Treatment strategies in recurrent esophageal or junctional cancer.

Little evidence is available about survival rates in patients with recurrent disease after potentially curative surgery for esophageal or junctional cancer. Only in limited occasions, potentially curative salvage strategies are available. The aim of this study is to analyze survival rates and patterns of dissemination, and to identify independent prognostic factors in a consecutive series of patients who develop recurrent esophageal or junctional cancer. Between 1994 and 2015, patients who developed disease recurrence after neoadjuvant chemo(radio)therapy followed by radical esophagectomy for esophageal or junctional cancer were retrospectively analyzed. The Kaplan-Meier estimates were performed to calculate and compare overall survival between patients with different patterns of dissemination and to compare between different treatment strategies. Furthermore, univariate and multivariate Cox-regression analyses were performed to identify independent prognostic factors for post recurrence survival. In this study, we included 219 patients. The median overall survival of all included patients was 3.2 months (range: 0.0-101.1 months). The median overall survival in patients with exclusively locoregional recurrence (n = 23, 10.8%) was 4.9 months (range: 0.1- 55.6) and 2.9 months (range: 0.0-101.1) in patients who had distant metastases (n = 189, 89.2%), P = 0.003. Patients who received treatment aimed at complete tumor eradication (n = 28, 13.7%) had a median overall survival of 13.6 months (range: 1.1-101.1) and palliative treated patients (n = 94, 46.1%) of 4.7 months (range: 0.3-25.6), P < 0.001. In a selected group of patients survival of more than 20 months was achieved. Univariate and multivariate Cox-regression analysis showed that a higher age at the diagnosis of recurrent disease (hazard ratio: 1.087, P ≤ 0.001), an irradical resection of the primary tumor (hazard ratio: 3.355, P = < 0.001), the number of positive lymph nodes after neoadjuvant therapy (hazard ratios: ypN2 = 1.724 (P = 0.024) and ypN3 = 2.082 (P = 0.028) and the presence of a single hematogenous distant metastases (hazard ratio: 2.281, P = 0.003) or more than one hematogenous distant metastasis (hazard ratio: 2.385, P = 0.005) were associated with a shorter postrecurrence survival. The prognosis of patients who develop recurrent esophageal or junctional cancer is poor. In a selected group of patients however relatively long survival can be achieved. This offers new perspectives to improve treatment strategies and survival rates.

Clinical and biological effects of demethylating agents on solid tumours - A systematic review.

BACKGROUND: It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours. METHODS: We conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted. RESULTS: Fifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes. CONCLUSION: Demethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours.

Wear of ultra-high molecular weight polyethylene against damaged and undamaged stainless steel and diamond-like carbon-coated counterfaces.

The wear of ultra-high molecular weight polyethylene (UHMWPE) in artificial joints and the resulting wear debris-induced osteolysis remains a major clinical concern in the orthopaedic sector. Third-body damage of metallic femoral heads is often cited as a cause of accelerated polyethylene wear, and the use of ceramic femoral heads in the hip is gaining increasing favour. In the knee prostheses and for smaller diameter femoral heads, the application of hard surface coatings, such as diamond-like carbon, is receiving considerable attention. However, to date, there has been little or no investigation of the tribology of these coatings in simulated biological environments. In this study, diamond-like carbon (DLC) has been compared to stainless steel in its undamaged form and following simulated third-body damage. The wear of UHMWPE was found to be similar when sliding against undamaged DLC and stainless steel counterfaces. DLC was found to be much more damage resistant than DLC. Under test conditions that simulate third-body damage to the femoral head, the wear of UHMWPE was seven times lower against DLC than against stainless steel (P < 0.05). The study shows DLC has considerable potential as a femoral bearing surface in artificial joints.

Toxicity of particulate silicon carbide for macrophages, fibroblasts and osteoblast-like cells in vitro.

There is widespread interest in the use of interfacial layers in the preparation of diamond and diamond-like carbon (DLC) coatings. These DLC coatings deposited onto metal substrates with a silicon carbide (SiC) interfacial layer exhibit improved adhesion and show promise as wear-retardant coatings for biomedical implants. Although the DLC coatings show excellent biocompatibility in vitro, they may be susceptible to damage within the biological environment, leading to exposure of the interfacial silicon carbide. We have investigated the effects of two forms of silicon carbide (alpha-SiC and beta-SiC) on macrophages, fibroblasts and bone cells in vitro. Both alpha- and beta-SiC are well-tolerated by cells at concentrations of up to 0.1 mg/ml but cause severe cytotoxicity at a concentration of 1 mg/ml. If SiC is to be used as an interfacial layer on biomedical implants, the quality of the DLC coating must be optimised to minimise the risk of film breakdown.

[The clinically unrecognized colorectal cancer in a patient autopsy sample]. / Das klinisch unerkannte kolorektale Karzinom im Sektionsgut.

