Myeloablative busulfan/cytoxan conditioning versus reduced-intensity fludarabine/melphalan conditioning for allogeneic hematopoietic stem cell transplant in patients with acute myelogenous leukemia.

Fludarabine and melphalan (Flu/Mel) has emerged as a more tolerable chemotherapy-based conditioning regimen compared with busulfan and cyclophosphamide (Bu/Cy) for allogeneic stem cell transplant (allo-hematopoietic stem cell transplantation (HSCT)) patients with acute myelogenous leukemia (AML). We conducted a retrospective review of a single-institution database including patients with AML who received allo-HSCT following conditioning with Mel/Flu or Bu/Cy-based regimens. We performed descriptive statistical analysis to examine patient demographics and clinical outcomes. We identified 156 patients meeting criteria between 2005 and 2014. Overall, patients conditioned with Bu/Cy were significantly younger, but more likely to be treated in an earlier era than those receiving Flu/Mel. Regimen choice was not associated with relapse rates (RR), relapse-free survival (RFS), or overall survival (OS) on both univariate and multivariable analyses. Bu/Cy was associated with increased non-relapse mortality (NRM) on multivariable analysis. These findings demonstrate that Flu/Mel provides non-inferior disease control and could be an appropriate regimen for selected patients.

The effects of androgen deprivation therapy on cardiac function and heart failure: implications for management of prostate cancer.

Conflicting clinical evidence regarding the possible association between androgen deprivation therapy (ADT) with heart failure in men with prostate cancer is reviewed, including 2 population-based registries showing such an association, and 1 showing no association. Studies of the effects of androgens on cardiomyocyte contractility at the molecular level, the effects of testosterone on the cardiovascular system, particularly cardiac function, and the beneficial effects of testosterone therapy for patients with heart failure might help illuminate this controversy. Future studies are needed to evaluate the effect of ADT on end points of heart failure. The authors weigh the possible adverse effects of ADT on cardiac function and heart failure against its known benefits to cancer outcomes, defined according to published, randomized trials, in a discussion of the implications of the preclinical and clinical literature on the management of prostate cancer in men at risk for heart failure. In the absence of conclusive evidence that ADT causes heart failure, the authors discuss clinical situations in which ADT may be delayed, given on a short-term or intermittent basis, or withheld from treatment with the goal of reducing the risks of heart failure without compromising prostate cancer outcomes.

High-dose radiotherapy with or without androgen deprivation therapy for intermediate-risk prostate cancer: cancer control and toxicity outcomes.

PURPOSE: To evaluate the impact of short-course androgen deprivation therapy (ADT) on cancer control outcomes and toxicity in intermediate-risk prostate cancer treated with dose-escalated external beam radiotherapy (high-dose radiotherapy [HDRT]). METHODS AND MATERIALS: Demographic, disease, and treatment characteristics of prostate cancer patients at 2 institution consortiums were charted. Of 296 men with intermediate-risk prostate cancer (defined as ≥T2b, prostate-specific antigen level >10 ng/mL, or Gleason score [GS] of 7, with none of the following: ≥T3, prostate-specific antigen level >20 ng/mL, GS ≥8, or positive nodes) treated with HDRT to a dose of 72 Gy or greater, 123 received short-course ADT and 173 did not. Univariate and multivariate analyses on biochemical failure-free survival (BFFS) (including subset analysis by disease factors) and on overall survival (OS) were performed, as were comparisons of gastrointestinal (GI) and genitourinary (GU) toxicity rates. RESULTS: For the whole group, the median dose was 75.6 Gy; the minimum follow-up was 2 years, and the median follow-up was 47.4 months. For ADT vs. no ADT, the 5-year BFFS rate was 86% vs. 79% (p = 0.138) and the 5-year OS rate was 87% vs. 80% (p = 0.159). On multivariate analysis, percent positive cores (PPC) (p = 0.002) and GS (p = 0.008) were significantly associated with BFFS, with ADT showing a trend (p = 0.055). The impact of ADT was highest in the subsets with PPC greater than 50% (p = 0.019), GS 4+3 (p = 0.078), and number of risk factors greater than 1 (p = 0.022). Only intensity-modulated radiotherapy use (p = 0.012) and GS (p = 0.023) reached significance for OS, and there were no significant differences in GU or GI toxicity. CONCLUSIONS: Although the use of ADT with HDRT did not influence BFFS, our study suggests a benefit in patients with PPC greater than 50%, GS 4+3, or multiple risk factors. No OS benefit was shown, and ADT was not associated with additional radiotherapy-related GI or GU toxicity.

Matched cohort analysis of outcomes of definitive radiotherapy for prostate cancer in human immunodeficiency virus-positive patients.

PURPOSE: To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT). METHODS AND MATERIALS: A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity-modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate-only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months). RESULTS: The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p < 0.001, p < 0.001, p = 0.003, and p < 0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm(3). CONCLUSIONS: Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population.

Evaluation of automatic atlas-based lymph node segmentation for head-and-neck cancer.

