Search

BACKGROUND: Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial. METHODS: The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m2 followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m2 per day on days -2 and -1 (total melphalan dose 140 mg/m2), or a melphalan dose of 200 mg/m2 on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178. FINDINGS: Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group. INTERPRETATION: These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma. FUNDING: This study was funded in part by the National Institutes of Health (NIH) through MD Andersons Cancer Center Support Grant (CA016672).

BACKGROUND AND PURPOSE: Glioblastoma exhibits profound intratumoral heterogeneity in perfusion. Particularly, low perfusion may induce treatment resistance. Thus, imaging approaches that define low perfusion compartments are crucial for clinical management. MATERIALS AND METHODS: A total of 112 newly diagnosed glioblastoma patients were prospectively recruited for maximal safe resection. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were calculated from diffusion and perfusion imaging, respectively. Based on the overlapping regions of lowest rCBV quartile (rCBVL) with the lowest ADC quartile (ADCL) and highest ADC quartile (ADCH) in each tumor, two low perfusion compartments (ADCH-rCBVL and ADCL-rCBVL) were identified for volumetric analysis. Lactate and macromolecule/lipid levels were determined from multivoxel MR spectroscopic imaging. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meiers and multivariate Cox regression analyses, to evaluate the effects of compartment volume and lactate level on survival. RESULTS: Two compartments displayed higher lactate and macromolecule/lipid levels compared to contralateral normal-appearing white matter (each P

BackgroundPrevious simultaneous liver-kidney (SLK) transplant allocation was based on serum creatinine, a metric that disadvantaged women relative to men. A recent SLK transplant policy change uses estimated glomerular filtration rate (eGFR), which accounts for sex-based differences in creatinine.MethodsTo understand the impact of this new policy, we analyzed nonstatus 1 adults listed for liver transplantation (LT) from May 2007 to July 2014, excluding those with exceptions. We defined patients who met the new SLK policy as having an eGFR

BackgroundHistorically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality.MethodsEighteen trauma centers prospectively enrolled all adult trauma patients at the time of death during December 2015 to August 2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed.ResultsOne thousand five hundred thirty-six patients were enrolled with a median age of 55 years (interquartile range, 32-75 years), 74.5% were male. Penetrating mechanism (n = 412) patients were younger (32 vs. 64, p < 0.0001) and more likely to be male (86.7% vs. 69.9%, p < 0.0001). Falls were the most common mechanism of injury (26.6%), with gunshot wounds second (24.3%). The most common overall primary COD was traumatic brain injury (TBI) (45%), followed by exsanguination (23%). Traumatic brain injury was nonsurvivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p < 0.0001) and penetrating patients exsanguination (51.7% vs. 12.5%, p < 0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI as the most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p < 0.0001). Most deaths were deemed disease-related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care.ConclusionExsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research.Level of evidenceEpidemiologic, level II.

BACKGROUND:Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined. METHODS:This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival. RESULTS:Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively). CONCLUSIONS:Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial.

BackgroundPembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.Patients and methodsPatients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).ResultsKEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.ConclusionsThis 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.Clinical trial registryClinicalTrials.gov, NCT01295827.

BackgroundWe previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.MethodsWe randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.ResultsOf 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.ConclusionsThe addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).

IntroductionHydrogen sulfide (H2S) is found in petroleum, natural gas, and decaying organic matter. Terrorist groups have attempted to use it in enclosed spaces as a chemical weapon. Mass casualty scenarios have occurred from industrial accidents and release from oil field sites. There is no FDA approved antidote for sulfide poisoning. We have previously reported that intravenous cobinamide is effective for sulfide poisoning. A rapid-acting antidote that is easy to administer intramuscularly (IM) would be ideal for use in a prehospital setting. In this study, we assessed survival in sulfide-poisoned swine treated with IM cobinamide.MethodsEleven swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals ventilated spontaneously with a FiO2 of 0.21. Sodium hydrosulfide (NaHS, 8 mg/mL) was infused intravenously at 0.9 mg/kg.min until apnea or severe hypotension. Animals were randomly assigned to receive cobinamide (4 mg/kg), or no treatment at the apnea/hypotension trigger. The NaHS infusion rate was sustained for 1.5 min post trigger, decreased to 0.2 mg/kg.min for 10 min, and then discontinued.ResultsThe amount of NaHS required to produce apnea or hypotension was not statistically different in both groups (cobinamide: 9.0 mg/kg ±6.1; saline: 5.9 mg/kg ±5.5; mean difference: -3.1, 95% CI: -11.3, 5.0). All of the cobinamide treated animals survived (5/5), none of the control (0/6) animals survived (p

PurposeIncreased rates of toxicity have been described after stereotactic body radiation therapy (SBRT) for central lung tumors within 2 cm of the proximal bronchial tree (PBT). Recent studies have defined a new class of ultracentral tumors. We report our experience treating ultracentral, central, and paramediastinal tumors with SBRT and compare toxicity, disease control, and survival rates.Methods and materialsWe reviewed the records of patients with central lung tumors treated with SBRT between September 2009 and July 2017. Tumors were classified as central if within 2 cm of the PBT, ultracentral if the planning target volume touched the PBT or esophagus, and paramediastinal if touching mediastinal pleura. Actuarial rates of grades 2+ and 3+ toxicity, local control (LC), and overall survival were assessed using the Kaplan-Meier method and compared using a log-rank test. Toxicity was scored with the Common Terminology Criteria for Adverse Events, version 4.03.ResultsWe identified 68 patients with 69 central lung tumors, including 14 ultracentral, 15 paramediastinal, and 39 central tumors. Fifty-three patients were treated for early stage lung cancer and 15 for lung metastases. The prescribed dose ranged from 40 Gy to 60 Gy over 3 to 8 fractions. Most patients were treated using 5 fractions (83%), followed by 8 fractions (10%). Median follow-up was 19.7 months (range, 3.3-78.3 months). The 2-year estimates of LC (89%, 85%, and 93%, respectively; P = .72) and overall survival (76%, 73%, and 72%, respectively; P = .75) for ultracentral, central, and paramediastinal tumors were similar. Ultracentral tumors had an increased risk of grade 2+ toxicity (57.6% vs 14.2% vs 7.1%; P = .007) at 2 years. One patient with an ultracentral tumor developed grade 5 respiratory failure.ConclusionsThe oncologic outcomes after SBRT for ultracentral, central, and paramediastinal lung tumors were similar, with LC exceeding 85% at 2 years using predominantly 5-fraction schedules. Ultracentral lung tumors were associated with an increased risk of toxicity in our patient cohort. Additional studies are needed to minimize toxicity for ultracentral tumors.

