Biomedical subjects

Brian M Wolpin

Publications and source records attributed to Brian M Wolpin.

3 recordsLinked to original sources

PubMed2006

Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer.

BACKGROUND: In this study, the maximum tolerated dose and toxicity profile of FOLFIRI (infusional fluorouracil [5-FU]/leucovorin/irinotecan) plus gefitinib (an oral inhibitor of the epidermal growth factor receptor) were evaluated as first-line therapy in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Sixteen patients participated in this study. Oral gefitinib was administered at 250 mg or 500 mg daily in 2 dose-escalation cohorts. FOLFIRI was administered without dose escalation on a 14-day cycle with treatment on day 1 with irinotecan 180 mg/m2, leucovorin 200 mg/m2, and 5-FU 400 mg/m2 bolus, followed by 5-FU 2400 mg/m2 continuous infusion over 46 hours. RESULTS: The maximum tolerated dose of gefitinib was 250 mg, with diarrhea and neutropenia noted as the principal dose-limiting toxicities. Dose reductions in 5-FU and irinotecan were required in 4 patients because of diarrhea and 1 patient because of neutropenia. A partial response was observed in 25% of patients, and 56% had stable disease for > 12 weeks, corresponding to a disease control rate of 81%. CONCLUSION: These findings suggest that gefitinib can be safely combined with FOLFIRI as first-line treatment of metastatic CRC and support the safety of further investigations of EGFR tyrosine kinase inhibitors with multiagent chemotherapy in this patient population.

Adenocarcinoma↗

PubMed2004

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML.

The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloid leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons were sequenced in samples from 53 patients with AML, 9 patients with acute lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three patients had novel point mutations at residue N841 that resulted in a change to isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation, receptor phosphorylation, and constitutive activation of signal transducer and activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), suggesting that the N841I mutation confers constitutive activity to the receptor. An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC(50) 10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 is the key residue in a hydrogen-bonding network that likely stabilizes the activation loop. These results suggest that mutations at N841 represent a significant new activating mutation in patients with AML and that patients with such mutations may respond to small-molecule FLT3 inhibitors such as PKC412.

Adult↗

PubMedDate not supplied

Learning to cope: how far is too close?

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital, founded The Kenneth B. Schwartz Center. The Schwartz Center is a nonprofit organization dedicated to advancing compassionate health care delivery, with the goal of providing hope to patients and support to caregivers. The Schwartz Center Rounds is a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, families, and caregivers, and gain insight and support from fellow staff members. The case is presented of a patient with a precipitous decline in health due to rapidly progressive, metastatic non-small cell lung cancer. The discussion at Schwartz Center Rounds centers on oncologists' feelings of failure and coping mechanisms when dealing with patients' deaths. This discussion is followed by a first-year oncology fellow's reaction to caring for this and other terminally ill patients. Then, to provide a broader framework in which to understand these issues, the emotional cost and measurable benefit of close relationships with patients is investigated. To conclude, further educational initiatives are advocated to assist both physicians-in-training and more senior clinicians in dealing with the difficult issues that arise when caring for very ill and dying patients.

Adaptation, Psychological↗