The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patient's prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P=0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P=0.0061) and p53-phospho (P=0.0064). Expression of p53 correlated with expression of p53-phospho (P<0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma

The curious compatibility of consensus, corporatism, and neoliberalism : The Finnish business community and the retasking of a corporatist welfare state

This article addresses the apparent paradox of simultaneous neoliberal change and welfare-statist, corporatist continuity by presenting an empirical case study of the advent of neoliberal ideas in Finland in the 1970s and 1980s. The article focuses on the attempts of a free-market think tank, EVA, and the employers’ association, STK, to advance policies such as economic deregulation, international competitiveness, welfare retrenchment, and active social and labour market policies through the neoliberal retasking of the corporatist Finnish welfare state. EVA and the STK utilised seemingly non-neoliberal means, that is an economic policy consensus and tripartite corporatist arrangements, and reformulated their content to better correspond with business interests. Instead of demolition, the outcome has been the redefinition and incremental transformation of the state from a provider of welfare to a promoter of competitiveness, productivity, and employment.Peer reviewe

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. Experimental cancer immunology and therap

c-myc Amplification Is Frequent in Esophageal Adenocarcinoma and Correlated with the Upregulation of VEGF-A Expression

BACKGROUND: Deregulation of c-myc plays a major role in the carcinogenesis of human malignancies. We investigated the amplification of the c-myc gene in a surgical series of Barrett cancers. METHODS: Primary resected esophageal (Barrett) adenocarcinomas (n = 84) were investigated for c-myc amplification using chromogene in situ hybridization. Tumor samples were assembled in a tissue microarray. c-myc gene dosage was correlated with clinicopathologic parameters, including the survival and gene expression of cyclo-oxygenases (COX-1 and COX-2) and proangiogenic growth factors (VEGF-A and VEGF-C). RESULTS: The majority (70 of 84; 83.3%) exhibited amplification of the c-myc gene. There were low-level amplifications in 63 (75.0%) cases and high-level amplifications in 7 (8.3%) cases. No amplification was found in 14(16.7%) cases. Tumors without c-myc amplification had lower VEGF-A, VEGF-C, and COX-2 expression levels than tumors with low-level and high-level c-myc amplification (statistically significant for VEGF-A; P = .0348). c-myc amplification was not correlated with clinicopathological parameters or survival. Only diffuse and mixed-type tumors, according to Lauren classification, exhibited c-myc amplifications more frequently (P = .0466). CONCLUSIONS: Amplifications of the c-myc gene are frequent in Barrett cancer. c-myc may be involved in the regulation of angiogenesis

Cervical spine motion during airway management: A cinefluoroscopic study of the posteriorly destabilized third cervical vertebrae in human cadavers

We conducted a randomized, controlled, crossover study to determine cervical spine motion for six airway management techniques in human cadavers with a posteriorly destabilized third cervical (C-3) vertebra. A destabilized C-3 segment was created in 10 cadavers (6-24 h postmortem). Cervical motion was recorded by continuous lateral fluoroscopy. The following airway management techniques were performed in random order on each cadaver with manual in-line stabilization applied: face mask ventilation (FM), laryngoscope-guided orotracheal intubation (OETT), fiberscope-guided nasal intubation (FOS-NETT), esophageal tracheal Combitube® (Kendall-Sheridan, Neustadt, Germany) insertion (ETC), intubating laryngeal mask insertion with fiberscope-guided tracheal intubation (ILM-OETT), and laryngeal mask airway insertion (LMA). Afterward, maximum head-neck flexion (FLEX-MAX) and maximum head-neck extension (EXT-MAX) without manual in-line stabilization was performed to determine maximum motion. The maximum posterior displacement of C-3 and the maximum segmental sagittal motion of C2-3 were determined. There was a significant increase in posterior displacement for the FM (1.9 ± 1.2 mm, P < 0.01), OETT (2.6 ± 1.6 mm, P < 0.0001), ETC (3.2 ± 1.6 mm, P < 0.0001), ILM-OETT (1.7 ± 1.3 mm, P < 0.01), LMA (1.7 ± 1.3 mm, P < 0.01), FLEX-MAX (3.7 ± 1.9 mm, P < 0.0001), EXT-MAX (1.8 ± 1.7, P < 0.01), however, not for FOS-NETT (0.1 ± 0.7 mm). Posterior displacement was less for the ILM-OETT and LMA than for the ETC (both P < 0.04). There were no significant increases in segmental sagittal motion with any airway manipulation other than with FLEX-MAX (-4.5 ± 4.0°, P < 0.01). Posterior displacement was similar to FLEX-MAX for the OETT and ETC; however, it was less for the FM, FOS-NETT, ILM-OETT, and LMA (all P < 0.01). Posterior displacement was similar to EXT-MAX for all airway manipulations other than for FOS-NETT (P < 0.001). For cervical motion and the techniques tested, the safest method of airway management in a patient with a posteriorly destabilized C-3 segment is FOS-NETT. LMA devices may be preferable to the ETC