Tumor budding outperforms ypT and ypN classification in predicting outcome of rectal cancer after neoadjuvant chemoradiotherapy

BACKGROUND: Budding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy. METHODS: A total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining. RESULTS: A budding rate of 36.9% (n = 38) by H&E and 55.6% (n = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15-6.44, p = 0.023; budding in IHC: HR 5.19, 95% CI 1.62-16.61, p = 0.006). CONCLUSION: Budding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance

Diagnostic Confidence of Run-Off CT-Angiography as the Primary Diagnostic Imaging Modality in Patients Presenting with Acute or Chronic Peripheral Arterial Disease

Objectives To investigate the reliability of CT-angiography of the lower extremities (run-off CTA) to derive a treatment decision in patients with acute and chronic peripheral artery disease (PAD). Materials and Methods 314 patients referred for run-off CTA were includ-ed in this retrospective study. First, diagnostic confidence of run-off CTA to derive a treat-ment decision was assessed in an interdisciplinary vascular conference using a 2 point scale (sufficient or not sufficient diagnostic confidence) and compared with the image quality eval-uated by two readers in consensus in four different levels (abdominopelvic, thigh, calf, foot arteries). Second, reliability of treatment decision was verified in all patients undergoing re-vascularization therapy. Results Diagnostic confidence of run-off CTA to derive a treatment deci-sion was sufficient in all patients with acute and in 97% of patients (215/221) with chronic PAD, whereas the rate of run-off CTA with non-diagnostic image quality was considerably higher in the calf and foot level (acute vs. chronic; calf: 28% vs.17%; foot: 52% vs. 20%). Reliability of treatment decision was superior for patients with chronic (123/133 = 92%) than for patients with acute PAD (64/78 = 82%, P = 0.02). Conclusion Run-off CTA is a reliable imaging modality for primary diag-nostic work-up of patients with acute and chronic PAD

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms

Animal experimental trials using rat colitis models

Ätiologie und Pathogenese der chronisch entzündlichen Darmerkrankungen, Morbus Crohn und Colitis ulcerosa, sind trotz zahlreicher neuer wissenschaftlicher Erkenntnisse ungeklärt. Das Ziel dieser Arbeit war es, den Stellenwert der Mikrozirkulation in diesem Zusammenhang zu evaluieren. Dazu erfolgten intravitalmikroskopische Untersuchungen am gesunden Darm sowie bei zwei verschiedenen Colitis-Modellen der Ratte. Bei der TNBS-Colitis kommt es im akuten, bei der Mitomycin C-Colitis im chronischen Stadium der Entzündung zu signifikanten Störungen der mukosalen Mikrozirkulation. Schließlich wurden im Rahmen einer Interventionsstudie verschiedene Substanzen appliziert. Es zeigt sich, dass die Gabe des selektiven Endothelin-A-Rezeptor-Antagonisten LU-135252 zu einer signifikanten Besserung sämtlicher Mirkozirkulationsparameter sowie auch der klinischen Befunde gegenüber der Kontroll-TNBS-Colitisgruppe führt. Die Zufuhr des selektiven COX-2-Inhibitors NS-398 hat denselben Effekt, wenn auch nicht so ausgeprägt. Der hemmende Einfluss beider Substanzen auf die Leukozyten–Endothel–Interaktion scheint hierbei eine Rolle zu spielen. Da die Endothelin-A-Rezeptor-Blockade allerdings hinsichtlich der Colitis-Aktivtät signifikant effektiver ist, muss ein weiterer Mechanismus im Sinne einer direkten Wirkung auf den kapillären Blutfluss vorliegen, was die pathogenetische Bedeutung der Mikrozirkulation für die Progression der Colitis unterstreicht.The etiology and pathogenesis of chronic inflammatory bowel disease, Crohn’s disease and ulcerative colitis, remains unclear despite numerous new scientific findings. The aim of this study was to evaluate the role of the microcirculation in this context. For this purpose, intravital microscopic examination of the healthy bowel and in two different rat colitis models was performed. Significant disturbances of the mucosal microcirculation were observed at the acute inflammatory stage of TNBS colitis and at the chronic stage of mitomycin C colitis. Finally, different substances were applied in an intervention study. Application of the selective endothelin-A receptor antagonist LU-135252 resulted in a significant improvement of all microcirculatory parameters and clinical findings compared to the control TNBS colitis group. The same effect, though not as pronounced, was seen with the selective COX-2 inhibitor NS-398. The inhibitory influence of the two substances on leukocyte-endothelium interaction seems to play a role. However, there may be another mechanism like a direct effect on capillary blood flow, since endothelin A receptor blockade is significantly more effective with regard to colitis activity, underscoring the pathogenetic role of the microcirculation on the progression of colitis