Prognostic significance of changes of tumor epidermal growth factor receptor expression after neoadjuvant chemoradiation in patients with rectal adenocarcinoma

PURPOSE: The aim of the present study was to examine the effect of neoadjuvant chemoradiation on tumor epidermal growth factor receptor (EGFR) expression in patients with locally advanced rectal adenocarcinoma. PATIENTS AND METHODS: A total of 53?patients with rectal adenocarcinoma (clinical stages?II and III) were studied. Neoadjuvant treatment consisted of 50.4?Gy/28 fractions external radiation with concomitant continuous 5-fluorouracil. Surgical resection was performed 4-6?weeks after the chemoradiation. EGFR expression in the pretreatment biopsies and in the resected specimens was assessed with immunohistochemistry. RESULTS: Patients with an increase of EGFR expression during chemoradiation had significantly shorter disease-free survival (DFS; p?=?0.003) and overall survival (OS; p?=?0.005) compared to patients with either no change or decrease in EGFR expression. The 5-year DFS in patients with increased EGFR expression was only 29% compared to 61% in patients without an increase of EGFR expression. Similarly, the 5-year OS of the patients with increased EGFR expression was 29% compared to 66% in patients without an increase of EGFR expression. All recurrences in patients who had an increase of EGFR expression occurred within the first 2?years after the treatment. The increase in EGFR expression was the only significant predictor of DFS (p?=?0.007) and OS (p?=?0.04) using multivariate Cox regression analysis. CONCLUSION: An increase of EGFR expression during chemoradiation may be associated with significantly shorter DFS and OS. The increase of EGFR could identify a population of patients in whom the effect of the treatment with anti-EGFR therapy should be studied.     

Nitrogen balance in premature babies during parenteral nutrition (author's transl)]

This paper represents a continuation of research into the nitrogen (N) balances in seriously premature babies. During parenteral nutrition an increased amount of 400 mg N/kg body weight/24 hrs. was administered in the form of L-aminoacids together with glucose and fat emulsion. No change in the amount of retained aminoacids occurred (some 80%). On the other hand several increased values of N-metabolites demonstrate that this dosis of aminoacids can be considered as the maximal value.     

Chemotherapy of primary and secondary liver tumors

Liver is the most common site of metastatic disease. Although primary liver tumors are relatively rare in the Czech Republic, liver tumors represent a frequently encountered problem because of high incidence of colorectal and pancreatic cancer. Regimens of systemic chemotherapy or biologic therapy are used for secondary liver tumors according the primary site. It was demonstrated in randomized clinical studies that some of these regimens significantly prolong survival. Although only palliative therapy is possible for most of the patients with liver metastases, resection should be considered in patients with isolated liver involvement. Liver resection represents a curative approach and long-term success seems to be enhanced by neoadjuvant (preoperative) chemotherapy or adjuvant (postoperative) hepatic arterial chemotherapy. Hepatic arterial chemotherapy is also effective in the palliative treatment of unresectable liver metastases. Although it is still uncertain whether hepatic arterial chemotherapy increases survival of patients compared to systemic chemotherapy, it may be regarded as the best available treatment in selected patients because of better palliation associated with higher objective response rate and less systemic toxicity. Along with systemic and hepatic arterial chemotherapy, other approaches are being currently investigated in the treatment of primary and secondary liver tumors, including the use of biologic agents, agents with non-cytotoxic mechanism of action, or chronomodulated chemotherapy.     

Pathological complete response in advanced gastrointestinal stromal tumor after imatinib therapy

Gastrointestinal stromal tumor (GIST) is a rare neoplasm exhibiting, in most cases, mutations of c-kit. Recently it has been demonstrated that a majority of GIST patients with c-kit mutations respond to therapy with imatinib, a c-kit tyrosine kinase inhibitor. Although the response rate in patients treated with imatinib in prospective clinical studies is above 50%, complete response is rare, and the data on the use of imatinib as neoaduvant therapy facilitating radical surgery is still scanty. Here, we report on a patient with metastatic gastric GIST who underwent surgery after 6 months of imatinib therapy. No tumor cells were detected on pathological examination of resection specimen. This case report indicates that a pathological complete response could be achieved with imatinib therapy in patients with GIST, but a wider experience and longer follow-up is necessary to appreciate the prognostic significance of pathological complete response in GIST.     

