Citations

Abstract Purpose: The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results: There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions: The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. Clin Cancer Res; 22(22); 5472–9. ©2016 AACR.

Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and deep venous thrombosis (DVT), is a major cause of morbidity and mortality of particular relevance for intensivists and hospitalists. Acute VTE is usually managed with parenteral unfractionated heparin or low-molecular-weight heparin, followed by an oral vitamin K antagonist. Data are lacking for optimal treatment of less common occurrences, such as upper extremity DVT, and for approaches such as thrombolysis for PE associated with early signs of hemodynamic compromise or inferior vena cava filters when anticoagulation is contraindicated. Direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are now added to the armamentarium of agents available for acute management of VTE and/or reducing the risk of recurrence. This review outlines an algorithmic approach to acute VTE treatment: from aggressive therapies when anticoagulation may be inadequate, to alternative choices when anticoagulation is contraindicated, to anticoagulant options in the majority of patients in whom anticoagulation is appropriate. Evidence-based guidelines and the most recent DOAC clinical trial data are discussed in the context of the standard of care. Situations and treatment approaches for which data are unavailable or insufficient are identified. VTE therapy in care transitions is discussed, as are choices for secondary prevention.

Study Design. Prospective cohort study. Objective. To characterize the accuracy of patient recollection of preoperative symptoms after lumbar spine surgery. Summary of Background Data. Although patient-reported outcomes have become important in the evaluation of spine surgery patients, the accuracy of patient recall remains unknown. Methods. Patients undergoing lumbar decompression with or without fusion were enrolled. Back and leg Numeric Pain Scores and Oswestry Disability Indices were recorded preoperatively. Patients were asked to recall their preoperative status at a minimum of 1 year after surgery. Actual and recalled scores were compared using paired t tests and relations were quantified using Pearson correlation coefficients. Multivariable linear regression was used to identify factors that affected recollection. Results. Sixty-two patients with a mean age of 66.1 years were included. Compared to their preoperative scores, patients showed significant improvement in back pain (mean difference [MD] = −3.2, 95% CI −4.0 to −2.4), leg pain (MD −3.3, 95% CI −4.3 to −2.2), and disability (MD −25.0%, 95% CI −28.7 to −19.6). Patient recollection of preoperative status was significantly more severe than actual for back pain (MD +2.3, 95% CI 1.5–3.2), leg pain (MD +1.8, 95% CI 0.9–2.7), and disability (MD +9.6%, 95% CI 5.6–14.0). No significant correlation between actual and recalled scores with regards to back (r = 0.18) or leg (r = 0.24) pain and only moderate correlation with disability (r = 0.44) were seen. This was maintained across age, sex, and time between date of surgery and recollection. More than 40% of patients switched their predominant symptom from back pain to leg pain or leg pain to back pain on recall. Conclusion. Relying on patient recollection does not provide an accurate measure of preoperative status after lumbar spine surgery. Recall bias indicates the importance of obtaining true baseline scores and patient-reported outcomes prospectively and not retrospectively. Level of Evidence: 2

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non‐Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS‐R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population‐based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc.

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.