Publications by authors named "Wolff Schmiegel"

142 Publications

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Genet Med 2020 Dec 1. Epub 2020 Dec 1.

Department of Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.

Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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http://dx.doi.org/10.1038/s41436-020-01029-1DOI Listing
December 2020

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.

Int J Cancer 2021 Jan 13;148(1):106-114. Epub 2020 Oct 13.

Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.
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http://dx.doi.org/10.1002/ijc.33294DOI Listing
January 2021

Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.

Int J Cancer 2020 Nov 14;147(10):2801-2810. Epub 2020 Sep 14.

Department of Applied Tumor Biology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer research Center (DKFZ), and Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany.

BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC). Current international diagnostic guidelines recommend BRAF mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of BRAF testing in LS diagnostics. We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population-based patient cohorts. Sensitivity/specificity analysis of BRAF testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6%) harbored BRAF mutations. Six of seven LS patients with BRAF-mutant CRC and reported age were <50 years. Among 339 of 756 (44.8%) of BRAF mutations detected in unselected MSI CRC, only 2 of 339 (0.6%) BRAF mutations were detected in patients <50 years. The inclusion of BRAF testing led to high risk of missing LS patients and increased costs at age <50 years. BRAF testing in patients <50 years carries a high risk of missing a hereditary cancer predisposition and is cost-inefficient. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without BRAF testing.
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http://dx.doi.org/10.1002/ijc.33273DOI Listing
November 2020

Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database.

J Clin Med 2020 Jul 18;9(7). Epub 2020 Jul 18.

University of Manchester & Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome.

Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT.

Results: Risk-reducing hysterectomy and BSO are offered to _ and carriers in 20/21 (95%) contributing centers, to carriers in 19/21 (91%) and to carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years).

Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of , and variants but less so for carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
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http://dx.doi.org/10.3390/jcm9072290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408942PMC
July 2020

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Genet Med 2020 Sep;22(9):1569

Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0892-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462742PMC
September 2020

Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study.

BMC Cancer 2020 May 24;20(1):460. Epub 2020 May 24.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.

Methods: Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.

Results: The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.

Conclusions: The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
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http://dx.doi.org/10.1186/s12885-020-06926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245918PMC
May 2020

[Current recommendations for surveillance, risk reduction and therapy in Lynch syndrome patients].

Z Gastroenterol 2019 Nov 18;57(11):1309-1320. Epub 2019 Nov 18.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn.

Introduction:  Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (, and ). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers.

Methods:  The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany.

Results:  A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years.

Conclusion:  LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.
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http://dx.doi.org/10.1055/a-1008-9827DOI Listing
November 2019

Similar Adenoma Detection Rates in Colonoscopic Procedures of Patients with Spinal Cord Injury Compared to Controls.

Dig Dis Sci 2020 04 29;65(4):1197-1205. Epub 2019 Aug 29.

Department of Gastroenterology and Hepatology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany.

Background: Cancer is a major cause of death in patients with spinal cord injury (SCI). Preventive strategies, such as colonoscopy, deal with higher burdens that may lead to lower quality.

Aims: The primary objective was to evaluate the adenoma detection rate. Secondary objectives were to investigate other quality indicators regarding bowel preparation, sedation, and endoscopy.

Methods: Consecutive SCI patients who had undergone colonoscopy from 2003 to 2014 were assigned to a control group matched for age, gender, and year of procedure and reviewed retrospectively.

Results: Bowel preparation lasted longer (3.6 ± 1.5 vs. 1.2 ± 0.6 days, p = 0.001), achieved unsatisfactory cleansing results more often (23.7 vs. 3.6%) and caused more adverse events in 236 SCI compared to 414 control patients. Colonoscopy needed a longer time (36.9 vs. 25.0 min) and remained incomplete more often (24.6 vs. 4.6%), resulting in more re-colonoscopies (14.8 vs. 4.3%). Endoscopy- and sedation-related adverse events were equal. However, neither overall nor size-dependent polyp (30.9 vs. 34.8%), adenoma (21.2 vs. 21.0%), advanced adenoma (6.8 vs. 7.2%), or cancer (1.7 vs. 2.0%) detection rates differed.