Expression of mitochondrial uncoupling protein 3 and adenine nucleotide translocase 1 genes in developing rat heart: putative involvement in control of mitochondrial membrane potential

Postnatal maturation of the heart depends on the switch from glycolytic to oxidative metabolism and it is associated with decreasing tolerance to oxygen deprivation. Therefore, changes in composition and function of cardiac mitochondria during postnatal development require detailed characterization. Left-ventricular myocardium of prenatal, and 1-, 2-, 5-, 10-, 20-, 28-, 50-, 60-, and 90-d-old male Wistar rats was studied. The expression of uncoupling proteins (UCPs), adenine nucleotide translocase (ANT), and peroxisome proliferator-activated receptor alpha (PPARalpha) genes was characterized by northern blotting (UCP2), real-time quantitative RT-PCR (UCP2, UCP3, ANT1, ANT2, and PPARalpha), and by immunoblotting (UCP3). In isolated mitochondria, cytochromes a + a(3) were quantified by a spectrophotometry, and mitochondrial membrane potential (MMP) was measured using Rhodamine 123 (by spectrofluorimetry and flow cytometry). The specific content of cytochromes in mitochondria increased two-fold between birth and day 30, similarly, as the expression of ANT1 and PPARalpha genes. Postnatal activation in the expression of UCP2, UCP3, ANT1 and PPARalpha genes resulted in the expression maxima between days 20 and 30. The content/expression declined following day 20 (UCP2, UCP3, and PPARalpha) or 30 (cytochromes and ANT1), while expression of ANT2 declined continuously during the first month of life. In 1-d-old animals a single population of mitochondria with a relatively high MMP was observed; with increasing age, a second population of mitochondria with a significantly lower MMP appeared. The results support the view that mitochondrial energy conversion in heart changes during ontogeny and suggest the involvement of UCP3 and/or ANT1 in the control mechanism.     

Inflammation enhances the vaccination potential of CD40‐activated B cells in mice

Vaccination with antigen‐pulsed CD40‐activated B (CD40‐B) cells can efficiently lead to the in vivo differentiation of naive CD8⁺ T cells into fully functional effectors. In contrast to bone marrow‐derived dendritic cell (BMDC) vaccination, CD40‐B cell priming does not allow for memory CD8⁺ T‐cell generation but the reason for this deficiency is unknown. Here, we show that compared to BMDCs, murine CD40‐B cells induce lower expression of several genes regulated by T‐cell receptor signaling, costimulation, and inflammation (signals 1–3) in mouse T cells. The reduced provision of signals 1 and 2 by CD40‐B cells can be explained by a reduction in the quality and duration of the interactions with naive CD8⁺ T cells as compared to BMDCs. Furthermore, CD40‐B cells produce less inflammatory mediators, such as IL‐12 and type I interferon, and increasing inflammation by coadministration of polyriboinosinic‐polyribocytidylic acid with CD40‐B‐cell immunization allowed for the generation of long‐lived and functional CD8⁺ memory T cells. In conclusion, it is possible to manipulate CD40‐B‐cell vaccination to promote the formation of long‐lived functional CD8⁺ memory T cells, a key step before translating the use of CD40‐B cells for therapeutic vaccination.     

Comparison of clinical and laboratory characteristics during two major paediatric meningitis outbreaks of echovirus 30 and other non-polio enteroviruses in Germany in 2008 and 2013

