intermediate risk IPNs into low- or high-risk category (cNRI benign = 0.11 and cNRI malignant = 0.16). The addition of cancer, fungal, and imaging biomarkers improves the diagnostic accuracy for IPNs. Integrating a combination biomarker approach into the diagnostic algorithm of IPNs might decrease unnecessary invasive testing of benign nodules and reduce time to diagnosis for cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Trauma is the leading cause of mortality among children, underscoring the need for specialized child-centered care. The impact on presenting mechanisms of injury and outcomes during the evolution of independent pediatric trauma centers is unknown. The aim of this study was to evaluate the impact of our single center transition from an adult to American College of Surgeons–verified pediatric trauma center. Methods A retrospective analysis was performed of 1,190 children who presented as level I trauma activations between 2005 and 2016. Patients were divided into 3 chronological treatment eras: adult trauma center, early pediatric trauma center, and late pediatric trauma center after American College of Surgeons verification review. Comparisons were made using Pearson χ 2 , Wilcoxon rank sum, and Kruskal-Wallis tests. Results The predominant mechanism of injury was motor vehicle crash, with increases noted in assault/abuse (2% adult trauma center, 11% late pediatric trauma center). A decrease in intensive care admissions was identified during late pediatric trauma center compared with early pediatric trauma center and adult trauma center (51% vs 62.4% vs 67%, P  < .001), with concomitant increases in admissions to the floor and immediate operative interventions, but overall mortality was unchanged. Conclusion Transition to a verified pediatric trauma center maintains the safety expected of the American College of Surgeons certification, but with notable changes identified in mechanism of injury and improvements in resource utilization. [ABSTRACT FROM AUTHOR]

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P  = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P  = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P  = .03). For low recipient ALC (10th percentile, or .56 × 10 2 /µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 10 2 /µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing. [ABSTRACT FROM AUTHOR]

Background Extracorporeal membrane oxygenation is a resource-intensive mode of life-support potentially applicable when conventional therapies fail. Given the initial success of extracorporeal membrane oxygenation to support neonates and infants in the 1980s, indications have expanded to include adolescents, adults, and selected moribund patients during cardiopulmonary resuscitation. This single-institution analysis was conducted to evaluate programmatic growth, outcomes, and risk for death despite extracorporeal membrane oxygenation across all ages and diseases. Methods Beginning in 1989, we registered prospectively all extracorporeal membrane oxygenation patient data with the Extracorporeal Life Support Organization. We queried this registry for our institution-specific data to compare the parameter of “discharge alive” between age groups (neonatal, pediatric, adult), disease groups (respiratory, cardiac, cardiopulmonary resuscitation), and modes of extracorporeal membrane oxygenation (veno-venous; veno-arterial). Extracorporeal membrane oxygenation-specific complications (mechanical, hemorrhagic, neurologic, renal, cardiovascular, pulmonary, infectious, metabolic) were analyzed similarly. Descriptive statistics, Kaplan-Meier, and linear regression analyses were conducted. Results After 1,052 extracorporeal membrane oxygenation runs, indications have expanded to include adults, to supplement cardiopulmonary resuscitation, to support hemodialysis in neonates and plasmapheresis in children, and to bridge all age patients to heart and lung transplant. Overall survival to discharge was 52% and was better for respiratory diseases ( P < .001). Probability of individual survival decreased to <50% if pre-extracorporeal membrane oxygenation mechanical ventilation exceeded respectively 123 hours for cardiac, 166 hours for cardiopulmonary resuscitation, and 183 hours for respiratory diseases ( P = .013). Complications occurred most commonly among cardiac and cardiopulmonary resuscitation runs ( P < .001), the veno-arterial mode ( P < .001), and in adults ( P = .044). Conclusion Our extracorporeal membrane oxygenation program, an Extracorporeal Life Support Organization-designated Center of Excellence, has experienced substantial growth in volume and indications, including increasing age and disease severity. Considering the entire cohort, pre-extracorporeal membrane oxygenation ventilation exceeding 7 days was associated with an increased probability of death. [ABSTRACT FROM AUTHOR]

