Task Shifting and Skin Punch for the Histologic Diagnosis of Kaposi's Sarcoma in Sub-Saharan Africa: A Public Health Solution to a Public Health Problem.

Fueled by HIV, sub-Saharan Africa has the highest incidence of Kaposi's sarcoma (KS) in the world. Despite this, KS diagnosis in the region is based mostly on clinical grounds. Where biopsy is available, it has traditionally been excisional and performed by surgeons, resulting in multiple appointments, follow-up visits for suture removal, and substantial costs. We hypothesized that a simpler approach - skin punch biopsy - would make histologic diagnosis more accessible. To address this, we provided training and equipment for skin punch biopsy of suspected KS to three HIV clinics in East Africa. The procedure consisted of local anesthesia followed by a disposable cylindrical punch blade to obtain specimens. Hemostasis is facilitated by Gelfoam®. Patients removed the dressing after 4 days. From 2007 to 2013, 2,799 biopsies were performed. Although originally targeted to be used by physicians, biopsies were performed predominantly by nurses (62%), followed by physicians (15%), clinical officers (12%) and technicians (11%). There were no reports of recurrent bleeding or infection. After minimal training and provision of inexpensive equipment (USD 3.06 per biopsy), HIV clinics in East Africa can integrate same-day skin punch biopsy for suspected KS. Task shifting from physician to non-physician greatly increases access. Skin punch biopsy should be part of any HIV clinic's essential procedures. This example of task shifting may also be applicable to the diagnosis of other cancers (e.g., breast) in resource-limited settings.

New Zealand national retrospective cohort study of survival outcomes of patients with metastatic melanoma receiving immune-checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have increased overall survival (OS) in metastatic melanoma in all clinical trials to date. However, pivotal trial populations were not representative of the real-world population in New Zealand. Real-world treatment effectiveness studies help evaluate the value of public pharmaceutical expenditure. AIM: To determine the survival outcomes of New Zealand patients with unresectable or metastatic melanoma treated with pembrolizumab or nivolumab. METHODS: This is a national retrospective cohort study. Patients with advanced unresectable or metastatic melanoma who received publicly funded immune-checkpoint inhibitors (ICIs) from 2017 to 2019 were included. Individual patient data were extracted from national administrative databases. The primary endpoint was OS, and secondary endpoints included OS by age, duration of treatment, posttreatment survival, and 30-day mortality from last pharmaceutical claim. RESULTS: Five hundred ninety-seven patients were included, with a median follow-up of 25 months. One-year OS was 72%, the 2-year OS estimate was 60%, and median OS not reached. Survival did not differ by dichotomized age (≥70 vs. <70 year old), hazard ratio (HR) .94 (95% confidence interval (CI): .72-1.22; p = .62). Median duration of treatment was 9.0 months (95% CI: 7.9-10.1). Median post-treatment survival for the subgroup who had ceased treatment was 12.0 months (95% CI: 9.0-14.0). For the sample as a whole, the estimated 30-day mortality from last pharmaceutical claim was 15.7%. CONCLUSION: OS in our New Zealand real-world population is comparable to pivotal clinical trials and real-world data (RWD) from other countries. These findings support the achievement of health gains from use of ICI in advanced unresectable and metastatic melanoma.

Lessons learned from development of docetaxel.

BACKGROUND: Docetaxel has benefited from focused evaluation of its preclinical pharmacology and pharmacokinetics, as well as the evolving areas that are becoming significant to cancer drug development: pharmacogenetics, population pharmacokinetics, and in vivo quantitative pharmacology. OBJECTIVE: This review juxtaposes the evolution of clinical use of docetaxel and the efforts to limit its observed clinical variability through understanding of its fundamental pharmacology. METHODS: The clinical review portion of this paper focuses on the examples of breast and lung cancer, to highlight the empiric process that have defined the current drug development process. The exploration of published reports on the clinical pharmacology of docetaxel is then reviewed to emphasize the rich resources available for future development of docetaxel in malignancy. RESULTS/CONCLUSION: As docetaxel moves forward in development, the knowledge gained in the evolution of docetaxel thus far can be leveraged in a model-based drug development schema to effectively use this body of data to make informed decisions about future dose/drug combinations and maximize the chance of further successes in the clinical arena.

A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors.

PURPOSE: Enoticumab (REGN421) is a fully human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. EXPERIMENTAL DESIGN: Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W). RESULTS: Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non-small cell lung cancer bronchoalveolar-type with a ß-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3> 6 months). CONCLUSIONS: Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. Clin Cancer Res; 21(12); 2695-703. ©2015 AACR.