Ahmad Zarzour

The Effect of a Neutropenic Diet on Infection and Mortality Rates in Cancer Patients: A Meta-Analysis

Neutropenic diets (ND) are often prescribed to cancer patients aiming to reduce infection risk. The goal of this meta-analysis was to determine if ND indeed reduced the risk of infection and death in cancer patients compared to regular diets (RD). We identified studies in cancer patients that compared the effect of ND vs. RD on the risk of infections and mortality of any cause. The overall effect was calculated by use of a random effects model. Four studies were identified encompassing 918 patients. There was no difference in major infection or mortality rates between ND and RD groups. When analyzing for the overall composite outcome of any infection or fever, the hazard ratio was significantly higher in the ND arm (relative risk = 1.18, confidence interval: 1.05 to 1.34, P= 0.007). When the analysis was restricted to only the randomized trials, both groups had a comparable composite outcome. This meta-analysis shows no superiority with respect to mortality or infection of using a neutropenic diet in cancer patients. Larger studies are needed that study a broader range of nutritional issues, including the microbiome, in this patient population. Until then, it may be time to relax the restrictions of ND.

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed-treatment comparison

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP‐CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP‐CML and enrolling 2,456 patients were included. Follow‐up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%IS) achievement with second‐generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed‐treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR4.5 ≤ 0.0032%IS) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new‐generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow‐up period. It is important to note out that MTC is not a substitute for well‐conducted RCTs investigating direct comparisons.

Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP‐CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP‐CML and enrolling 2,456 patients were included. Follow‐up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%IS) achievement with second‐generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed‐treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR4.5 ≤ 0.0032%IS) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new‐generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow‐up period. It is important to note out that MTC is not a substitute for well‐conducted RCTs investigating direct comparisons.

The complexity of interpreting genomic data in patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML.

Approach to Management of Thrombotic Thrombocytopenic Purpura at University of Cincinnati

Thrombotic Thrombocytopenic Purpura (TTP) is a rare hematologic emergency, congenital or acquired, characterized by ischemic damage of various organs because of platelet aggregation. It is the common name for adults with microangiopathic hemolytic anemia, thrombocytopenia, with or without neurologic or renal abnormalities, and without another etiology; children without renal failure are also described as TTP. Plasma exchange (PE) is the main stay of treatment in combination with steroids and immunosuppressive therapies. The monoclonal antibody against CD20 Rituximab decreases the production of antibodies from B lymphocytes and it is used for antibodies-mediated diseases including TTP. We present our data on retrospective analysis of rituximab in treatment of TTP at University of Cincinnati in a series of 22 patients from 1997 to 2009. Our results showed that PE with immunosuppressive therapy resulted in decreased duration of PE, relapse rate, and increased duration of remission in patients with TTP.

Prolonged Survival in a Patient with Metastatic Vasoactive Intestinal Peptide Producing Pancreatic Neuroendocrine Tumors

VIPomas are rare neuroendocrine tumors that secrete vasoactive intestinal peptide. They are detected in 1 in ten million people per year. The majority of these tumors arises within the pancreas, but may also arise as other VIP-secreting tumors as in bronchogenic carcinoma, colon carcinoma, ganglioneuroblastoma, pheochromocytoma, hepatoma and adrenal tumors. They are characterized by profound diarrhea, hypokalemia, and achlorhydria and were first described by Verner and Morrison in 1958. It was also named pancreatic cholera as the cholera toxin acts; the Vasoactive Intestinal Peptide (VIP) causes elevation of the cyclic adenosine monophosphate, resulting in intestinal smooth muscle relaxation, inhibition of electrolyte absorption and profound secretory diarrhea. We are reporting a case involving a 42 year old male patient who presented with intermittent attacks of watery diarrhea up to 10 times per day for 3 weeks mostly worsening in the last 3 days prior to seeking medical advice. Stool studies were negative, but patient had hyperglycemia and mild hyponatremia. Further evaluation revealed a pancreatic mass with multiple hepatic focal lesions encountered in abdominal ultrasound and CT scan. Ultrasound guided biopsy revealed metastatic pancreatic endocrine carcinoma with VIP expression. Serum VIP level was elevated to 496 (Normal <100). We report a case of metastatic well-differentiated VIPoma treated mainly with long acting octreotide and streptozocin/5fluorouracil combination showing marked improvement of symptoms, minimal response of the tumor size but more significantly, more than 2 year period survival/follow up in a patient that was not a candidate for surgical resection. Review of literature focused on cases with metastatic VIPoma who were not surgical candidates, but had prolonged survival of more than 2 years disease. We reviewed the different therapeutic options offered for this patient population exploring the response rates, survival and recent recommendations.

