Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

PURPOSE: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. PATIENTS AND METHODS: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. RESULTS: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. CONCLUSION: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.     

Morphine-induced suppression of saccharin intake is correlated with elevated corticosterone levels

Rats suppress intake of a saccharin conditioned stimulus (CS) when paired with a drug of abuse. This phenomenon, however, is not uniform across all subjects and is greater following exposure to stress and in animals that more readily self-administer drugs of abuse. The present study was designed to examine these individual differences in intake suppression following seven saccharin-morphine pairings. Plasma corticosterone also was evaluated both before and after conditioning in order to determine whether the magnitude of CS suppression is, or is not, related to circulating corticosterone levels. The findings indicated that, while all rats were exposed to the same number of saccharin-morphine pairings, only half of these animals actually suppressed intake of the saccharin CS. Moreover, the results showed that greater suppression of CS intake was associated with higher corticosterone levels at test (r=-0.84, P<0.0001). Taken together, the results demonstrate that individual differences affect not only the reduction in CS intake following taste-drug pairings, but also the associated cue-induced elevation in circulating corticosterone.     

Focal denervation alters cellular phenotypes and survival in the developing rat olfactory bulb

Several studies have demonstrated that contact between the olfactory nerve and the forebrain is critical for normal olfactory bulb development. Removal of the embryonic olfactory placode results in a failure of the olfactory bulb to form, as well as causing other forebrain malformations. The current study introduces a technique that permits removal of contact between specific regions of the olfactory nerve and the bulb early in development, without causing damage to other brain regions, and without removing the peripheral olfactory organ. The manipulation, which involves insertion of a small Teflon chip between the cribriform plate and the bulb, prohibits growth of new axons into the "shadow" region behind the implant. Focal denervation of the olfactory bulb causes a decrease in bulb and layer sizes, a reduction in mitral cell number, and changes to bulb architecture. Using a battery of antibodies (OMP, MAP2, TuJ1, calretinin, calbindin, parvalbumin, TH, and GAD), we further demonstrated that 1) focal denervation alters the relationship between the olfactory nerve and the bulb, 2) the fine structure of cells in denervated regions is disrupted, and 3) cellular phenotypes change in response to loss of afferent contact. These results suggest that contact between the olfactory nerve and the bulb is important for maintaining bulb architecture and cell survival, structure, and phenotype. They also point to focal denervation as a useful technique for examining the role of neural contact in olfactory development and maintenance of the central nervous system.     

Satisfaction with provider communication among Spanish-speaking Medicaid enrollees.

OBJECTIVE: To determine if differences between English- and Spanish-speaking parents in ratings of their children's health care can be explained by need for interpretive services. METHODS: Using the Consumer Assessment of Health Plans Survey-Child-Survey (CAHPS), reports about provider communication were compared among 3 groups of parents enrolled in a Medicaid managed care health plan: 1) English speakers, 2) Spanish speakers with no self-reported need for interpretive services, and 3) Spanish speakers with self-reported need for interpretive services. Parents were asked to report how well their providers 1) listened carefully to what was being said, 2) explained things in a way that could be understood, 3) respected their comments and concerns, and 4) spent enough time during medical encounters. Multivariate logistic regression was used to compare the ratings of each of the 3 groups while controlling for child's gender, parent's gender, parent's educational attainment, child's health status, and survey year. RESULTS: Spanish-speaking parents in need of interpretive services were less likely to report that providers spent enough time with their children (odds ratio = 0.34, 95% confidence interval = 0.17-0.68) compared to English-speaking parents. There was no statistically significant difference found between Spanish-speaking parents with no need of interpretive services and English-speaking parents. CONCLUSIONS: Among Spanish- versus English-speaking parents, differences in ratings of whether providers spent enough time with children during medical encounters appear to be explained, in part, by need for interpretive services. No other differences in ratings of provider communication were found.     

Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer.

OBJECTIVES: Intestinal alkaline sphingomyelinase, by exerting a major role in dietary sphingomyelin digestion, is responsible for the generation of messengers able to trigger the rapid turnover and apoptosis in intestinal epithelial cells. Markedly reduced mucosal alkaline sphingomyelinase activity has been associated with human colorectal neoplasms. The aim of this study was to analyze the alkaline sphingomyelinase activity in feces from healthy subjects and colorectal adenocarcinoma patients and to correlate it with the enzyme activity in intestinal tissues. MATERIALS AND METHODS: The enzyme activity was measured both in the intestinal samples from 12 healthy controls and 51 patients with colorectal adenocarcinoma (tumoral and paratumoral tissue) and in the fecal samples of 34 healthy subjects and 29 patients with adenocarcinoma. The relation between sphingomyelinase activity and Dukes' stage, cell differentiation degree, age, and gender was also analyzed. RESULTS: Alkaline sphingomyelinase was significantly decreased (P < 0.001; mean reduction >90%) in tumoral intestinal mucosa of patients compared with controls independently of Dukes' stage and tumor differentiation grade. Interestingly, the enzyme activity in histologically normal paratumoral tissues was statistically lower than control samples (P < 0.001). As occurs in neoplastic tissues, a relevant mean reduction (P < 0.0001; almost 90%) of alkaline sphingomyelinase was revealed in stool samples from tumor patients when compared with controls. CONCLUSION: These findings may have implications for cancer biology and perhaps also for the design of clinical test, thus suggesting that the fecal sphingomyelinase activity could really reflect the human intestinal mucosa enzyme level and could represent a new marker for human colorectal adenocarcinoma, mainly taking into account its early appearance in intestinal neoplasms.     

