Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

Background NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Results There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer

Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

A summary of the 2012 JHU CLSP workshop on zero resource speech technologies and models of early language acquisition

We summarize the accomplishments of a multi-disciplinary workshop exploring the computational and scientific issues surrounding zero resource (unsupervised) speech technologies and related models of early language acquisition. Centered around the tasks of phonetic and lexical discovery, we consider unified evaluation metrics, present two new approaches for improving speaker independence in the absence of supervision, and evaluate the application of Bayesian word segmentation algorithms to automatic subword unit tokenizations. Finally, we present two strategies for integrating zero resource techniques into supervised settings, demonstrating the potential of unsupervised methods to improve mainstream technologies.</p

Long-Term Outcomes of C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis in Children

Introduction: The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts. Methods: We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G. Results: Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4–292.4] vs. 93.7 [range 70.7–116.6] μmol/l, P = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range −8.1 to 298.1) vs 99.1 (range 46.3–151.9) μmol/l, P = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9–73.0) vs. −3.0 (range −23.1 to 17.2) ml/min per 1.73 m2, P = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9–415.7] mg/mmol). Conclusion: This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control

Risk of Surgical Site Infection (SSI) following Colorectal Resection Is Higher in Patients With Disseminated Cancer: An NCCN Member Cohort Study.

BACKGROUNDSurgical site infections (SSIs) following colorectal surgery (CRS) are among the most common healthcare-associated infections (HAIs). Reduction in colorectal SSI rates is an important goal for surgical quality improvement.OBJECTIVETo examine rates of SSI in patients with and without cancer and to identify potential predictors of SSI risk following CRSDESIGNAmerican College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data files for 2011-2013 from a sample of 12 National Comprehensive Cancer Network (NCCN) member institutions were combined. Pooled SSI rates for colorectal procedures were calculated and risk was evaluated. The independent importance of potential risk factors was assessed using logistic regression.SETTINGMulticenter studyPARTICIPANTSOf 22 invited NCCN centers, 11 participated (50%). Colorectal procedures were selected by principal procedure current procedural technology (CPT) code. Cancer was defined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes.MAIN OUTCOMEThe primary outcome of interest was 30-day SSI rate.RESULTSA total of 652 SSIs (11.06%) were reported among 5,893 CRSs. Risk of SSI was similar for patients with and without cancer. Among CRS patients with underlying cancer, disseminated cancer (SSI rate, 17.5%; odds ratio [OR], 1.66; 95% confidence interval [CI], 1.23-2.26; P=.001), ASA score ≥3 (OR, 1.41; 95% CI, 1.09-1.83; P=.001), chronic obstructive pulmonary disease (COPD; OR, 1.6; 95% CI, 1.06-2.53; P=.02), and longer duration of procedure were associated with development of SSI.CONCLUSIONSPatients with disseminated cancer are at a higher risk for developing SSI. ASA score &gt;3, COPD, and longer duration of surgery predict SSI risk. Disseminated cancer should be further evaluated by the Centers for Disease Control and Prevention (CDC) in generating risk-adjusted outcomes.Infect Control Hosp Epidemiol 2018;39:555-562