Zachary Thompson

An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.

Promoting Physical Activity Among Youth Through Community‐Based Prevention Marketing

BACKGROUND Community-based prevention marketing (CBPM) is a program planning framework that blends community-organizing principles with a social marketing mind-set to design, implement, and evaluate public health interventions. A community coalition used CBPM to create a physical activity promotion program for tweens (youth 9-13 years of age) called VERB Summer Scorecard. Based on the national VERB media campaign, the program offered opportunities for tweens to try new types of physical activity during the summer months. METHODS The VERB Summer Scorecard was implemented and monitored between 2004 and 2007 using the 9-step CBPM framework. Program performance was assessed through in-depth interviews and a school-based survey of youth. RESULTS The CBPM process and principles used by school and community personnel to promote physical activity among tweens are presented. Observed declines may become less steep if school officials adopt a marketing mind-set to encourage youth physical activity: deemphasizing health benefits but promoting activity as something fun that fosters spending time with friends while trying and mastering new skills. CONCLUSIONS Community-based programs can augment and provide continuity to school-based prevention programs to increase physical activity among tweens.

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Background:Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer.Methods:The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women.Results:Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers.Conclusions:Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.

A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer.

PURPOSE This study describes practitioner knowledge and practices related to BRCA testing and management and explores how training may contribute to practice patterns. METHODS A survey was mailed to all BRCA testing providers in Florida listed in a publicly available directory. Descriptive statistics characterized participants and their responses. RESULTS Of the 87 respondents, most were community-based physicians or nurse practitioners. Regarding BRCA mutations, the majority (96%) recognized paternal inheritance and 61% accurately estimated mutation prevalence. For a 35-year-old unaffected BRCA mutation carrier, the majority followed national management guidelines. However, 65% also recommended breast ultrasonography. Fewer than 40% recognized the need for comprehensive rearrangement testing when BRACAnalysis(®) was negative in a woman at 30% risk. Finally, fewer than 15% recognized appropriate testing for a BRCA variant of uncertain significance. Responses appeared to be positively impacted by presence and type of cancer genetics training. CONCLUSIONS In our sample of providers who order BRCA testing, knowledge gaps in BRCA prevalence estimates and appropriate screening, testing, and results interpretation were identified. Our data suggest the need to increase regulation and oversight of genetic testing services at a policy level, and are consistent with case reports that reveal liability risks when genetic testing is conducted without adequate knowledge and training.

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

Preventing eye injuries among citrus harvesters: the community health worker model.

OBJECTIVES Although eye injuries are common among citrus harvesters, the proportion of workers using protective eyewear has been negligible. We focused on adoption of worker-tested safety glasses with and without the presence and activities of trained peer-worker role models on harvesting crews. METHODS Observation of 13 citrus harvesting crews established baseline use of safety eyewear. Nine crews subsequently were assigned a peer worker to model use of safety glasses, conduct eye safety education, and treat minor eye injuries. Safety eyewear use by crews was monitored up to 15 weeks into the intervention. RESULTS Intervention crews with peer workers had significantly higher rates of eyewear use than control crews. Intervention exposure time and level of worker use were strongly correlated. Among intervention crews, workers with 1 to 2 years of experience (odds ratio [OR] = 2.89; 95% confidence interval [CI] = 1.11, 7.55) and who received help from their peer worker (OR = 3.73; 95% CI = 1.21, 11.57) were significantly more likely to use glasses than were other intervention crew members. CONCLUSIONS Adaptation of the community health worker model for this setting improved injury prevention practices and may have relevance for similar agricultural settings.

Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers

BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management (CRM) strategies varies by service provider. Using a registry‐based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling (GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi‐squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers.

Temporal Trends in Demographics and Overall Survival of Non-Small-Cell Lung Cancer Patients at Moffitt Cancer Center From 1986 to 2008

BACKGROUND An assessment of historical trends in patient survival is important to determine the progress toward patient outcomes and to reveal where advancements must be made. The goal of this study was to assess changes in demographics and overall survival of non-small-cell lung cancer (NSCLC) patients who were seen at Moffitt Cancer Center spanning 22 years. METHODS This analysis included 4,997 NSCLC patients who were treated at our institute over 5 time periods: 1986 to 1988, 1991 to 1993, 1996 to 1998, 2001 to 2003, and 2006 to 2008. Kaplan-Meier survival curves and the log-rank statistic were used to assess changes in 5-year survival rates over the 5 time periods, and multivariable hazard ratios were estimated from Cox proportional hazards models. RESULTS From 1986 to 2008 we observed statistically significant increases in the percentage of patients over the age of 70 years, women, never-smokers and former smokers, and patients with stage I tumors. Over the same time period the median survival time statistically significantly increased from 1.09 years (95% confidence interval [CI], 0.95-1.34, P < .001) to 2.27 years (95% CI, 2.07-2.46, P < .001), and the overall 5-year survival rate for all patients significantly increased from 14.7% to 31.1% (P < .001). Among stage I patients, the 5-year survival rate increased from 31.7% to 54.0% (P < .001), 13.3% to 36.0% for stage II (P < .001), 10.5% to 21.7% for stage III (P < .001), and 3.4% to 9.6% for stage IV (P < .001). CONCLUSIONS This analysis demonstrated important temporal changes in the demographics and improvements in overall survival of NSCLC patients treated at our institute from 1986 to 2008. The 5-year survival rates and median survival time of patients diagnosed with NSCLC has significantly improved across all stages, including patients with late-stage disease.

