Phase II Study of Dasatinib (BMS‐354825) in Patients With Metastatic Adenocarcinoma of the Pancreas

Background.

Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC.

Methods.

Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected.

Results.

Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8–6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6–3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival.

Conclusion.

Single-agent dasatinib does not have clinical activity in metastatic PDAC.     

Use of the Complete Rockall Score and the Forrest Classification to Assess Outcome in Patients with Non-variceal Upper Gastrointestinal Bleeding Subject to After-hours Endoscopy: A Retrospective Cohort Study

Objectives:

To evaluate the usefulness of the Forrest classification and the complete Rockall score with customary cut-off values for assessing the risk of adverse events in patients with upper gastrointestinal bleeding (UGI-B) subject to after-hours emergency oesophago-gastro-duodenoscopy (E-EGD) within six hours after admission.

Methods:

The medical records of patients with non-variceal UGI-B proven by after-hours endoscopy were analysed. For ''high risk'' situations (Forrest stage Ia–IIb/complete Rockall score > 2), univariate analysis was conducted to evaluate odds ratio for reaching the study endpoints (30-day and one-year mortality, re-bleeding, hospital stay ≥ 3 days).

Results:

During the study period (75 months), 86 cases (85 patients) met the inclusion criteria. Patients ''age was 66.36 ± 14.38 years; 60.5% were male. Mean duration of hospital stay was 15.21 ± 19.24 days. Mortality rate was 16.7% (30 days) and 32.9% (one year); 14% of patients re-bled. Univariate analysis of post-endoscopic Rockall score ≥ 2 showed an odds ratio of 6.09 for death within 30 days (p = 0.04). No other significant correlations were found.

Conclusion:

In patients with UGI-B subject to after-hours endoscopy, a ''high-risk'' Rockall score permits an estimation of the risk of death within 30 days but not of re-bleeding. A ''high-risk '' Forrest score is not significantly associated with the study endpoints.     

Initial evaluation of a continuous speech recognition program for radiology

The aims of this work were to measure the accuracy of one continuous speech recognition product and dependence on the speaker's gender and status as a native or nonnative English speaker, and evaluate the product's potential for routine use in transcribing radiology reports. IBM MedSpeak/Radiology software, version 1.1 was evaluated by 6 speakers. Two were nonnative English speakers, and 3 were men. Each speaker dictated a set of 12 reports. The reports included neurologic and body imaging examinations performed with 6 different modalities. The dictated and original report texts were compared, and error rates for overall, significant, and subtle significant errors were computed. Error rate dependence on modality, native English speaker status, and gender were evaluated by performing ttests. The overall error rate was 10.3 +/- 3.3%. No difference in accuracy between men and women was found; however, significant differences were seen for overall and significant errors when comparing native and nonnative English speakers (P = .009 and P = .008, respectively). The speech recognition software is approximately 90% accurate, and while practical implementation issues (rather than accuracy) currently limit routine use of this product throughout a radiology practice, application in niche areas such as the emergency room currently is being pursued. This methodology provides a convenient way to compare the initial accuracy of different speech recognition products, and changes in accuracy over time, in a detailed and sensitive manner.     

Acanthamoeba keratitis: a comprehensive photographic reference of common and uncommon signs

There has been a significant increase in the number of reported cases of Acanthamoeba keratitis reported internationally over the last 24 months. Diagnosing Acanthamoeba keratitis is often difficult and part of the difficulty is attributed to the variability of presentation. This article provides a comprehensive photographic reference of common and uncommon clinical signs of Acanthamoeba keratitis.     

Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors

Purpose

The purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.

Methods

This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.

Results

Forty-five subjects were enrolled. No difference in dose-normalized AUC_0–last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.

Conclusion

Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.     

Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone

BACKGROUND: Identifying predictive biomarkers is important to optimally treat patients. This analysis evaluated the association of K-ras, BRAF, and PIK3CA gene mutations with tumor resistance to panitumumab alone. PATIENTS AND METHODS: From 3 phase II panitumumab metastatic colorectal cancer (mCRC) studies, 62 of 533 patient samples were available. Mutations were identified from genomic DNA by sequencing. RESULTS: Of the 62 samples, 24 (38.7%) harbored a K-ras mutation, and 38 (61.3%) were wild type. In the wild-type K-ras group, 11% of patients had a partial response (PR), 53% had stable disease (SD), and 37% had progressive disease (PD). In the mutant K-ras group, 21% of patients had SD, and 79% of patients had PD; there were no responses. The absence of a K-ras mutation was associated with response to panitumumab (PR vs. SD vs. PD; P = .0028). The hazard ratio for wild-type versus mutant K-ras was 0.4 (95% CI, 0.2-0.7) for progression-free survival and 0.5 (95% CI, 0.3-0.9) for overall survival. Four patients had a V600E BRAF mutation, and 2 patients had a PIK3CA mutation. CONCLUSION: These data suggest that patients with mCRC with activating K-ras mutations are less likely to respond to panitumumab alone. The small sample size limits us from defining a predictive role of PIK3CA and BRAF mutations for panitumumab treatment.