Summary Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in ...patients with SCLC who progressed after one or more previous regimens. Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov , number NCT01928394. Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 8% vs none) and diarrhoea (none vs 3 5% vs 1 2%). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Funding Bristol-Myers Squibb.
Summary Background Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of ...nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. Methods In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov , NCT01928394. Findings Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9–16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3–35·4) of 78 patients. Grade 3–4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four 5%), elevated amylase (three 4%), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two 3% each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. Funding Bristol-Myers Squibb.
Objective To assess readmission rates identified by 3M-Potentially Preventable Readmissions software (3M-PPRs) in a national cohort of children's hospitals. Study design A total of 1 719 617 ...hospitalizations for 1 531 828 unique patients in 58 children's hospitals from 2009 to 2011 from the Children's Hospital Association Case-Mix Comparative database were examined. Main outcome measures included rates, diagnoses, and costs of potentially preventable readmissions (PPRs) and all-cause readmissions. Results The 7-, 15-, and 30-day rates by 3M-PPRs were 2.5%, 4.1%, and 6.2%, respectively. Corresponding all-cause readmission rates were 5.0%, 8.7%, and 13.3%. At 30 days, 60.6% of all-cause readmissions were considered nonpreventable by 3M-PPRs, more than one-half of which were related to malignancies. The percentage of readmissions rated as potentially preventable was similar at all 3 time intervals. Readmissions after chemotherapy, acute leukemia, and cystic fibrosis were all considered nonpreventable, and at least 80% of readmissions after index admissions for sickle cell crisis, bronchiolitis, ventricular shunt procedures, asthma, and appendectomy were designated potentially preventable. Total costs for all readmissions were $1.7 billion; PPRs accounted for 27.3% of these costs. The most costly readmissions were associated with ventricular shunt procedures ($26.5 million/year), seizures ($15.5 million/year), and sickle cell crisis ($15.0 million/year). Conclusions Rates of PPRs were significantly lower than all-cause readmission rates more than one-half of which were caused by exclusion of malignancies. Annual costs of PPRs, although significant in the aggregate, appear to represent a much smaller cost-savings opportunity for children than for adults. Our study may help guide children's hospitals to focus readmission reduction strategies on areas where the financial vulnerability is greatest based on 3M-PPRs.
Background Prognostic uncertainty is one barrier to engaging in goals-of-care discussions in chronic kidney disease (CKD). The surprise question (“Would you be surprised if this patient died in the ...next 12 months?”) is a tool to assist in prognostication. However, it has not been studied in non−dialysis-dependent CKD and its reliability is unknown. Study Design Observational study. Setting & Participants 388 patients at least 60 years of age with non−dialysis-dependent CKD stages 4 to 5 who were seen at an outpatient nephrology clinic. Predictor Trinary (ie, Yes, Neutral, or No) and binary (Yes or No) surprise question response. Outcomes Mortality, test-retest reliability, and blinded inter-rater reliability. Measurements Baseline comorbid conditions, Charlson Comorbidity Index, cause of CKD, and baseline laboratory values (ie, serum creatinine/estimated glomerular filtration rate, serum albumin, and hemoglobin). Results Median patient age was 71 years with median follow-up of 1.4 years, during which time 52 (13%) patients died. Using the trinary surprise question, providers responded Yes, Neutral, and No for 202 (52%), 80 (21%), and 106 (27%) patients, respectively. About 5%, 15%, and 27% of Yes, Neutral, and No patients died, respectively ( P < 0.001). Trinary surprise question inter-rater reliability was 0.58 (95% CI, 0.42-0.72), and test-retest reliability was 0.63 (95% CI, 0.54–0.72). The trinary surprise question No response had sensitivity and specificity of 55% and 76%, respectively (95% CIs, 38%-71% and 71%-80%, respectively). The binary surprise question had sensitivity of 66% (95% CI, 49%-80%; P = 0.3 vs trinary), but lower specificity of 68% (95% CI, 63%-73%; P = 0.02 vs trinary). Limitations Single center, small number of deaths. Conclusions The surprise question associates with mortality in CKD stages 4 to 5 and demonstrates moderate to good reliability. Future studies should examine how best to deploy the surprise question to facilitate advance care planning in advanced non−dialysis-dependent CKD.
Background Neoadjuvant therapy is integral in the treatment of locally advanced esophageal cancer. Despite increasing acceptance of minimally invasive approaches to esophagectomy, there remain ...concerns about the safety and oncologic soundness after neoadjuvant therapy. We examined outcomes in patients undergoing open and minimally invasive (MIE) Ivor Lewis esophagectomy after neoadjuvant therapy. Methods This was a retrospective series of 130 consecutive patients with esophageal cancer undergoing Ivor Lewis esophagectomy with curative intention after neoadjuvant therapy at a tertiary academic center (2008 to 2012). Results An open procedure was performed in 74 patients (56.9%), and 56 (43.1%) underwent MIE after neoadjuvant therapy. MIE patients had shorter median intensive care unit ( p = 0.002) and hospital lengths of stay ( p < 0.0001). The incidence of postoperative complications was similar (open: 54.8% vs MIE: 41.1%, p = 0.155). However, observed respiratory complications were significantly reduced after MIE (8.9%) compared with open (29.7%; p = 0.004). Anastomotic leak rates were similar (open: 1.4% vs. MIE: 0%, p = 1.00). Mortality at 30 and 90 days was comparable (open: 2.7% and 4.1% vs MIE: 0% and 1.8%, p = 0.506 and p = 0.634, respectively). Complete resection rates and the number of collected lymph nodes was similar. Overall survival rates at 5 years were similar (open: 61% vs MIE: 50%, p = 0.933). MIE was not a significant predictor of overall survival (hazard ratio, 1.07; 95% confidence interval, 0.61 to 1.87; p = 0.810). Conclusions MIE proves its safety after neoadjuvant therapy because it leads to faster progression during the early postoperative period while reducing pulmonary complications. Open and MIE approaches appear equivalent with regards to perioperative oncologic outcomes after neoadjuvant therapy. Long-term outcomes need further validation.
Abstract Background Despite the lethality of injuries to the heart, optimizing factors that impact mortality for victims that do survive to reach the hospital is critical. Methods From 2003-2012, ...prehospital data, injury characteristics and clinical patient factors were analyzed for victims with penetrating cardiac injuries (PCIs) at an urban, level I trauma center. Results Over the 10 year study, 80 PCI patients survived to reach the hospital. Of the 21 factors analyzed, prehospital CPR (OR= 30), scene time > 10 minutes (OR=58), resuscitative thoracotomy (OR = 19), and massive left hemothorax (OR = 15) had the greatest impact on mortality. Cardiac tamponade physiology demonstrated a “protective” effect for survivors to the hospital (OR = 0.08). Conclusion Trauma surgeons can improve mortality after PCI by minimizing time to the operating room for early control of hemorrhage. In PCI patients, tamponade may provide a physiologic advantage (lower mortality) compared to exsanguination.
Objectives To determine whether social determinants of health (SDH) risk adjustment changes hospital-level performance on the 30-day Pediatric All-Condition Readmission (PACR) measure and improves ...fit and accuracy of discharge-level models. Study design We performed a retrospective cohort study of all hospital discharges meeting criteria for the PACR from 47 hospitals in the Pediatric Health Information database from January to December 2014. We built four nested regression models by sequentially adding risk adjustment factors as follows: chronic condition indicators (CCIs); PACR patient factors (age and sex); electronic health record-derived SDH (race, ethnicity, payer), and zip code-linked SDH (families below poverty level, vacant housing units, adults without a high school diploma, single-parent households, median household income, unemployment rate). For each model, we measured the change in hospitals' readmission decile-rank and assessed model fit and accuracy. Results For the 458 686 discharges meeting PACR inclusion criteria, in multivariable models, factors associated with higher discharge-level PACR measure included age <1 year, female sex, 1 of 17 CCIs, higher CCI count, Medicaid insurance, higher median household income, and higher percentage of single-parent households. Adjustment for SDH made small but significant improvements in fit and accuracy of discharge-level PACR models, with larger effect at the hospital level, changing decile-rank for 17 of 47 hospitals. Conclusions We found that risk adjustment for SDH changed hospitals' readmissions rate rank order. Hospital-level changes in relative readmissions performance can have considerable financial implications; thus, for pay for performance measures calculated at the hospital level, and for research associated therewith, our findings support the inclusion of SDH variables in risk adjustment.
To determine visual acuity improvement in children with strabismic and combined strabismic-anisometropic (combined-mechanism) amblyopia treated with optical correction alone and to explore factors ...associated with improvement.
Prospective, multicenter, cohort study.
We included 146 children 3 to <7 years old with previously untreated strabismic amblyopia (n = 52) or combined-mechanism amblyopia (n = 94).
