Failure to complete adjuvant chemotherapy is associated with adverse survival in stage III colon cancer patients

Two recent North American studies have shown that completion of 5-fluorouracil (5FU)-based adjuvant chemotherapy is a major prognostic factor for the survival of elderly stage III colon cancer patients. The aim of the present study was to confirm this finding in a population-based series from Australia. The study cohort comprised 851 stage III colon cancer patients treated by surgery alone and 461 who initiated the Mayo chemotherapy regime. One-third of patients who initiated chemotherapy failed to complete more than three cycles of treatment. Independent predictors for failure to complete were treatment in district or rural hospitals, low socioeconomic index and treatment by a low-volume surgeon. Patients who failed to complete chemotherapy showed worse cancer-specific survival compared not only to those who completed treatment (HR=2.24; 95% confidence interval (CI) (1.66–3.03), P<0.001) but also to those treated by surgery alone (HR=1.37; 95% CI (1.09–1.72), P=0.008). The current and previous studies demonstrate the importance of completing adjuvant 5-FU-based chemotherapy for colon cancer. Further prospective studies are required to identify better the physiological and socioeconomic factors responsible for failure to complete chemotherapy so that appropriate improvements in health service delivery can be made

Secondary omental and pectoralis major double flap reconstruction following aggressive sternectomy for deep sternal wound infections after cardiac surgery

<p>Abstract</p> <p>Background</p> <p>Deep sternal wound infection after cardiac surgery carries high morbidity and mortality. Our strategy for deep sternal wound infection is aggressive strenal debridement followed by vacuum-assisted closure (VAC) therapy and omental-muscle flap reconstrucion. We describe this strategy and examine the outcome and long-term quality of life (QOL) it achieves.</p> <p>Methods</p> <p>We retrospectively examined 16 patients treated for deep sternal wound infection between 2001 and 2007. The most recent nine patients were treated with total sternal resection followed by VAC therapy and secondary closure with omental-muscle flap reconstruction (recent group); whereas the former seven patients were treated with sternal preservation if possible, without VAC therapy, and four of these patients underwent primary closure (former group). We assessed long-term quality of life after DSWI by using the Short Form 36-Item Health Survey, Version 2 (SF36v2).</p> <p>Results</p> <p>One patient died and four required further surgery for recurrence of deep sternal wound infection in the former group. The duration of treatment for deep sternal wound infection in the recent group was significantly shorter than that in previous group (63.4 ± 54.1 days vs. 120.0 ± 31.8 days, respectively; p = 0.039). Despite aggressive sternal resection, the QOL of patients treated for DSWI was only minimally compromised compared with age-, sex-, surgical procedures-matched patients without deep sternal wound infection.</p> <p>Conclusions</p> <p>Aggressive sternal debridement followed by VAC therapy and secondary closure with an omental-muscle flap is effective for deep sternal wound infection. In this series, it resulted in a lower incidence of recurrent infection, shorter hospitalization, and it did not compromise long-term QOL greatly.</p

Plasma pharmacokinetics after combined therapy of gemcitabine and oral S-1 for unresectable pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>The combination of gemcitabine (GEM) and S-1, an oral 5-fluorouracil (5-FU) derivative, has been shown to be a promising regimen for patients with unresectable pancreatic cancer.</p> <p>Methods</p> <p>Six patients with advanced pancreatic cancer were enrolled in this pharmacokinetics (PK) study. These patients were treated by oral administration of S-1 30 mg/m²twice daily for 28 consecutive days, followed by a 14-day rest period and intravenous administration of GEM 800 mg/m²on days 1, 15 and 29 of each course. The PK parameters of GEM and/or 5-FU after GEM single-administration, S-1 single-administration, and co-administration of GEM with pre-administration of S-1 at 2-h intervals were analyzed.</p> <p>Results</p> <p>The maximum concentration (Cmax), the area under the curve from the drug administration to the infinite time (AUCinf), and the elimination half-life (T1/2) of GEM were not significantly different between GEM administration with and without S-1. The Cmax, AUCinf, T1/2, and the time required to reach Cmax (Tmax) were not significantly different between S-1 administration with and without GEM.</p> <p>Conclusion</p> <p>There were no interactions between GEM and S-1 regarding plasma PK of GEM and 5-FU.</p

