A Poissonian Model of Indel Rate Variation for Phylogenetic Tree Inference.

While indel rate variation has been observed and analyzed in detail, it is not taken into account by current indel-aware phylogenetic reconstruction methods. In this work, we introduce a continuous time stochastic process, the geometric Poisson indel process, that generalizes the Poisson indel process by allowing insertion and deletion rates to vary across sites. We design an efficient algorithm for computing the probability of a given multiple sequence alignment based on our new indel model. We describe a method to construct phylogeny estimates from a fixed alignment using neighbor joining. Using simulation studies, we show that ignoring indel rate variation may have a detrimental effect on the accuracy of the inferred phylogenies, and that our proposed method can sidestep this issue by inferring latent indel rate categories. We also show that our phylogenetic inference method may be more stable to taxa subsampling than methods that either ignore indels or indel rate variation. [evolutionary stochastic process; indel rate variation; Poisson indel process; TKF91.].

A Retrospective Review of Chemotherapy for Patients with Small Bowel Adenocarcinoma in British Columbia.

Background: Small bowel adenocarcinoma (SBA) is associated with a poor prognosis. It is an uncommon malignancy and therefore difficult to study. Randomized phase III trials are not available to guide best approaches. The Provincial Cancer Registry of the British Columbia Cancer Agency contains long-term data on patients with SBA. The authors analyzed characteristics and treatment outcomes for SBA patients diagnosed between 1990 and 2008. Material and methods: Charts of 150 patients with a histological diagnosis of SBA were retrospectively analyzed. Epidemiological and treatment data were collected. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Baseline characteristics, such as median age at diagnosis (64.5 years), tumor stage (I-II 33%, III-IV 58%, unknown 9%), and location (duodenum 48%, jejunum 31%, ileum 21%) were consistent with published data. 55% of patients had a positive family history of cancer. DFS and OS of 29 patients treated with adjuvant chemotherapy were not significantly different to that of 47 patients without (p = 1 and p = 0.211, respectively). In the palliative setting patients treated with polychemotherapy (21 patients) had statistically better OS than patients treated with monochemotherapy (12 patients) (p = 0.0228). Conclusions: Our study suggests a survival benefit for advanced-stage SBA patients treated with poly- versus monochemotherapy. This, however, was a retrospective analysis with several potential confounders. Nevertheless, our study adds to the evidence suggesting that chemotherapy may be beneficial for patients with SBA, at least in the palliative setting.

Asian Versus Non-Asian Outcomes in Nasopharyngeal Carcinoma: A North American Population-based Analysis.

OBJECTIVES: The effect of ethnicity on nasopharyngeal cancer (NPC) outcomes is unclear. This retrospective analysis examines survival and the impact of concurrent chemoradiation (chemoRT) among Asian and non-Asian patients. METHODS: Subjects included 380 consecutive patients with NPC treated at a Canadian institution from 2000 to 2009. Five-year Kaplan-Meier progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) were compared between Asian (n=279) and non-Asian (n=101) subjects. Multivariable analysis was performed using Cox regression modeling. Two-variable interaction terms with concurrent chemoRT were used to examine whether concurrent chemoRT conferred different effects among subgroups. RESULTS: Asian subjects presented with earlier stage (P=0.005), were younger, had better performance status, and were less likely smokers (all P<0.001). Survival among Asian versus non-Asian subjects with stage I/II NPC were: PFS 68% versus 59% (P=0.04), DSS 87% versus 77% (P=0.08), and OS 84% versus 74% (P=0.003). Corresponding rates with stage III/IVA/IVB disease were PFS 49% versus 42% (P=0.12), DSS 72% versus 46% (P=0.001), and OS 70% versus 44% (P<0.001). On multivariable analysis, Asian ethnicity, age below 65 years, ECOG performance status 0-1, early stage, staging MRI use, and concurrent chemoRT were associated with improved DSS and OS (P<0.05). On testing interactions with concurrent chemoRT, Asian versus non-Asian ethnicity was significant (hazard ratio 3.9), suggesting that concurrent chemoRT conferred more benefit among non-Asian compared with Asian subjects. CONCLUSIONS: In this population-based study, Asian ethnicity was associated with improved DSS and OS. Concurrent chemoRT conferred more benefit among non-Asian compared with Asian subjects.

Timing of Hip Fracture Surgery and 30-Day Outcomes.

