Hepatocyte growth factor-modulated rat Leydig cell functions

Hepatocyte growth factor (HGF) regulates many cellular functions acting through c-Met, its specific tyrosine kinase receptor. We previously reported that in prepuberal rats HGF is secreted by the peritubular myoid cells during the entire postnatal testicular development and by the Sertoli cells only at puberty. We have also demonstrated that germ cells at different stages of development express c-Met and that HGF modulates germ cell proliferation and apoptosis. In the present article, we extend our study to the interstitial compartment of the testis and demonstrate that the c-Met protein is present on Leydig cells. The receptor is functionally active as demonstrated by the detected effects of HGF. We report in this article that HGF significantly increases the amount of testosterone secreted by the Leydig cells and decreases the number of Leydig cells undergoing apoptosis. The antiapoptotic effect of HGF is mediated by caspase-3 activity because the amount of the active fragment of the enzyme is decreased in Leydig cells cultured in the presence of HGF. However, treatment with the growth factor does not modify the expression levels of caspase-3 mRNA. These data indicate that HGF regulates the functional activities of Leydig cells. Interestingly, the steroidogenetic activity of the cells is increased by HGF in cultured explants of testicular tissues as well as the antiapoptotic effect of HGF. Therefore, our data indicate that HGF has a crucial role in the regulation of male fertility.     

A new priority policy for patients with hepatocellular carcinoma awaiting liver transplantation within the model for end-stage liver disease system.

The best prioritization of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation under the model for end-stage liver disease (MELD) allocation system is still being debated. We analyzed the impact of a MELD adjustment for HCC, which consisted of the addition of an extra score (based on the HCC stage and waiting time) to the native MELD score. The outcome was analyzed for 301 patients with chronic liver disease listed for liver transplantation between March 1, 2001 and February 28, 2003 [United Network for Organ Sharing (UNOS)-Child-Turcotte-Pugh (CTP) era, 163 patients, 28.8% with HCC] and between March 1, 2003 and February 28, 2004 (HCC-MELD era, 138 patients, 29.7% with HCC). In the HCC-MELD era, the cumulative dropout risk at 6 months was 17.6% for patients with HCC versus 22.3% for those patients without HCC (P = NS), similar to that in the UNOS-CTP era. The cumulative probability of transplantation at 6 months was 70.3% versus 39.0% (P = 0.005), being higher than that in the UNOS-CTP era for patients with HCC (P = 0.02). At the end of the HCC-MELD era, 12 patients with HCC (29.3%) versus 57 without HCC (58.8%) were still on the list (P = 0.001). Both native and adjusted MELD scores were higher (P < 0.05) and progressed more in patients with HCC who dropped out than in those who underwent transplantation or remained on the list (the initial-final native MELD scores were 17.3-23.1, 15.5-15.6, and 12.8-14.1, respectively). The patients without HCC remaining on the list showed stable MELD scores (initial-final: 15.1-15.4). In conclusion, the present data support the strategy of including the native MELD scores in the allocation system for HCC. This model allows the timely transplantation of patients with HCC without severely affecting the outcome of patients without HCC.     

Respiratory function changes after chemotherapy: an additional risk for postoperative respiratory complications?

BACKGROUND: Patients receiving chemotherapy for lung cancer usually modify their lung function during treatment with increases in forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC) and decreases in lung diffusion for carbon monoxide (DLCO). This prospective study was designed to evaluate functional changes in forced expiratory volume in 1 second, forced vital capacity, and DLCO after three courses of induction chemotherapy with cisplatinum and gemcitabine in stage IIIa lung cancer patients and to assess their impact on respiratory complications after lung resection. METHODS: From March 1998 to January 2001, 30 consecutive patients with N2 nonsmall cell lung cancer had surgical resection after neoadjuvant treatment. Pre-chemotherapy and postchemotherapy results of standard respiratory function tests and DLCO were compared in patients with and without postoperative respiratory complications. RESULTS: All 30 patients completed the chemotherapy protocol without respiratory complications. Significant improvements (p < 0.05) were recorded after chemotherapy in transition dyspnea score, PaO(2) (mean value from 79.8 to 86.4 mm Hg), forced expiratory volume in 1 second % (from 78.1% to 87.5%) and forced vital capacity % (from 88.1% to 103.3%). Lung diffusion for carbon monoxide was significantly impaired after chemotherapy (from 74.1% to 65.7%; p = 0.0006), as well as DLCO adjusted for alveolar volume (from 92.8% to 77.4%; p < 0.0001). One patient died after surgery and 4 patients (13.3%) experienced postoperative respiratory complications. Compared with patients without complications, these 4 patients had higher mean increase in FEV(1) after chemotherapy (+26.8% vs + 6.7%; p = 0.025), but greater mean decrease in DLCO/Va (-27.8% vs -13.6%; p = 0.03). Impact of change in DLCO on postoperative respiratory complications was not confirmed by multiple logistic regression analysis (p = 0.16). CONCLUSIONS: In lung cancer patients, forced expiratory volume in 1 second and forced vital capacity assessed after neoadjuvant chemotherapy are not reliable indicators of the likelihood of respiratory complications after surgery. The risk of respiratory complication may be directly linked to loss of DLCO/Va. Lung diffusion for carbon monoxide assessed after neoadjuvant chemotherapy is probably the most sensitive risk indicator of respiratory complications after surgery. We recommend that DLCO studies be performed before and after chemotherapy in lung cancer patients undergoing induction therapy.     

Long‐term preclinical magnetic resonance imaging alterations in sporadic Creutzfeldt–Jakob disease

An asymptomatic 74‐year‐old woman, on follow‐up for a carotid body tumor, showed magnetic resonance imaging (MRI) focal restricted diffusion confined to the left temporal and occipital cortices. Thirteen months later, diffusion‐weighted images revealed a bilateral cortical ribbon sign involving all lobes. After 1 month, the patient developed gait instability and cognitive decline rapidly evolving to severe dementia and death within 3 months. Prion protein gene sequence, molecular, and neuropathological studies confirmed the diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) MM1 subtype. Here we show the kinetics of MRI changes and prion spreading in preclinical sCJD MM1. Ann Neurol 2016;80:629–632     

Centenarians and supercentenarians: a black swan. Emerging social,medical and surgical problems

Background

Five percent of all patients with breast cancer have distant metastatic disease at initial presentation. Because metastatic breast cancer is considered to be an incurable disease, it is generally treated with a palliative intent. Recent non-randomized studies have demonstrated that (complete) resection of the primary tumor is associated with a significant improvement of the survival of patients with primary metastatic breast cancer. However, other studies have suggested that the claimed survival benefit by surgery may be caused by selection bias. Therefore, a randomized controlled trial will be performed to assess whether breast surgery in patients with primary distant metastatic breast cancer will improve the prognosis.

Design

Randomization will take place after the diagnosis of primary distant metastatic breast cancer. Patients will either be randomized to up front surgery of the breast tumor followed by systemic therapy or to systemic therapy, followed by delayed local treatment of the breast tumor if clinically indicated. Patients with primary distant metastatic breast cancer, with no prior treatment of the breast cancer, who are 18 years or older and fit enough to undergo surgery and systemic therapy are eligible. Important exclusion criteria are: prior invasive breast cancer, surgical treatment or radiotherapy of this breast tumor before randomization, irresectable T4 tumor and synchronous bilateral breast cancer. The primary endpoint is 2-year survival. Quality of life and local tumor control are among the secondary endpoints. Based on the results of prior research it was calculated that 258 patients are needed in each treatment arm, assuming a power of 80%. Total accrual time is expected to take 60 months. An interim analysis will be performed to assess any clinically significant safety concerns and to determine whether there is evidence that up front surgery is clinically or statistically inferior to systemic therapy with respect to the primary endpoint.

Discussion

The SUBMIT study is a randomized controlled trial that will provide evidence on whether or not surgery of the primary tumor in breast cancer patients with metastatic disease at initial presentation results in an improved survival.

Trial registration

NCT01392586.     

Hospital volume, margin status, and long-term survival after pancreaticoduodenectomy for pancreatic adenocarcinoma

An association between hospital surgical volume and short- and long-term outcomes after pancreatic surgery has been demonstrated. Identification of specific factors contributing to this relationship is difficult. In this study, the authors evaluated if margin status can be identified as a measure of surgical quality, affecting overall survival, as a function of hospital pancreaticoduodenectomy volume. A systematic review of the literature was performed. Two models for analysis were created, dividing the 18 studies identified into quartiles and two quantiles based on the average annual hospital pancreatectomy volume. Regression modeling and analysis of variance were used to find an association between hospital volume, margin status, and survival. Increasing hospital volume was associated with a significantly increased negative margin status rate: 55 per cent for low-volume, 72 per cent for medium-volume, 74.3 per cent for high-volume, and 75.7 per cent for very high-volume centers (P = 0.008). The negative margin status rates were 64 per cent and 75.1 per cent for volume centers with less and more than 12 pancreaticoduodenectomies/year, respectively (P = 0.04). Low-volume centers negatively affected both margin positive resection and 5-year survival rates, compared with high-volume centers. Margin status rate after pancreaticoduodenectomy could, therefore, be considered a measure of quality for selection of hospitals dedicated to pancreatic surgery.     