The use of pharmacogenomics for selection of therapy in non-small-cell lung cancer.

Introduction Performance status (PS) is the only known clinical predictor of outcome in patients with advanced non-small-cell lung cancer (NSCLC), although pharmacogenomic markers may also correlate with outcome. The aim of our study was to correlate clinical and pharmacogenomic measures with overall survival. Methods This was an IRB approved, retrospective study in which the medical records of 50 patients with advanced NSCLC from 1998–2008 were reviewed, and gender, race, PS, and chemotherapy regimens were documented. Stromal expression of pharmacogenomic markers (VEGFR, ERCC1, 14-3-3σ, pAKT, and PTEN) was measured. Clinical factors and pharmacogenomics markers were compared to overall survival using a Cox proportional hazards model. Results Forty patients received platinum-based therapy. Median age was 65 years. Improved PS, female gender, and gemcitabine therapy were significantly associated with longer overall survival (P = 0.004, P = 0.04, and P = 0.003, respectively). Age was not associated with survival. Caucasians had better overall survival in comparison to African Americans with median survival of 14.8 months versus 10.4 months (P = 0.1). Patients treated with platinum-based therapy had better survival of 15 months versus 8 months for non-platinum based therapy (P = 0.01). There was no significant association between any of the pharmacogenomics markers and overall survival other than in patients treated with platinum, in whom ERCC1 negativity was strongly associated with longer survival (P = 0.007). Conclusion ERCC1 negativity with platinum therapy, gemcitabine therapy, good PS, and female gender all correlated with improved overall survival in patients with advanced NSCLC.

Phase II Clinical Trial of Gefitinib for the Treatment of Chemonaïve Patients with Advanced Non-small Cell Lung Cancer with Poor Performance Status

Background Patients with advanced non-small cell lung cancer (NSCLC) have no curative treatment options; therefore, improving their quality of life (QOL) is an important goal. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, is a safe oral agent that may be of benefit to a specific population of NSCLC. Patients and Methods A Phase II clinical trial included chemonaïve patients with advanced NSCLC and poor performance status (PS). Response rate, progression-free survival, overall survival, QOL using the Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire, and Trial Outcome Index (TOI) were evaluated. Results Twelve out of 19 enrolled patients were evaluable. The median age for the evaluable patients was 68.8 years (59.7–74.6). Out of all the patients, 7 (58.3%) had adenocarcinoma and 5 (41.7%) had squamous cell carcinoma. The median duration of treatment was 62.5 days (26.5–115.0) in the evaluable patients. Grade 3/4 toxicities included fatigue, rash, diarrhea, and nausea. One patient had partial response, eight patients had stable disease (SD), and three patients progressed. The median overall survival for the evaluable population was 4.9 months (2.3–16). The median progression-free survival was 3.7 months (1.9–6.6). TOI was marginally associated with the overall survival, with a hazard ratio of 0.92 (95% confidence interval: 0.84, 1.0) (P = 0.061). FACT-L score and the TOI were highly correlated (r = 0.96, P < 0.0001). TOI scores were higher in African Americans compared to Caucasians and increased with age. Conclusion Our results suggest that gefitinib use in patients with NSCLC and poor PS may improve the QOL of older patients and African American patients.