ObjectiveTo determine, in a large, multiethnic/multiracial, prospective inception cohort of patients with systemic lupus erythematosus (SLE), the frequency, attribution, clinical, and autoantibody associations with lupus psychosis and the short- and long-term outcomes as assessed by physicians and patients.MethodsPatients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and the Short Form 36 (SF-36) were recorded. Time to event and linear regressions were used as appropriate.ResultsOf 1,826 SLE patients, 88.8% were female and 48.8% were Caucasian. The mean ± SD age was 35.1 ± 13.3 years, the mean ± SD disease duration was 5.6 ± 4.2 months, and the mean ± SD follow-up period was 7.4 ± 4.5 years. There were 31 psychotic events in 28 of 1,826 patients (1.53%), and most patients had a single event (26 of 28 [93%]). In the majority of patients (20 of 25 [80%]) and events (28 of 31 [90%]), psychosis was attributed to SLE, usually either in the year prior to or within 3 years of SLE diagnosis. Positive associations (hazard ratios [HRs] and 95% confidence intervals [95% CIs]) with lupus psychosis were previous SLE NP events (HR 3.59 [95% CI 1.16-11.14]), male sex (HR 3.0 [95% CI 1.20-7.50]), younger age at SLE diagnosis (per 10 years) (HR 1.45 [95% CI 1.01-2.07]), and African ancestry (HR 4.59 [95% CI 1.79-11.76]). By physician assessment, most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient-reported SF-36 summary and subscale scores.ConclusionPsychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short- and long-term outlooks are good for most patients, although careful follow-up is required.

Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.

BackgroundPaediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS.MethodsIn this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death.FindingsBetween May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14-20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10-15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26-41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16-36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62-0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58-0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58-0·70; p=0·01).InterpretationThe PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS.FundingUniversity of Southern California Clinical Translational Science Institute, Sainte Justine Children's Hospital, University of Montreal, Canada, Réseau en Santé Respiratoire du Fonds de Recherche Quebec-Santé, and Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine.

INTRODUCTION: Noncompaction cardiomyopathy (NCCM) patients may develop sustained ventricular arrhythmias (VA). Currently no known electrocardiogram (ECG) parameter has demonstrated predictive value for VA development. The spatial QRS-T angle has demonstrated ability to identify VA in other cardiomyopathy populations. METHODS: A total of 39 patients with NCCM, defined by compact to non-compact ratio of >2.3 by magnetic resonance imaging, were assessed. The first ECG taken at time of MRI was assessed utilizing the heart rate, the QRS duration (QRSd), the corrected QT interval (QTc), and the spatial QRS-T angle (SPQRS-T angle, three-dimensional angle between the QRS and T-wave vectors) were assessed. RESULTS: Eight patients developed VA (20.5%). Median time to event was 3 months (95% CI 1.0 to 24.0 months). There were no significant differences between baseline ejection fraction or fractional shortening. Baseline median heart rate, spatial QRS-T angles, and indexed left ventricular end-diastolic volumes were all significantly higher in patients with VA development (p-value

Direct oral anticoagulants (DOACs) are at least as efficacious and safe as warfarin among non-valvular atrial fibrillation (NVAF) patients; limited evidence is available regarding NVAF patients with heart failure (HF). US Medicare enrollees with NVAF and HF initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected. Propensity score matching and Cox models were used to estimate the risk of stroke/systemic embolism (SE), major bleeding (MB), and major adverse cardiac events (MACE) comparing DOACs versus warfarin and DOACs versus DOACs. We identified 10,570 apixaban-warfarin, 4,297 dabigatran-warfarin, 15,712 rivaroxaban-warfarin, 4,263 apixaban-dabigatran, 10,477 apixaban-rivaroxaban, and 4,297 dabigatran-rivaroxaban matched pairs. Compared to warfarin, apixaban had lower rates of stroke/SE (hazard ratio = 0.64, 95% confidence interval = 0.48-0.85), MB (hazard ratio = 0.66, 0.58-0.76), and MACE (hazard ratio = 0.73,0.67-0.79); dabigatran and rivaroxaban had lower rates of MACE (hazard ratio = 0.87,0.77-0.99; hazard ratio = 0.84, 0.79-0.89, respectively). Rivaroxaban had a lower stroke/SE rate (hazard ratio = 0.65, 0.52-0.81) and higher MB rate (hazard ratio = 1.18, 1.08-1.30) versus warfarin. Compared to dabigatran and rivaroxaban, apixaban had lower MB (hazard ratio = 0.71, 0.57-0.89; hazard ratio = 0.55, 0.49-0.63) and MACE rates (hazard ratio = 0.80, 0.69-0.93; hazard ratio = 0.86, 0.79-0.94), respectively. All DOACs had lower MACE rates versus warfarin; differences were observed in stroke/SE and MB. Our findings provide insights about OAC therapy among NVAF patients with HF.

Lymphoma is the most common hematopoietic tumour in dogs and is remarkably similar to the human disease. Tumour biomarker discovery is providing new tools for diagnostics and predicting therapeutic response and clinical outcome. MicroRNAs are small non-coding RNAs that participate in post-transcriptional gene regulation and their aberrant expression can impact genes involved in cancer. The aim of this study was to characterize microRNA expression in lymph nodes and plasma from dogs with multicentric B or T cell lymphoma compared to healthy control dogs. We further compared expression between lymph nodes and corresponding plasma samples and assessed changes in expression at relapse compared to time of diagnosis. Lastly, we investigated microRNAs for association with clinical outcome in patients treated with CHOP chemotherapy. A customized PCR array was utilized to profile 38 canine target microRNAs. Quantification was performed using real time RT-qPCR and relative expression was determined by the delta-delta Ct method. In lymph nodes, there were 16 microRNAs with significantly altered expression for B cell lymphoma and 9 for T cell lymphoma. In plasma, there were 15 microRNAs altered for B cell lymphoma and 3 for T cell lymphoma. The majority of microRNAs did not have correlated expression between lymph node and plasma and only 8 microRNAs were significantly different between diagnosis and relapse. For B cell lymphoma, 8 microRNAs had differential expression in the non-remission group compared to dogs that completed CHOP in complete remission. Four of these microRNAs were also altered in patients that died prior to one-year. Kaplan-Meier survival curves for high versus low microRNA expression revealed that 10 microRNAs were correlated with progression-free survival and 3 with overall survival. This study highlights microRNAs of interest for canine multicentric lymphoma. Future goals include development of microRNA panels that may be useful as biomarkers with the intent to provide improved outcome prediction to veterinary cancer patients.

Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies.

BackgroundPatients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.MethodsRTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.FindingsBetween June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.InterpretationFor patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.FundingNational Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.

Using a well-established model species for demographic, behavioural and aging research, the Mediterranean fruit fly (Ceratitis capitata), we explored whether nutritional stress early in adult life affects the sexual performance and survival in older ages. To do so we established two different protein starvation (PS) protocols that included the elimination of proteinaceous diet either before or after sexual maturity of male medflies. The frequency of sexual signalling and the age of death were daily recorded. Sexual signalling is directly related with male mating success in this model system. PS early in adult life results in high mortality rates (similar to sugar-only fed males), which are gradually restored in more advanced ages. Provision of a proteinaceous diet following early-life PS increases straightaway male sexual signalling to levels similar with those having continuous access to proteinaceous diet. Switching diet regimes from a protein-free to a protein-rich one progressively compensates mortality rates. Apparently, males prioritize sexual signalling over lifespan. PS after attaining sexual maturity significantly reduces both longevity and sexual performance. Access to protein only early in life is insufficient to support lifetime energy-consuming behaviours such as sexual signalling. Continuous access to a proteinaceous diet determines both lifetime sexual performance and longevity. Early in life PS males prioritize the allocation of nutritional elements, when available, in sexual activities over soma-maintenance.

Natural killer (NK) cells have increasingly become a target of interest for immunotherapies. NK cells express killer immunoglobulin-like receptors (KIRs), which play a vital role in immune response to tumors by detecting cellular abnormalities. The genomic region encoding the 16 KIR genes displays high polymorphic variability in human populations, making it difficult to resolve individual genotypes based on next generation sequencing data. As a result, the impact of polymorphic KIR variation on cancer phenotypes has been understudied. Currently, labor-intensive, experimental techniques are used to determine an individual's KIR gene copy number profile. Here, we develop an algorithm to determine the germline copy number of KIR genes from whole exome sequencing data and apply it to a cohort of nearly 5000 cancer patients. We use a k-mer based approach to capture sequences unique to specific genes, count their occurrences in the set of reads derived from an individual and compare the individual's k-mer distribution to that of the population. Copy number results demonstrate high concordance with population copy number expectations. Our method reveals that the burden of inhibitory KIR genes is associated with survival in two tumor types, highlighting the potential importance of KIR variation in understanding tumor development and response to immunotherapy.

IntroductionPrognosis after resection of hepatocellular carcinoma (HCC) is highly variable. Compared to clinicopathologic factors, the use of molecular markers to predict outcome has not been well studied. We investigated the prognostic importance of thymidylate synthase (TS) gene expression and polymorphisms in patients after resection of HCC.MethodsPatients who underwent complete resection of HCC for whom tissue was available were identified. TS gene expression level and polymorphisms were determined in HCC specimens. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazard models.ResultsThe study included 67 patients. In univariate analysis, variables that negatively influenced survival included TNM stage, microvascular invasion, and high TS expression. For the high TS expression group, median survival was 54 months and 5-year actuarial survival was 47%. For the low TS expression group, median survival was not reached and the 5-year actuarial survival was 91%. In multivariate analysis, only high TS expression remained an independent predictor of poor survival (HR = 10.77, 95% CI 1.36-84.91; P = 0.02). TS gene polymorphisms were not associated with TS expression or overall survival.ConclusionsHigh TS expression predicts poor outcome after resection of HCC. Molecular markers might be robust predictors of patient outcome after resection of HCC.

Physical activity (PA) is important from birth to promote health and motor development. Parents of young children are gatekeepers of opportunities for PA, yet little is known about their perceptions of PA. We describe the development of the Parent Perceptions of Physical Activity Scale (PPPAS) across two studies (N = 241 parents). In Study 1, 143 parents of infants and toddlers recruited from neonatal intensive care units (NICUs) and childcare centers completed a 48-item PPPAS. In Study 2, 98 parents of premature infants completed the revised 34-item PPPAS. Study 1 principal components analysis (PCA) identified three components (benefits of, barriers to, and perceived influence on PA), and the scale was reduced. Scores for Perceived Barriers to PA were significantly different between groups, U = 1,108, z = -4.777, p < .0001, with NICU parents reporting more barriers to PA than childcare parents. In Study 2, PCA revealed the same components, and the scale was further reduced to 25 items. Three subscales measuring perceived benefits of, barriers to, and influence over an infant's PA produced Cronbach's alphas of .93, .85, .81, respectively. Results demonstrated sufficient construct validity and internal consistency of PPPAS scores, supporting its use in future PA research.