Acute Appendicitis: Still a Surgical Disease? Results from a Propensity Score-Based Outcome Analysis of Conservative Versus Surgical Management from a Prospective Database

Objective

The aim of the present study was to compare the outcomes of conservative versus surgical treatment for acute appendicitis.

Background

Although acute appendicitis is a common disease, great debate exists regarding the appropriate management of patients. Conservative treatment has shown positive results in several RCTs, eliciting questions about indications to surgery, therapeutic appropriateness and ethical conduct.

Methods

Data were prospectively collected; a Propensity Score-based matching method was implemented in order to reduce bias arising from characteristics of the patients; a proportion of patients (69 in total) were excluded to obtain two comparable groups of study (1a). Main outcomes of the study were: failure rate, in-hospital length of stay (at first admission and cumulative), post-discharge absence from work. Within the medical group, failure was defined as the necessity for appendectomy after conservative treatment, while it was identified with complications and negative appendectomy within the surgical group (Failure 1). In parallel, an additional definition of failure was proposed (Failure 2) and excluded negative appendectomy from the reasons for failure within the surgical group (5b).

Results

The failure rate for the conservative treatment resulted to be inferior, as compared to the surgical treatment (16.5 vs. 28.4%, OR 0.523 p = 0.019), considering negative appendectomy as a reason for failure. When excluding negative appendectomy from the definition of failure, medical and surgical treatment appeared to perform equally (failure rate: 16.5 vs. 18.3%, OR 1.014 p = 0.965). Patients managed conservatively showed to have a shorter length of stay at first admission than the patients who underwent appendectomy (3.11 vs. 4.11 days, β = ?0.628 days, p < 0.0001). A lower number of lost work days after discharge resulted from a conservative approach (6 vs. 14.64 days, β = ?8.7 days, p < 0.0001).

Conclusions

Considering each outcome as part of a wide-angle analysis, the conservative management of acute appendicitis resulted to be safe and effective in the selected group of patients. In terms of failure rate, the medical treatment resulted to perform as effectively as surgical treatment, if negative appendectomy was excluded from failure, or better, when negative appendectomy was included in the definition of failure. A diminished length of stay during the first admission and a reduced number of lost work days were evident with a conservative approach. The comparison between medical and surgical treatment for acute appendicitis requires a change in perspective, from a spare ‘effectiveness analysis’ to a more thorough ‘appropriateness analysis’: in the present study, the conservative treatment showed to address the clinical requirements in terms of therapeutic appropriateness. Although acute appendicitis is considered a ‘surgical disease’, increasing evidence supports the effectiveness and safety of a conservative approach for selected groups of patients.

     

18,X,Y aneuploidies and transmission electron microscopy studies in spermatozoa from five carriers of different reciprocal translocations

We analysed ejaculated spermatozoa from five infertile men with different balanced reciprocal translocations to contribute to the study of meiotic segregation of chromosomes 18, X and Y and also to evaluate sperm morphology by transmission electron microscopy （TEM） analysis. Conventional lymphocyte karyotype analyses highlighted dif- ferent reciprocal balanced translocations： t（12; 13）, t（4;9）, t（X;8）, t（8; 10） and t（3; 16）. Semen analysis was performed by light and TEM. Fluorescence in situ hybridization was performed directly on sperm nuclei using centromeric probes for chromosomes 18, X and Y. The carriers of the balanced reciprocal translocations considered in the present study showed a very similar pattern of sperm pathologies： diffused presence of apoptosis and immaturity. All patients showed meiotic segregation derangements, highlighted by the presence of sperm diploidies and sex chromosome disomies particularly related to the failure of the first meiotic division. However, an increased incidence of chromosome 18 aneuploidy was detected in spermatozoa from t（X;8） and t（8;10） carriers. We have also reported values from sex chromosomes such as t（X;8）, although the X chromosome was involved in translocation. Since patients with reciprocal translocations and spermatogenetic impairment are candidates for intracytoplasmic sperm injection cycles, the study of sperm parameters, and particularly of the level of aneuploidy rates, would provide better information for couples at risk and would contribute to the data in the literature for a better understanding of the effects of chromosomal rearrangement on the whole meiotic process and, in particular, on chromosomes not involved in translocation.