Prognostic significance of smoking in addition to established risk factors in patients with Dukes B and C colorectal cancer: a retrospective analysis.

PURPOSE: To investigate the prognostic significance of smoking in addition to established risk factors in patients with Dukes stage B and C colorectal cancer (CRC). METHODS: 291 consecutive non-selected CRC patients were studied retrospectively. Twenty-three variables were examined using a regression statistical model to identify relevant prognostic factors related to disease free survival (DFS) and overall survival (OS). RESULTS: On multivariate analysis DFS was found to be negatively affected in patients with a smoking history of ≤10 pack-years vs. non-smokers (p<0.016). Additionally, performance status (PS)<90 (p<0.001), Dukes stage C (p<0.001) and elevated tumor markers (p<0.001) at the time of diagnosis were found to adversely affect DFS. Smoking also had a significant association with relapse. Patients with a smoking history of ≤10 pack-years had 2.45 (p<0.018) higher risk of recurrence compared to patients with no smoking history. OS was influenced by Karnofsky performance status (PS), Dukes stage, and elevated tumor markers. In particular patients with PS< 90 had a 4.69-fold higher risk of death (p<0.001) than patients with better PS. Stage C disease was associated with 2.27-fold higher risk of death (p<0.001) than stage B disease, and patients with elevated tumor markers at the time of diagnosis had 2.74-fold higher risk of death (p<0.014) when compared to those whose tumor markers were normal at presentation. CONCLUSION: Our study associates smoking and relapse incidence in non-clinical- trial CRC patients and reiterates the prognostic significance of PS, stage and tumor markers at the time of diagnosis.

The significance of DNA image cytometry and Edmondson-Steiner grading on prognosis after curative resection of hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the commonest primary cancer of the liver. Hepatic resection remains the main curative option, although the incidence of disease recurrence in the remaining hepatic parenchyma is high and accounts for the leading cause of death post resection. For this reason, the need to identify prognostic factors which may determine treatment response and survival is of paramount importance. In this study we assessed whether DNA image cytometry and Edmondson-Steiner grading could be used as prognostic factors in a cohort of patients with HCC undergoing radical hepatic resection. METHODS: Forty-four patients with HCC who underwent radical resection were retrospectively analyzed. Histological grading according to Edmondson and Steiner and DNA ploidy using DNA image cytometry, were the two parameters analyzed. Pearson's x(2) or Fisher's exact tests were used to test for any associations between categorical variables. Univariate semi-parametric Cox proportional hazard regression models were used to assess the effect of explanatory variables on death. All reported p values were based on two-sided tests and compared to a significance level of 0.05. RESULTS: In univariate Cox regression analysis, adverse survival outcome was strongly associated with high DNA score and advanced histological grading. Patients with ploidy score >2.2 had 3.95 times higher probability of death, as compared to those with ploidy score ≤ 2.2. Edmondson-Steiner grades III and IV were also associated with 20.49 and 34.47 higher probability of death respectively as compared to grade I. CONCLUSION: Our results validate the prognostic significance of DNA image cytometry and Edmondson-Steiner grading following curative resection of HCC.

Extended fungal skin infection due to Aureobasidium pullulans.

Black yeasts are a rare cause of infections especially in Europe, yet their pathological significance is increasing, particularly in cases of immunosuppression. We report a 53-year-old immunocompetent woman with an extensive skin infection due to Aureobasidium pullulans, who responded well to treatment with liposomal amphotericin B.

Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial.

BACKGROUND: The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib-a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)-in a patient population representative of clinical practice. Primary analysis data are presented. PATIENTS AND METHODS: Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points. RESULTS: Evaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0-44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7-71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6-48.1) in patients with metastatic BCC. CONCLUSIONS: The primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control. CLINICALTRIALS.GOV: NCT01367665.

Palliative gastrectomy and other factors affecting overall survival in stage IV gastric adenocarcinoma patients receiving chemotherapy: a retrospective analysis.

OBJECTIVE: Most patients with gastric cancer present with locally advanced or metastatic disease and usually receive palliative therapy. We sought to identify factors influencing overall survival in patients with stage IV gastric cancer receiving palliative chemotherapy. PATIENTS AND METHODS: The records of 311 patients with histological diagnosis of gastric adenocarcinoma were retrospectively reviewed and 17 clinicopathological and therapeutic parameters were evaluated for their influence on overall survival. RESULTS: In multivariate analysis nine factors were found to independently influence survival: no previous palliative gastrectomy [Hazard ratio (HR, 12; CI 7.969-18.099)], single agent chemotherapy instead of combination chemotherapy (HR, 1.35; CI 1.068-1.721), histological grade III (HR, 1.39; 95% CI 1.098-1.782), the presence of hepatic (HR, 1.6; 95% CI 1.246-2.073) and abdominal metastasis (HR, 1.33; 95% CI 1.039-1.715), CA 72-4 > 7 U/L (HR, 1.39; 95% CI 1.026-1.887), LDH > 225 U/L (HR, 1.72; 95% CI 1.336-2.236], need for blood transfusions (HR, 1.58; 95% CI 1.213-2.082), and weight loss > 5% (HR, 1.96; 95% CI 1.352-2.853) at the time of initial diagnosis. Patients were stratified as low (0-2 factors), intermediate (3-6 factors) and high (7-9 factors) risk and the median survival was 76, 40 and 11 weeks, respectively. CONCLUSION: Nine clinical and laboratory factors that adversely affect survival in patients with stage IV gastric cancer who receive chemotherapy were identified. Their concurrent presence seems to have an additive effect as patients with seven to nine factors have the worse prognosis. Palliative gastrectomy and combination chemotherapy appear to be associated with improved survival.