Conclusion: Despite intensified protocols, bowel preparation shows inferior results in SCI patients; colonoscopy needs more effort to succeed but achieves a comparable quality.
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http://dx.doi.org/10.1007/s10620-019-05814-0DOI Listing
April 2020

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Genet Med 2020 01 24;22(1):15-25. Epub 2019 Jul 24.

Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
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http://dx.doi.org/10.1038/s41436-019-0596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371626PMC
January 2020

Digital droplet PCR-based chimerism analysis for monitoring of hematopoietic engraftment after allogeneic stem cell transplantation.

Int J Lab Hematol 2019 Oct 21;41(5):615-621. Epub 2019 Jun 21.

IMBL Medical Clinic, Ruhr-University Bochum, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany.

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative approach for multiple hematologic diseases. The success of alloHSCT is evaluated by analyzing the proportion of living donor cells in blood and bone marrow samples of the recipient (chimerism analysis). To monitor the engrafted cells, donor's individual genetic markers are analyzed in peripheral blood and bone marrow samples, usually by using short tandem repeat (STR) analysis. An alternative method to measure chimerism is based on insertion and deletion markers (InDels) analyzed by digital droplet PCR (ddPCR); however, this approach is rarely evaluated in clinical practice.

Methods: In this study, we examined the usefulness of ddPCR-based chimerism analysis against the standard STR analysis in samples around day+30 after alloHSCT in clinical practice using peripheral blood and bone marrow samples.

Results: The median absolute difference between ddPCR and STR analysis was 0.55% points for bone marrow chimerisms and 0.25% points for peripheral blood chimerisms, respectively, including variation in the range of maximum 2% for both methods. The results of every single sample gave the same clinical message.

Conclusion: According to our data, chimerism analysis by ddPCR has an excellent correlation with STR-based analyses. Due to its fast and easy applicability, the ddPCR technique is suitable for chimerism monitoring in clinical practice.
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http://dx.doi.org/10.1111/ijlh.13073DOI Listing
October 2019

Phenotype of histologically suspected drug-induced colitis; results of a comparative, retrospective cohort study.

Scand J Gastroenterol 2019 Jul 19;54(7):855-862. Epub 2019 Jun 19.

Department of Gastroenterology and Hepatology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH , Bochum , Germany.

Drug-induced colitis (DiC) is a rarely reported form of colonopathy and data about the clinical and endoscopic characteristics are scarce. The aim was to investigate the phenotype of DiC. Patients in a retrospective case control study were assigned to either DiC or one of two age- and gender-matched control groups (non-inflammatory controls and inflammatory colitis from other causes) based on histopathological findings. Patients' basic characteristics, symptoms, biochemical results and endoscopic appearance were collected. Statistical analysis included ANOVA, the chi-squared test and two-tailed t-test. A total of 211 patients with DiC were included (97 males, age 62.1 ± 16.1 years, BMI 25.9 ± 6.1 kg m). In comparison to both control groups, DiC patients presented higher ASA and ECOG-scores and more particularly atherosclerotic comorbidities. The most abundant symptoms were abdominal pain (51.8%), diarrhoea (50.7%) and haematochezia (24.3%). The red blood cell count demarcated anaemia (12.7 ± 2.3 mg/dl) and C-reactive protein was slightly elevated (2.7 ± 5.2 mg/dl). The endoscopic features included erythema (46.9%), oedema (29.9%), erosions (29.9%) and ulcers (14.7%). The inflammation affected the rectum rarely (2.4%) but affected the rest of the colon without predilection in a segmental manner (<.05). The severity of DiC was mostly mild (85.7%). The phenotype of DiC differs slightly from that of colitis from other causes. Taking the clinical features into account might help to confirm drug-induced aetiology once the pathologist has raised the suspicion.
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http://dx.doi.org/10.1080/00365521.2019.1630674DOI Listing
July 2019

Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12.

J Clin Oncol 2019 12 31;37(34):3212-3222. Epub 2019 May 31.

University of Frankfurt, Frankfurt, Germany.

Purpose: Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established.

Patients And Methods: We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity.

Results: Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% 27%) and compliance with CRT higher in group B (91%, 78%, and 76% 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B ( < .001), but not group A ( = .210), fulfilled the predefined statistical hypothesis.

Conclusion: Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.
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http://dx.doi.org/10.1200/JCO.19.00308DOI Listing
December 2019

Monocytes-neutrophils-ratio as predictive marker for failure of first induction therapy in AML.