No hypoperfusion is produced in the epicardium during application of myocardial topical negative pressure in a porcine model

ABSTRACT: BACKGROUND: Topical negative pressure (TNP), commonly used in wound therapy, has been shown to increase blood flow and stimulate angiogenesis in skeletal muscle. We have previously shown that a myocardial TNP of -50 mmHg significantly increases microvascular blood flow in the myocardium. When TPN is used in wound therapy (on skeletal and subcutaneous tissue) a zone of relative hypoperfusion is seen close to the wound edge. Hypoperfusion induced by TNP is thought to depend on tissue density, distance from the negative pressure source, and the amount negative pressure applied. When applying TNP to the myocardium, a significant, long-standing zone of hypoperfusion could theoretically cause ischemia, and negative effects on the myocardium. The current study was designed to elucidate whether hypoperfusion was produced during myocardial TNP. METHODS: Six pigs underwent median sternotomy. Laser Doppler probes were inserted horizontally into the heart muscle in the LAD area, at depths of approximately, 1-2 mm. The microvascular blood flow was measured before and after the application of a TNP. Analyses were performed before left anterior descending artery (LAD) occlusion (normal myocardium) and after 20 minutes of LAD occlusion (ischemic myocardium). RESULTS: A TNP of -50 mmHg induced a significant increase in microvascular blood flow in normal myocardium (**p = 0.01), while -125 mmHg did not significantly alter the microvascular blood flow. In ischemic myocardium a TNP of -50 mmHg induced a significant increase in microvascular blood flow (*p = 0.04), while -125 mmHg did not significantly alter the microvascular blood flow. CONCLUSION: No hypoperfusion could be observed in the epicardium in neither normal nor ischemic myocardium during myocardial TNP

Overexpression of sphingosine kinase 1 is associated with salivary gland carcinoma progression and might be a novel predictive marker for adjuvant therapy

<p>Abstract</p> <p>Background</p> <p>Overexpression of sphingosine kinase-1 (SPHK1) has been demonstrated to be associated with the development and progression in various types of human cancers. The current study was to characterize the expression of SPHK1 in salivary gland carcinomas (SGC) and to investigate the association between SPHK1 expression and progression of SGC.</p> <p>Methods</p> <p>The expression of SPHK1 was examined in 2 normal salivary gland tissues, 8 SGC tissues of various clinical stages, and 5 pairs of primary SGC and adjacent salivary gland tissues from the same patient, using real-time PCR and western blot analysis. Furthermore, the SPHK1 protein expression was analyzed in 159 clinicopathologically characterized SGC cases by immunohistochemistry. Statistical analyses were performed to determine the prognostic and diagnostic associations.</p> <p>Results</p> <p>SPHK1 expression was found to be markedly upregulated in SGC tissues than that in the normal salivary gland tissues and paired adjacent salivary gland tissues, at both mRNA and protein levels. Statistical analysis revealed a significant correlation of SPHK1 expression with the clinical stage (<it>P </it>= 0.005), T classification (<it>P </it>= 0.017), N classification (<it>P </it>= 0.009), M classification (<it>P </it>= 0.002), and pathological differentiation (<it>P </it>= 0.013). Patients with higher SPHK1 expression had shorter overall survival time, whereas patients with lower SPHK1 expression had better survival. Importantly, patients in the group without adjuvant therapy who exhibited high SPHK1 expression had significantly lower overall survival rates compared with those with low SPHK1 expression. Moreover, multivariate analysis suggested that SPHK1 expression might be an independent prognostic indicator for the survival of SGC patients.</p> <p>Conclusions</p> <p>Our results suggest that SPHK1 expression is associated with SGC progression, and might represent as a novel and valuable predictor for adjuvant therapy to SGC patients.</p

