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Supplemental Figure S3. Racemic distribution of clinical drug.

Purpose: We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes.Experimental Design: Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer–specific survival in ovarian cancer cases.Results: Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the R-enantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11–0.88).Conclusions: Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac. Clin Cancer Res; 21(22); 5064–72. ©2015 AACR.

Supplemental methods, Supplemental tables S1-S3, Supplemental Figure S1-S8 Legends. Supplemental methods for IHC of patient TMA, qPCR of patient cDNA, HPLC protocol, and GTPase activity of patient cells. Figure legends for supplemental figures S1-S8 are included. Supplemental table S1 - Patient Characteristics for IHC Microarrays OV1005 and OV8010. Supplemental table S2 - Patient Characteristics for cDNA Microarray. Supplemental table S3 - Ketorolac enantiomer concentration in serum or peritoneal fluids

Supplemental Figures S4-S7. Supplemental Figure S4 - Survival estimates based on Cox-regression for Stage I (AJCC) with completion of chemotherapy. Supplemental Figure S5 - Survival estimates based on Cox-regression for Stage II (AJCC) with completion of chemotherapy. Supplemental Figure S6 - Survival estimates based on Cox-regression for Stage III (AJCC) with completion of chemotherapy. Supplemental Figure S7 - Survival estimates based on Cox-regression for Stage IV (AJCC) with completion of chemotherapy.

Demographic and clinical indicators have been described to support identification of coccidioidomycosis (CM); however, the interplay of these conditions has not been explored in a clinical setting. In 2019, we enrolled 392 participants in a cross-sectional study for suspected CM in emergency room and inpatient units within Coccidioides endemic regions. We aimed to develop a predictive CM model among participants presenting with suspected CM. We applied LASSO (least absolute shrinkage and selection operator) to select predictors of CM and report results from univariable and multivariable logistic regression models. Univariable models identified elevated eosinophil count as a significant predictive feature of CM in both inpatient and outpatient settings. Our multivariable outpatient model identified rash (OR=9.74, p= 0.047, 95%CI=1.03–92.24) as a predictor of CM. Our results suggest preliminary support for the development of a CM prediction model for use in the clinical setting.

To provide one of the first prospective reports examining neuropsychological outcomes for children treated with 1800 cGy whole brain radiotherapy (WBRT) and prophylactic chemotherapy versus prophylactic chemotherapy alone for acute lymphoblastic leukemia (ALL). Acute and long-term neuropsychological toxicities associated with WBRT are compared.This multisite study included 188 children, ages 4-21 years at enrollment, who were assessed with standardized neuropsychological tests at 9, 21, and 48 months after diagnosis with intermediate risk ALL. All participating children were receiving treatment on a parent study CCG105.Verbal intelligence (VIQ) scores for children receiving WBRT was significantly lower than VIQ for prophylactic chemotherapy at the 48-month time point (p 0.05). A significant cross-level interaction between time since diagnosis and treatment condition was observed (p 0.05). WBRT did not result in differences in PIQ; both groups of children demonstrated comparable increases in PIQ. Neuropsychological findings at 48 months after diagnosis indicated diminished performance in neuromotor, visual-motor coordination, and executive functioning for children receiving WBRT. Academic achievement was unaffected by WBRT at 4 years after diagnosis.The measurement of verbal and performance IQ as a primary endpoint in ALL clinical trials is critical to characterizing neuropsychological late effects. A trajectory of decline in neuropsychological functioning, specifically verbal IQ, was observed. Missing data within the trial occurred at random and did not impact results observed. The impact of WBRT becomes evident at 48 months after diagnosis, suggesting the need for long-term follow-up beyond the time frame typically used in Phase III trials.

Background. Andes virus (ANDV)–related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. Methods. Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/ fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. Results. Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P= .43). We observed no significant difference in mortality between treatment groups (P=.41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P= .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. Conclusions. Although methylprednisolone appears to be safe, it did not provide significant clinical benefi tt o patients. Our results do not support the use of methylprednisolone for HCPS. Clinical Trials Registration. NCT00128180.