Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC).

BACKGROUND: Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. METHODS: In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. RESULTS: In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DISCUSSION: Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

Multicenter phase II study evaluating docetaxel and cisplatin as neoadjuvant induction regimen prior to surgery or radiochemotherapy with docetaxel, followed by adjuvant docetaxel therapy in chemonaive patients with NSCLC stage II, IIIA and IIIB (TAX-AT 1.203 Trial).

OBJECTIVES: Neoadjuvant therapy with a platinum based doublet is an option in NSCLC patients with upfront resectable disease. However, the role of neoadjuvant induction in stages IIIA and IIIB and in initially not resectable patients is unclear. PATIENTS AND METHODS: In this phase II trial, 78 patients with locally advanced NSCLC, of whom 56 were considered not resectable at initial diagnosis, were treated with three neoadjuvant cycles of docetaxel and cisplatin and subjected to radical surgery if resectable. Definitive radiochemotherapy (RCT) using weekly docetaxel was the prespecified alternative if patients were not resectable at restaging. The primary objective was response to neoadjuvant induction. RESULTS: After induction, 36 (46%) were radically operated and 24 (31%) were treated with RCT. Overall, 32 patients (41%) completed the entire study plan. Partial response to induction therapy was observed in 43 patients (55%); furthermore, 19 of 56 initially not resectable cases (34%) became resectable upon induction. Median progression-free (PFS) and overall survival (OS) were 8.5 and 16.4 months for the whole cohort. Encouragingly, conversion to resectability was predictive for favorable outcome. On the other hand, patients who were not resectable at restaging and received RCT were characterized by a rather unfavorable prognosis (5-year and 10-year OS, whole cohort: 20% and 12%; RCT: 8% and 0%; surgery: 37% and 24%, respectively). CONCLUSION: Neoadjuvant induction with the doublet docetaxel/cisplatin and subsequent radical resection resulted in favorable survival. Of note, conversion to resectability was mandatory for the chance of cure in patients considered initially not resectable.

Small steps of improvement in small-cell lung cancer (SCLC) within two decades: a comprehensive analysis of 484 patients.

BACKGROUND: It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade. METHODS: All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol. RESULTS: A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age < 70 years and absence of LDH elevation in the palliative setting. CONCLUSIONS: In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.

Fine-tuning of substrate architecture and surface chemistry promotes muscle tissue development.

Tissue engineering has been increasingly brought to the scientific spotlight in response to the tremendous demand for regeneration, restoration or substitution of skeletal or cardiac muscle after traumatic injury, tumour ablation or myocardial infarction. In vitro generation of a highly organized and contractile muscle tissue, however, crucially depends on an appropriate design of the cell culture substrate. The present work evaluated the impact of substrate properties, in particular morphology, chemical surface composition and mechanical properties, on muscle cell fate. To this end, aligned and randomly oriented micron (3.3±0.8 µm) or nano (237±98 nm) scaled fibrous poly(ε-caprolactone) non-wovens were processed by electrospinning. A nanometer-thick oxygen functional hydrocarbon coating was deposited by a radio frequency plasma process. C2C12 muscle cells were grown on pure and as-functionalized substrates and analysed for viability, proliferation, spatial orientation, differentiation and contractility. Cell orientation has been shown to depend strongly on substrate architecture, being most pronounced on micron-scaled parallel-oriented fibres. Oxygen functional hydrocarbons, representing stable, non-immunogenic surface groups, were identified as strong triggers for myotube differentiation. Accordingly, the highest myotube density (28±15% of total substrate area), sarcomeric striation and contractility were found on plasma-coated substrates. The current study highlights the manifold material characteristics to be addressed during the substrate design process and provides insight into processes to improve bio-interfaces.

Kinetic analysis of the reaction between d(TTGGCCAA) and [Pt(NH3)3(H2O)]2+ by enzymatic degradation of the products and ESI and MALDI mass spectrometries.