Hepatocyte growth factor promotes cancer cell migration and angiogenic factors expression: a prognostic marker of human esophageal squamous cell carcinomas.

PURPOSE: Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, play important roles in tumor development and progression. In this study, we measured the serum HGF levels in patients with esophageal squamous cell carcinoma (ESCC) to evaluate its relationships with clinicopathologic features and the role of HGF in ESCC. EXPERIMENTAL DESIGN: One hundred and forty-nine patients with ESCC were studied. Pretherapy serum was collected and ELISA was used to detect the concentrations of HGF, vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8). The function of HGF was shown by invasion chamber assay. RESULTS: Pretherapy serum HGF was found to be significantly higher in patients with ESCC than in control subjects. The levels of HGF correlated significantly with advanced tumor metastasis stage and survival. Multivariate analyses showed that serum HGF level in cell migration was an independent prognostic factor. Increased HGF serum levels correlated positively with serum levels of VEGF and IL-8. Our results also showed that HGF was overexpressed in ESCC tissues and cell lines. In vitro study showed that HGF could stimulate ESCC cell to express VEGF and IL-8 and markedly enhance invasion and migration of ESCC cells. Furthermore, HGF-induced IL-8 and VEGF expression was dependent on extracellular signal-regulated kinase signaling pathways. The inhibition of extracellular signal-regulated kinase activation reduced HGF-mediated IL-8 and VEGF expression. CONCLUSIONS: Our results suggest that serum HGF may be a useful biomarker of tumor progression and a valuable independent prognostic factor in patients with ESCC. HGF may be involved in the progression of ESCC as an autocrine/paracrine factor via enhancing angiogenesis and tumor cell invasion and migration.     

Fibrinolytic system after laparoscopic cholecystectomy

BACKGROUND: Deep-vein thrombosis (DVT) and pulmonary embolism (PE) are the most important causes of morbility and mortality in patients submitted to surgical intervention: some peculiar factors of laparoscopic surgery can modify their risk. The aim of this study is to evaluate possible variations of the fibrinolytic system after cholecystectomy. METHODS: Eighteen patients affected by symptomatic and non-complicated gallstones have been included in this study. They were divided into two groups of nine patients each: the first group was submitted to laparoscopic cholecystectomy (LC) and the second to open cholecystectomy (OC). Antitrombin III (ATIII), fibrinogen degradation products (FDP), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) have been evaluated preoperatively and 6, 12, 24 and 48 hours after the operation. RESULTS: The levels of ATIII did not present significantly variations. The FDP in both groups were significantly increased 48 hours after open cholecystectomy. Levels of PAI instead were increased in comparison to the basal values at 6, 12, 24, 48 hours with p < 0.05; p < 0.01 and p < 0.05 respectively in patients submitted to OC, in the LC group no variations were observed; a comparison between the groups showed a significant modification (p < 0.05) only at the 12th hour. CONCLUSIONS: The early mobilization of patients in the postoperative course and the lower invasion of LC can oppose the prothrombotic effect in the lower limbs.     

Consumption of vegetables and fruits and risk of subtypes of head–neck cancer in the Netherlands Cohort Study

There is limited prospective data on the relationship between consumption of vegetables and fruits and the risk of head–neck cancer (HNC) subtypes [i.e., oral cavity cancer (OCC), oro‐/hypopharyngeal cancer (OHPC) and laryngeal cancer (LC)]. Therefore, we investigated these associations within the Netherlands Cohort Study, in which 120,852 participants completed a 150‐item food frequency questionnaire at baseline in 1986. After 20.3 years of follow‐up, 415 cases of HNC (131 OCC, 88 OHPC, three oral cavity/pharynx unspecified or overlapping and 193 LC) and 3,898 subcohort members were available for case–cohort analysis using Cox proportional hazards models. Total vegetable and fruit consumption was inversely associated with risk of HNC overall [multivariable‐adjusted rate ratios for highest vs. lowest quartile: 0.61, 95% confidence interval (CI) 0.44–0.85, p trend 0.002] and all HNC subtypes, with the strongest associations for OCC. Total vegetable intake and total fruit intake were also associated with a decreased risk of HNC overall and HNC subtypes. No significant interaction was found between vegetable and fruit intake and alcohol consumption or cigarette smoking. In conclusion, in this large‐scale cohort study, consumption of vegetables and fruits was associated with a decreased risk of HNC overall and all subtypes. Consumption of vegetables and fruits (or of specific groups of them) may protect against HNC and its subtypes.     

TP53 mutation and survival in aggressive B cell lymphoma

TP53 is mutated in 20–25% of aggressive B‐cell lymphoma (B‐NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B‐NHL, we investigated TP53 gene mutations within the RICOVER‐60 trial. Of 1,222 elderly patients (aged 61–80 years) enrolled in the study and randomized to six or eight cycles of CHOP‐14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index‐Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B‐symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event‐free (EFS), progression‐free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI‐factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.