The TWIST score is a 5-component physical examination score used to aid in diagnosis of testicular torsion (TT) and could lessen need for radiologic testing in certain clinical scenarios. TWIST use was not previously widespread at our institution. The primary objective of this quality improvement study was to achieve 100% compliance in TWIST utilization among urology and ED residents and to assess for score concordance between ED and urology assessments. Secondary goals were correlation of TWIST components with need for orchiectomy. ED staff were educated about the TWIST score and asked to complete assessment for patients presenting with acute scrotal pain. Simultaneously, an electronic medical record-based dot phrase was introduced for urology trainees to complete an independent TWIST evaluation. Spearman correlation was performed to assess association between ED and Urology TWIST scores. Multivariable logistic regression was performed to assess association of TWIST score components and need for orchiectomy. 103 patients presented to the ED from 3/2018–11/2020 with a complaint of acute scrotal pain; 47 were diagnosed with torsion. As compared to our retrospective cohort, the documentation rate of complete TWIST score components on exam rose from 9% to 98% (P < 0.001) on ED evaluation and 16%–66% on urology evaluation (P < 0.001). Rates of repeat ultrasound for patient's transferred between facilities was similar (58% vs. 63%; p = 0.66) as was median time to OR (160 min vs. 145 min; p = 0.5). Using TWIST cutoff of >5 yielded a specificity of 94.5% for diagnosis of torsion, with corresponding strong correlation between ED and urology scores (rho = 0.71). A firm testicle was noted on urology evaluation in 100% of orchiectomy patients (vs. 61% of salvage patients) with persistent association after controlling for duration of symptoms (OR 28.1; P = 0.016). Through two-pronged quality improvement efforts, we significantly improved utilization of the TWIST score by ED and urology staff for workup of patients with acute testicular pain. We confirmed the high sensitivity and specificity of the TWIST score and demonstrated inter-rater reliability between ED and urology assessments. On prospective analysis, testicular firmness on exam was predictive of need for orchiectomy. The TWIST score is an accurate diagnostic tool for both ED and urology providers in workup of children with acute scrotal pain, with a normal score essentially ruling out the condition. Future work should aim at minimizing unnecessary testing in patients demonstrated to be at high risk for torsion. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives KRAS mutations are the most commonly found mutations in patients with non-small cell lung cancer (NSCLC) adenocarcinoma histology. The clinical implications of KRAS mutations in patients with advanced NSCLC are not well defined. We sought to determine if there is a correlation between KRAS mutation status, response to cytotoxic chemotherapy, and survival in patients with metastatic or recurrent NSCLC. Materials and methods Patients with metastatic or recurrent NSCLC and tumor mutation analyses were analyzed for response to conventional chemotherapy. The presence or absence of tumor mutations was assessed with the SNaPshot assay, which detects >40 somatic mutations in eight genes, including KRAS . ALK fluorescence in-situ hybridization analysis was done separately. Associations between KRAS mutation status and response to chemotherapy and survival were assessed. Results We identified 80 patients with metastatic or recurrent NSCLC and a KRAS activating mutation, and we compared these patients to 70 patients who were pan negative (no detectable mutation by the SNaPshot assay and ALK negative). Patients with KRAS -mutant advanced NSCLC demonstrated a significantly shorter progression-free survival in response to first line chemotherapy (4.5 months versus 5.7 months, p = 0.008) compared to pan-mutation negative patients. Overall survival was also significantly shorter in patients with KRAS -mutant advanced NSCLC compared to patients without KRAS activating mutations (8.8 months versus 13.5 months, p = 0.038). Conclusions Within this single institution retrospective analysis, patients with advanced NSCLC and a KRAS activating mutation exhibited inferior responses to cytotoxic chemotherapy and decreased survival compared to patients with advanced NSCLC and no KRAS mutation. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is common in autism spectrum disorder (ASD). Children with OSA can present with a range of symptoms including loud snoring, excessive daytime sleepiness, and changes in cognitive function. Some of these symptoms can overlap with and exacerbate symptoms of ASD, potentially delaying OSA diagnosis in children with both conditions. The primary objective of this study was to assess between-group difference in OSA symptomatology and age at OSA diagnosis in children with and without ASD. A retrospective chart review was conducted on 166 pediatric patients (<18 years) with OSA undergoing adenotonsillectomy at a single academic institution between 2019 and 2021. The control group consisted of 91 patients (54.9% male) without ASD. The ASD group included 75 patients (88.0% male). Autism severity was scored on a 1–4 scale using a novel methodology. Statistical analyses included Wilcoxon rank sum tests for continuous variables, chi-squared tests for categorical variables, and multivariable analyses as needed. There was a significant between-group difference in total number of reported OSA symptoms (p < 0.001), with more symptoms reported in patients with ASD. Within the ASD group, lower autism severity was associated with an increased number of reported OSA symptoms (p = 0.006). There was not a significant between-group difference in age at OSA diagnosis (p = 0.999); however, lower autism severity was associated with an increased age at diagnosis (p = 0.002). These findings suggest that OSA may present with a higher symptom burden in children with ASD, particularly for children with lower ASD severity, who often experience delays in OSA diagnosis. These findings and their clinical implications merit further explanation. [ABSTRACT FROM AUTHOR]

Many phytochemicals in fruits and vegetables have been shown to have cancer-inhibitory effects in animal studies. These effects on cancer, however, have not been clearly demonstrated in human studies. This study investigated the association between fruit and vegetable intakes and the risk of adenomatous polyps. Participants were part of the Tennessee Colorectal Polyp Study. Eligible participants aged 40-75 y were recruited from patients undergoing colonoscopy at 2 medical centers in Nashville, Tennessee from 2003 to 2005. Cases had at least one adenoma and controls were polyp free. Dietary intake was assessed using a self-administered FFQ. Associations between dietary intakes and adenoma risk were evaluated using unconditional logistic regression with restricted cubic function spline. In multivariate analyses of 764 cases and 1517 controls, increased intakes of total fruits, berries, fruit juice, and green leafy vegetables were associated with reduced adenoma risk. The odds ratio for upper tertile intake compared with lower was 0.66(95% CI = 0.51-0.86) for total fruits, 0.64 (95% Cl = 0.47-0.87) for berries, 0.72 (95% CI = 0.56-0.92) for fruit juice, and 0.74 (95% CI = 0.58-0.961 for green vegetables. This study provides additional evidence that high total fruit intake and certain fruit and vegetable intakes may be associated with a reduced risk of colorectal adenomas. [ABSTRACT FROM AUTHOR]