The kinetics of the reaction between the octanucleotide d(TTGGCCAA) in the single-stranded form in pure water and the platinum complex [Pt(NH3)3(H2O)]2+ was investigated by electrospray ionization and matrix-assisted laser desorption/ionization (MALDI) mass spectrometries coupled with enzymatic degradation of the adducts. These methods led to the determination of specific rate constants of platination. The global rate constant characteristic of the formation of adducts on each 5'- or 3'-guanine were measured by electrospray ionization analysis. The ratios between the 5'- and 3'-adducts were determined from enzymatic degradation of the final reaction mixture and MALDI analysis. The platination in water is approximately eight times faster than in 0.1 M NaClO4. The selectivity of platination is a factor of 2 in favor of the 5'-guanine, and similar to that observed for the reaction between d(CTGGCTCA) and [Pt(NH3)3(H2O)]2+ in 0.1 M NaClO4.

2-(fluorine-18)-fluoro-2-deoxy-D-glucose PET in detection of pancreatic cancer: value of quantitative image interpretation.

PURPOSE: To evaluate use of positron emission tomography (PET) versus computed tomography (CT) in detection of pancreatic cancer and determine the value of quantitative and visual image interpretation of these techniques. MATERIALS AND METHODS: Within 8 weeks before surgery, 73 patients with suspected pancreatic cancer or chronic pancreatitis underwent imaging with CT and with static PET after injection of 250-350 MBq of 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (FDG). Focal FDG uptake, considered a sign of malignancy, was calculated with standardized uptake values (SUVs) 60 minutes after injection. RESULTS: With FDG PET, pancreatic carcinoma was correctly diagnosed in 41 (95%) of 43 patients, and chronic pancreatitis in 27 (90%) of 30 patients. With an SUV cutoff value of 1.53, both sensitivity and specificity for detection of malignancy were 93%. With CT, pancreatic cancer was correctly diagnosed in 33 (80%) of 41 patients, whereas results in seven (26%) of 27 patients with chronic pancreatitis were false-positive (specificity, 74%). CONCLUSION: FDG PET enabled reliable differentiation of pancreatic adenocarcinoma from chronic pancreatitis. The sensitivity and specificity of visual image interpretation with FDG PET was statistically significantly higher (P < .05) than with CT.

[Positron emission tomography. Introduction of a new procedure in diagnosis of urologic tumors and initial clinical results]. / Positronenemissionstomographie. Einführung eines neuen Verfahrens in die Diagnostik urologischer Tumoren und erste klinische Ergebnisse.

Correct preoperative staging of malignant tumors is a prerequisite for an adequate therapy. This is not always possible with the imaging techniques available. Often, only an exploratory laparotomy can give the final diagnosis. Therefore, the search is on for a non-invasive technique for staging. Positron emission tomography (PET) is a new method in nuclear medicine; it is used for the diagnosis of primary tumors, for staging, and for follow-up after therapy. With PET, biochemical pathways and physiological functions are studied, in contrast to CT and MRI, with which anatomy and morphology are examined. In our department PET was used in 26 patients with invasive bladder cancer, in 11 patients with renal cell carcinoma and in 1 patient for follow-up after testicular cancer. The primary bladder tumor was found in 85% of cases; in 4 a non-organ-confined tumor was diagnosed preoperatively. Specificity in staging of lymph nodes was 86% (18/21); in 3 patients lymph nodes were false-positive on PET. However, in 5 patients all lymph node metastases were found by PET. Renal cell carcinoma were found in 8 out of 9 patients; in 2 patients with high-grade tumors an FDG-uptake defect was found. Lymph node staging was accurate in 9 patients without metastases and in 2 with metastases. One patient had a slightly enlarged retroperitoneal lymph node in the follow-up of a non-seminomatous germ cell tumor, which was positive on PET. Histology confirmed that it was the only positive lymph node within the whole specimen after retroperitoneal lymphadenectomy. PET gives new insights in uro-oncology by examination of the metabolism. Our initial results are promising and warrant further studies.

[Myocardial infarction in pregnancy]. / Der Myokardinfarkt in der Schwangerschaft.