Blood Cells Mol Dis 2019 07 18;77:103-108. Epub 2019 Apr 18.

Department of Medicine, Knappschaftskrankenhaus Bochum-Langendreer, Ruhr University Bochum, Germany.

Introduction: Acute myeloid leukemia (AML) is, if untreated, a fatal hematologic neoplasia. Failure of the first induction chemotherapy is a hallmark for a poor prognosis. Early recognition of therapy failure is crucial for planning further therapies. Therefore, international guidelines recommend a bone marrow biopsy around day 14 after the beginning of induction therapy. Hypocellular bone marrow on day 14 is still gold standard for therapy assessment and further therapy strategy. Despite this, non-invasive ways for the evaluation of induction therapy were looked for in the past years.

Methods: We collected peripheral blood cell counts and routine laboratory values of patients treated with "7 + 3" induction therapy. Ratios of absolute cell counts of monocytes and neutrophils (MNR) were calculated daily, and the values were compared in patients with failure of the first induction therapy and patients with therapy response.

Results: 54 patients were included, 12 of which had failure of first induction therapy. The MNR following therapy was highly correlated with the bone marrow results. With the right cut-off, the MNR provides a valid and reliable tool for identification of patients with failure of first induction therapy with a sensitivity of 83.3% and a specificity of 87.8% on day 18.

Conclusions: We propose a novel and non-invasive method for detection of failure of first induction therapy in patients with de novo AML and "7 + 3" induction therapy. The MNR is free of cost since the required cell counts are performed routinely for each patient undergoing intensive chemotherapy.
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http://dx.doi.org/10.1016/j.bcmd.2019.04.008DOI Listing
July 2019

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.

Lancet 2019 05 11;393(10184):1948-1957. Epub 2019 Apr 11.

Tagestherapiezentrum am ITM, III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany.

Background: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours.

Methods: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m epirubicin and 60 mg/m cisplatin on day 1 plus either 200 mg/m fluorouracil as continuous intravenous infusion or 1250 mg/m capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m docetaxel, 85 mg/m oxaliplatin, 200 mg/m leucovorin and 2600 mg/m fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644.

Findings: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.

Interpretation: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX.

Funding: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.
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http://dx.doi.org/10.1016/S0140-6736(18)32557-1DOI Listing
May 2019

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report.

Hered Cancer Clin Pract 2019 28;17. Epub 2019 Feb 28.

4Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway.

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair () variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.

Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.

Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 , 45 _, 10 and 1 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively ( = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier ( = 0.14).

Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for carriers.
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http://dx.doi.org/10.1186/s13053-019-0106-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394091PMC
February 2019

Triggers of histologically suspected drug-induced colitis.

World J Gastroenterol 2019 Feb;25(8):967-979

Institute of Pathology, Ruhr-University Bochum, Bochum 44789, Germany.

Background: Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents. Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.

Aim: To investigate potential triggers of drug-induced colitis (DiC).

Methods: We conducted a retrospective, observational case control study. Patients were assigned to DiC or one of two age- and gender-matched control groups (non-inflammatory controls and inflammatory colitis of another cause) based on histopathological findings. Histopathology was reassessed in a subset of patients (28 DiC with atherosclerosis, DiC without atherosclerosis and ischaemic colitis each) for validation purposes. Medical history was collected from the electronic database and patient records. Statistical analysis included chi-squared test, -test, logistic and multivariate regression models.

Results: Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa (7% of all screened colonoscopic biopsy samples); a total of 633 patients were included equally matched throughout the three groups (291 males, mean age: 62.1 ± 16.1 years). In the univariate analysis, DiC was associated with diuretics, dihydropyridines, glycosides, ASS, platelet aggregation inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), statins and fibrates, and with atherosclerosis, particularly coronary heart disease, and hyperlipoproteinaemia. Echocardiographic parameters did not show substantial differences. In the multivariate analysis only fibrates [odds ratio (OR) = 9.1], NSAIDs (OR = 6.7) and atherosclerosis (OR = 2.1) proved to be associated with DiC. Both DiC reassessment groups presented milder inflammation than ischaemic colitis. The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.

Conclusion: Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC. Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.
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http://dx.doi.org/10.3748/wjg.v25.i8.967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397729PMC
February 2019

Acute myeloid leukemia with central diabetes insipidus.