Viral meningitis is mainly caused by non-polio enteroviruses (NPEV). Large-scale data on the clinical characteristics between different outbreaks within the same region are lacking. This study aimed to analyse a possible influence of the circulating NPEV genotype on the disease outcome of affected children. A retrospective cohort study analysing two major outbreaks of NPEV meningitis in Germany in 2008 and 2013 was conducted in cooperation with the National Reference Centre for Poliomyelitis and Enteroviruses (NRC PE) and five German children’s hospitals. A total of 196 patients with laboratory-confirmed NPEV meningitis were enrolled. In 2008, children with NPEV meningitis had significantly higher fever and showed more behavioural changes and less back pain. To better define typical findings in echovirus 30 (E-30) meningitis, patients were split into the following three groups: E-30 positive patients, patients with “Non E-30” infection and patients with “Untyped” NPEV infection. E-30 positive patients were significantly older and their disease course was more acute, with early admission to but also early discharge from hospital. E-30 positive patients showed a significantly higher rate of headache and meningism, and a lower rate of diarrhoea and clinically defined septicaemia when compared to the others. Regarding laboratory testing, E-30 positive patients presented with significantly elevated peripheral blood neutrophil counts when compared to patients with “Non E-30” or “Untyped” NPEV infection. In conclusion, E-30 meningitis in children shows a characteristic pattern of clinical features. To further characterise NPEV strains worldwide, continuous surveillance and typing of NPEV strains causing central nervous system disease is warranted.     

Effects of Melatonin on Ischemia and Reperfusion Injury of the Rat Heart

Effects of melatonin on various manifestations of ischemia/reperfusion injury of the isolated perfused rat heart were examined. Ischemia- and reperfusion-induced ventricular arrhythmias were studied under constant flow in hearts subjected to 10, 15 or 25 min of regional ischemia (induced by LAD coronary artery occlusion) and 10-min reperfusion. Melatonin was added to the perfusion medium 5 min before ischemia at concentrations of 10 mol/l or 10 nmol/l and was present throughout the experiment. Recovery of the contractile function was evaluated under constant perfusion pressure after 20-min global ischemia followed by 40-min reperfusion. Hearts were treated with melatonin at a high concentration (10 mol/l) either 5 min before ischemia only (M1) or 5 min before ischemia and during reperfusion (M2) or only during reperfusion (M3). At the high concentration, melatonin significantly reduced the incidence of reperfusion-induced ventricular fibrillation and decreased arrhythmia score (10% and 2.2 ± 0.3, respectively) as compared with the corresponding untreated group (62% and 4.1 ± 0.3, respectively); the low concentration had no effect. This substance did not affect the incidence and severity of ischemic arrhythmias. Melatonin (M2, M3) significantly improved the recovery of the contractile function as compared with the untreated group; this protection did not appear if melatonin was absent in the medium during reperfusion (M1). Our results show that melatonin, in accordance with its potent antioxidant properties, effectively protects the rat heart against injury associated with reperfusion. It appears unlikely that melatonin is cardioprotective at physiological concentrations.     

Insulin-like growth factor-I stimulates erythropoiesis when administered enterally

BACKGROUND: Insulin-like growth factors I and II (IGF-I and IGF-II) are potent growth factors involved in development. IGF-I stimulates proliferation of erythropoietic progenitors and parenteral IGF-I administration stimulates in vivo erythropoiesis in animals. IGF-I and IGF-II are both present in mammalian milks and when milk-borne, are resistant to neonatal gastrointestinal degradation. Whether milk-borne IGF-I or IGF-II regulates neonatal erythropoiesis in not known. We hypothesized that physiological doses of enteral IGFs stimulate erythropoiesis in suckling rats. METHODS: Eight day-old Sprague Dawley rats were artificially fed for 4 days with rat milk substitute (RMS) or RMS supplemented with physiological levels of IGF-I or IGF-II. Rats fed IGF-I and IGF-II were compared to control RMS. Blood and marrow were collected; measures of red cell mass, measures of erythropoietic stimulus, and indices of iron status were measured. RESULTS: Rats fed IGF-I had higher hemoglobin (Hb) levels (100 +/- 10 g/l), compared to those fed RMS (94 +/- 9) or IGF-II (91 +/- 6), p < 0.001. After IGF-I supplementation, red blood cell counts (RBC) (p < 0.04) and hematocrits (p < 0.002) were also higher. Plasma erythropoietin (Epo) levels, reticulocytes, plasma iron and erythrocyte iron incorporation were similar. CONCLUSION: Intact enteral IGF-I reaches distal erythropoietic tissue resulting in greater red cell mass, but not by increasing plasma Epo levels or by altering cellular iron transport.