Citations

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.

Abstract Background A documented penicillin allergy is associated with increased morbidity including length of hospital stay and an increased incidence of resistant infections attributed to use of broader‐spectrum antibiotics. The aim of the systematic review was to identify whether inpatient penicillin allergy testing affected clinical outcomes during hospitalization. Methods We performed an electronic search of Ovid MEDLINE /PubMed, Embase, Web of Science, Scopus, and the Cochrane Library over the past 20 years. Inpatients having a documented penicillin allergy that underwent penicillin allergy testing were included. Results Twenty‐four studies met eligibility criteria. Study sample size was between 24 and 252 patients in exclusively inpatient cohorts. Penicillin skin testing ( PST ) with or without oral amoxicillin challenge was the main intervention described (18 studies). The population‐weighted mean for a negative PST was 95.1% [ CI 93.8‐96.1]. Inpatient penicillin allergy testing led to a change in antibiotic selection that was greater in the intensive care unit (77.97% [ CI 72.0‐83.1] vs 54.73% [ CI 51.2‐58.2], P <.01). An increased prescription of penicillin (range 9.9%‐49%) and cephalosporin (range 10.7%‐48%) antibiotics was reported. Vancomycin and fluoroquinolone use was decreased. Inpatient penicillin allergy testing was associated with decreased healthcare cost in four studies. Conclusions Inpatient penicillin allergy testing is safe and effective in ruling out penicillin allergy. The rate of negative tests is comparable to outpatient and perioperative data. Patients with a documented penicillin allergy who require penicillin should be tested during hospitalization given its benefit for individual patient outcomes and antibiotic stewardship.

Significance Focal adhesion kinase (FAK) is an intensely studied protein involved in many medically relevant biological processes, including cancer. Despite the large interest in FAK, a promising strategy to target FAK therapeutically is elusive. Here, we show that a region within the FAK protein that contains autophosphorylation site tyrosine (Y) 397 is essential for FAK activity in vivo. Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer. Our findings are significant because they further delineate FAK function in vivo and identify the MYO1E–FAK interaction as a possible Achilles’ heel for cancer.

668 Background: Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2. Overall survival (OS) and progression-free survival (PFS) in 2nd line FOLFIRI based treatment for metastatic colorectal cancer (mCRC) were improved with RAM therapy versus PBO in the RAISE trial. Recent work suggests mCRC primary tumor location is both prognostic and predictive; with improved OS and therapy-specific sensitivity observed in left (L)- vs right (R)-sided tumors. Given these findings, the RAISE trial data was subjected to post-hoc analysis to determine if sidedness influenced RAM efficacy. Methods: Primary tumor site was obtained. L-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum, while R-CRC included transverse, ascending colon and cecum. OS/PFS in L and R subgroups were analyzed via Kaplan-Meier method and unstratified log-rank test (treatments within subgroup), unstratified Cox proportional hazards model (estimate hazard ratio [HR] and 95% CI), and Wald test (treatment-by-subgroup interaction). Results: Tumor location was available for 1012/1072 (94%) patients, 699 L- and 313 R-CRC. Baseline characteristics were balanced between arms. RAM treatment enhanced L-CRC median OS by 2.5 mo (median 14.5 vs 12.0 mo) with a HR (95% CI) = 0.807 (0.675, 0.965), P = 0.019; compared to a 1.1 mo increase in median OS in R-CRC vs PBO (12.7 vs 11.6) with a HR (95% CI) = 0.971 (0.750, 1.258), P = 0.823; and, RAM enhanced L-CRC median PFS by 1.6 mo (6.0 vs 4.4 mo) and HR (95% CI) = 0.776 (0.664, 0.906), P = 0.001 compared to a 1.1 mo increase in median PFS R-CRC vs PBO (5.6 vs 4.5) with a HR (95% CI) = 0.855 (0.674, 1.084), P = 0.197. The treatment-by-subgroup interaction for both OS and PFS was not significant ( P = 0.276, 0.578, respectively). Conclusions: Despite L-CRC patients having longer OS/PFS and a seemingly stronger RAM treatment effect than R-CRC, the non-significant interaction test cannot verify sidedness as being predictive of RAM efficacy. The current study confirms ramucirumab benefits mCRC patients regardless primary tumor location. Clinical trial information: NCT01183780.

593 Background: Cancer stem cells or stemness-high cancer cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutics and targeted agents. Methods: This study was performed to assess signs of anti-tumor activity of napabucasin in combination with FOLFIRI +/- Bev in CRC pts. Napabucasin was administered at 240 mg BID. FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2 infusion) +/- Bev 5 mg/kg was administered biweekly until disease progression or other discontinuation criterion. pSTAT3 status of archival tumor tissue was assayed by immunohistochemistry using the H-score with pSTAT3highdefined as ≥ 5% pSTAT3+ cancer cells and tumor stroma staining at ≥ 2+ intensity. Results: 63 CRC pts with an average of >2 prior therapy lines were enrolled. No pharmacokinetic interactions or dose-limiting toxicity was observed. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. 25 pts had grade 3 AEs, including diarrhea (14), fatigue (4), dehydration (2), electrolyte imbalance (4), nausea (1) and weight loss (1) resolved with dose reduction and supportive care. Among 63 pts enrolled who received RECIST evaluation, disease control (CR+PR+SD) was observed in 49 pts (86%) with an overall response (CR+PR) of 28% with 1 pt achieving CR. Clinical trial information: NCT02024607. Conclusions: This phase Ib/II study suggests napabucasin may sensitize chemorefractory CRC to FOLFIRI +/- Bev. Encouraging signs of synergistic activity between napabucasin and FOLFIRI was observed in CRC pts regardless of pSTAT3 status.[Table: see text]

Abstract Quantitative evaluation of passive tension in a muscle is important in tendon transfer surgeries, however, currently appropriate intraoperative measurement techniques are lacking. Objective : Intramuscular pressure (IMP) is explored as an application to access force. Approach : The tibialis anterior (TA) in New Zealand white rabbits ( n = 9) was used to test the hypothesis of a strong correlation between the IMP, muscle force, and length. This study also helped to develop intraoperative techniques for future human studies evaluating various insertion techniques (parallel versus perpendicular). Main results : The Pearson correlation between IMP and force for all trials was 0.74 ± 0.30. Separating out the parallel insertion from the perpendicular insertion revealed a significantly higher correlation for parallel, 0.91 ± 0.13 versus 0.56 ± 0.32. Significance : These data indicate IMP sensors can be used to assess force in a single muscle and the parallel insertion method should be used. New findings • What is the central question of this study? Successful outcomes of tendon and muscle transfers depend on proper muscle tension. A near linear relationship has been seen between muscle force and intramuscular pressure. This study aims to develop an intraoperative technique for assessing passive muscle tension using intramuscular pressure. • What is the main finding and its importance? The findings from this study reveal a high correlation between pressure and passive tension in a single muscle. The techniques developed in this study will allow the translation to a human model. The work will help to improve surgical outcomes and aim to retain muscle strength in the patient following procedures such as tendon and muscle transfers.