Mutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with advanced sarcoma. Larger, prospective studies are necessary to confirm these findings.

2047 Background: Enzastaurin, an orally administered potent PKC inhibitor, is an anti-angiogenic agent that also suppresses PI3K/AKT to inhibit tumor cell proliferation and induce tumor cell death. Preclinical data suggest that the combination of enzastaurin and pemetrexed (Alimta) produced additive or synergistic antitumor activity in tumor specimens. This phase 1b study evaluated the safety, pharmacokinetic (PK) interaction, and antitumor activity of enzastaurin when combined with pemetrexed. Methods: Patients (pts) with advanced or metastatic cancer and an ECOG status of 0–2 received an intravenous dose of 500 mg/m2 pemetrexed on day 1 and an oral dose of 500 mg enzastaurin once daily, (after day 4 in cycle 1) in repeat 21-day cycles for up to 6 cycles. In cycle 1, a loading dose of 1200 mg enzastaurin (400 mg/3×/day) was given on day 4. Pts were also given oral folic acid daily and vitamin B12 every 9 weeks for the duration of pemetrexed therapy, and 5–7 days before cycle 1. Results: Blood samples for PK analysis of enzastaurin (n = 21) were collected on day 21 of cycle 1 and day 1 of cycle 2, and for analysis of pemetrexed (n = 22) on day 1 of cycle 1 and cycle 2. Steady-state concentration [geometric mean (%CV)] of total analytes (enzastaurin and its metabolites) was 1270 nM (126%) when administered alone and 1130 nM (100%) when administered with pemetrexed. Thus, no significant differences in exposures were observed when combined with pemetrexed. Clearance of pemetrexed was the same when dosed either with enzastaurin (2.48 L/h/m2) or as a single agent (2.62 L/h/m2). Safety data from the first 2 cycles are consistent with the known toxicity profile of pemetrexed. No grade 3 or 4 toxicity was reported following the loading dose of 1200 mg enzastaurin. Conclusions: Preliminary data suggest that there is no significant PK interaction between enzastaurin and pemetrexed, and that the combination is well tolerated. The current study is ongoing and subsequent analyses will document tumor responses and safety for longer-term treatment of enzastaurin combined with pemetrexed. This first PK study of enzastaurin and pemetrexed will help determine if enzastaurin has an additive clinical benefit to pemetrexed treatment and support future studies in NSCLC and mesothelioma. [Table: see text]

Hypophosphatasia (HPP) is caused by loss‐of‐function mutations in ALPL resulting in decreased alkaline phosphatase (ALP) activity. Metatarsal stress fracture (MSF) is a common clinical feature of hypophosphatasia in adults. In this study, the primary objectives were to determine whether new cases of ALPL variants could be identified in patients with MSF and who also had serum ALP concentration below the reference range and to phenotype their clinical course. Electronic health records were queried for adult patients with MSF using International Classification of Disease codes (ICD‐9, ICD‐10CM) and ALP measurements. Patients with ALP levels below the normal limit were invited to receive mutational analysis of ALPL and to complete the following surveys: the Short Form 36 version 2 (SF36v2), the Brief Pain Inventory‐Short Form (BPI), and the Health Assessment Questionnaire Disability Index (HAQ‐DI). Cases with and controls without ALPL pathogenic variants were compared by survey scores and clinical variables relevant to fracture. In 1611 patients with MSF presenting to a podiatry clinic (10/1/2011–10/1/2017), 937 had ALP measurement, of whom 13 (1.4%) had ALP levels below the lower normal limit. In eight patients consenting to participate, two had heterozygous pathogenic ALPL variants. ALPL variants were found in 2 of 1611 patients (0.12%) with MSF, 2 patients of 937 (0.21%) in those with MSF and any ALP measurement, and 2 of 13 patients (15%) in MSF and decreased ALP level. Cases versus controls rated lower scores on eight of eight SF36v2 scales (range, 0–100); higher scores for worst pain (8.0 vs. 0.8) and average pain (6.0 vs. 0.7) on the BPI (range, 0–10); and higher standard disability score (1.4 vs. 0) on the HAQ‐DI (range, 0–3). These data provide proof‐of‐concept for HPP case identification in patients presenting to a podiatry clinic with MSF, suggesting a search for historically low ALP levels may be a useful step for consideration of HPP diagnosis, and supports a prospective study to determine an optimal case‐finding strategy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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120.8] months, p=0.077). Overall survival was significantly longer in the Lymph node dissection group (No dissection vs. Lymph node dissection: 44.0 [31.1e56.9] months vs. 90.0 [51.1e158.9] months, p=0.027). Conclusion: Radical surgery including an adequate lymph node dissection area and suitable harvested lymph nodes appears to improve oncologic outcomes for intrahepatic cholangiocarcinoma.