Abstract: Semiquantitative analysis mode in inductively coupled plasma mass spectrometry (ICP-MS) has been popularly used for fast screening purposes. Although the benefit of it has been studied by many researchers, its performance of application in real-world routine analyses has not been reported. In this study, we evaluated the reliability of semiquantitative analysis mode through inter-laboratory comparison using two different ICP-MS systems with one multi-element calibration standard. The suitability of semiquantitative analysis mode in routine analysis laboratory was demonstrated by evaluating its application in different laboratories and in real production laboratory practices. Twenty one elements were measured, namely, Be, B, Al, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Ag, Cd, Sn, Sb, Ba, Tl, and Pb in various fresh water reference samples. Good results concerning accuracy (relative percentage error within 10%) and reproducibility (relative standard deviation lower than 5%) were obtained in more than 90% analyzed samples at concentrations equal to or greater than 10 times the detection limit (DL). Semiquantitative analysis mode also enabled the determination of elements that are not present in the calibration standard. The results demonstrated the potential of semiquantitative analysis mode as a reliable approach in routine laboratory determination of simple matrices, where high throughput and cost-effectiveness are desired, as well as in emergency situations where speed of analysis is critical and quite often limited sample information is available. [Copyright &y& Elsevier]

Background: Topical, intraocular, oral, and parenteral steroids might increase intraocular pressure (IOP), but little is known regarding the effect of nasal steroid spray. Objective: We sought to examine the effect of discontinuing nasal steroid sprays on IOP in patients with glaucoma. Methods: A retrospective chart review of patients with glaucoma using nasal steroids was performed. Averaged IOP for each pair of eyes was determined for presteroid use, steroid use, and 2 consecutive poststeroid use (poststeroid 1 and poststeroid 2) examinations. Results: Twenty-four eyes of 12 patients taking nasal steroids were identified. The mean IOP for each pair of eyes was 15.4 ± 4.3 mm Hg (range, 9-23.5 mm Hg) for the presteroid use examination, 18.0 ± 3.8 mm Hg (range, 12-24.5 mm Hg) for the steroid use examination, 14.5 ± 3.3 mm Hg (range, 9.5-20 mm Hg) for poststeroid use examination 1, and 14.8 ± 3.4 mm Hg (range, 95-22.0 mm Hg) for poststeroid use examination 2. Eleven patients experienced decreased averaged IOP at poststeroid use examination 1 after steroid discontinuation at a mean of 35 ± 14 days and continued to maintain this decrease on the poststeroid use examination 2 visit at a mean of 191 ± 150 days. A significant increase between presteroid and steroid use examination IOPs (P = .007) and a significant decrease between steroid use and both poststeroid use 1 (P < .001) and poststeroid use 2 (P = .011) examination IOPs were observed. No significant difference between presteroid use and either poststeroid use examination IOPs (P = 1.00) was found. Many patients met their target pressures and were able to avoid or delay additional glaucoma therapy. Conclusion: A significant reduction in IOP occurred with nasal steroid discontinuation in patients with glaucoma. Nasal steroids might contribute to IOP increase, and inquiry as to whether a patient has glaucoma before medication initiation is warranted. [Copyright &y& Elsevier]

Highlights • Extracorporeal photopheresis is used to treat chronic graft-versus-host disease. • In a highly pretreated cohort, 62% of patients responded to this treatment. • Treatment was associated with a meaningful decrease in prednisone dose. • Overall, global severity and body surface area redness decreased with treatment. • Response was not associated with frequency of regulatory T cells. Abstract Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft-versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic,.09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the provider's response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to.14 mg/kg, P <.001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD. [ABSTRACT FROM AUTHOR]

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome are reported. We determined the outcome of 29 children with FLT3/ITD–positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in 4 pediatric centers. Eleven patients (38%) received matched related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)–based regimens. No patients experienced transplantation-related mortality. Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% confidence interval [CI], 20.4% to 54.9%). Two-year disease-free survival (DFS) and overall survival (OS) were 65.3% (95% CI, 45.1% to 79.6%) and 82.2% (95% CI, 58.5% to 91.3%), respectively. There was no difference in the DFS of patients who received transplants from related donors versus the DFS of those who received transplants from alternative donors (hazard ratio [HR], 2.64; 95% CI, .79 to 8.76; P = .10), using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR, 1.42; 95% CI, 1.04 to 1.93; P = .03). The use of TBI in the preparative regimen was associated with superior DFS (HR, .29; 95% CI, .08 to .99; P = .04) and OS (HR, .07; 95% CI, .01 to .62; P = .002). We conclude that allogeneic HSCT improves DFS and OS in children with FLT3/ITD–positive AML compared with what has been reported in those treated with chemotherapy alone. [ABSTRACT FROM AUTHOR]