Blood Cells Mol Dis 2019 05 24;76:45-52. Epub 2019 Jan 24.

Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Germany.

While acute myeloid leukemia (AML) is the most common type of acute leukemia in adulthood, the constellation of AML associated with central diabetes insipidus (CDI) is rare and typically occurs in patients with chromosome 3 or 7 abnormalities. This subgroup of AML is associated with a poor clinical outcome. In this report, we present a young woman with AML and concurrent CDI in the presence of inversion(3)(q21q26). The AML was refractory to the induction therapy "7 + 3". Afterwards, the patient underwent allogenic stem cell transplantation (alloHSCT) and is still remaining in complete remission (CR) from AML as well as CDI 440 days after alloHSCT. Subsequently, in the largest study concerning patients with AML and CDI reported so far, we discuss additional cases from the literature. We demonstrated that patients with AML and CDI belong to the adverse prognostic group and clearly benefit from alloHSCT.
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http://dx.doi.org/10.1016/j.bcmd.2019.01.005DOI Listing
May 2019

Efficacy of bevacizumab in first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis.

Eur J Cancer 2019 01 23;106:37-44. Epub 2018 Nov 23.

Department of Internal Medicine III, Comprehensive Cancer Center Munich, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany.

Background: This systematic review and meta-analysis aims to evaluate the additive effect of bevacizumab when combined with first-line chemotherapy in metastatic colorectal cancer (mCRC).

Methods: We searched EMBASE, MEDLINE, the Cochrane Library in April 2018. When possible, data were pooled to estimate summary effects. The present analysis evaluated treatment related efficacy based on progression-free survival (PFS) and overall survival (OS). The analysis was performed to define the overall effect and the effect observed in currently used chemotherapy regimens.

Results: Seven randomised studies were included. In the analysis of the overall effect, PFS (hazard ratio [HR] 0.71, p < 0.00001) and OS (HR 0.85, p = 0.0008) clearly favoured bevacizumab plus chemotherapy versus chemotherapy alone. When the analysis was focused on currently used chemotherapy excluding 5-FU bolus regimens and including only infusional 5-FU plus irinotecan or oxaliplatin, the addition of bevacizumab prolonged PFS (HR 0.79, p < 0.0001) but not OS (HR 0.92, p = 0.18). However, addition of bevacizumab to fluoropyrimidine monotherapy lead to a significant prolongation of PFS (HR 0.57, p < 0.00001) and OS (HR 0.83, p = 0.03).

Conclusion: The present meta-analysis demonstrates that the effect of bevacizumab on survival is not consistent throughout the included regimens. Considering only presently used regimens, a significant effect on PFS and OS was only observed when bevacizumab was added to fluoropyrimidine monotherapy.
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http://dx.doi.org/10.1016/j.ejca.2018.10.009DOI Listing
January 2019

Direct-acting antivirals-based therapy decreases hepatic fibrosis serum biomarker microfibrillar-associated protein 4 in hepatitis C patients.

Clin Mol Hepatol 2019 03 19;25(1):42-51. Epub 2018 Nov 19.

Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany.

Background/aims: An estimated 80 million people worldwide are infected with viremic hepatitis C virus (HCV). Even after eradication of HCV with direct acting antivirals (DAAs), hepatic fibrosis remains a risk factor for hepatocarcinogenesis. Recently, we confirmed the applicability of microfibrillar-associated protein 4 (MFAP4) as a serum biomarker for the assessment of hepatic fibrosis. The aim of the present study was to assess the usefulness of MFAP4 as a biomarker of liver fibrosis after HCV eliminating therapy with DAAs.

Methods: MFAP4 was measured using an immunoassay in 50 hepatitis C patients at baseline (BL), the end-of-therapy (EoT), and the 12-week follow-up visit (FU). Changes in MFAP4 from BL to FU and their association with laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelets, the AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4), and albumin were analyzed.

Results: MFAP4 serum levels were representative of the severity of hepatic fibrosis at BL and correlated well with laboratory parameters, especially APRI (Spearman correlation, R²=0.80). Laboratory parameters decreased significantly from BL to EoT. MFAP4 serum levels were found to decrease from BL and EoT to FU with high statistical significance (Wilcoxon P<0.001 for both).