Optical treatment was provided as spectacles (prescription based on a cycloplegic refraction) that were worn for the first time at the baseline visit. Visual acuity with spectacles was measured using the Amblyopia Treatment Study HOTV visual acuity protocol at baseline and every 9 weeks thereafter until no further improvement in visual acuity. Ocular alignment was assessed at each visit.
Visual acuity 18 weeks after baseline.
Overall, amblyopic eye visual acuity improved a mean of 2.6 lines (95% confidence interval CI, 2.3-3.0), with 75% of children improving ≥ 2 lines and 54% improving ≥ 3 lines. Resolution of amblyopia occurred in 32% (95% CI, 24%-41%) of the children. The treatment effect was greater for strabismic amblyopia than for combined-mechanism amblyopia (3.2 vs 2.3 lines; adjusted P = 0.003). Visual acuity improved regardless of whether eye alignment improved.
Optical treatment alone of strabismic and combined-mechanism amblyopia results in clinically meaningful improvement in amblyopic eye visual acuity for most 3- to <7-year-old children, resolving in at least one quarter without the need for additional treatment. Consideration should be given to prescribing refractive correction as the sole initial treatment for children with strabismic or combined-mechanism amblyopia before initiating other therapies.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Background As worldwide life expectancy rises, the number of candidates for surgical treatment of esophageal cancer over 70 years will increase. This study aims to examine outcomes after ...esophagectomy in elderly patients. Methods This study is a retrospective review of 474 patients undergoing esophagectomy for cancer during 2002 to 2011. A total of 334 (70.5%) patients were less than 70 years old (group A), 124 (26.2%) 70 to 79 years (group B), and 16 (3.4%) 80 years or greater (group C). We analyzed the effect of age on outcome variables including overall and disease specific survival. Results Major morbidity was observed to occur in 115 (35.6%) patients of group A, 58 (47.9%) of group B, and 10 (62.5%) of group C ( p = 0.010). Mortality, both 30-day and 90-day was observed in 2 (0.6%) and 7 (2.2%) of group A, 4 (3.2%) and 7 (6.1%) of group B, and 1 (6.3%) and 2 (14.3%) of group C, respectively ( p = 0.032 and p = 0.013). Anastomotic leak was observed in 16 (4.8%) patients of group A, 6 (4.8%) of group B, and 0 (0%) of group C ( p = 0.685). Anastomotic stricture (defined by the need for ≥ 2 dilations) was observed in 76 (22.8%) of group A, 13 (10.5%) of group B, and 1 (6.3%) of group C ( p = 0.005). Five-year overall and disease specific survival was 64.8% and 72.4% for group A, 41.7% and 53.4% for group B, 49.2% and 49.2% for group C patients ( p = 0.0006), respectively. Conclusions Esophagectomy should be carefully considered in patients 70 to 79 years old and can be justified with low mortality. Outcomes in octogenarians are worse suggesting esophagectomy be considered on a case by case basis. Stricture rate is inversely associated to age.
Background The objective of this study was to evaluate the influence of total number of resected lymph nodes, lymph node ratio, and the number of lymph node stations sampled on prognosis in patients ...with early stage non-small cell lung cancer (NSCLC) treated with video-assisted thoracoscopic surgery (VATS). Methods Five hundred and fifty patients who underwent VATS lobectomy or segmentectomy for early clinical stage NSCLC were retrospectively analyzed from 2006 to 2012. Disease-free survival (DFS) and overall survival (OS) were compared for cutoff values of total number of resected lymph nodes (RNs) and lymph node stations (LNS) using Kaplan-Meier methods and Cox proportional hazard models. Results Lobectomy was performed in 493 (90%) patients with a median follow-up of 2.7 years. Median age was 68 (range, 29 to 92 years) and 342 (62%) were female. Pathologic stage I, II, and III was observed in 434 (79%), 80 (14.5%) and 36 (6.5%) patients, respectively. The N0, N1, and N2 pathologic nodal status was observed in 485 (88%), 38 (7%), and 27 (5%) patients, respectively. Nodal upstaging was observed in 11.3% (59 of 550) in the total cohort and 15% (49 of 332) in patients who underwent LNS greater than 3 compared with 5% (10 of 218) in patients with LNS 3 or less ( p < 0.01). Multivariate analysis identified LNS greater than 3 as a negative independent predictor for DFS (hazard ratio 2.36, p = 0.003) and OS (hazard ratio 1.77, p = 0.046). Conclusions Sampling greater than 3 LNS and greater than 10 RNs was associated with an increase in nodal upstaging. Only LNS greater than 3 was found to be an independent predictor of mortality in VATS lobectomy and segmentectomy in clinical early-stage NSCLC.
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