The goal of this study was to determine the proportion of patients admitted with a hip fracture to participating American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) hospitals who were treated within the United Kingdom's National Institute for Health and Care Excellence (NICE) time-to-hip-fracture-surgery benchmark. The secondary goals were to identify factors associated with missing the benchmark and to determine whether the benchmark was associated with improved 30-day patient outcomes. Patients aged 60 years or older who underwent hip fracture surgery between 2005 and 2013 were identified from the ACS-NSQIP database. Of the 26,066 patients who met the enrollment criteria, 71.4% were treated within the NICE benchmark. Many variables, including sex, race, procedure type, and hip fracture diagnosis, were statistically significant predictors of missing the benchmark (P<.001). Meeting the NICE benchmark was not associated with reductions in major complications (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.83-1.05; P=.234); however, it was associated with reductions in 30-day mortality (OR, 0.88; 95% CI, 0.78-0.99; P=.028), minor complications (OR, 0.92; 95% CI, 0.84-0.995; P=.038), and postoperative length of stay (beta=-0.77; P<.001). Current practice at participating ACS-NSQIP hospitals is compatible with the NICE time-to-surgery benchmark. However, the findings highlight the importance of further prospective investigation to monitor the effect of early-treatment benchmarks on 30-day patient outcomes. [Orthopedics. 2016; 39(6):361-368.].

Less toxic chemotherapy improves uptake of all lines of chemotherapy in advanced non-small-cell lung cancer: a 10-year retrospective population-based review.

BACKGROUND: Over the past decade, well tolerated second-line therapies for advanced non-small-cell lung cancer have been approved including erlotinib and pemetrexed in addition to docetaxel. We hypothesize that the introduction of less toxic chemotherapy has increased treatment of advanced non-small-cell lung cancer resulting in improved survival. METHODS: The BC Cancer Agency provides cancer care to 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in four 1-year time cohorts; C1 baseline (1998) and 6 months after the provincial approval of C2 docetaxel (2001), C3 erlotinib (2006), and C4 pemetrexed (2007). RESULTS: Two-thousand six-hundred and twenty-three patients were referred and 720 had systemic therapy. Characteristics: M/F 55%/45%, median age 67 (33-101), ECOG PS <=1/>=2/unknown 33%/56%/11%, squam/nonsquam/NOS 18%/41%/41%. More patients received first-line chemotherapy over time; 16%, 23%, 34%, and 33% C1-C4 respectively. In C1-C4 uptake of second line (21%, 27%, 37% and 55%) increased. Second-line docetaxel was frequently used in C2 (51%) but usage decreased in C4 to 7% versus erlotinib 50% and pemetrexed 26%. The median overall survival in the best supportive care group remained stable over time; however, increased use of systemic therapy was associated with improved survival C1 9.4 m versus C4 11.8 m (p = 0.023). CONCLUSIONS: This population-based data set represents the trend of treatments over time at community and tertiary care cancer treatment sites. Over a 10-year period an increased proportion of patients were treated with first-line chemotherapy and an even greater number with second-/third-line treatment with an associated improvement in overall survival.

A population-based review of the feasibility of platinum-based combination chemotherapy after tyrosine kinase inhibition in EGFR mutation positive non-small cell lung cancer patients with advanced disease.

INTRODUCTION: The IPASS trial demonstrated superior progression free survival for Asian, light/never smoking, advanced, pulmonary adenocarcinoma patients treated with first-line gefitinib compared to carboplatin/paclitaxel, of which 59% of those tested were epidermal growth factor receptor (EGFR) mutation positive. In IPASS 39% of gefitinib treated patients went on to receive platin based polychemotherapy. We hypothesized that in a population-based setting fewer patients receive second-line platin based chemotherapy than those enrolled in a clinical trial. METHODS: The Iressa Alliance program provided standardized EGFR mutation testing and appropriate access to gefitinib to all patients in British Columbia with advanced, non squamous non small cell lung cancer (NSCLC). We retrospectively analyzed clinical, pathologic data and outcomes for all patients tested in this program between March 2010 and June 2011. RESULTS: A total of 548 patients were referred for testing and 22% of patients were mutation positive. Baseline characteristics of mutation negative and mutation positive; median age 67/65, male 41%/31%, Asian 15%/51%, never smoker 21%/58%, stage IV 80%/91%. Median overall survival was 12 months in mutation negative patients and not yet reached in mutation positive (p<0.0001). In mutation positive patients 5% of patients had a complete response, 46% partial response, 34% stable disease, 6% progressive disease. Twenty percent of patients continued on gefitinib after radiographic progression and clinical stability. Sixty-one gefitinib treated patients progressed at the time of analysis; 10% of patients received further gefitinib only, 38% platinum based doublet, 8% other chemotherapy and 44% no further treatment. Performance status most strongly predicted for delivery of second line chemotherapy. CONCLUSIONS: This North American population based study shows similar efficacy of gefitinib in mutation positive patients compared to the IPASS trial. Contrary to our hypothesis, delivery of second line chemotherapy was feasible in a significant proportion of gefitinib treated patients.