Conclusion: Our findings indicate that viral eradication resulted in reduced MFAP4 serum levels, presumably representing a decrease in hepatic fibrogenesis or fibrosis. Hence, MFAP4 may be a useful tool for risk assessment in hepatitis C patients with advanced fibrosis after eradication of the virus.
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http://dx.doi.org/10.3350/cmh.2018.0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435967PMC
March 2019

Screening and surveillance in hereditary gastrointestinal cancers: Recommendations from the European Society of Digestive Oncology (ESDO) expert discussion at the 20th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona, June 2018.

Eur J Cancer 2018 11 18;104:91-103. Epub 2018 Oct 18.

Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Germany.

Patients with hereditary gastrointestinal (GI) cancers represent a substantial fraction of the overall affected population. Although awareness for hereditary GI cancer syndromes is on the rise, identification of patients and measures of surveillance are often unclear in everyday clinical routine. Therefore, the European Society of Digestive Oncology expert discussion 2018 at the World Congress on Gastrointestinal Cancer focussed on screening and surveillance of hereditary colorectal, gastric and pancreatic cancers. An international panel of experts and opinion leaders developed the here presented recommendations based on published evidence and on profound clinical expertise to facilitate clinical routine in identification and caretaking of patients with familial GI cancers.
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http://dx.doi.org/10.1016/j.ejca.2018.09.004DOI Listing
November 2018

Creeping Fat Assessed by Small Bowel MRI Is Linked to Bowel Damage and Abdominal Surgery in Crohn's Disease.

Dig Dis Sci 2019 01 1;64(1):204-212. Epub 2018 Oct 1.

Department of Gastroenterology and Hepatology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany.

Background: Crohn's disease (CD) leads to bowel damage and surgery in a significant proportion of patients.

Aims: The aim of the study was to evaluate the predictive value of creeping fat assessed by small bowel MRI in CD patients.

Methods: CD patients undergoing small bowel MRI were included in a retrospective observational cohort study. Clinical findings were extracted and correlated with radiological outcome measures. Logistic regression analysis was performed to assess predictors associated with a complicated course and surgery within 2 years and long-term follow-up.

Results: Ninety patients (49% female, median follow-up 93 months) were included. Creeping fat was identified in 21.1%. Of these patients, 68% and 79% developed bowel damage (p < .05) and 42% and 63% of patients revealing creeping fat underwent surgery within 2 years following MRI and total follow-up, respectively. The presence of creeping fat [odds ratio (OR) 4.0], inflammatory stenosis (OR 3.7), multisegmental (small) bowel (OR 4.5 and 3.8), and proximal small bowel inflammation (OR 5.0) were associated with inferior outcome (p < .05) in a univariate analysis. Creeping fat was independently associated with a disabling course, bowel damage, and surgery (OR 3.5 each, p < .05) in a multivariate analysis model.

Conclusion: Creeping fat identified by small bowel MRI is associated with a complicated course and abdominal surgery in CD. Our data adds evidence that small bowel MRI facilitates risk stratification in order to define a patient at risk of disease-related complications in CD. [DRKS00011727, www.germanctr.de/ ].
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http://dx.doi.org/10.1007/s10620-018-5303-1DOI Listing
January 2019

Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention.

Rofo 2019 Apr 24;191(4):298-310. Epub 2018 Sep 24.

Radiology, München, Germany.

The updated German S3 guidelines "Colorectal Carcinoma" were created as part of the oncology program of the Association of the Scientific Medical Societies (AWMF), German Cancer Society and the German Cancer Aid under the auspices of the German Society for Digestive and Metabolic Disorders (DGVS) and they replace the previous guidelines from 2013. The main changes in the updated guidelines include the latest recommendations regarding endoscopy and adjuvant/neoadjuvant therapies as well as a complete restructuring of the section regarding therapeutic approach in metastases and in the palliative situation. The present manuscript discusses the importance of the current recommendations for radiological diagnosis and treatment and is intended to enhance the quality of patient information and patient care by widespread distribution. KEY POINTS::   · Radiological recommendations for treating patients with colorectal carcinoma are presented.. · The different possibilities of radiological imaging for diagnosis are documented in detail.. · Radiologists should be acquainted with the different possibilities of oncological intervention in patients with colorectal carcinoma.. CITATION FORMAT: · Vogl TJ, Pereira PL, Schreyer AG et al. Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention. Fortschr Röntgenstr 2019; 191: 298 - 310.
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http://dx.doi.org/10.1055/a-0721-1947DOI Listing
April 2019

No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies.