An evaluation of 27,543 postmortem records revealed that 29 percent of colon carcinomas and 16.9 per cent of rectum carcinomas had not been identified until postmortem investigation (186 cases). The rate of false diagnosis have decreased from 1954 by 12.5 per cent for colon carcinoma and by 20.8 per cent for rectum carcinoma. They still amounted to 27.7 per cent for patients above 65 years of age and to 11.5 per cent for younger patients. They were 31.6 per cent for carcinoma of the right colon half and 20.6 per cent for left-side colon carcinoma. On admission to hospital, tumour stages III and IV were recorded form 52.7 per cent of all patients hospitalized for colon carcinoma and from 30.8 per cent of those with rectum carcinoma. Sixty-four patients died within 72 hours form hospitalization and another 27 within one week.

Reversal of diabetes by isogeneic transplantation of cultured pancreatic islets.

Pancreatic islets were isolated by collagenase digestion from female Wistar rats and cultured at 20 mmol/l glucose. The enhancement of Mg++ concentration from 0.8 mmol/l up to 5.3 mmol/l had a protecting effect on the glucose-induced insulin release in the subsequent short-time incubation and prevented the age-depending decrease of B-cell function. About 1,000 cultured islets injected into portal vein normalized the plasma glucose of streptozotocin-diabetic rats. The plasma glucose patterns during the glucose load were nearly identical to healthy controls. These findings suggest that the cultured islets maintain the ability to secrete insulin in response to glucose in vitro as well as in vitro and that such islets can reverse an experimentally induced diabetes.

[Islet cell culture as a method of short-term preservation before islet transplantation]. / Die Inselkultur als eine Methode zur Kurzzeitpräservation vor Inseltransplantationen.

Pancreatic islets were isolated by collagenase digestion of the pancreas from inbred Wistar rats and cultured at 20 mmol/l glucose and 5.3 mmol/l Mg++ for 4 days. About 1,000 cultured islets injected into the portal vein normalized the plasma glucose of severe diabetic rats induced by streptozotocin (45 mg/kg body weight). Spontaneous recovery of streptozotocin-treated rats was not observed in diabetic controls. Although the insulin response of transplanted rats after i.v. glucose injection (5 mmol per kg body weight) was significantly below control animals, the amount of insulin released was obviously sufficient to sustain a persisting normoglycemia of fed animals up to 1 year. The sufficient preservation of insulin content (I) and the rapid depletion of amylase content (A) of collagenase-treated pancreas fragments cultured for 48 h resulted in a significant rise in the I/A ratio. Because islet isolation is associated with islet loss, especially in the human pancreas, the short term culture enhances hopefully the possibilities for successful transplantation.

Effects of goldthioglucose on hormone secretion of pancreatic rat islets in vitro.

Goldthioglucose enhanced independently of glucose but related to dose the insulin secretion of pancreatic rat islets in vitro. The stimulatory action is additive to that of glucose, is not inhibited by mannoheptulose and not connected with an altered glucose-utilization. The gold thioglucose-induced insulin secretion is diminished in the presence of epinephrine and Mg++, respectively, and characterized by a uniphasic response peaking at 15 min. In the absence of glucose goldthioglucose did not modify the pancreatic glucagon secretion.

Delayed or biphasic glucose-induced insulin secretion of pancreatic islets isolated from spiny mice (Acomys cahirinus) : relation to age of animals.

The dynamics of insulin release from spiny mouse perifused pancreatic islets was investigated. In agreement with earlier studies we found no initial (0-10 min) insulin secretion in response to glucose in islets prepared from mice up to 35 weeks of age. The islets of animals older than 40 weeks, however, were characterized by greater insulin content, and a restored typical biphasic insulin secretion profile. The results suggest that immediate glucose response is modified by environmental or other factors related to age.

Effects of sulphydryl reagents on pancreatic glucagon secretion in vitro.

The effect of sulphydryl reagents on glucagon secretion of isolated Wistar rats islets was studied. Chloromercuribenzene-p-sulphonic acid (CMBS) is a strong stimulator of glucagon secretion, whereas 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) markedly inhibited the hormone release. The effect of CMBS could not be suppressed by 20 mM glucose, but in the presence of 1 mM 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulphonic acid (SITS), and is independent of the glucagon content of islets. The results let us assume that sulphydryl-groups of pancreatic A-cells are involved in the regulation of glucagon secretion.

Investigations on isolated islets of Langerhans in vitro. XIII. Experiments concerning the preparation conditions with collagenase.

During the digestion of pancreatic pieces with collagenase for prepartion of isolated islets the enzymes in incubation medium (collangenolytic and/or proteolytic) can alter the secretion behavior of A- and B-cells. Insulin release after such an enzymatic attack is characterized by an enhanced basal secretion and a diminished and delayed glucose response. Overdigestion results in a decreased glucagon secretion in response to arginine, a diminished insulin content, and a decreased thiol-protein-disulfide-oxidoreductase activity of the islets. Increased albumin concentrations did not prevent the collagenase effect.