Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.

Background: Gene expression profiling is a highly sensitive technique which is used for profiling tumor samples for medical prognosis. RNA quality and degradation influence the analysis results of gene expression profiles. The impact of this influence on the profiles and its medical impact is not fully understood. As patient samples are very valuable for clinical studies, it is necessary to establish criteria for the RNA quality to be able to use these samples in later analysis.Methods: To investigate the effects of RNA integrity on gene expression profiling, whole genome expression arrays were used. We used tumor biopsies from patients diagnosed with locally advanced rectal cancer. To simulate degradation, the isolated total RNA of all patients was subjected to heat-induced degradation in a time-dependent manner. Expression profiling was then performed and data were analyzed bioinformatically to assess the differences.Results: The differences introduced by RNA degradation were largely outweighed by the biological differences between the patients. Only a relatively small number of probes (275 out of 41,000) show a significant effect due to degradation. The genes that show the strongest effect due to RNA degradation were, especially, those with short mRNAs and probe positions near the 5' end.Conclusions: Degraded RNA from tumor samples (RIN > 5) can still be used to perform gene expression analysis. A much higher biological variance between patients is observed compared to the effect that is imposed by degradation of RNA. Nevertheless there are genes, very short ones and those with the probe binding side close to the 5' end that should be excluded from gene expression analysis when working with degraded RNA. These results are limited to the Agilent 44 k microarray platform and should be carefully interpreted when transferring to other settings.

CA19-9 values are regularly measured in patients with pancreatic cancer. Certainly, its potential as a biomarker has been compromised by false negative results in CA19-9 negative patients and false positive results in benign pancreatico-biliary diseases. For detection of PDAC recurrence, however, CA19-9 might play an important role. The aim of this study is to analyze the accuracy of CA19-9 for detecting recurrence of pancreatic cancer. All included patients were treated either at the University Medical Center Goettingen, or at the Department of Interdisciplinary Oncology and Pneumonology, DRK-Kliniken Nordhessen, Kassel. We analyzed data of 93 patients with pancreatic cancer in the training set and 41 in the validation set, both retrospectively. Pre- and postoperative CA19-9 values and results of imaging techniques were compared. We performed ROC-analysis. The association between longitudinally measured CA19-9 values and relapse was studied with a joint model between a random effects model for the longitudinal CA19-9 measurements and a Cox proportional hazards models for the survival data. In the test set (n = 93 patients) the median follow-up time was 644 days (22 months). Overall, 71 patients (76.3%) developed recurrence during follow-up. Patients with CA19-9 values of <10kU/l were considered as CA19-9 negative patients (n = 11) and excluded from further analysis. Among the rest, approximately 60% of the patients showed significantly elevated CA19-9 prior to detection of recurrence by imaging techniques. Recurrence was shown by 2.45 times elevated CA19-9 values with 90% positive predictive value. In the validation set, 2.45 times elevated CA19-9 values showed recurrence with 90% sensitivity and 83,33% specificity, with an area under the curve of 95%. Based on measured CA19-9 values during follow-up care, the joint model estimates in recurrence-free patients the probability of recurrence-free survival. CA19-9 elevation is an early and reliable sign for PDAC recurrence. On the strength of a very high accuracy in CA19-9 positive patients, it should be considered to use CA19-9 for therapy decision even without a correlate of imaging technics. Using the joint model, follow-up care of PDAC patients after curative therapy can be stratified.

PURPOSE: In patients with peritoneal metastasis (PM) from gastric cancer (GC), chemotherapy is the treatment of choice. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are still being debated. This randomized, controlled, open-label, multicenter phase III trial (EudraCT 2006-006088-22; ClinicalTrials.gov identifier: NCT02158988 ) explored the impact on overall survival (OS) of HIPEC after CRS. PATIENTS AND METHODS: Adult patients with GC and histologically proven PM were randomly assigned (1:1) to perioperative chemotherapy and CRS alone (CRS-A) or CRS plus HIPEC (CRS + H). HIPEC comprised mitomycin C 15 mg/m² and cisplatin 75 mg/m² in 5 L of saline perfused for 60 minutes at 42°C. The primary end point was OS; secondary endpoints included progression-free survival (PFS), other distant metastasis-free survival (MFS), and safety. Analyses followed the intention-to-treat principle. RESULTS: Between March 2014 and June 2018, 105 patients were randomly assigned (53 patients to CRS-A and 52 patients to CRS + H). The trial stopped prematurely because of slow recruitment. In 55 patients, treatment stopped before CRS mainly due to disease progression/death. Median OS was the same for both groups (CRS + H, 14.9 [97.2% CI, 8.7 to 17.7] months v CRS-A, 14.9 [97.2% CI, 7.0 to 19.4] months; P = .1647). The PFS was 3.5 months (95% CI, 3.0 to 7.0) in the CRS-A group and 7.1 months (95% CI, 3.7 to 10.5; P = .047) in the CRS + H group. The CRS + H group showed better MFS (10.2 months [95% CI, 7.7 to 14.7] v CRS-A, 9.2 months [95% CI, 6.8 to 11.5]; P = .0286). The incidence of grade ≥3 adverse events (AEs) was similar between groups (CRS-A, 38.1% v CRS + H, 43.6%; P = .79). CONCLUSION: This study showed no OS difference between CRS + H and CRS-A. PFS and MFS were significantly better in the CRS + H group, which needs further exploration. HIPEC did not increase AEs.

