Citations

271 Background: Epidermal growth factor inhibitors show some benefit in the treatment of advanced pancreatic cancer. A trial to evaluate the incorporation of Pmab into a conventional multimodality regimen and continuation as maintenance therapy was conducted in pts with LA disease. Methods: Pts with ECOG PS 0-1, preserved organ function and tumor encompassed within standard radiation fields were eligible. Pmab 6 mg/kg on days 1, 15, 29 and continuous infusion 5-FU 225 mg/m2/d or capecitabine 825 mg/m2 were given with RT. Pts then received weekly gemcitabine 1000 mg/m2 and Pmab on days 1, 15 for three 4-week cycles. Maintenance Pmab was then continued for additional 6 months. RT consisted of 45 Gy to the tumor and regional nodes with a 5.4 Gy boost using conformal techniques. Primary endpoint of one-year survival (OS) with secondary endpoints progression-free survival (PFS), confirmed tumor response, and adverse events (at least possibly related) are reported. Results: 51 pts (23 M: 28 F) were enrolled with a median age of 65 (range: 43-84). Twenty-two pts (43%) received at least 1 cycle of post-chemo-RT, while 29 patients only received chemo-RT. All 51 pts have ended treatment with pts going off study because of: progression (39%), adverse events (27%), refusal (25%), and other reasons (8%). Frequently occurring maximum grade 3/4 AEs across the entire treatment course (chemo-RT + post-chemo-RT chemo) are shown below. With a median follow-up of 12.3 months, survival at 12 months is 50.2% (95% CI: 37.9-66.5%), median survival 12.1 mos (95% CI: 6.8-15.9) and median PFS 7.4 mos (95% CI: 3.7-8.6). Confirmed response rate was 5.9% (1-CR, 2-PR). Conclusions: The addition of Pmab to a conventional chemo-RT regimen provides benefit in terms of median survival. This is similar to reports of other EGFR inhibitors in LA disease. Adverse events, especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy. [Table: see text]

419 Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing. Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status. Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80). Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients. [Table: see text] [Table: see text]

238 Background: Dual inhibition of the EGFR pathway using erlotinib and the monoclonal antibody panitumumab results in greater antitumor activity in preclinical pancreatic cancer models. A trial evaluating this approach was conducted. Methods: A safety analysis was initially performed with 6 patients at P 4 mg/kg every two weeks, E 100 mg daily, G 1000 mg/m2 weekly of a 28-day cycle. PGE was well tolerated with a grade 3 fatigue as only dose-limiting toxicity. Patients (pts) were then randomized to either PGE or GE alone. Eligibility included: no prior chemo, ECOG PS 0-1, bilirubin <2x UL, AST <2.5x UL. CT scans every 2 cycles. Results: 93 pts (46-GE; 47-PGE) were randomized from January to August, 2010. Median age 61 years and 65% male. ECOG PS 0 (51%) and PS 1 (49%). No significant differences in baseline characteristics observed between treatment arms. 81 pts evaluable for AEs; 37 (46%) had a maximum grade 3 (at least possibly related to treatment), and 12 (15%) maximum grade 4 or 5. Treatment arms similar with respect to the overall AEs with exception grade 1-3 acneiform rash, GE (65%) vs. PGE (85%). Commonly occurring grade 4 AEs (at least possibly related) consisted of thrombosis (3 pts) and thrombocytopenia (2 pts). Two grade 5 events occurred in PGE arm—duodenal hemorrhage (possibly related) and pancolitis with multisystem failure (unlikely). An additional PGE pt died 30 days off study (grade 5 CHF, possibly). 54 patients (67%; 31-GE, 23-PGE) ended treatment; 38 (70%) for disease progression (24-GE; 14-PGE). Other reasons for treatment discontinuation: AEs (9; 17%), pt refusal (4; 7%), death on study (2; 4%), other (1). In 81 pts with at least 1 cycle of chemotherapy, the median PFS for GE 2.0 months and 3.3 months for PGE. Accrual for the study was recently completed and overall and 6-month survival data will be presented. Conclusions: This study involved an initial run-in design to define tolerable doses of dual EGFR inhibitors, PGE, in pancreatic cancer patients. Although preliminary, the randomized phase II portion has been completed and differences between GE and PGE in terms of relevant clinical outcomes, PFS, are observed. No significant financial relationships to disclose.

AbstractTwo‐wing flyingfish (Exocoetus spp.) are widely distributed, epipelagic, mid‐trophic organisms that feed on zooplankton and are preyed upon by numerous predators (e.g., tunas, dolphinfish, tropical seabirds), yet an understanding of their speciation and systematics is lacking. As a model of epipelagic fish speciation and to investigate mechanisms that increase biodiversity, we studied the phylogeny and biogeography of Exocoetus, a highly abundant holoepipelagic fish taxon of the tropical open ocean. Morphological and molecular data were used to evaluate the phylogenetic relationships, species boundaries, and biogeographic patterns of the five putative Exocoetus species. We show that the most widespread species (E. volitans) is sister to all other species, and we find no evidence for cryptic species in this taxon. Sister relationship between E. monocirrhus (Indo‐Pacific) and E. obtusirostris (Atlantic) indicates the Isthmus of Panama and/or Benguela Barrier may have played a role in their divergence via allopatric speciation. The sister species E. peruvianus and E. gibbosus are found in different regions of the Pacific Ocean; however, our molecular results do not show a clear distinction between these species, indicating recent divergence or ongoing gene flow. Overall, our phylogeny reveals that the most spatially restricted species are more recently derived, suggesting that allopatric barriers may drive speciation, but subsequent dispersal and range expansion may affect the distributions of species.

Objective: To describe the practice of intubation of the critically ill at a single academic institution, Mayo Clinic’s campus in Rochester, Minnesota, and to report the incidence of immediate postintubation complications. Patients and Methods: Critically ill adult (≥18 years) patients admitted to a medical–surgical intensive care unit from January 1, 2013, to December 31, 2014, who required endotracheal intubation included. Results: The final cohort included 420 patients. The mean age at intubation was 62.9 ± 16.3 years, with 58% (244) of the cohort as male. The most common reason for intubation was respiratory failure (282 [67%]). The most common airway device used was video laryngoscopy (204 [49%]). Paralysis was used in 264 (63%) patients, with ketamine as the most common sedative (194 [46%]). The most common complication was hypotension (170 [41%]; 95% confidence interval [CI]: 35.7-45.3) followed by hypoxemia (74 [17.6%]; 95% CI: 14.1-21.6), with difficult intubation occurring in 20 (5%; 95% CI: 2.9-7.3). Conclusion: We found a high success rate of first-pass intubation in critically ill patients (89.8%), despite the procedure being done primarily by trainees 92.6% of the time; video was the preferred method of laryngoscopy (48.6%). Although our difficult intubation (4.8%) and complication rates typically associated with the act of intubation such as aspiration (1.2%; 95% CI: 0.4-2.8) and esophageal intubation (0.2%; 95% CI: 0.01-1.3) are very low compared to other published rates (8.09%), postintubation hypotension (40.5%) and hypoxemia (17.6%) higher.