The role of gamma/delta T cell receptor positive cells in pregnancy.

PROBLEM: Due to the lack of classical HLA antigens on the trophoblast, fetal antigens are possibly presented in a non major histocompatibility complex (MHC) restricted way. Decidual gammadelta T cells, which significantly increase in number during pregnancy, might play a role in recognition of fetal antigens and also in determining the quality of the response to these antigens. Our study was aimed at investigating the role of this cell population in progesterone-dependent immunomodulation. METHOD OF STUDY: Peripheral lymphocytes from healthy pregnant women and from habitual aborters were tested by immunocytochemistry for the presence of gamma/delta T cell receptor (TCR) and progesterone receptor. To investigate the effect of treatment with a pan anti gamma/delta antibody, lymphocytes were incubated for 3 hr with the antibody, and then interleukin (IL)-10, IL-12 and progesterone-induced blocking factor (PIBF) expression (by immuno-cytochemistry) as well as natural killer (NK) cell activity were determined. RESULTS: In peripheral blood of healthy pregnant women the percentage of gamma/delta TCR+ cells was significantly higher (P < 0.001) than in that of recurrent aborters or of non-pregnant individuals. Ninety-seven percent of gamma/delta TCR+ pregnancy lymphocytes expressed progesterone receptor. Binding of a specific antibody to the gamma/delta TCR inhibited PIBF- as well as IL-10 production, whereas it increased NK activity and IL-12 expression. CONCLUSIONS: These data suggest the role of gamma/delta TCR-bearing lymphocytes in progesterone-dependent immunomodulation.

Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass 45S5 dissolution.

The effect of the ionic products of Bioglass 45S5 dissolution on the gene-expression profile of human osteoblasts was investigated by cDNA microarray analysis of 1,176 genes. Treatment with the ionic products of Bioglass 45S5 dissolution increased the levels of 60 transcripts twofold or more and reduced the levels of five transcripts to one-half or less than in control. Markedly up-regulated genes included RCL, a c-myc responsive growth related gene, cell cycle regulators such as G1/S specific cyclin D1, and apoptosis regulators including calpain and defender against cell death (DAD1). Other significantly up-regulated genes included the cell surface receptors CD44 and integrin beta1, and various extracellular matrix regulators including metalloproteinases-2 and -4 and their inhibitors TIMP-1 and TIMP-2. The identification of differentially expressed genes by cDNA microarray analysis has offered new insights into the mode of action of bioactive glasses and has proven to be an effective tool in evaluating their osteoproductive properties.

Ionic products of bioactive glass dissolution increase proliferation of human osteoblasts and induce insulin-like growth factor II mRNA expression and protein synthesis.

Bioglass 45S5 is an osteoproductive material, which resorbs by releasing its constitutive ions into solution. Treatment with the ionic products of Bioglass 45S5 dissolution in DMEM for 4 days increased human osteoblast proliferation to 155% of control. Two days after treatment, differential gene expression was analyzed by cDNA microarrays. Expression of a potent osteoblast mitogenic growth factor, insulin-like growth factor II (IGF-II), was increased to 290%. Additionally, there was a 168% increase in the concentration of unbound IGF-II protein in the conditioned media of treated osteoblasts. Expression levels of IGFBP-3, an IGF-II carrier protein, metalloproteinase-2 and cathepsin-D were also increased to 200, 340, and 310% of control levels, respectively. Metalloproteinase-2 and cathepsin-D are proteases that cleave IGF-II from its carrier proteins, resulting in the release of the unbound biologically active IGF-II. We suggest that the stimulatory effect of the ionic products of Bioglass 45S5 dissolution on osteoblast proliferation may be mediated by IGF-II.

Bioglass 45S5 stimulates osteoblast turnover and enhances bone formation In vitro: implications and applications for bone tissue engineering.

We investigated the concept of using bioactive substrates as templates for in vitro synthesis of bone tissue for transplantation by assessing the osteogenic potential of a melt-derived bioactive glass ceramic (Bioglass 45S5) in vitro. Bioactive glass ceramic and bioinert (plastic) substrates were seeded with human primary osteoblasts and evaluated after 2, 6, and 12 days. Flow cytometric analysis of the cell cycle suggested that the bioactive glass-ceramic substrate induced osteoblast proliferation, as indicated by increased cell populations in both S (DNA synthesis) and G2/M (mitosis) phases of the cell cycle. Biochemical analysis of the osteoblast differentiation markers alkaline phosphatase (ALP) and osteocalcin indicated that the bioactive glass-ceramic substrate augmented osteoblast commitment and selection of a mature osteoblastic phenotype. Scanning electron microscopic observations of discrete bone nodules over the surface of the bioactive material, from day 6 onward, further supported this notion. A combination of fluorescence, confocal, transmission electron microscopy, and X-ray microprobe (SEM-EDAX) examinations revealed that the nodules were made of cell aggregates which produced mineralized collagenous matrix. Control substrates did not exhibit mineralized nodule formation at any point studied up to 12 days. In conclusion, this study shows that Bioglass 45S5 has the ability to stimulate the growth and osteogenic differentiation of human primary osteoblasts. These findings have potential applications for tissue engineering where this bioactive glass substrate could be used as a template for the formation of bioengineered bone tissue.