A compare between myocardial topical negative pressure levels of -25 mmHg and -50 mmHg in a porcine model

<p>Abstract</p> <p>Background</p> <p>Topical negative pressure (TNP), widely used in wound therapy, is known to stimulate wound edge blood flow, granulation tissue formation, angiogenesis, and revascularization. We have previously shown that application of a TNP of -50 mmHg to the myocardium significantly increases microvascular blood flow in the underlying tissue. We have also shown that a myocardial TNP levels between -75 mmHg and -150 mmHg do not induce microvascular blood flow changes in the underlying myocardium. The present study was designed to elucidate the difference between -25 mmHg and -50 mmHg TNP on microvascular flow in normal and ischemic myocardium.</p> <p>Methods</p> <p>Six pigs underwent median sternotomy. The microvascular blood flow in the myocardium was recorded before and after the application of TNP using laser Doppler flowmetry. Analyses were performed before left anterior descending artery (LAD) occlusion (normal myocardium), and after 20 minutes of LAD occlusion (ischemic myocardium).</p> <p>Results</p> <p>A TNP of -25 mmHg significantly increased microvascular blood flow in both normal (from 263.3 ± 62.8 PU before, to 380.0 ± 80.6 PU after TNP application, * <it>p </it>= 0.03) and ischemic myocardium (from 58.8 ± 17.7 PU before, to 85.8 ± 20.9 PU after TNP application, * <it>p </it>= 0.04). A TNP of -50 mmHg also significantly increased microvascular blood flow in both normal (from 174.2 ± 20.8 PU before, to 240.0 ± 34.4 PU after TNP application, * <it>p </it>= 0.02) and ischemic myocardium (from 44.5 ± 14.0 PU before, to 106.2 ± 26.6 PU after TNP application, ** <it>p </it>= 0.01).</p> <p>Conclusion</p> <p>Topical negative pressure of -25 mmHg and -50 mmHg both induced a significant increase in microvascular blood flow in normal and in ischemic myocardium. The increase in microvascular blood flow was larger when using -25 mmHg on normal myocardium, and was larger when using -50 mmHg on ischemic myocardium; however these differences were not statistically significant.</p

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Acute and Persistent Mycobacterium tuberculosis Infections Depend on the Thiol Peroxidase TPX

The macrophage is the natural niche of Mycobacterium tuberculosis infection. In order to combat oxidative and nitrosative stresses and persist in macrophages successfully, M. tuberculosis is endowed with a very efficient antioxidant complex. Amongst these antioxidant enzymes, TpX is the only one in M. tuberculosis with sequence homology to thiol peroxidase. Previous reports have demonstrated that the M. tuberculosis TpX protein functions as a peroxidase in vitro. It is the dominant antioxidant which protects M. tuberculosis against oxidative and nitrosative stresses. The level of the protein increases in oxidative stress. To determine the roles of tpx gene in M. tuberculosis survival and virulence in vivo, we constructed an M. tuberculosis strain lacking the gene. The characteristics of the mutant were examined in an in vitro stationary phase model, in response to stresses; in murine bone marrow derived macrophages and in an acute and an immune resistant model of murine tuberculosis. The tpx mutant became sensitive to H2O2 and NO compared to the wild type strain. Enzymatic analysis using bacterial extracts from the WT and the tpx mutant demonstrated that the mutant contains reduced peroxidase activity. As a result of this, the mutant failed to grow and survive in macrophages. The growth deficiency in macrophages became more pronounced after interferon-γ activation. In contrast, its growth was significantly restored in the macrophages of inducible nitric oxide synthase (iNOS or NOS2) knockout mice. Moreover, the tpx mutant was impaired in its ability to initiate an acute infection and to maintain a persistent infection. Its virulence was attenuated. Our results demonstrated that tpx is required for M. tuberculosis to deal with oxidative and nitrosative stresses, to survive in macrophages and to establish acute and persistent infections in animal tuberculosis models

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome