Pathology Case Study: Pigmented Lesion

This is a case study presented by the University of Pittsburgh Department of Pathology in which a 69-year-old man has a pigmented lesion on his right ear. Visitors are given the patient history and microscopic description, including images, and are given the opportunity to diagnose the patient. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to use to introduce or test student learning in dermatologic pathology

A phase 1b multicenter study of TAS-102 in combination with irinotecan in patients with advanced recurrent or unresectable gastric and gastroesophageal adenocarcinoma after at least one line of treatment with a fluoropyrimidine and platinum-containing regimen

TAS-102 is approved for treatment of refractory metastatic gastroesophageal carcinoma (mGEC). This study sought to determine whether the combination of TAS-102 with irinotecan (TASIRI) was safe and effective in previously treated mGEC. This was a single-arm phase 1b study for patients (pts) with mGEC previously treated with at least one line of fluoropyrimidine and platinum-containing regimen. TAS-102 was given at 25 mg/m2 twice daily on days 1 to 5 with irinotecan 180 mg/m2 on day 1 of a 14-day cycle. The primary endpoint was progression-free survival at 6 months ≥ 35% (PFS-6). 20 Pts were enrolled. The study met its primary endpoint. PFS-6 is 40% (95% CI 19.3-60.0). Median PFS and overall survival are 5.3 months and not reached, respectively. 17 of 20 pts had measurable disease by RECIST criteria. Of the 17, 13 had stable disease and 4 had progressive disease as best response (8 pts had tumor shrinkage < 30%). The disease control rate was 75%. In exploratory analyses, mutations in homologous recombination deficiency genes were associated with inferior PFS (P < 0.03). The most common any grade (G) treatment-related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (20%) and neutropenia (10%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls

Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-β/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy

Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-β/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy