BackgroundBody 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.MethodsWe 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.ResultsMost 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.ConclusionsPatients 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.

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. The Oncologist 2014; 19:536-544 Implications for Practice: Constitutive and transientendogenous inhibitors of STAT3 maintain pathway homeostasis in the cell.The potential use of STAT3 inhibitors in hematological malignancies is reviewed due to recent discoveries in the field.

Cancer of unknown primary (CUP) is a rare and challenging clinical diagnosis, fraught with uncertainties for both patients and oncologists. Although realistic conversations about prognosis can aid informed decision-making regarding patient care, models that can actually provide reliable and individualized estimates of survival for patients with CUP are lacking. Traditional risk stratification models pool patients at either good or poor risk which limit a meaningful patient-provider dialogue. Using this large multicenter cohort of 926 patients with CUP, we developed and validated a robust prognostic model and nomogram to predict overall survival with superior performance (concordance probability estimate of 0.69 and concordance index of 0.71) compared to traditional prognostic classifiers. This model uses universally available baseline factors to ensure feasibility of use in diverse clinical settings and is available as a web-based application.Personalized prognostication with this CUP nomogram can not only aid informed clinical decisions but also trial selection/stratification.Research.

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 5 0.0002). Multivariate analysis demonstrated that a history of VTE (P < 0.0001), pancreatic cancer (P 5 0.007), and platelet count >440 3 10 9 /L (P 5 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. 84:408-413, 2009. V

4599 Background: Pancreatic cancer is virtually always lethal, and the only FDA-approved therapies–gemcitabine and erlotinib–produce objective responses in less than 10% of patients. Curcumin (diferuloyl methane) is a plant-derived dietary ingredient that suppresses NF-κB and numerous other pathways relevant to pancreatic cancer and has potent preclinical anti-tumor activity. Herein, we evaluated the safety and potential antitumor activity of curcumin against advanced pancreatic cancer, and its impact on biologic correlates. Methods: Patients received 8 grams of curcumin by mouth daily for two months and were then restaged. Maintenance therapy was continued at the same dose and schedule until disease progression. Results: Twenty-five patients were enrolled as of the date of analysis, with 21 evaluable for response. Circulating curcumin was detectable, albeit at low steady-state levels (about 31 ng/ml), suggesting poor oral bioavailability. To date, two patients have had prolonged stable disease (8 and 12+ months). Interestingly, one patient had a brief, but marked tumor regression (73%) (accompanied by significant increases (4–35-fold) in serum cytokine (interleukin-6 (IL-6), IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) levels). No toxicities have been observed. Curcumin down-regulated expression of NF-κB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells (PBMC) from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers)although the decrease did not reach statistical significance for p65. Curcumin was determined in patient plasma samples after enzymatic digestion with glucuronidase enzyme. While there was considerable variation in plasma curcumin levels from patient to patient, drug levels peaked at 22–41 ng/ml and remained relatively constant over the entire 4 week experimental period. Conclusions: We conclude that oral curcumin is well tolerated and, despite its limited absorption, has biologic activity in patients with pancreatic cancer. [Table: see text] No significant financial relationships to disclose.