BackgroundPembrolizumab, a PD-1 immune checkpoint inhibitor, is approved as first-line (1L) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) as monotherapy or in combination with platinum and 5-fluorouracil chemotherapy. Limited data exist on the use of these regimens in real-world settings.ObjectiveOur primary objectives were to describe baseline characteristics and real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) among individuals with R/M HNSCC receiving approved 1L pembrolizumab therapies. We also aimed to identify baseline factors associated with choice of 1L pembrolizumab therapy and with rwOS.MethodsThis was a retrospective cohort study of adults with R/M HNSCC receiving 1L pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We used Kaplan-Meier analyses to assess real-world outcomes, logistic regression modeling to identify factors associated with choice of 1L pembrolizumab therapy, and Cox proportional hazards models to identify factors associated with rwOS.ResultsThe study population included 431 individuals receiving 1L pembrolizumab monotherapy and 215 receiving 1L pembrolizumab plus chemotherapy. The use of 1L pembrolizumab monotherapy was associated with higher baseline combined positive score for PD-L1 expression, older age, higher Eastern Cooperative Oncology Group performance status (ECOG PS), laryngeal tumor site, and human papillomavirus (HPV)-positive tumor status. The pembrolizumab monotherapy group had a median (95% CI) rwOS of 12.1 (9.2–15.1) months, rwToT of 4.2 (3.5–4.6) months, and rwTTNT of 6.5 (5.4–7.4) months. Among this group, HPV-positive tumor status and lower ECOG PS were associated with longer rwOS, and oral cavity tumor site with shorter rwOS. The pembrolizumab plus chemotherapy cohort had a median (95% CI) rwOS of 11.9 (9.0–16.0) months, rwToT of 4.9 (3.8–5.6) months, and rwTTNT of 6.6 (5.8–8.3) months. In this group, HPV-positive tumor status was associated with longer rwOS.ConclusionsThis study adds to clinical trial data by summarizing real-world treatment outcomes with 1L pembrolizumab-containing therapies in a more heterogeneous population. Overall survival outcomes in both treatment groups were similar to those observed in the registration clinical trial. These findings support the use of pembrolizumab as standard of care for R/M HNSCC.

Background: The duration of forensic psychiatric care is in Sweden not determined at the time of sentencing; instead, offenders are regularly evaluated, often with regard to risk of criminal recidivism. The length and justifiability of such a sanction have been greatly debated; however, previous estimates of treatment duration based on datasets delimited to discharged patients--have provided an uncertain groundwork for these deliberations. The aim of this study was to use a more suitable approach to calculate average duration of forensic psychiatric care and to examine the relationship between length of treatment and subsequent recidivism after discharge. Methods: This retrospective cohort study focused on offenders sentenced to forensic psychiatric care in Sweden between 2009 and 2019 and registered in the Swedish National Forensic Psychiatric Register (n = 2064), with a follow-up period until May 2020. We used Kaplan-Meier estimator to calculate and visualize treatment duration including analyses comparing levels of relevant variables, and then evaluated criminal recidivism in patients discharged from treatment between 2009 and 2019 (n = 640), after stratification for the same variables and dichotomization by treatment duration. Results: The median duration of forensic psychiatric care was estimated to 89.7 months (95% CI 83.2-95.8). Treatment was longer in offenders who committed violent crimes, suffered from psychosis, or had a history of substance use disorder, and in offenders whose sentences included special court supervision. The cumulative incidence of recidivism in patients discharged from treatment was estimated to 13.5% at 12 months (95% CI 10.6-16.2) and 19.5% at 24 months (95% CI 16.0-22.8). Corresponding cumulative incidence of violent crime post discharge was 6.3% at 12 months (95% CI 4.3-8.3) and 9.9% at 24 months (95% CI 7.3-12.4). Among other findings, in patients without a history of substance use disorder and patients whose sentences did not include special court supervision, recidivism was significantly higher in those with a shorter treatment duration. Conclusion: Using the entirety of a suitable, contemporary, prospectively enrolled cohort of mentally ill offenders, we were able to estimate--with greater accuracy than previous studies--the average duration of Swedish forensic psychiatric care and rate of subsequent criminal recidivism. [ABSTRACT FROM AUTHOR]

