Role of nutritional indices in predicting outcomes of vascular surgery.

BACKGROUND: Malnutrition is frequent among vascular surgery patients, given their age, chronic comorbidities, and poor functional status, and it is believed to increase their operative risk. We aimed to assess the combined use of recent significant weight loss (>10% body mass) and serum albumin levels as a nutritional status index to predict outcomes. METHODS: We analyzed vascular surgery data from the American College of Surgeons National Surgical Quality Improvement Program database (2005-2012; N = 238,082) to compare operative death (in-hospital and 30-day operative death) across eight nutritional status groups based on weight loss (yes/no) and albumin category: very low albumin level (VL-Alb; <2.50 g/dL), low albumin level (L-Alb; 2.50-3.39 g/dL), normal albumin level (N-Alb; 3.40-4.39 g/dL), and high albumin level (H-Alb; 4.40-5.40 g/dL). Risk-adjusted odds ratios (AOR) with 95% confidence intervals were estimated by multivariable logistic regression (N-Alb [no weight loss], reference). RESULTS: The study population included 113,936 patients for whom albumin level was available (age, 67 ± 13 years; 60.2% male). Operative death was documented in 5160 (4.53%) patients. The eight-category nutritional status was more predictive of operative death than age alone (C statistic, 0.74 vs 0.63). A high discrimination multivariable model for operative death was derived (C statistic, 0.851). Low albumin level was associated with increased death that worsened in case of weight loss: VL-Alb + WL, AOR = 3.83 (3.03-4.83); VL-Alb, AOR = 3.36 (3.06-3.69); L-Alb + WL, AOR = 2.46 (1.98-3.05); and L-Alb, AOR = 1.99 (1.84-2.15). Weight loss was associated with increased death even if albumin level was normal: N-Alb + WL, AOR = 1.77 (1.34-2.35); and H-Alb + WL, AOR = 1.91 (0.69-5.31). H-Alb was protective (AOR = 0.65 [0.55-0.76]). CONCLUSIONS: Nutritional status predicts outcomes of vascular surgery. Serum albumin level and weight loss should be incorporated in patients' risk stratification.

The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has shown promising efficacy in limited preclinical studies. We used a panel of human ERMS and ARMS cell lines and xenografts to evaluate the effects of SAHA as a therapeutic agent in both RMS subtypes. SAHA decreased cell viability by inhibiting S-phase progression in all cell lines tested, and induced apoptosis in all but one cell line. Molecularly, SAHA-treated cells showed activation of a DNA damage response, induction of the cell cycle inhibitors p21Cip1 and p27Kip1 and downregulation of Cyclin D1. In a subset of RMS cell lines, SAHA promoted features of cellular senescence and myogenic differentiation. Interestingly, SAHA treatment profoundly decreased protein levels of the driver fusion oncoprotein PAX3-FOXO1 in ARMS cells at a post-translational level. In vivo, SAHA-treated xenografts showed increased histone acetylation and induction of a DNA damage response, along with variable upregulation of p21Cip1 and p27Kip1. However, while the ARMS Rh41 xenograft tumor growth was significantly inhibited, there was no significant inhibition of the ERMS tumor xenograft RD. Thus, our work shows that, while SAHA is effective against ERMS and ARMS tumor cells in vitro, it has divergent in vivo effects . Together with the observed effects on the PAX3-FOXO1 fusion protein, these data suggest SAHA as a possible therapeutic agent for clinical testing in patients with fusion protein-positive RMS.

Interplay between p53 and Ink4c in spermatogenesis and fertility.

The tumor suppressor p53, and the cyclin-dependent kinase inhibitor Ink4c, have been both implicated in spermatogenesis control. Both p53-/- and Ink4c-/- single knockout male mice are fertile, despite testicular hypertrophy, Leydig cell differentiation defect, and increased sperm count in Ink4c-/- males. To investigate their collaborative roles, we studied p53-/- Ink4c-/- dual knockout animals, and found that male p53-/- Ink4c-/- mice have profoundly reduced fertility. Dual knockout male mice show a marked decrease in sperm count, abnormal sperm morphology and motility, prolongation of spermatozoa proliferation and delay of meiosis entry, and accumulation of DNA damage. Genetic studies showed that the effects of p53 loss on fertility are independent of its downstream effector Cdkn1a. Absence of p53 also partially reverses the hyperplasia seen upon Ink4c loss, and normalizes the Leydig cell differentiation defect. These results implicate p53 in mitigating both the delayed entry into meiosis and the secondary apoptotic response that occur in the absence of Ink4c. We conclude that the cell cycle genes p53 and Ink4c collaborate in sperm cell development and differentiation, and may be important candidates to investigate in human male infertility conditions.

Wilms tumor: Successes and challenges in management outside of cooperative clinical trials.

OBJECTIVE/BACKGROUND: Management of Wilms tumor (WT) in children depends on a multidisciplinary approach to treatment, and outcomes have significantly improved as reported by cooperative group clinical trials. Here, we review the clinical outcomes of patients with WT and identify challenges and barriers encountered in multidisciplinary management outside of cooperative clinical trials. METHODS: We retrospectively reviewed the clinical records of 35 children with WT treated between April 2002 and June 2013 at the Children's Cancer Institute in Lebanon. RESULTS: Upfront resection was performed in 23 cases. Biopsies were performed for Stage V tumors (n=4), those with unresectable tumors or inferior vena caval thrombus (n=5), and patients who had partial surgery performed elsewhere prior to presentation (n=2). One patient died due to toxicity prior to surgery. The tumor was Stage I in eight patients, Stage II in five patients, Stages III and IV in nine patients each, and bilateral (Stage V) in four patients. Adherence to The National Wilms Tumor Study-5 recommendations was adequate. At the time of analysis, 30 patients were free of disease and four patients had relapse-all having metastatic disease initially. CONCLUSION: The National Wilms Tumor Study-5 therapy resulted in favorable outcomes in children with nonmetastatic Wilms tumor in the setting of a multidisciplinary approach to therapy and resolution of financial barriers to medical care. Upstaging due to prior intervention and lung radiation therapy to all those with computed tomography-detected lung nodules may both have resulted in overtreatment of a subset of patients. Finally, the relatively high incidence of bilateral tumors suggests the need for further genetic and molecular studies in this patient population.

p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells.

The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19(Arf) expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E-3-(4'-hydroxyl-3'-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.