Abstract: The optimal healthcare model for follow-up of allogeneic hematopoietic stem cell transplantation (HSCT) recipients after day 100 is not clear. We previously demonstrated that longitudinal follow-up at the transplant center using a multidisciplinary approach is associated with superior survival. Recent data suggest that increased distance from the transplant center is associated with inferior survival. A dedicated long-term transplant clinic (LTTC) was established in 2006 at our center. We hypothesized that geographic distance would not be associated with inferior outcome if patients are followed in the LTTC. We studied 299 consecutive patients who underwent HSCT and established care in an LTTC. The median distance from the transplant center was 118 miles (range, 1 to 1591). The 75th percentile (170 miles) was used as the cut-off to analyze the impact of distance from the center on outcome (219 patients ≤75th percentile; 80 patients >75th percentile). The 2 groups were balanced for pretransplant characteristics. In multivariate analyses adjusted for donor type, Center for International Blood and Marrow Transplant Research risk, and transplant regimen intensity, distance from transplant center did not impact outcome. Our study suggests that geographic distance from the transplant center is not associated with inferior outcome when follow-up care is delivered via a dedicated LTTC incorporating well-coordinated multidisciplinary care. [Copyright &y& Elsevier]

The mortality rate triples for the 50% of patients diagnosed with new-onset post-transplant diabetes mellitus (PTDM) after HLA-identical allogeneic hematopoietic cell transplant (HCT) (Griffith, BBMT 2011). Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is increasingly utilized for patients with hematological disorders but without a conventional HLA-matched donor; however, the effects of PTDM after haplo-HCT is unknown. We examined the incidence, outcomes, and risk factors for PTDM in patients undergoing haplo-HCT. Patients receiving haplo-HCT with PTCY at Vanderbilt-Ingram Cancer Center (n= 65) were retrospectively analyzed for PTDM diagnosis (defined as a random blood glucose ≥200 mg/dL). Exclusion criteria included non-haplo-HCTs, second HCT, or pre-existing diabetes mellitus. The primary outcome was the incidence of new-onset PTDM by day 100. Secondary outcomes included: cumulative incidence (CI) of grades 2-4 graft-versus-host disease (GVHD), time to systemic steroids, PTDM risk factors, overall survival (OS), disease free survival (DFS), and non-relapse mortality (NRM). PTDM was diagnosed in 14 (21.5%) patients at a median of 18 days after haplo-HCT (range, 8-72 days). Hyperglycemia preceded grade 2-4 GVHD and steroids in 12 (85.7%) patents. Clinical characteristics including ablative conditioning and GVHD did not predict PTDM development (Table 1). OS was decreased in the PTDM group (Figure 1). Among haplo-HCT recipients with cancer (n= 41) DFS was lower and the CI of relapse was increased in PTDM patients (Figure 1). Similar to HLA-identical transplants, PTDM occurs frequently, precedes alloreactivity, and leads to inferior survival following haplo-HCT. Interestingly, glucose metabolism appears to be associated with relapse risk. Prophylaxis/treatment of PTDM may improve outcomes after conventional and haplo-HCT. [ABSTRACT FROM AUTHOR]

Abstract: A series of amino analogs of 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (1) were synthesized to improve aqueous solubility, while retaining high affinity for the human galanin Gal3 receptor. A very potent analog (9e, 1,3-dihydro-1-[3-(2-pyrrolidinylethoxy)phenyl]-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one, K i =5nM) shows good selectivity and solubility of 48μg/mL at pH 7.4. [Copyright &y& Elsevier]

Purpose: Although concurrent chemoradiotherapy can now achieve demonstrated long-term survival in patients with locally advanced non–small-cell lung cancer (LANSCLC), it is difficult to predict which patients will benefit most from this therapeutic approach. Studies have suggested that local control, and the response to therapy, may be linked to improved survival; however, detailed analysis of the impact of tumor response to chemoradiotherapy on survival has not been thoroughly reported. Therefore, we sought to determine the impact of the response rate on survival for patients who were treated with combined modality therapy for LANSCLC. Methods and Materials: We reviewed the data from 116 patients enrolled between 1994 and 1997 in three trials investigating paclitaxel-based concurrent chemoradiotherapy for LANSCLC. Tumor size measurements were assessed immediately before and 2 months after completion of combined modality therapy to determine the response and to calculate the percentage of decrease in tumor size. Results: Patients with a response (complete or partial) had an improved 4-year overall survival rate compared with patients with no response (stable or progressive disease; 21.1% vs. 3.3%, p <0.0001) in the 109 assessable patients. Progression-free survival also improved significantly with response. An analysis of the percentage of decrease in tumor size vs. survival was performed (n = 74) using Cox proportion model analysis. After combined modality therapy, a 20%, 40%, 60%, 80%, and 100% decrease in tumor size conferred a 39%, 63%, 78%, 86%, and 92% reduction in risk of death compared with a 0% decrease in tumor size (p <0.0001). Conclusion: The response by conventional response criteria correlated strongly with improved overall survival and progression-free survival and an increasing percentage of decrease in tumor size resulted in a reduction in the risk of death. Additional investigation of the degree of response as a factor predictive of improved therapeutic efficacy, translating into improved survival, is warranted. [Copyright &y& Elsevier]

Abstract: The capillary electrophoresis (CE) method combined with a sequential extraction was applied to determine the distribution of Fe, Zn, Cu, Mn and Cd in urban ambient air PM2.5 samples. PM2.5 was collected on Teflon filters with dichotomous sampler, and the modified extraction procedure following the BCR leaching procedure was used to chemically fractionate metals into “easily exchangeable” with water, “acid extractable” with 0.11mol/l acetic acid, “reducible” with 0.1mol/l hydroxylamine hydrochloride acidified to pH 2.0 with nitric acid, and “oxidisable” with oxidation by 8.8mol/l hydrogen peroxide (H2O2) followed by extraction with 1.0mol/l ammonium acetate. Based on the obtained results it was concluded that the application of the studied methodology provides chemical fractionation data that reflect the general sources and potential health hazards of the studied metals. [Copyright &y& Elsevier]

• Programmed necroptosis is increased in MDS as suggested by increased RIPK1 in erythroid precursors. • Programmed necroptosis contributes to ineffective hematopoiesis in MDS. • Inhibiting RIPK1 improves erythroid colony-forming ability of human MDS. Myelodysplastic syndrome (MDS) is characterized by persistent cytopenias and evidence of morphologic dysplasia in the bone marrow (BM). Excessive hematopoietic programmed cell death (PCD) and inflammation have been observed in the bone marrow of patients with MDS, and are thought to play a significant role in the pathogenesis of the disease. Necroptosis is a major pathway of PCD that incites inflammation; however, the role of necroptosis in human MDS has not been extensively investigated. To assess PCD status in newly diagnosed MDS, we performed immunofluorescence staining with computational image analysis of formalin-fixed, paraffin-embedded BM core biopsies using cleaved caspase-3 (apoptosis marker) and necroptosis markers (receptor-interacting serine/threonine-protein kinase 1 [RIPK1], phospho-mixed lineage kinase domain-like protein [pMLKL]). Patients with MDS, but not controls without MDS or patients with de novo acute myeloid leukemia, had significantly increased expression of RIPK1 and pMLKL but not cleaved caspase-3, which was most evident in morphologically low-grade MDS (<5% BM blasts) and in MDS with low International Prognostic Scoring System risk score. RIPK1 expression highly correlated with the distribution of CD71+ erythroid precursors but not with CD34+ blast cells. We found that necroptosis is upregulated in early/low-grade MDS relative to control participants, warranting further study to define the role of necroptosis in the pathogenesis of MDS and as a potential biomarker for the diagnosis of low-grade MDS. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction Haploidentical bone marrow transplant (haplo-BMT) with post-transplant cyclophosphamide (PTCy) has increased curative options for patients with sickle cell disease (SCD), with near universal donor availability. However, this approach is associated with increased risk of graft failure, delayed engraftment, and early viral reactivation. Limited knowledge exists regarding immune reconstitution (IR) following haplo-BMT. We hypothesized that the immunomodulatory properties of the pre-transplant conditioning and PTCy contribute to increased early infectious risk and late effects. Objective To characterize IR and impact on infection and late effects post haplo-BMT for SCD. Methods We examined clinical outcomes and IR in 23 patients with severe SCD who received haplo-BMT in the context of a collaborative consortium involving three centers (France, London, U.S.). Common conditioning included fludarabine 150 mg/m2 total, cyclophosphamide 14.5 mg/kg x2, thiotepa 10 mg/kg x1, and thymoglobulin 4.5 mg/kg total, and total body irradiation 200 cGy x1. 18/23 received pre-conditioning with azathioprine 3 mg/kg/day, hydroxyurea 30 mg/kg/day, and hyper-transfusion. Graft source was bone marrow, and 20/23 donors were mobilized with filgrastim 10 mcg/kg/day x 5 days. PTCy (50 mg/kg/day x2), MMF, and sirolimus were given for GvHD prophylaxis. Cellular subsets analyzed included CD4, CD8, NK, and B cells. Patients deceased or without IR data were excluded. Results Table 1 shows patient and donor characteristics. Median total nucleated and CD34 cell doses were 4.9 × 10(9)/kg and 4.69 × 10(6)/kg, respectively. Among engrafted patients, those who received preconditioning had delayed platelet recovery (mean 35 days vs 27, p = 0.002), but higher median CD4 absolute cell count (cells/mL) at D+30 (43 vs 41), D+60 (190 vs 98), D+90 (229 vs 191), D+180 (304 vs 308), D+360 (1255 vs 394) compared to those without, respectively. While not statistically significant either, similar patterns were seen for CD8 and CD19 cells. Post-transplant infections were mostly viral, and occurred in the majority of patients 69.6% (16/23), Figure 2. Conclusion Delayed early IR and viral reactivation/infections were observed following haplo-BMT with PTCy for SCD. Further prospective studies are needed to better characterize IR following this approach to optimize immune-prophylaxis. [ABSTRACT FROM AUTHOR]