Myocardial infarction during pregnancy and puerperium is very rare. Increased awareness of its possible occurrence is important for diagnosis. We report on a 37-year-old woman without coronary risk factors who suffered an anterior septal infarction in the last trimester. Coronary angiography one month after normal delivery and two months after infarction revealed normal coronary arteries. Ventriculography showed anteroseptal akinesia. The assumed etiology of myocardial infarction appears to be coronary spasm. A history of vasospasm in other vascular beds, migraine and Raynaud's phenomenon support this hypothesis. The literature is reviewed with special emphasis on clinical picture, prognosis, etiology and management of myocardial infarction during pregnancy.

The consequences of continuous haemofiltration on lung mechanics and extravascular lung water in a porcine endotoxic shock model.

Endotoxinaemia (E. coli endotoxin, 0.111.B4) and pulmonary hypertension were evoked in 20 swine, randomly assigned to receive either zero-balanced venovenous haemofiltration (HF) with an ultrafiltration and replacement rate of 600 ml/h (HF group, n = 10) or to undergo an uninfluenced spontaneous course (E group, n = 10) during a constant infusion of endotoxin until the end of the experiment. Endotoxin-induced pulmonary dysfunction was assessed on the basis of extravascular lung water (EVLW) using a thermo-dye technique via a fiberoptic intra-aortic probe, gas exchange and lung mechanics, the latter derived by a pressure-volume loop (P/V loop) of the respiratory system (super syringe, flow 30 ml/s, tidal volume 600 ml). A comparable increase in alveolo-arterial oxygen difference and a constant EVLW was observed in both groups. The progressive deterioration of hysteresis area and compliance parameters by endotoxinaemia was significantly blunted by HF. Independent of an impact on pulmonary oedema zero-balanced HF modifies endotoxin induced lung injury, probably by the convective transport of mediator substances.

[Endoscopic study of digestive lesions caused by the use of nonsteroidal anti-inflammatory agents in rheumatic patients]. / Etude endoscopique des lésions digestives provoquées par l'utilisation d'anti-inflammatoires non stéroïdiens chez des patients rhumatisants.

44 patients treated with NSAID for a period of over 2 months for a rheumatic disease underwent fibroscopic endoscopy of the upper gastrointestinal tract. Gastric lesions were found to be more frequent than those of the esophagus or duodenum. They occur in men in particular and are not correlated with symptoms or clinical findings. They are likewise unaffected by the presence of inflammatory arthropathy or simultaneous ingestion of coffee or drugs or smoking. Lesions may improve despite continued use of NSAID.

[Deep leg vein thrombosis during skiing. A case report]. / Tiefe Beinvenenthrombose beim Skisport. Ein kasuistischer Beitrag.

An unusual case is reported of deep vein thrombosis of the leg which occurred on skis without direct trauma. Since no vascular malformation or coagulation disorder were found, the findings strongly support the diagnosis of "thrombose par effort" (effort thrombosis).

[Boletus luridus and alcohol. Case report]. / Hexenröhrling (Boletus luridus) mit Alkohol. Ein kasuistischer Beitrag.

When ingested with alcohol, certain drugs (e.g. cephalosporins, sulfonylurea, metronidazole, griseofulvin, chloramphenicol), calcium cyanamide, dimethyl formamide and certain mushrooms cause a disulfiram-alcohol type reaction. Three cases of a disulfiram-alcohol type reaction after ingestion of Boletus luridus and alcohol are described. No serious symptoms were observed. In contrast to Coprinus atramentarius, the toxin of Boletus luridus is unknown.

Percutaneous transhepatic cholangiography with the Chiba needle.

Ninety patients with suspected pathology of the biliary tract were submitted to percutaneous transhepatic cholangiography. Forty-two of 43 dilated biliary tracts and 32 of 47 without dilatation were successfully entered. Except for fever following the procedure in two patients, there was no major complication. This technic was of prime importance in the management of patients with suspected pathology of the biliary tract.

Comparison of anesthetic agents in the sea otter.

Five anesthetic agents (C1744, etorphine, fentanyl, ketamine hydrochloride, and halothane) were tested to establish the dosage of a safe, effective, short-acting anesthetic for use in the sea otter. Etorphine, at a dosage of 0.75 mg per adult otter and used in conjunction with diazepam, at a dosage of 1.25 mg per adult otter, met most of the requirements for use under field conditions. Halothane, administered through an anesthetic machine, proved to be effective for use in a veterinary hospital.