STAT3 inhibitors: finding a home in lymphoma and leukemia.

The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is an active mediator of cytokine signaling in the pathogenesis of solid and hematologic malignancies. The seven-member STAT family is composed of latent cytoplasmic transcription factors that are activated by phosphorylation intertwined in a network with activation that ultimately leads to cell proliferation. An activated kinase enzyme phosphorylates one STAT factor or more, which shuttle to the nucleus to regulate gene expression, promoting cell survival. Somatic STAT3 mutations have been recently reported in large granular lymphocytic leukemia, aplastic anemia, and myelodysplastic syndrome. Furthermore, the relationship between BCL6 and STAT3 in diffuse large B-cell lymphomas, particularly on the activated B-cell subtype, needs to be further explored. The search for therapeutic STAT3 inhibitors that abrogate the JAK/STAT pathway is currently under way. Targeting the STAT pathway, which seems to be critical in tumorigenesis, is promising for multiple malignancies including lymphoma and leukemia. In this paper, we review mechanisms of action, failures, and successes of STAT3 inhibitors.

Body composition, symptoms, and survival in advanced cancer patients referred to a phase I service.

BACKGROUND: Body weight and body composition are relevant to the outcomes of cancer and antineoplastic therapy. However, their role in Phase I clinical trial patients is unknown. METHODS: We reviewed symptom burden, body composition, and survival in 104 patients with advanced cancer referred to a Phase I oncology service. Symptom burden was analyzed using the MD Anderson Symptom Assessment Inventory(MDASI); body composition was evaluated utilizing computerized tomography(CT) images. A body mass index (BMI)≥25 kg/m² was considered overweight. Sarcopenia, severe muscle depletion, was assessed using CT-based criteria. RESULTS: Most patients were overweight (n = 65, 63%); 53 patients were sarcopenic (51%), including 79% of patients with a BMI<25 kg/m² and 34% of those with BMI≥25 kg/m². Sarcopenic patients were older and less frequently African-American. Symptom burden did not differ among patients classified according to BMI and presence of sarcopenia. Median (95% confidence interval) survival (days) varied according to body composition: 215 (71-358) (BMI<25 kg/m²; sarcopenic), 271 (99-443) (BMI<25 kg/m²; non-sarcopenic), 484 (286-681) (BMI≥25 kg/m²; sarcopenic); 501 d (309-693) (BMI≥25 kg/m²; non-sarcopenic). Higher muscle index and gastrointestinal cancer diagnosis predicted longer survival in multivariate analysis after controlling for age, gender, performance status, and fat index. CONCLUSIONS: Patients referred to a Phase I clinic had a high frequency of sarcopenia and a BMI≥25 kg/m², independent of symptom burden. Body composition variables were predictive of clinically relevant survival differences, which is potentially important in developing Phase I studies.

Clinical outcomes and factors predicting development of venous thromboembolic complications in patients with advanced refractory cancer in a Phase I Clinic: the M. D. Anderson Cancer Center experience.

Venous thromboembolism (VTE) is common in patients with advanced cancer and may influence patient eligibility for clinical studies, quality of life, and survival. We reviewed the medical records of 220 consecutive patients seen in the Phase I Clinical Trials Program at M. D. Anderson Cancer Center to determine the frequency of VTE, associated characteristics, and clinical outcomes. Twenty-three (10.5%) patients presenting to the Phase I Clinic had a history of VTE; 26 (11.8%) patients subsequently developed VTE, with a median follow-up of 8.4 months. These included nine (39%) patients with and 17 (8.6%) without a history of VTE (P < 0.0001). The most common events were deep venous thromboses of the extremities and pulmonary emboli. The median survival of patients with and without a history of VTE was 4.7 and 10.9 months, respectively (P = 0.0002). Multivariate analysis demonstrated that a history of VTE (P < 0.0001), pancreatic cancer (P = 0.007), and platelet count >440 x 10(9)/L (P = 0.026) predicted new VTE episodes. In conclusion, this retrospective analysis demonstrated that a history or new development of VTE was noted in 40 (18%) of 220 patients seen in our Phase I Clinic. A prognostic score that can be used to predict time to development of and frequency of VTE is proposed. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.