We aim to define the dynamic interplay between neurovascular-specific comorbidities and in-hospital complications on outcomes (functional outcome and mortality), length of stay (LOS), and cost of hospital stay. The 2012–2015 National Inpatient Sample (NIS) was queried for intracranial aneurysm treatment after subarachnoid hemorrhage using International Classification of Diseases, Ninth Revision codes. Neurovascular comorbidity index (NCI) was aggregated. NIS–Subarachnoid Hemorrhage Severity Score (NIS-SSS) was used as a Hunt-Hess grade proxy. In-hospital complications were medical complications, surgical complications, seizures, and cerebral vasospasm. Outcomes were functional outcome (modified Rankin Scale [mRS]–equivalent measure), in-hospital mortality, LOS, and cost. Multivariable logistic regression models were built for mRS equivalent and in-hospital mortality. Multivariable linear regression models in log scale were built for LOS and cost. A total of 5353 patients were included. The median NCI was 4.00 (interquartile range [IQR], 0.00–7.00) and 2882 patients (54%) had in-hospital complication. Higher NCI (odds ratio [OR], 1.13 if NCI = 1; OR, 2.05 if NCI = 7; P < 0.001) was associated with any complication, seizure (OR, 1.11, NCI = 1; OR, 1.60, NCI = 7; P < 0.001), medical complication (OR, 1.18, NCI = 1; OR, 2.50, NCI = 7; P < 0.001), surgical complication (OR, 1.13, NCI = 1; OR, 1.91, NCI = 7; P < 0.001), and cerebral vasospasm (OR, 1.09, NCI = 1; OR, 1.49, NCI = 7; P < 0.001). Patients with higher NCI (OR, 1.06, NCI = 1; OR, 1.95, NCI = 7; P < 0.001) or with in-hospital complication (P < 0.001) had poorer mRS equivalent outcome. Similar trends were observed for other outcomes including in-hospital mortality, LOS, and cost. Neurovascular comorbidities are the primary driver of poor mRS equivalent outcome, in-hospital mortality, higher LOS, and higher cost after ruptured intracranial aneurysm procedural treatment. The conditional event of complication influences patients with moderate comorbidities more so than those with low or high comorbidities. [ABSTRACT FROM AUTHOR]

This study investigates the relationship between neurovascular comorbidities and in-hospital complications in determining functional outcome, mortality, length of stay (LOS), and cost of stay. Patients were identified from the 2012–2015 National Inpatient Sample (NIS) using International Classification of Diseases, Ninth Revision codes for unruptured intracranial aneurysm (UIA) treatment in patients without subarachnoid hemorrhage. In-hospital complications were divided into medical complications, surgical complications, and seizures. Primary outcomes were functional outcome measured by modified Rankin Scale (mRS)–equivalent measure, in-hospital mortality, LOS, and cost. Multivariable logistic regression models were built for mRS-equivalent and in-hospital mortality. Multivariable linear regression models in log scale were built for LOS and cost. A total of 7398 procedurally managed patients with UIA were included (median age, 58 years; 75% female; 66% white; 43% private insurance). Higher Neurovascular Comorbidities Index (NCI) was associated with seizure (odds ratio [OR], 1.11 if NCI = 1; OR, 2.49 if NCI = 7; P < 0.001), medical complication (OR, 1.21, NCI = 1; OR, 3.46, NCI = 7; P < 0.001), and surgical complication (OR, 1.25, NCI = 1; OR, 3.47, NCI = 7; P < 0.001). NCI remained significantly predictive of poor mRS-equivalent outcome (OR, 1.20, NCI = 1; OR, 5.79, NCI = 7; P < 0.001), in-hospital mortality (OR, 1.98, NCI = 1; OR, 10.9, NCI = 7; P < 0.001), LOS (coefficient dependent on multiple variables, P < 0.001), and cost (coefficient dependent on multiple variables, P < 0.001) after adjustment. Neurovascular comorbidities are the primary driver of poor mRS-equivalent outcome, in-hospital mortality, higher LOS, and higher cost after procedural treatment of UIA. The conditional event of complication influences patients with fewer comorbidities more so than those with no comorbidities or high comorbidities. It is imperative to precisely account for these factors to optimize targeted resource allocation and increase the value of care for patients with UIA. [ABSTRACT FROM AUTHOR]