Objectives: In this study we aimed to assess the clinicopathological characteristics and long‐term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) having distinct steatosis distribution patterns. Methods: Clinicopathological data of 238 individuals with biopsy‐confirmed NAFLD were collected. Nonalcoholic steatohepatitis‐clinical research network (NASH‐CRN) and steatosis, activity and fibrosis (SAF)/fatty liver inhibition of progression (FLIP) algorithm were used. Cumulative incidence of liver‐related events (LREs) was compared by Kaplan–Meier analysis. Univariate and multivariate logistic regression analyses were used to identify independent predictors for steatosis distribution. Results: Eligible patients were categorized into three groups based on their steatosis distribution, including azonal steatosis (AS) (62 [26.1%]), perivenular steatosis (PVS) (147 [61.8%]), and the pan‐acinar steatosis (PAS) groups (29 [12.1%]). There were significantly higher ballooning grade and disease activity (P < 0.05), more severe fibrosis (P < 0.001), and a higher cumulative incidence of LREs (hazard ratio [HR] 8.0, 95% confidence interval [CI] 2.34–27.35, P < 0.0001) in the AS group than in the PVS and PAS groups after a median of 3.6‐year follow‐up. Multivariate logistic regression analysis revealed age (odds ratio [OR] 1.11, 95% CI 1.06–1.16, P < 0.001) might be independently associated with AS distribution, and PNPLA3 rs738409 CG/GG genotype (OR 3.36, 95% CI 0.98–11.47, P = 0.053) might also play a role. Conclusions: AS is associated with more severe disease activity and fibrosis stage in NAFLD, and predisposes toward poor prognosis. Age might be an independent predictor for AS in NAFLD, while PNPLA3 rs738409 CG/GG genotype might also play a role. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effectivity and toxicity of monotherapy with computed tomography-guided high-doserate brachytherapy (CT-HDRBT) vs. combination therapy of transarterial chemoembolization with irinotecan (irinotecan- TACE) and CT-HDRBT in patients with large unresectable colorectal liver metastases (CRLM) with a diameter of > 3 cm. Material and methods: Forty-four retrospectively matched patients with unresectable CRLM were treated either with mono-CT-HDRBT or with a combination of irinotecan-TACE and CT-HDRBT (n = 22 in each group). Matching parameters included treatment, disease, and baseline characteristics. National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) were used to evaluate treatment toxicity and the Society of Interventional Radiology classification was applied to analyze catheter-related adverse events. Statistical analysis involved Cox regression, Kaplan-Meier estimator, log-rank test, receiver operating characteristic curve analysis, Shapiro-Wilk test, Wilcoxon test, paired sample t-test, and McNemar test. P-values < 0.05 were deemed significant. Results: Combination therapy ensued longer median progression-free survival (PFS: 5/2 months, p = 0.002) and significantly lower local (23%/68%, p < 0.001) and intrahepatic (50%/95%, p < 0.001) progress rates compared with mono-CT-HDRBT after a median follow-up time of 10 months. Additionally, tendencies for longer local tumor control (LTC: 17/9 months, p = 0.052) were found in patients undergoing both interventions. After combination therapy, aspartate and alanine aminotransferase toxicity levels increased significantly, while total bilirubin toxicity levels showed significantly higher increases after monotherapy. No catheter-associated major or minor complications were identified in each cohort. Conclusions: Combining irinotecan-TACE with CT-HDRBT can improve LTC rates and PFS compared with mono- CT-HDRBT in patients with unresectable CRLM. The combination of irinotecan-TACE and CT-HDRBT shows satisfying safety profiles. [ABSTRACT FROM AUTHOR]

Background/Aims: Endoscopic ultrasonography (EUS) provides high-resolution images and is superior to computed tomography (CT) scan in diagnosing small pancreatic ductal adenocarcinoma (PDAC). As a result, the use of EUS for early detection of PDAC has attracted attention. This study aimed to identify the clinical and radiological characteristics of patients with PDAC diagnosed by EUS but not found on CT scan. Methods: The medical records of patients diagnosed with PDAC at 12 tertiary referral centers in Korea from January 2003 to April 2019 were reviewed. This study included patients with pancreatic masses not clearly observed on CT scan but identified on EUS. The clinical characteristics and radiological features of the patients were analyzed, and survival analysis was performed. Results: A total of 83 patients were enrolled. The most common abnormal CT findings other than a definite mass was pancreatic duct dilatation, which was identified in 61 patients (73.5%). All but four patients underwent surgery. The final pathologic stages were as follows: IA (n=31, 39.2%), IB (n=8, 10.1%), IIA (n=20, 25.3%), IIB (n=17, 21.5%), III (n=2, 2.5%), and IV (n=1, 1.4%). The 5-year survival rate of these patients was 50.6% (95% confidence interval, 38.8% to 66.7%). Elevated liver function testing and R1 resection emerged as significant predictors of mortality in the multivariable Cox regression analysis. Conclusions: This multicenter study demonstrated favorable long-term prognosis in patients with PDAC diagnosed by EUS but indeterminate on CT scan. EUS should be considered for patients with suspected PDAC but indeterminate on CT scan.

Abstract Background Colorectal cancer (CRC) is the second most common cancer in women and the third most common cancer in men worldwide, with an increasing trend in its incidence in Asian countries. In the present study, we aimed to describe the 13-year results of patients with CRC based on the Shiraz Colorectal Cancer Surgery (SCORCS) registry system in patients with a pathologically confirmed diagnosis of colon cancer (CC) and rectal cancer (RC) undergoing surgery. Methods Between 2007 and 2020, 811 patients, including 280 patients with CC and 531 patients with RC, registered in SCORCS, were included in the present study. The information collected for this study included demographic characteristics of the patients, primary clinical presentations, laboratory findings before surgery, radiologic and colonoscopy results, and surgical procedures. Death was confirmed by the physician as “CRC-related”. The data were analyzed by SPSS software version 21; life table and Kaplan-Meier curve were used for evaluating the overall survival, recurrence, and metastasis rates and Log-Rank test or Breslow test to check significant differences between the subgroups. The Cox proportional regression model was fitted to evaluate the prognostic factors of survival recurrence and metastasis. Results Laparoscopy was performed in 60% of patients (66% in RC and 51% in CC), laparotomy in 32% (27% in RC and 41% in CC), and 7% required conversion. The median time of follow-up was 29 months in all patients; 28 months in patients with RC, and 33 months in patients with CC; 1, 3, and 5 years’ survival rate was 90, 70, and 63% for all the patients, 89%, 67%, and 58% for RC and 90%, 74%, and 71% for CC, respectively (P = 0.009). The Cox regression analysis revealed tumor stages II, (P = 0.003, HR:2.45, 95% CI;1.34–4.49), III, (P ≤ 0.001, HR:3.46, 95% CI;1.88–6.36) and IV, (P ≤ 0.001, HR:6.28, 95% CI;2.73–14.42) in RC and stage IV, (P = 0.03, HR:9.33, 95% CI;1.1-76.37) in CC were the significant survival prognostic factors. The metastasis and recurrence of the tumors occurred earlier in patients with RC than CC (P = 0.001 and 0.03, respectively). Conclusions Long-term follow-up of patients with CRC in an Iranian population indicated the significance of screening for diagnosis of early stages and improved survival of the patients.

BackgroundThere are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).MethodsIn a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.ResultsWritten informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.ConclusionsThe use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

PurposeEsophageal, gastroesophageal junction, and gastric adenocarcinoma (herein gastroesophageal adenocarcinomas) are associated with poor prognosis and limited systemic treatment options. To further understand the genomic landscape of gastroesophageal cancers and its clinical correlations, circulating tumor DNA (ctDNA) from patients' plasma was evaluated using next-generation sequencing (NGS).Experimental designWe analyzed genomic alterations of 55 patients (mostly advanced disease; 9, surgically resectable) with gastroesophageal adenocarcinomas using clinical-grade NGS performed on plasma-derived ctDNA (54-73 gene panel). The test detects single-nucleotide variants, as well as copy number amplifications, fusions, and indels in selected genes.ResultsSeventy-six percent of patients (42/55) had ≥1 genomic alteration [including variants of unknown significance (VUS)] and 69.1% (38/55) had ≥1 characterized alteration (excluding VUSs). The median number of alterations per patient was 2 (range, 0-15). TP53 (50.9%, 28/55), PIK3CA (16.4%, 9/55), ERBB2 (14.5%, 8/55), and KRAS (14.5%, 8/55) genes were most frequently affected characterized alterations. Thirty-one patients also had tissue NGS. Concordance between tissue and ctDNA ranged from 61.3% (TP53 alterations) to 87.1% (KRAS alterations). ERBB2 alterations were significantly associated with poor overall survival (HR, 14.06; 95% confidence interval, 2.44-81.03; P = 0.003 multivariate analysis). Among patients with ≥1 alteration, no 2 patients had identical molecular portfolios. All patients with ≥1 characterized alteration had theoretically targetable alterations by an FDA-approved agent (on- or off-label). Illustrative case treated with cognate agent is presented.ConclusionsEvaluation of ctDNA by NGS among patients with gastroesophageal adenocarcinoma is feasible. Patients harbored heterogeneous patterns of genomics, with most having alterations that are potentially pharmacologically tractable.

In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009.

AimsLittle is known regarding the risk of atherosclerotic cardiovascular disease (ASCVD) conferred by changes in the volume and density of ascending thoracic aorta calcium (ATAC) over time. We evaluated changes in ATAC volume and density scores and incident ASCVD events.Methods and resultsThe Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of individuals without baseline clinical ASCVD. Ascending thoracic aorta calcium was measured from baseline and follow-up (mean interval 2.4 years) cardiac computed tomography (CT). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation for events after the follow-up exam adjusted for ASCVD risk factors, baseline ATAC and coronary artery calcium (CAC) volume and density, and changes in CAC volume and density. Among 5887 participants, 296 (5.0%) had detectable ATAC at baseline, follow-up, or both exams. A total of 403 events occurred over 9.5 years. An increase in ATAC volume was associated with coronary heart disease (CHD) (HR 1.90, 95% CI 1.14-3.16), ASCVD (HR 1.93, 95% CI 1.26-2.94), and ischaemic stroke (HR 2.14, CI 1.21-3.78). An increase in ATAC density was inversely associated with CHD (HR 0.29, 95% CI 0.14-0.60) and ASCVD (HR 0.42, 95% CI 0.23-0.76), but not stroke (HR 0.61, CI 0.23-1.61).ConclusionAscending thoracic aorta calcium is uncommon on serial cardiac CT. However, changes in ATAC volume and density are both associated with incident ASCVD events, but in opposite directions. Serial assessments in those with baseline ATAC may provide insight into an individual's trajectory of ASCVD risk.

IntroductionCytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor-1 inhibitor pembrolizumab.Patients and methodsPatients with advanced, platinum-refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose-limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression-free survival (PFS).ResultsTwelve patients were enrolled in the initial cohorts; 6 in each arm. One DLT was seen in each arm: Grade 3 hypophosphatemia (arm A), Grade 3 diarrhea (arm B). Adverse events of Grade >3 were observed in 7 (54%), the most common being anemia (6; 50%), fatigue (6; 50%), hyponatremia (4; 33%) and neutropenia (3; 25%), with no treatment-related deaths. There were 5 confirmed responses (1 complete, 4 partial), with an ORR of 42% and disease control rate (DCR) of 58%. Arm A had an ORR of 50% and DCR of 67%, whereas arm B had an ORR of 33% and DCR of 50%. Median PFS was 4.8, 5.7, and 3.7 months for the overall cohort, arm A, and arm B, respectively.ConclusionPembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum-refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted.

ObjectivesTo evaluate the impact of previous local treatment on survival in men with newly diagnosed metastatic castration-resistant prostate cancer.MethodsWe carried out a retrospective study of patients newly diagnosed with metastatic castration-resistant prostate cancer in the year 2000 or later from eight Veterans Affairs Medical Centers. Patients were categorized based on prior local therapy (none, prostatectomy ± radiation or radiation alone). Overall and cancer-specific survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression models were used to test the association between prior local treatment and survival.ResultsOf 729 patients, 284 (39%) underwent no local treatment, 176 (24%) underwent radical prostatectomy ± radiation and 269 (37%) underwent radiation alone. On multivariable analysis, men with prior prostatectomy had improved overall (hazard ratio 0.71, P = 0.005) and cancer-specific survival (hazard ratio 0.55, P

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.

BackgroundThe combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial.MethodsIn our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients.Findings76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n=65, 86%), increased transaminases (n=24, 32%), increased bilirubin (n=13, 17%), pancreatitis (n=13, 17%), hypertension (n=12, 16%), bleeding (n=10, 13%), and skin rash (n=9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use; neither death occurred after protocol revision.InterpretationThe combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive  acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted.FundingTakeda Oncology.

