TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer.

PURPOSE: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer. EXPERIMENTAL DESIGN: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m(2) on days 1 and 2) and mitomycin (6 mg/m(2) on day 2), administered every 3 weeks for 2-10 cycles in the neoadjuvant setting. RESULTS: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >/=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen. CONCLUSION: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.     

Response to pretransplant hypomethylating agents influences the outcome of allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndromes

This study describes a retrospective analysis on the transplant outcome of 56 consecutive patients with myelodysplastic syndrome (MDS) according to their response to hypomethylating agents (HMA). While 2‐yr disease‐free survival (DFS) of patients who transformed to acute myeloid leukemia (n = 12) was 25%, that of the remaining patients with MDS according to response to HMA was 73.1%, 68.1%, 50.0%, and 20.8% in G‐COR (group of continuous response, n = 19), G‐NoC (group of no change, n = 15), G‐LOR (group of loss of response, n = 6), and G‐DP (group of disease progression, n = 4), respectively. When dichotomized as G‐COR/G‐NoC versus G‐LOR/G‐DP, significantly different 2‐yr DFS (71.0% vs. 33.3%; P = 0.004) and relapse (14.1% vs. 46.7%; P = 0.016) were demonstrated. On multivariate analysis, G‐LOR/G‐DP [hazard ratio (HR), 3.91; P = 0.008] and poor karyotype at transplantation (HR, 2.69; P = 0.017) were the significant predictors for poor DFS, as G‐LOR/G‐DP was for relapse (HR, 6.28; P = 0.011). DFS was significantly poor in patients with any of the two predictors in all MDS (81.5% vs. 34.9%; P = 0.001) or higher‐risk MDS (HrMDS) at the time of HMA (80.7% vs. 29.2%; P = 0.005). G‐COR showed a trend of better DFS compared with G‐NoC among HrMDS (74.6% vs. 36.5%; P = 0.090). These results implicate the significance of response to HMA on hematopoietic stem cell transplantation (HSCT) outcomes and support the need for future study to verify the suggested strategy of proceeding to transplantation before LOR or DP, especially for HrMDS.     

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.     

Risk factors for newly developed osteoporotic vertebral compression fractures following treatment for osteoporotic vertebral compression fractures

Background context

It has been reported that newly developed osteoporotic vertebral compression fractures (OVCFs) occur at a relatively high frequency after treatment. While there are many reports on possible risk factors, these have not yet been clearly established.

Clinical features in adult patients with in-hospital cardiovascular events with confirmed 2009 Influenza A (H1N1) virus infection: Comparison with those without in-hospital cardiovascular events

BackgroundComprehensive data regarding in-hospital cardiovascular events of adults with confirmed 2009 influenza A (H1N1) (2009 H1N1) infections are limited. The aim of this study was to determine the clinical characteristics, laboratory parameters, and electrocardiographic (ECG) findings for adults with 2009 H1N1 infections and to assess the differences in these parameters among adult patients with and without in-hospital cardiovascular events.MethodsSeventy-one patients were enrolled from the 2009 H1N1 registry database (our hospital registry of confirmed 2009 H1N1 infection during the year 2009) and divided according to the presence of in-hospital cardiovascular events. Six patients had cardiovascular events (CV group) and 65 did not (NCV group).ResultsThe CV group was more likely to be old (p = 0.023). Regarding co-morbidities, underlying coronary heart disease (p = 0.001), congestive heart failure (p = 0.001), diabetes (p = 0.001), and hypertension (p = 0.014) had significant influences on cardiovascular events. The CV group was also more likely to have chest pain (p = 0.034), dyspnea (p = 0.045), higher leukocyte count (p = 0.014), higher C-reactive protein (p = 0.010), higher glucose level (p = 0.001), and higher N-terminal probrain natriuretic peptide level (p = 0.010) than the NCV group. In addition, the CV group had a significantly higher in-hospital mortality rate (p = 0.010) and cardiac mortality rate (p = 0.001) than the NCV group. However, there were no significant differences in ECG findings between the two groups.ConclusionOur study demonstrated that the CV group had higher in-hospital and cardiac mortality rates than the NCV group. A meticulous therapeutic approach should be considered for elderly patients with 2009 H1N1 infections having coronary heart disease, congestive heart failure, diabetes, hypertension, and high levels of leukocyte count, hs-CRP, glucose, and NT-proBNP at the time of admission.     

Experimental Obstructive Jaundice Results in Oxidized Low-Density-Lipoprotein Accumulation in Surgical Wound of Rats

Introduction : Mounting evidence suggests that impaired wound healing is a well-defined consequence in obstructive jaundice and, as redox-regulated processes are relevant to wound healing, it is not unreasonable to suppose that oxidative stress associated with lipid peroxidation in cholestasis might be a systemic phenomenon probably comprising all tissues and organs, including wounds. The aim of the present investigation was to analyse the lipid peroxidation status of surgical wounds, in terms of oxidized low-density-lipoprotein (oxLDL) accumulation in experimental obstructive jaundice.

Methods : Sixteen Wistar-Albino rats weighing 200–230 gr were randomly divided into two groups. Group I (n = 8) was designed as the prolonged obstructive jaundice group and was subjected to bile duct ligation. Group II (Sham-control, n = 8) rats underwent laparotomy alone and bile duct was just dissected from the surrounding tissue. Histopathological evaluation, immunohistochemical screening and immunoflourescent staining of the surgical wound was conducted to the bile-duct ligated rats and control group on the 21^st postoperative day.

Results : Wound healing was found to be impaired in jaundiced rats histopathologically. When compared with the control group, significant positive oxLDL staining and intracellular accumulation of TNF-a, IL-2 and iL-6 was detected in the wound sections of the prolonged obstructive jaundice group.

Conclusion : Our present data is the first in the literature, indicating significant oxLDL accumulation in surgical wounds of cholestatic rats, which might be one of the results of systemic oxidative stress leading to deficient healing capacity as a consequence of persistent inflammation.