Spina bifida disproportionally affects low-and-middle-income countries. We describe myelomeningocele surgical outcomes in Zambia and predictors of postoperative complications and mortality. This 2-center retrospective cohort study includes children who underwent surgical treatment for myelomeningocele in Lusaka, Zambia from 2017 to 2019. Primary outcomes included mortality and 30-day postoperative complications. Seventy-five patients were identified. Median age at first neurosurgical evaluation was 9 days (interquartile range [IQR], 6–21) and at surgery was 21 days (IQR 15–36). Lumbosacral myelomeningocele was most common (73%, n = 54). At first preoperative evaluation, 28% of the neural tube defects were deemed infected (n = 21), and 30% were leaking cerebrospinal fluid (n = 21). Postoperatively, 7% of patients died (n = 5), whereas 31% experienced a complication (n = 23). Most common complications included wound dehiscence (n = 10, 42%) and wound purulence (n = 6, 25%). Median follow-up duration was 41 days (IQR, 6–128). On univariable analysis, mortality was significantly associated with shorter follow-up duration (5 days [IQR, 2–7] vs. 46 days [IQR, 12–132]; P = 0.02) and any complication (P < 0.001). No variable was significantly associated with postoperative complication; however, 2 variables that notably neared significance were preoperative infection of the lesion (P = 0.05) and longer surgical delay (P = 0.06). Most patients born with myelomeningocele in Zambia present for first neurosurgical evaluation after 1 week of age. Preoperative infection of the lesion and postoperative complications are relatively common, and complications are a significant predictor of postoperative mortality. Further investigation into preoperative efforts to mitigate risk of postoperative complications and mortality is warranted. [ABSTRACT FROM AUTHOR]

• Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. • Fasting pretransplant glucose levels identified PTDM susceptibility. • Insulin resistance could be targeted for prevention and treatment of PTDM after HCT. New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P =.005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P =.648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P =.047) and decreased peripheral/skeletal muscle uptake (P =.031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P =.039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT. [ABSTRACT FROM AUTHOR]

Highlights • Anatomic skin distribution is described in 182 incident cGVHD Consortium patients. • Erythema, the most common feature, was widespread but spared the lower extremities. • Sclerosis, more common than anticipated, rarely involved the head, neck, and scalp. • Deep sclerotic features were most common in the upper and lower extremities. • A high level of symmetry of extremity involvement was observed. ABSTRACT Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (n = 71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (n = 4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (n = 14; 8%) and lower extremities (n = 14; 8%). More than one-half of patients with erythema (n = 107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (n = 16; 30.2%). [ABSTRACT FROM AUTHOR]

Highlights • We report a 9% incidence of CLABSI in an outpatient hematopoietic transplant cohort. • Gram-positive cocci were implicated in the majority of CLABSIs. • Matched unrelated and haploidentical donor transplants are at higher risk of CLABSI. • CLABSI may be associated with increased risk of 6-month mortality post-transplant. Abstract Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line–associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P =.0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P =.0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P <.001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations. [ABSTRACT FROM AUTHOR]

Background: Pathologic stage (pStage) IA and IB non-small-cell lung cancer (NSCLC) has a median survival time of 119 and 81 months, respectively. We describe the outcomes of veterans with pStage I NSCLC.Methods: A retrospective review of 78 patients with pStage I NSCLC who underwent cancer resection was performed at the Tennessee Valley Veterans Affairs Hospital between 2005 and 2010. All-cause 30-day, 90-day, and overall mortality were determined. Survival was assessed with the Kaplan-Meier and Cox proportional hazards methods.Results: There were 55 (71%) pStage IA and 23 (29%) IB patients. Thirty- and 90-day mortality was 3.8% (3 of 78) and 6.4% (5 of 78), respectively. Median survival was 59 and 28 months for pStage 1A and 1B, respectively. Postoperative events were associated with impaired survival on multivariable analysis (hazard ratio, 1.26, P = .03).Conclusions: Veterans with pStage I NSCLC at our institution have poorer survival than the general population. More research is needed to determine the etiology of this disparity. [ABSTRACT FROM AUTHOR]