Temporal trends from 1986 to 2008 in overall survival of small cell lung cancer patients.

OBJECTIVES An assessment of temporal trends in patient survival is important to determine the progress toward patient outcomes and to reveal where advancements must be made. This study assessed temporal changes spanning 22years in demographics, clinical characteristics, and overall survival of small cell lung cancer (SCLC) patients. MATERIALS AND METHODS This analysis included 1032 SCLC patients spanning two time-periods from the H. Lee Moffitt Cancer Center and Research Institute: 1986-1999 (N=410) and 2000-2008 (N=622). Kaplan-Meier survival curves and log-rank statistics were used to assess survival rates across the two time-periods and multivariable Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS The overall 5-year survival rate significantly increased from 8.3% for the 1986-1999 time-period to 11.0% (P<0.001) for the 2000-2008 time-period, and the median survival time increased from 11.3months (95% CI 10.5-12.7) to 15.2months (95% CI 13.6-16.6). We also observed significant increases in stage-specific median survival times and survival rates across the two time-periods. A multivariable Cox proportional hazards model for the entire cohort revealed significant increased risk of death for patients diagnosed in 1986-1999 (HR=1.29; 95% CI 1.11-1.49), patients diagnosed between 60 and 69years of age (HR=1.33; 95% CI 1.04-1.49) and over 70years of age (HR=1.63; 95% CI 1.26-2.11), men (HR=1.33; 95% CI 1.16-1.53), patients with no first course treatment (HR=2.17; 95% CI 1.57-3.00) and extensive stage SCLC (HR=2.79; 95% CI 2.35-3.30). CONCLUSION This analysis demonstrated significant improvements in overall and stage-specific median survival times and survival rates of SCLC patients treated at the Moffitt Cancer Center from 1986 to 2008.

Serum albumin as a stable predictor of prognosis during initial treatment in patients with diffuse large B cell lymphoma.

Dear Editor, Low serum albumin has been identified as a prognostic indicator in several hematologic malignancies including diffuse large B cell lymphoma (DLBCL) [1]. In both the preand post-rituximab era, pre-treatment of serum albumin <37 g/L has been shown to be a poor prognostic factor in patients with DLBCL [2, 1]. Since serum albumin does not change greatly over time, we hypothesized that serum albumin may be a stable biomarker during treatment in patients with DLBCL. Our study aims to determine whether serum albumin remains a stable prognostic factor when measured at different points during treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL. After obtaining Institutional Review Board approval, patients at the Moffitt Cancer Center with DLBCL who underwent chemotherapy with R-CHOP between 2007 and 2010 were identified using the institutional database. Clinical and treatment data at baseline, prior to each cycle of chemotherapy and 4 weeks after treatment, were recorded and summary statistics were calculated. Patients with missing serum albumin data were excluded from that particular analysis. The clinical outcomes, overall survival (OS), and progression free survival (PFS) were analyzed using a univariate Cox Proportional Hazard model with serum albumin <37 or ≥37 g/L. A total of 124 patients were initially identified. Thirty-six patients were excluded for not having serum albumin data or due to treatment at an outside institution. The majority of the patients were male (63.6 %), 64.8 % received 6 cycles of RCHOP, 63 (71.6 %) had complete response as best response, and 7 (19.3 %) relapsed [1]. Serum albumin remained a predictor of PFS and OS at baseline prior to cycles 1, 2, and 4 of R-CHOP. At 4 weeks after R-CHOP, serum albumin was a predictor of OS, but not of PFS (Table 1). Serum albumin values were statistically different when compared between cycles 1 vs. 2 (p = 0.004), but not between other cycles, indicating that serum albumin levels were stable throughout R-CHOP. Our analysis indicates that serum albumin levels during treatment of R-CHOP remain stable and that serum albumin <37 g/L may predict survival at the start of treatment prior to cycle 2, prior to cycle 4, and 4 weeks after during treatment of DLBCL with R-CHOP. Other biomarkers including Creactive protein, lymphocyte count, and beta2-microglobulin levels have been suggested to be predictors of survival in patients with DLBCL during treatment or at relapse [3–6]. Serum albumin is easily collected and may be a better indicator of comorbid status than age and/or a marker of worsening tumor biology [1]. We suspect that when used in conjunction with other clinical indicators, serum albumin may help to identify patients who may relapse or require additional therapy to better identify an “at-risk” group of patients. The results of this small sample size should be confirmed prior to using serum albumin as a prognostic marker over the course of treatment in DLBCL treated with R-CHOP. J. Eatrides : C. Bello Division of Hematological Malignancies, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA