Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.

BACKGROUND: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.

Trends in US hospitalization rates and rhythm control therapies following publication of the AFFIRM and RACE trials.

INTRODUCTION: The impact of trials comparing rate versus rhythm control for AF on subsequent use of rhythm control therapies and hospitalizations at a national level has not been described. METHODS AND RESULTS: We queried the Healthcare Cost & Utilization Project on the frequency of hospital admissions and performance of specific rhythm control procedures from 1998-2006. We analyzed trends in hospitalization for AF as principal diagnosis before and after the publication of key rate versus rhythm trials in 2002. We also reviewed the use of electrical cardioversion and catheter ablation as principal procedures during hospital admissions for any cause and for AF as principal diagnosis. We additionally appraised the overall outpatient utilization of antiarrhythmic drugs during this same time frame using IMS Health's National Prescription Audit.™ Admissions for AF as a principal diagnosis increased at 5%/year from 1998-2002. Following publication of the AFFIRM and RACE trials in 2002, admissions declined by 2%/year from 2002-2004, before rising again from 2004-2006. In-hospital electrical cardioversion followed a similar pattern. National prescription volumes for antiarrhythmic drugs grew at <1% per year from 2002 to 2006, with a marked decline in the use of class I-A agents, while catheter ablations during admissions for AF as the principal diagnosis increased at 30% per year. CONCLUSION: The use of rhythm control therapies in the US declined significantly in the first few years after publication of AFFIRM and RACE. This trend reversed by 2005, at which time rapid growth in the use of catheter ablation for AF was observed.

Positron emission tomography-computed tomography predictors of progression after DA-R-EPOCH for PMBCL.

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [18F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning-derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance (P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis (P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression.

Molecular biology of bladder cancer.

Classic as well as more recent large-scale genomic analyses have uncovered multiple genes and pathways important for bladder cancer development. Genes involved in cell-cycle control, chromatin regulation, and receptor tyrosine and PI3 kinase-mammalian target of rapamycin signaling pathways are commonly mutated in muscle-invasive bladder cancer. Expression-based analyses have identified distinct types of bladder cancer that are similar to subsets of breast cancer, and have prognostic and therapeutic significance. These observations are leading to novel therapeutic approaches in bladder cancer, providing optimism for therapeutic progress.

Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients.

PURPOSE: High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer, with highly variable prognosis, poorly understood risk factors, and considerable debate about the role of early cystectomy. We aimed to address these questions through a meta-analysis of outcomes and prognostic factors. METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology abstracts were searched for cohort studies in HGT1. We pooled data on recurrence, progression, and cancer-specific survival from 73 studies. RESULTS: Five-year rates of recurrence, progression, and cancer-specific survival were 42% (95% CI, 39% to 45%), 21% (95% CI, 18% to 23%), and 87% (95% CI, 85% to 89%), respectively (56 studies, n = 15,215). In the prognostic factor meta-analysis (33 studies, n = 8,880), the highest impact risk factor was depth of invasion (T1b/c) into lamina propria (progression: hazard ratio [HR], 3.34; P < .001; cancer-specific survival: HR, 2.02; P = .001). Several other previously proposed factors also predicted progression and cancer-specific survival (lymphovascular invasion, associated carcinoma in situ, nonuse of bacillus Calmette-Guérin, tumor size > 3 cm, and older age; HRs for progression between 1.32 and 2.88, P ≤ .002; HRs for cancer-specific survival between 1.28 and 2.08, P ≤ .02). CONCLUSION: In this large analysis of outcomes and prognostic factors in HGT1 bladder cancer, deep lamina propria invasion had the largest negative impact, and other previously proposed prognostic factors were also confirmed. These factors should be used for prognostication and patient stratification in future clinical trials, and depth of invasion should be considered for inclusion in TNM staging criteria. This meta-analysis can also help define selection criteria for early cystectomy in HGT1 bladder cancer, particularly for patients with deep lamina propria invasion combined with other risk factors.

Predictors of ascending aortic dilation in bicuspid aortic valve disease: a five-year prospective study.

BACKGROUND: Bicuspid aortic valves are associated with aortic dilation and dissection. There is a paucity of prospective studies evaluating changes in aortic size over time in adult subjects with bicuspid aortic valves. METHODS: A total of 115 subjects with asymptomatic bicuspid aortic valves were enrolled from 2003 to 2008 and followed prospectively over 5 years. Clinical and family histories, as well as transthoracic echocardiograms, were obtained at baseline, and echocardiograms were performed annually thereafter. RESULTS: The mean age of subjects was 41.8 ± 12.8 years, and 61% were male. Ascending aortic size at baseline averaged 35.5 ± 5.6 mm and increased in 71.1% of subjects (mean, 0.66 ± 0.05 mm/y; range, 0.2-2.3 mm/y) over an average of 4.8 years. In 15.6% of subjects, the rate of change exceeded 1 mm/y. The average rate of ascending aortic dilation for all subjects was 0.47 ± 0.05 mm/y (P < .001). A family history of aortic valve disease was associated with progression in both unadjusted (P = .029) and logistic regression analyses adjusted for age, gender, and body surface area (odds ratio, 13.7; P = .021). Multivariate analysis did not find leaflet orientation or moderate to severe aortic valve dysfunction as independent predictors of aortic dilation. CONCLUSIONS: We found that in subjects with bicuspid aortic valve, studied prospectively, there was an annual rate of ascending aortic dilation of 0.47 mm/y. In contrast to previous reports, leaflet orientation and aortic valve dysfunction were not independent predictors of aortic dilation. A family history of aortic valve disease was associated with a significantly increased risk of increasing ascending aortic size.

Addition of B-Type Natriuretic Peptide to Existing Clinical Risk Scores Enhances Identification of Patients at Risk for Atrial Fibrillation Recurrence After Pulmonary Vein Isolation.

INTRODUCTION: Predicting which patients will be free from atrial fibrillation (AF) after pulmonary vein isolation (PVI) remains challenging. Clinical risk prediction scores show modest ability to identify patients at risk for AF recurrence after PVI. B-type natriuretic peptide (BNP) is associated with risk for incident and recurrent AF but is not currently included in existing AF risk scores. We sought to evaluate the incremental benefit of adding preoperative BNP to existing risk scores for predicting AF recurrence during the 6 months after PVI. METHODS: One hundred sixty-one patients with paroxysmal or persistent AF underwent an index PVI procedure between 2010 and 2013; 77 patients (48%) had late AF recurrence after PVI (>3 months post-PVI) over the 6-month follow-up period. RESULTS: A BNP greater than or equal to 100 pg/dL (P=0.01) and AF recurrence within 3 months after PVI (P<0.001) were associated with late AF recurrence in multivariate analyses. Addition of BNP to existing clinical risk scores significantly improved the areas under the curve for each score, with an integrated discrimination improvement of 0.08 (P=0.001) and a net reclassification improvement of 60% (P=0.001) for all risk scores. CONCLUSIONS: Circulating BNP levels are independently associated with late AF recurrence after PVI. Inclusion of BNP significantly improves the discriminative ability of CHADS2, CHA2DS2-VASc, R2CHADS2, and the HATCH score in predicting clinically significant, late AF recurrence after PVI and should be incorporated in decision-making algorithms for management of AF. B-R2CHADS2 is the best score model for prediction of late AF recurrence.

A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma.

CONTEXT: The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit. OBJECTIVE: To update the current evidence on the role of NC and AC for UTUC patients. EVIDENCE ACQUISITION: We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed. EVIDENCE SYNTHESIS: No randomized trials investigated the role of AC for UTUC. There was one prospective study (n=36) investigating adjuvant carboplatin-paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin-based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21-0.89; p=0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24-0.99; p=0.048). Benefit was not seen for non-cisplatin-based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤ 93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22-0.76; p=0.005). CONCLUSIONS: There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility. PATIENT SUMMARY: After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.

Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials.

CONTEXT: The role of adjuvant chemotherapy remains poorly defined for the management of muscle-invasive bladder cancer (MIBC). The last meta-analysis evaluating adjuvant chemotherapy, conducted in 2005, had limited power to fully support its use. OBJECTIVE: To update the current evidence of the benefit of postoperative adjuvant cisplatin-based chemotherapy compared with control (ie, surgery alone) in patients with MIBC. EVIDENCE ACQUISITION: A comprehensive literature review was performed to identify all randomized controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy with control for patients with MIBC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to May 2013. An updated systematic review and meta-analysis was performed. EVIDENCE SYNTHESIS: A total of 945 patients included in nine RCTs (five previously analyzed, one updated, and three new) were examined. For overall survival, the pooled hazard ratio (HR) across all nine trials was 0.77 (95% confidence interval [CI], 0.59-0.99; p=0.049). For disease-free survival, the pooled HR across seven trials reporting this outcome was 0.66 (95% CI, 0.45-0.91; p=0.014). This disease-free survival benefit was more apparent among those with positive nodal involvement (p=0.010). CONCLUSIONS: This updated and improved meta-analysis of randomized trials provides further evidence of an overall survival and disease-free survival benefit in patients with MIBC receiving adjuvant cisplatin-based chemotherapy after radical cystectomy.

Is AF Ablation Cost Effective?

The use of catheter ablation to treat AF is increasing rapidly, but there is presently an incomplete understanding of its cost-effectiveness. AF ablation procedures involve significant up-front expenditures, but multiple randomized trials have demonstrated that ablation is more effective than antiarrhythmic drugs at maintaining sinus rhythm in a second-line and possibly first-line rhythm control setting. Although truly long-term data are limited, ablation, as compared with antiarrrhythmic drugs, also appears associated with improved symptoms and quality of life and a reduction in downstream hospitalization and other health care resource utilization. Several groups have developed cost effectiveness models comparing AF ablation primarily to antiarrhythmic drugs and the model results suggest that ablation likely falls within the range generally accepted as cost-effective in developed nations. This paper will review available information on the cost-effectiveness of catheter ablation for the treatment of atrial fibrillation, and discuss continued areas of uncertainty where further research is required.