Relapse remains a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Graft-versus-tumor effect is primarily mediated by donor T cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a critical inhibitor of T cell proliferation. Single nucleotide polymorphisms (SNPs) in CTLA-4 may affect immune responses. We hypothesized that CTLA-4 SNPs will be associated with disease control after allo-HCT. One hundred sixty-four adult patients with the availability of pretransplantation recipient and donor DNA samples were included in this analysis. Ten tagSNPs of the CTLA-4 gene were identified. Donor CTLA-4 SNP rs4553808 was associated with decreased relapse-free survival (RFS) (P = .019) and overall survival (OS) (P = .033). In multivariable analysis of an additive genetic model, genotype of CTLA-4 SNP rs4553808 was an independent risk factor for inferior RFS (hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.10-2.71, P = .017) and OS (HR = 1.84, 95% CI 1.13-3.0, P = .015). CTLA-4 SNPs can be used to identify high-risk patient subsets that may benefit from preemptive immunomodulation to decrease relapse rates and improve survival. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Mouse double-minute 2 (MDM2) SNP309 polymorphism (T>G) has been correlated with an increased risk of cancer in multiple tumor types. MDM2 overexpression has shown to be weakly associated with distant tumor metastases, and down-regulation of MDM2 via antisense oligonucleotides in vitro has resulted in the radiosensitization of prostate cancer cell lines. Based on these results, we decided to evaluate the role of MDM2 SNP309 in the context of histopathologic parameters and clinical outcomes in prostate cancer tumors. Materials and methods: The population consisted of 212 consecutive prostate cancer patients who underwent radical prostatectomy between 1997 and 1999 at Vanderbilt University Medical Center. Two hundred eight of the samples were successfully genotyped for the MDM2 SNP309 polymorphism. Correlations between the polymorphism, recurrence, and survival data were analyzed using univariate and multivariate genetic models. Results: The only prognostic factor predictive of overall survival in our study was Gleason score (P < 0.005). Using χ2 analysis, we determined that the MDM2 SNP309 polymorphism had no significant association with race (P = 0.7512), patient''s age at diagnosis (P = 0.6820), pre-prostatectomy PSA level (P = 0.8606), Gleason''s score (P = 0.4839), surgical margin status (P = 1.0000), extracapsular extension (P = 0 .6175), and disease stage (P = 0.4945). In addition, there was no significant difference in 3-year recurrence-free survival (P = 0.218), or 8-year overall survival (P = 0.376). Conclusions: Our study finds no evidence for association of the MDM2 SNP309 polymorphism with clinicopathologic variables, recurrence risk, and overall survival outcome in prostate cancer. [Copyright &y& Elsevier]

Purpose: To evaluate whether selected high-risk matrix metalloproteinase-7 single nucleotide polymorphisms influence clinicopathologic outcomes in patients with early-stage prostate cancer. Methods and Materials: Two hundred twelve prostate cancer patients treated with radical prostatectomy were evaluated with a median follow-up of 9.8 years. Genotyping was performed using hybridization with custom-designed allele-specific probes. Three single nucleotide polymorphisms within the matrix metalloproteinase-7 gene were assessed with respect to age at diagnosis, margin status, extracapsular extension, lymph node involvement, recurrence-free survival, and overall survival in paraffin-embedded prostate tissue specimens from patients with early-stage prostate cancer who underwent radical prostatectomy. Results: Rs10895304 was the sole significant polymorphism. The A/G genotype of rs10895304 had a statistically significant association with recurrence-free survival in postprostatectomy patients (p = 0.0061, log-rank test). The frequency of the risk-reducing genotype (A/A) was 74%, whereas that of the risk-enhancing genotypes (A/G and G/G) were 20% and 6%, respectively. Multivariable Cox regression analyses detected a significant association between rs10895304 and recurrences after adjustment for known prognostic factors. The G allele of this polymorphism was associated with increased risk of prostate cancer recurrence (adjusted hazards ratio, 3.375; 95% confidence interval 1.567–7.269; p < 0.001). The other assayed polymorphisms were not significant, and no correlations were made to other clinical variables. Conclusions: The A/G genotype of rs10895304 is predictive of decreased recurrence-free survival in patients with clinically localized prostate cancer. Our data suggest that for this subset of patients, prostatectomy alone may not be adequate for local control. This is a novel and relevant marker that should be evaluated for improved risk stratification of patients who may be candidates for adjuvant radiation therapy to improve local control. [Copyright &y& Elsevier]

Posttransplantation diabetes mellitus (PTDM) is a frequent complication after allogeneic stem cell transplantation (allo-SCT), important for its negative impact on cardiovascular health. Risk factors for PTDM are not well defined. We conducted a prospective study to investigate the risk factors and incidence for PTDM in the first 100 days after allo-SCT. A total of 84 patients completed the study, 60% of whom developed PTDM. In a multivariate logistic regression model, pretransplantation c-peptide level (>3.6 ng/mL; odds ratio [OR], 5.9; 95% confidence interval [CI], 1.77-20.22; P = .004), unrelated donor allo-SCT (OR, 4.3; 95% CI, 1.34-14.2; P = .014), and peak steroid dose >1 mg/kg/day (OR, 5.09; 95% CI, 1.19-23.2; P = .035) were identified as independent predictors of PTDM. In addition, overall survival (OS) was inferior in patients with PTDM compared with those without PTDM (mean survival, 2.26 years vs 2.7 years; P = .021). Pretransplantation c-peptide level greater than the cohort median (>3.6 ng/mL) also was associated with inferior OS (mean, 1.7 years vs 2.9 years; P = .012). In a multivariate Cox proportional hazards model, high-risk disease (hazard ratio [HR], 2.34; 95% CI, 1.09-5.28; P = .029) and pretransplantation c-peptide level >3.6 ng/mL (HR, 1.05; 95% CI, 1.01-1.09; P = .013) were independent predictors of OS when adjusted for systemic steroids and regimen intensity. We suspect that diabetes mellitus in the immediate posttransplantation period may be mediated via an inflammatory pathway that contributes to insulin resistance in the host adipose tissue. Our study is the first to report the risk factors of early PTDM in patients undergoing allo-SCT and identifies pretransplantation c-peptide as an independent predictor of diabetes and survival. [ABSTRACT FROM AUTHOR]