BackgroundSeveral distinct risk factors for arrhythmia recurrence and mortality following ventricular tachycardia (VT) ablation have been described. The effect of concurrent risk factors has not been assessed so far; thus, it is not yet possible to estimate these risks for a patient with several comorbidities. The aim of the study was to identify specific risk groups for mortality and VT recurrence using the Survival Tree (ST) analysis method.MethodsIn 1251 patients 16 demographic, clinical and procedure-related variables were evaluated as potential prognostic factors using ST analysis using a recursive partitioning algorithm that searches for relationships among variables. Survival time and time to VT recurrence in groups derived from ST analysis were compared by a log-rank test. A random forest analysis was then run to extract a variable importance index and internally validate the ST models.ResultsLeft ventricular ejection fraction, implantable cardioverter defibrillator/cardiac resynchronization device, previous ablation were, in hierarchical order, identified by ST analysis as best predictors of VT recurrence, while left ventricular ejection fraction, previous ablation, Electrical storm were identified as best predictors of mortality. Three groups with significantly different survival rates were identified. Among the high-risk group, 65.0% patients were survived and 52.1% patients were free from VT recurrence; within the medium- and low-risk groups, 84.0% and 97.2% patients survived, 72.4% and 88.4% were free from VT recurrence, respectively.ConclusionsOur study is the first to derive and validate a decisional model that provides estimates of VT recurrence and mortality with an effective classification tree. Preprocedure risk stratification could help optimize periprocedural and postprocedural care.

BackgroundSarcopenia, characterized by low muscle mass, associates with mortality in patients with cirrhosis. Skeletal muscle area in a single computed tomography image at the level of the third lumbar vertebrate (L3) is a valid representative of whole body muscle mass. Controversy remains regarding applicability of psoas muscle to identify patients at greater risk of mortality. We aimed to determine psoas muscle index (PMI) association with skeletal muscle index (SMI) and to evaluate the capacity of PMI to predict liver transplant waitlist mortality.MethodsWe evaluated listed adult patients with cirrhosis from 2012 to 2013 at four North American liver transplant centres. From L3 computed tomography images within 3 months of listing, we determined SMI and PMI expressed by cm2 /m2 . Low SMI was defined as SMI  0.7, P

BackgroundA doxorubicin (DOX)-based chemotherapy protocol, CHOP, is the most effective treatment for canine high-grade B-cell lymphoma; however, the cost and time requirements associated with this protocol are not feasible for many pet owners. An alternative treatment option is the use of DOX, the most effective drug, in combination with prednisone. Prior studies with single-agent DOX included dogs with T-cell lymphoma, a known negative prognostic factor, which may have resulted in shorter reported survival times than if dogs with B-cell lymphoma were analyzed separately. The purpose of this study was to evaluate the outcome of dogs with high-grade B-cell lymphoma when treated with DOX and prednisone with or without L-asparaginase (L-ASP). Identification of prognostic factors was of secondary interest.ResultsThirty-three dogs were included in the study; 31 dogs were evaluable for response with an overall response rate of 84%. The median progression free survival (PFS) and overall survival (OS) were 147 days and 182 days, respectively. The one-year survival fraction was 23%. No variable other than protocol completion was found to be significant for either PFS or OS including historical prognostic factors such as substage, thrombocytopenia, and body weight.ConclusionsDogs with high-grade B-cell lymphoma treated with DOX and prednisone with or without L-ASP have similar response rates, PFS, and OS to prior studies that did not differentiate between lymphoma immunophenotype. This protocol is not a replacement for CHOP; however, it is an alternative if time and cost are factors, while providing therapeutic benefit greater than prednisone alone.

BackgroundLow absolute lymphocyte count (ALC) has previously been established as a marker of poor prognosis in multiple cancer types. There is growing evidence that ALC may also be associated with response to immunotherapy. This study explores whether response to PD1 inhibitors in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is associated with pretreatment ALC.MethodsThirty-four R/M HNSCC patients who received either nivolumab or pembrolizumab between January 2014 and May 2018 at Johns Hopkins were identified retrospectively. Pretreatment blood counts in patients with and without clinical benefit from PD1 inhibitors were compared. Time-to-progression analyses were performed by dichotomizing the study cohort with the threshold of ALC 600 cells/μl, which is approximately 1.5 standard deviations away from treatment-naïve baseline mean.ResultsPatients with lower ALC appeared to have significantly less clinical benefit from anti-PD1 therapy. Those patients with pretreatment ALC

BackgroundMortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients.MethodsA single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure.ResultsOf 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (plogrank = 0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30-0.87; p = 0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69-2.32; p = 0.45). Formal interaction testing confirmed NAC*ANA interaction (p = 0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p = 0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients.ConclusionNAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP.

BackgroundOvarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients.ResultsWe have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays. These paclitaxel resistant ovarian cells demonstrate: (1) Increased IC50 for paclitaxel and docetaxel (10 to 75-fold) and cross-resistance to anthracyclines (2) Reduced cell apoptosis in the presence of paclitaxel (3) Gene depletion involving mitotic regulators BUB1 mitotic checkpoint serine/threonine kinase, cyclin BI (CCNB1), centromere protein E (CENPE), and centromere protein F (CENPF), and (4) Functional data validating gene depletion among mitotic regulators.ConclusionsWe have generated model systems to explore drug resistance in ovarian cancer, which have revealed a key pathway related to the spindle assembly checkpoint underlying paclitaxel resistance in ovarian cell lines.

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG.MethodsWe performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT.ResultsThirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to 6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.

PurposeRecent data indicate consolidative radiation therapy improves progression-free survival (PFS) for patients with oligometastatic non-small cell lung cancer (NSCLC). Data on long-term outcomes are limited.Methods and materialsThis prospective, multicenter, single-arm, phase 2 trial was initiated in 2010 and enrolled patients with oligometastatic NSCLC. Oligometastatic disease was defined as a maximum of 5 metastatic lesions for all disease sites, including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Patients achieving a partial response or stable disease after 3 to 6 cycles of platinum-based chemotherapy were treated with CRT to the primary and metastatic sites of disease, followed by observation alone. The primary endpoint was PFS, with secondary endpoints of local control, overall survival (OS), and safety.ResultsTwenty-nine patients were enrolled between October 2010 and October 2015, and 27 were eligible for consolidative radiation therapy. The study was closed early because of slow accrual but met its primary endpoint for success, which was PFS >6 months (P

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N6-mA.

TGF-β is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-β (L-TGF-β) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-β. Binding of L-TGF-β to integrin αvβ8 results in activation of TGF-β. We engineered and used αvβ8 antibodies optimized for blocking or detection, which - respectively - inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect β8 in human tumors. Inhibition of αvβ8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. β8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-β, suggesting that tumor cell αvβ8 serves as a platform for activating cell-surface L-TGF-β presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to β8 inhibition with major increases in chemokine and tumor-eliminating genes. High β8 expression in tumor cells is seen in 20%-80% of various cancers, which rarely coincides with high PD-L1 expression. These data suggest tumor cell αvβ8 is a PD-1/PD-L1-independent immunotherapeutic target.

Background Coronary artery calcium (CAC) predicts cardiovascular disease (CVD) events; however, less is known about how its prognostic implications vary by race/ethnicity. Methods and Results A total of 38 277 whites, 1621 Asians, 977 blacks, and 1349 Hispanics from the CAC Consortium (mean age 55 years, 35% women) were followed over a median of 11.7 years. Modeling CAC in continuous and categorical (CAC=0; CAC 1-99; CAC 100-399; CAC ≥400) forms, we assessed its predictive value for all-cause and CVD mortality by race/ethnicity using Cox proportional hazards and Fine and Gray competing-risk regression, respectively. We also assessed the impact of race/ethnicity on risk within individual CAC strata, using whites as the reference. Models were adjusted for traditional cardiovascular risk factors. Increased CAC was associated with higher total and CVD mortality risk in all race/ethnicity groups, including Asians. However, the risk gradient with increasing CAC was more pronounced in blacks and Hispanics. In Fine and Gray subdistribution hazards models adjusted for traditional cardiovascular risk factors and CAC (continuous), blacks (subdistribution hazard ratio 3.4, 95% confidence interval, 2.5-4.8) and Hispanics (subdistribution hazard ratio 2.3, 95% confidence interval, 1.6-3.2) showed greater risk of CVD mortality when compared with whites, while Asians had risk similar to whites. These race/ethnic differences persisted when CAC=0. Conclusions CAC predicts all-cause and CVD mortality in all studied race/ethnicity groups, including Asians and Hispanics, who may be poorly represented by the Pooled Cohort Equations. Blacks and Hispanics may have greater mortality risk compared with whites and Asians after adjusting for atherosclerosis burden, with potential implications for US race/ethnic healthcare disparities research.

PurposeApproximately 10% to 20% of patients will have a recurrence after urethroplasty. Initial management of these recurrences is often by urethral dilation or direct vision internal urethrotomy. In the current study we describe the outcomes of endoscopic management of stricture recurrence after bulbar urethroplasty.Materials and methodsWe retrospectively reviewed bulbar urethroplasty data from 5 surgeons in the TURNS (Trauma and Urologic Reconstruction Network of Surgeons). Men who underwent urethral dilation or direct vision internal urethrotomy for urethroplasty recurrence were identified. Recurrence was defined as the inability to pass a 17Fr cystoscope through the area of reconstruction. The primary outcome was the success rate of recurrence management. Comparisons were made between urethral dilation and direct vision internal urethrotomy, and then between endoscopic management of recurrences after excision and primary anastomosis urethroplasty vs substitutional repairs using time to event statistics.ResultsIn 53 men recurrence was initially managed endoscopically. Median time to urethral stricture recurrence after urethroplasty was 5 months. At a median followup of 5 months the overall success rate was 42%. Success after urethral dilation was significantly less than after direct vision internal urethrotomy (1 of 10 patients or 10% vs 21 of 43 or 49%, p

Given the increasing incidence of hepatocellular carcinoma (HCC) and regional variation in liver transplantation (LT) rates for HCC, we investigated temporal and geographic disparities in LT and wait-list dropout. LT candidates receiving Model for End-Stage Liver Disease (MELD) exception from 2005 to 2014 were identified from the United Network for Organ Sharing database (n = 14,320). Temporal differences were compared across 2 eras (2005-2009 and 2010-2014). Regional groups were defined based on median wait time as long-wait region (LWR; regions 1, 5, and 9), mid-wait region (MWR; regions 2, 4, 6, 7, and 8), and short-wait region (SWR; regions 3, 10, and 11). Fine and Gray competing risk regression estimated risk of wait-list dropout as hazard ratios (HRs). The cumulative probability of LT within 3 years was 70% in the LWR versus 81% in the MWR and 91% in the SWR (P < 0.001). From 2005-2009 to 2010-2014, median time to LT increased by 6.0 months (5.6 to 11.6 months) in the LWR compared with 3.8 months (2.6 to 6.4 months) in the MWR and 1.3 months (1.0 to 2.3 months) in the SWR. The cumulative probability of dropout within 3 years was 24% in the LWR versus 16% in the MWR and 8% in the SWR (P < 0.001). From 2005-2009 to 2010-2014, the LWR also had the greatest increase in probability of dropout. Risk of dropout was increased in the LWR (HR, 3.5; P < 0.001) and the MWR (HR, 2.2; P < 0.001) compared with the SWR, and year of MELD exception 2010-2014 (HR, 1.9; P < 0.001) compared with 2005-2009. From 2005-2009 to 2010-2014, intention-to-treat 3-year survival decreased from 69% to 63% in the LWR (P < 0.001), 72% to 69% in the MWR (P = 0.008), and remained at 74% in the SWR (P = 0.48). In conclusion, we observed a significant increase in wait-list dropout in HCC patients in recent years that disproportionately impacted LWR patients. Widening geographical disparities call for changes in allocation policy as well as enhanced efforts at increasing organ donation and utilization.