Combination chemotherapy with mitomycin C,vindesine and melphalan for refractory metastatic breast cancer

Summary A combination of mitomycin C, vindesine and melphalan was administered to 33 patients with heavily pretreated refractory breast cancer. The overall response rate was 27% with a mean duration of more than 10.2 months. A stabilization with a mean duration of 5.1 months was seen in 56% of cases, while 20% of patients progressed. Gastrointestinal toxicity, mostly grade 1 or 2 nausea/vomiting was seen in 85% of cases, grade 1 or 2 leukopenia in 60% of patients, and grade 1 or 2 thrombocytopenia in 42%. Considering the good compliance of this regimen and the poor prognosis of patients with refractory advanced breast cancer, this combination can be useful as a palliative treatment of breast carcinoma.Abbreviations MMC mitomycin C - VDS vindesine - L-PAM melphalan     

Do catastrophizing and autonomic-reduced flexibility mediate pain outcomes in chronic headache?

Neurological Sciences - Maladaptive cognitive strategies and reduced autonomic flexibility have been reported in chronic pain conditions. No study to date addressed the effects of maladaptive...     

Clinical relevance of thymidylate synthase expression in the signet ring cell histotype component of colorectal carcinoma

Thymidylate Synthase (TS) is the key enzyme for DNA synthesis pathways and is inhibited by 5-Fluorouracil (5FU). The aim of this work was to study TS expression and the proliferation rate in the different histological types of colorectal carcinoma (CRC). 50 patients with CRC were included in this study and evaluated immunohistochemically using the monoclonal antibodies, TS106 and Ki67. 20 tumours were of the intestinal type, 15 cases were signet ring cell carcinoma (SRCCs) and 15 cases were “mixed-type”, with at least two different histological components. Intestinal and mucinous histotypes were positive for TS and Ki67, while “signet ring cell” samples were negative or showed only weak and focal positivity for both the TS and Ki67 antibodies. Our results show that signet ring cells (that are also often present in intestinal and mucinous carcinomas), are in the post-mitotic phase of the cell cycle and show a low proliferation index and TS expression. As TS is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU), we can hypothesise that TS expression levels in the different histotypes of CRC could affect the potential responsiveness of these tumours to fluoropyrimidine chemotherapy, with a low efficacy being expected in signet ring cell areas.     

Antioxidant defenses in a B16 melanoma line resistant to doxorubicin: an in vivo study.

A B16 melanoma line was repeatedly transplanted subcutaneously in C57BL/6 mice. On day 4 after every transplant, the animals were treated with doxorubicin (DXR), 10 mg/kg i.p. The aim of the work was to develop an in-vivo model of resistance to the antiblastic in order to analyze some possible mechanistic aspects of the process in the course of time. After 16 transplants and treatments the melanoma completely lost its sensitivity to the antiproliferative effects of maximal tolerated doses of DXR and showed over-expression of P-glycoprotein. Compared to the parental line, the in vitro resistance index was 4.6. After 27 transplants and treatments the melanoma did not increase its in vitro resistance to DXR further, and this resistance was completely reversed by verapamil. The behavior of the antioxidant defenses (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, glutathione reductase and glutathione) was evaluated after 4, 16 and 27 transplants and treatments with DXR. At no stage did the treated melanoma show any variation in the antioxidant enzymes. Compared to the parental counterpart its glutathione levels were elevated after four treatments (+80%), when, however, the line was still sensitive to the in vivo effects of DXR, and after 16 treatments (+30%). Instead, no variation of the glutathione content was seen after 27 treatments with DXR. These results seem to exclude the possibility that the antioxidant defenses play a major role in the resistance of this B16 melanoma line to DXR. On the other hand, the low but, however, 'clinically' significant resistance of the tumor to the antiblastic seems mainly related to the mechanisms linked to the P-glycoprotein over-expression.     

Flexible versus rigid endoscopy in the management of esophageal foreign body impaction: systematic review and meta-analysis

Background

Foreign body (FB) impaction accounts for 4% of emergency endoscopies in clinical practice. Flexible endoscopy (FE) is recommended as the first-line therapeutic option because it can be performed under sedation, is cost-effective, and is well tolerated. Rigid endoscopy (RE) under general anesthesia is less used but may be advantageous in some circumstances. The aim of the study was to compare the efficacy and safety of FE and RE in esophageal FB removal.

Methods

PubMed, MEDLINE, Embase, and Cochrane databases were consulted matching the terms “Rigid endoscopy AND Flexible endoscopy AND foreign bod*”. Pooled effect measures were calculated using an inverse-variance weighted or Mantel-Haenszel in random effects meta-analysis. Heterogeneity was evaluated using I² index and Cochrane Q test.

Results

Five observational cohort studies, published between 1993 and 2015, matched the inclusion criteria. One thousand four hundred and two patients were included; FE was performed in 736 patients and RE in 666. Overall, 101 (7.2%) complications occurred. The most frequent complications were mucosal erosion (26.7%), mucosal edema (18.8%), and iatrogenic esophageal perforations (10.9%). Compared to FE, the estimated RE pooled success OR was 1.00 (95% CI 0.48–2.06; p?=?1.00). The pooled OR of iatrogenic perforation, other complications, and overall complications were 2.87 (95% CI 0.96–8.61; p?=?0.06), 1.09 (95% CI 0.38–3.18; p?=?0.87), and 1.50 (95% CI 0.53–4.25; p?=?0.44), respectively. There was no mortality.

Conclusions

FE and RE are equally safe and effective for the removal of esophageal FB. To provide a tailored or crossover approach, patients should be managed in multidisciplinary centers where expertise in RE is also available. Formal training and certification in RE should probably be re-evaluated.

     

Bariatric Surgery to Reduce Mortality in US Adults. A Public Health Perspective from the Analysis of the American National Health and Nutrition Examination Survey Linked to the US Mortality Register

Background

Type II obesity represents a major pandemic and public health threat in high-income countries. Type II obesity increases the risk of all-cause and specific-cause mortality, and it is widely acknowledged that bariatric surgery represents the only effective therapeutic option in these patients. The aim of the present study was to estimate US population attributable risk for all-cause and cause-specific mortality in type II obese subjects undergoing weight loss as resulting from bariatric surgery alone and supplemented with behavioral intervention.

Methods

The American National Health and Nutrition Examination Survey linked to the US death registry updated to 2011 was used to estimate type II obesity prevalence and all-cause and specific cause of death for type II obese adults undergoing weight loss. Multivariate adjusted proportional hazard Cox models were used to estimate mortality risks. Statistical analyses were performed on the most updated version of the database (June 2017).

Results

A monotone positive trend for type II obesity was observed during the period 1999–2014 (p < 0.001). According to trend analysis, the rate of type II obesity in US adults is expected to rise up to 8.5%. Two- to sevenfold increased risk of all-cause and specific-cause mortality was observed for type II obese participants when compared to type I obese and overweight participants. Population attributable risk for all-cause and specific-cause mortality for type II obese subjects undergoing weight loss was ranging between 6 and 34%.

Conclusions

Bariatric surgery supplemented with behavioral intervention can result in a relevant reduction of mortality if extensively applied to the US population.

     

Personalized therapeutic strategies in HER2-driven gastric cancer

Gastric Cancer - Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them...     

Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form

Transferrin receptor-2 is a transmembrane protein whose expression is restricted to hepatocytes and erythroid cells. Transferrin receptor-2 has a regulatory function in iron homeostasis, since its inactivation causes systemic iron overload. Hepatic transferrin receptor-2 participates in iron sensing and is involved in hepcidin activation, although the mechanism remains unclear. Erythroid transferrin receptor-2 associates with and stabilizes erythropoietin receptors on the erythroblast surface and is essential to control erythrocyte production in iron deficiency. We identified a soluble form of transferrin receptor-2 in the media of transfected cells and showed that cultured human erythroid cells release an endogenous soluble form. Soluble transferrin receptor-2 originates from a cleavage of the cell surface protein, which is inhibited by diferric transferrin in a dose-dependent manner. Accordingly, the shedding of the transferrin receptor-2 variant G679A, mutated in the Arginine-Glycine-Aspartic acid motif and unable to bind diferric transferrin, is not modulated by the ligand. This observation links the process of transferrin receptor-2 removal from the plasma membrane to iron homeostasis. Soluble transferrin receptor-2 does not affect the binding of erythropoietin to erythropoietin receptor or the consequent signaling and partially inhibits hepcidin promoter activation only in vitro. Whether it is a component of the signals released by erythropoiesis in iron deficiency remains to be investigated. Our results indicate that membrane transferrin receptor-2, a sensor of circulating iron, is released from the cell membrane in iron deficiency.