PURPOSE: To evaluate if automatic atlas-based lymph node segmentation (LNS) improves efficiency and decreases inter-observer variability while maintaining accuracy. METHODS AND MATERIALS: Five physicians with head-and-neck IMRT experience used computed tomography (CT) data from 5 patients to create bilateral neck clinical target volumes covering specified nodal levels. A second contour set was automatically generated using a commercially available atlas. Physicians modified the automatic contours to make them acceptable for treatment planning. To assess contour variability, the Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm was used to take collections of contours and calculate a probabilistic estimate of the "true" segmentation. Differences between the manual, automatic, and automatic-modified (AM) contours were analyzed using multiple metrics. RESULTS: Compared with the "true" segmentation created from manual contours, the automatic contours had a high degree of accuracy, with sensitivity, Dice similarity coefficient, and mean/max surface disagreement values comparable to the average manual contour (86%, 76%, 3.3/17.4 mm automatic vs. 73%, 79%, 2.8/17 mm manual). The AM group was more consistent than the manual group for multiple metrics, most notably reducing the range of contour volume (106-430 mL manual vs. 176-347 mL AM) and percent false positivity (1-37% manual vs. 1-7% AM). Average contouring time savings with the automatic segmentation was 11.5 min per patient, a 35% reduction. CONCLUSIONS: Using the STAPLE algorithm to generate "true" contours from multiple physician contours, we demonstrated that, in comparison with manual segmentation, atlas-based automatic LNS for head-and-neck cancer is accurate, efficient, and reduces interobserver variability.

Concurrent chemotherapy with intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the larynx and oropharynx: a retrospective single-institution analysis.

BACKGROUND: We present outcome data from concurrent chemotherapy and intensity-modulated radiation therapy (IMRT) for squamous cell carcinoma (SCC) of the larynx and oropharyx. METHODS: Eighty patients with laryngeal (n = 15) or oropharyngeal (n = 65) SCC underwent concurrent IMRT and chemotherapy (cisplatin or carboplatin/paclitaxel). RESULTS: The 3-year overall survival (OS) and disease-free survival (DFS) were 81.2% and 78.3%, respectively, with a median follow-up of 31.2 months. There was a statistically significant correlation between OS and DFS with N classification (p = .0001), but not with disease site or T classification. Toxicities compared favorably with prior reports using conventional radiation therapy. CONCLUSIONS: This retrospective analysis reveals a very good outcome and an acceptable toxicity profile for patients with locally advanced SCC of the oropharynx and larynx treated with chemotherapy and IMRT concurrently.

Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: outcomes and toxicities.

PURPOSE: We report toxicity and survival data of human immunodeficiency virus (HIV)-infected men with anal carcinoma treated with combined modality therapy (CMT) of radiotherapy and concurrent chemotherapy. METHODS AND MATERIALS: A retrospective review was performed on the records of 17 HIV-positive patients with anal squamous cell carcinoma treated with CMT at our institution between 1991 and 2004. Radiotherapy consisted of 30.6 to 45 Gy to the pelvis, total dose of 50.4 to 59.4 Gy to initial gross disease, at 1.8 Gy/fraction. Chemotherapy consisted of 5-fluorouracil and either mitomycin C or cisplatin. The mean follow-up was 25.6 months (median, 15.6 months; range, 4.6-106 months). RESULTS: Significant acute skin and hematologic toxicity developed in 8 of 17 and 9 of 17 patients, respectively. One patient died 12 days after treatment of progressive disease and sepsis. Significant late toxic sequelae developed in 3 patients: 1 anorectal ulcer, 2 dermatologic (perianal ulceration, hemorrhagic perineal sores and suspected fissure). Fourteen of 15 patients with Stage I-III disease had a complete response; 2 complete responders subsequently had a relapse in the anorectum. For all patients, actuarial 18-month survival was 67%. For patients with Stage I-III disease, survival at last follow-up by low CD4 count (<200) vs. high count (>200) was 4 of 7 vs. 7 of 8, respectively; significant acute toxicities developed in 4 of 8 vs. 6 of 9, respectively. CONCLUSION: For HIV patients with anal carcinoma, CMT yields reasonable local control with significant acute complications. Survival is lower than in the general population, attributable more to the underlying infection than to the malignancy.

Differential patterns of apoptosis in response to aging in Drosophila.

Several lines of evidence suggest that programmed cell death may play a role in the aging process and the age-related functional declines of multicellular organisms. To pave the way for the use of Drosophila to rigorously test this hypothesis in a genetic model organism, this work examines the pattern of apoptosis in the adult fly during aging. The analysis across the lifespan of caspase activity and DNA fragmentation shows that apoptosis occurs in adult flies at all ages and that it is linked to physiological age. The results establish that under normal conditions, fly aging is coupled with a lifelong gradual increase of apoptosis within muscle cells and an activation of apoptosis in fat cells of old flies. The nervous system does not show signs of apoptosis. These time- and tissue-specific changes indicate that aging influences the levels and the nature of the cells that commit to apoptosis. The comparison with the apoptotic response to starvation and oxidative stresses strongly suggests that the lifelong increase in flight and leg muscles results from the accumulation of oxidative damage associated with aging. This finding presents an attractive mechanism to account for the decline of locomotor functions and muscle loss in the elderly and opens the way for the genetic analysis of sarcopenia in Drosophila.