Response of Locally Advanced Pancreatic Cancer to Intratumoral Injection of Large Surface Area Microparticle Paclitaxel: Initial Report of Safety and Clinical Outcome.

OBJECTIVES: Large surface area microparticle paclitaxel (LSAM-PTX) provides an intratumoral (IT) chemotherapeutic depot. Safety, tolerability, and tumor response to IT LSAM-PTX delivered by endoscopic ultrasound-fine needle injection were evaluated in subjects with unresectable locally advanced pancreatic cancer (LAPC). METHODS: Ten subjects treated in a dose escalation phase and 22 additional subjects receiving 2 injections, 4 weeks apart, of 15 mg/mL LSAM-PTX were followed for 12 months. Paclitaxel pharmacokinetics were evaluated, imaging at 3 and 6 months determined tumor response, and multiplex immunofluorescence was conducted to characterize local immune response. RESULTS: Most treatment-emergent adverse events were attributed to LAPC. Plasma paclitaxel levels were negligible. Eight subjects' tumors became resectable after IT LSAM-PTX, and 5 of 6 (83%) were resected with R0. Multiplex immunofluorescence of resected tumors demonstrated increased T cells, natural killer cells, and macrophages and decreased myeloid-derived suppressor cells. Six-month disease control rate was 94%, and median overall survival was 19.7 months in the 2-injection subjects. For nonresected and resected groups, overall survival times were 18.9 and 35.2 months, respectively. CONCLUSIONS: Neoadjuvant IT LSAM-PTX, in combination with SOC, was well tolerated and may provide benefits to LAPC patients, evidenced by enhanced immune response, improved disease control rate, restaging leading to surgery, and extended survival.

Early phase trial of intracystic injection of large surface area microparticle paclitaxel for treatment of mucinous pancreatic cysts.

Background and study aims Mucinous pancreatic cystic lesions (PCLs) have the potential for malignant transformation, for which the only accepted curative modality is surgery. A novel intracystic therapy with large surface area microparticle paclitaxel (LSAM-PTX) may treat PCLs without local or systemic toxicities. Safety and preliminary efficacy of LSAM-PTX for the treatment of PCLs administered by endoscopic ultrasound-guided fine-needle injection (EUS-FNI) was evaluated. Patients and methods Ten subjects with confirmed PCLs (size > 1.5 cm) received intracystic LSAM-PTX via EUS-FNI at volumes equal to those aspirated from the cyst in sequential cohorts at 6, 10, and 15 mg/mL in a standard "3 + 3" dose-escalation protocol. The highest dose with acceptable safety and tolerability was taken into the confirmatory phase where nine additional subjects received two injections of LSAM-PTX 12 weeks apart. Subjects were followed for 6 months after initial LSAM-PTX treatment for endpoints including: adverse events (AEs), tolerability, pharmacokinetic analysis of systemic paclitaxel drug levels, and change in cyst volume. Results Nineteen subjects completed the study. No dose-limiting toxicities, treatment-related serious AEs, or clinically significant laboratory changes were reported. Systemic paclitaxel concentrations did not exceed 3.5 ng/mL at any timepoint measured and fell below 1 ng/mL by Week 2, supporting the lack of systemic toxicity. By Week 24 a cyst volume reduction (10-78 %) was seen in 70.6 % of subjects. Conclusions Intracystic injection of LSAM-PTX into mucinous PCLs resulted in no significant AEs, a lack of systemic absorption, and resulted in reduction of cyst volume over a 6 month period.

Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer.

PURPOSE: We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: The trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses. Tumor recurrence was evaluated by cytology, cystoscopy, or biopsy. Pharmacokinetic analysis of blood and multiplex immunofluorescence of tumor microenvironment occurred pre- and post-LSAM-DTX. RESULTS: Nineteen subjects were enrolled, 14 with prior bacillus Calmette-Guérin exposure and 16 with ≥1 prior TURBT. Direct injection and intravesical LSAM-DTX were well tolerated. In the 3 lowest dose escalation cohorts the median recurrence-free survival was 5.4 months (10 patients, median followup 8.6 months). In the high-dose and expansion cohorts median recurrence-free survival was significantly increased (p <0.05, hazard ratio 0.29) to 12.2 months (9 patients, median followup 12.4 months). Systemic docetaxel exposure was negligible and increases in antitumor immune cells were found in the tumor microenvironment along with elevations in the PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitor targets. CONCLUSIONS: Post-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk nonmuscle-invasive bladder cancer. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrants investigation alone as well as in combination with immune checkpoint inhibitor therapy.

Evaluating the appropriateness of platelet transfusions compared with evidence-based platelet guidelines: An audit of platelet transfusions at 57 hospitals.

BACKGROUND: Platelet transfusions are used to prevent or control bleeding in patients with thrombocytopenia or platelet dysfunction. The pretransfusion platelet count threshold has been studied extensively in multiple patient settings yielding high-quality evidence that has been summarized in several comprehensive evidence-based platelet guidelines. STUDY DESIGN AND METHODS: A prospective 12-week audit of consecutive platelet transfusions using validated and evidence-based adjudication criteria was conducted. Patient demographic, laboratory, and transfusion details were collected with an electronic audit tool. Each order was adjudicated either electronically or independently by two transfusion medicine physicians. The aim was to determine platelet transfusion appropriateness and common scenarios with deviations from guidelines. RESULTS: Fifty-seven (38%) of 150 hospitals provided data on 1903 platelet orders, representing 90% of platelet usage in the region during the time period. Overall, 702 of 1693 adult (41.5%) and 133 of 210 pediatric orders (63.3%) were deemed inappropriate. The most common inappropriate platelet order was for prophylaxis in the absence of bleeding or planned procedure in patients with hypoproliferative thrombocytopenia and a platelet count over 10 x 109 /L (53% of inappropriate orders in adults and 45% in pediatrics). Platelet transfusions ordered with either a preprinted transfusion order set (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.44-2.73) or technologist prospective screening (OR, 1.40; 95% CI, 1.10-1.78) were more likely to be appropriate. CONCLUSION: There is a discrepancy between clinical practice and evidence-based platelet guidelines. Broad educational and system changes will be needed to align platelet transfusion practice with guideline recommendations.

Local administration of submicron particle paclitaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects without local or systemic toxicity: preclinical and clinical studies.

This report describes local administration of submicron particle paclitaxel (SPP) (NanoPac®: ~ 800-nm-sized particles with high relative surface area with each particle containing ~ 2 billion molecules of paclitaxel) in preclinical models and clinical trials evaluating treatment of carcinomas. Paclitaxel is active in the treatment of epithelial solid tumors including ovarian, peritoneal, pancreatic, breast, esophageal, prostate, and non-small cell lung cancer. SPP has been delivered directly to solid tumors, where the particles are retained and continuously release the drug, exposing primary tumors to high, therapeutic levels of paclitaxel for several weeks. As a result, tumor cell death shifts from primarily apoptosis to both apoptosis and necroptosis. Direct local tumoricidal effects of paclitaxel, as well as stimulation of innate and adaptive immune responses, contribute to antineoplastic effects. Local administration of SPP may facilitate tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Results of preclinical and clinical investigations described here suggest that local administration of SPP achieves clinical benefit with negligible toxicity and may complement standard treatments for metastatic disease.

Hospital-based transfusion error tracking from 2005 to 2010: identifying the key errors threatening patient transfusion safety.

BACKGROUND: This report provides a comprehensive analysis of transfusion errors occurring at a large teaching hospital and aims to determine key errors that are threatening transfusion safety, despite implementation of safety measures. STUDY DESIGN AND METHODS: Errors were prospectively identified from 2005 to 2010. Error data were coded on a secure online database called the Transfusion Error Surveillance System. Errors were defined as any deviation from established standard operating procedures. Errors were identified by clinical and laboratory staff. Denominator data for volume of activity were used to calculate rates. RESULTS: A total of 15,134 errors were reported with a median number of 215 errors per month (range, 85-334). Overall, 9083 (60%) errors occurred on the transfusion service and 6051 (40%) on the clinical services. In total, 23 errors resulted in patient harm: 21 of these errors occurred on the clinical services and two in the transfusion service. Of the 23 harm events, 21 involved inappropriate use of blood. Errors with no harm were 657 times more common than events that caused harm. The most common high-severity clinical errors were sample labeling (37.5%) and inappropriate ordering of blood (28.8%). The most common high-severity error in the transfusion service was sample accepted despite not meeting acceptance criteria (18.3%). The cost of product and component loss due to errors was $593,337. CONCLUSION: Errors occurred at every point in the transfusion process, with the greatest potential risk of patient harm resulting from inappropriate ordering of blood products and errors in sample labeling.