Excellent dosimetric characteristics were demonstrated for volumetric modulated arc therapy (VMAT) in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). In a single-center retrospective analysis, we tested whether these advantages may translate into significant clinical benefits. We compared VMAT to conventional 3D conformal radiotherapy (3DCRT) in patients, homogeneously treated according to the control arm of the CAO/ARO/AIO-04 trial. CRT consisted of pelvic irradiation with 50.4/1.8Gy by VMAT (n = 81) or 3DCRT (n = 107) and two cycles of 5-fluorouracil. Standardized total mesorectal excision surgery was performed within 4–6 weeks. The tumor regression grading (TRG) was assessed by the Dworak score. Acute and late toxicity were evaluated via the Common Terminology Criteria for Adverse Events and the Late effects of normal tissues scale, respectively. Side effects greater than or equal to grade 3 were considered high-grade. Median follow-up was 18.3 months in the VMAT group and 61.5 months in the 3DCRT group with no differences in TRG between them (p = 0.1727). VMAT treatment substantially reduced high-grade acute and late toxicity, with 5 % versus 20 % (p = 0.0081) and 6 % vs. 22 % (p = 0.0039), respectively. With regard to specific organs, differences were found in skin reaction (p = 0.019) and proctitis (p = 0.0153). VMAT treatment in preoperative CRT for LARC showed the potential to substantially reduce high-grade acute and late toxicity. Importantly, we could demonstrate that VMAT irradiation did not impair short-term oncological results. We conclude, that the reduced toxicity after VMAT irradiation may pave the way for more efficient systemic therapies, and hopefully improved patient survival in the multimodal treatment of LARC.

Introduction: Management of esophageal anastomotic leaks (AL) and esophageal perforations (EP) remains difficult and often requires an interdisciplinary treatment modality. For primary endoscopic management, self-expanding metallic stent (SEMS) placement is often considered first-line therapy. Recently, endoscopic vacuum therapy (EVT) has emerged as an alternative or adjunct for management of these conditions. So far, data for EVT in the upper gastrointestinal-tract is restricted to single centre, non-randomized trials. No studies on optimal negative pressure application during EVT exist. The aim of our study is to describe our centre’s experience with low negative pressure (LNP) EVT for these indications over the past 5-years. Patients and Methods: Between January 2014 and December 2018, 30 patients were endoscopically treated for AL (n = 23) or EP (n = 7). All patients were primarily treated with EVT and LNP between –20 and –50 mm Hg. Additional endoscopic treatment was added when EVT failed. Procedural and peri-procedural data, as well as clinical outcomes including morbidity and mortality, were analysed. Results: Clinical successful endoscopic treatment of EP and AL was achieved in 83.3% (n = 25/30), with 73.3% success using EVT alone (n = 22/30). Mean treatment duration until leak closure was 16.1 days (range 2–58 days). Additional treatment modalities for complete leak resolution was necessary in 10% (n = 3/30), including SEMS placement and fibrin glue injection. Mean hospital stay for patients with EP was shorter with 33.7 days compared to AL with 54.4 days (p = 0.08). Estimated preoperative 10-year overall survival (Charlson comorbidity score) was 39.4% in patients with AL and 59.9% in patients with EP (p = 0.26). A mean of 5.1 EVT changes (range 1–12) was needed in EP and 3.6 changes (range 1–13) in AL to achieve complete closure, switch to other treatment modality, or reach endoscopic failure (p = 0.38). Conclusion: LNP EVT enables effective minimally – invasive endoluminal leak closure from anastomotic esophageal leaks and EP in high-morbid patients. In this study, EVT was combined with other endoscopic treatment options such as SEMS placement or fibrin glue injection in order to achieve leak or perforation closure in the vast majority of patients (83.3%). Low aspiration pressures led to slower but still sufficient clinical results.