Gastroenterology 2018 11 29;155(5):1400-1409.e2. Epub 2018 Jul 29.

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

Background & Aims: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals).

Methods: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy).

Results: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy.

Conclusions: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.
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http://dx.doi.org/10.1053/j.gastro.2018.07.030DOI Listing
November 2018

Risk of Malignancy in Adenomas Detected During Screening Colonoscopy.

Clin Gastroenterol Hepatol 2018 11 11;16(11):1754-1761. Epub 2018 Jun 11.

Department of Medical Biometry and Epidemiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Background & Aims: A higher incidence of proximal interval cancers after colonoscopy has been reported in several follow-up studies. One possible explanation for this might be that proximally located adenomas have greater malignant potential. The aim of the present study was to assess the risk of malignancy in proximal versus distal adenomas in patients included in a large screening colonoscopy database; adenoma shape and the patients' age and sex distribution were also analyzed.

Methods: Data for 2007-2012 from the German National Screening Colonoscopy Registry, including 594,614 adenomas identified during 2,532,298 screening colonoscopies, were analyzed retrospectively. The main outcome measure was the rate of high-grade dysplasia (HGD) in adenomas, used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the rate of HGD found in adenomas were analyzed in relation to patient- and adenoma-related factors using multivariate analysis.

Results: HGD histology was noted in 20,873 adenomas (3.5%). Proximal adenoma locations were not associated with a higher HGD rate. The most significant risk factor for HGD was adenoma size (OR 10.36 ≥1 cm vs <1 cm), followed by patient age (OR 1.26 and 1.46 for age groups 65-74 and 75-84 vs 55-64 years) and sex (OR 1.15 male vs female). In comparison with flat adenomas as a reference lesion, sessile lesions had a similar HGD rate (OR 1.02) and pedunculated adenomas had a higher rate (OR 1.23). All associations were statistically significant (P ≤ .05).

Conclusions: In this large screening database, it was found that the rates of adenomas with HGD are similar in the proximal and distal colon. The presence of HGD as a risk marker alone does not explain higher rates of proximal interval colorectal cancer. We suggest that certain lesions (flat, serrated lesions) may be missed in the proximal colon and may acquire a more aggressive biology over time. A combination of endoscopy-related factors and biology may therefore account for higher rates of proximal versus distal interval colorectal cancer.
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http://dx.doi.org/10.1016/j.cgh.2018.05.043DOI Listing
November 2018

Propofol sedation during gastrointestinal endoscopy arouses euphoria in a large subset of patients.

United European Gastroenterol J 2018 May 4;6(4):536-546. Epub 2017 Oct 4.

3KRH Klinikum Agnes Karll Laatzen, Department of Internal Medicine and Gastroenterology, Laatzen, Germany.

Background: Propofol is recommended for sedation in gastrointestinal endoscopy (GE), but preliminary data suggest addictive potentials.

Objective: The objective of this article is to evaluate the frequency of predominantly euphoric reaction after GE and patients' subsequent reminiscences.

Methods: Eighty-two patients undergoing elective GE under propofol sedation were enrolled in a prospective observational study. The grade of anxiety, expectation or relief about the examination's result and affective state in terms of cheerfulness, relaxation, activation, sedation and anxiety were surveyed using a numeric rating scale (1 to 10) immediately before (t1), after GE (t2) and seven days (t3) later. Statistics: hierarchical cluster analysis, heat map, χ2 test and paired test.

Results: Mean propofol dosage was 264 ± 120 mg. Two clusters of mood changes emerged (t1 vs. t2). One ( = 46, 56.1%) was characterized by an unease reaction pattern with equal values regarding cheerfulness, relaxation and anxiety, while relaxation decreased; the other cluster showed a euphoric reaction pattern ( = 36, 43.9%) with markedly increased cheerfulness, relaxation and decreased anxiety. These effects intensified at recall (t3). Despite similar endoscopy results, euphoric cluster patients rated these more positively.

Conclusion: Propofol induces euphoria in nearly half of the patients undergoing elective GE with persisting, even enhanced reminiscence (germanctr.de, trial number DRKS00011202).
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http://dx.doi.org/10.1177/2050640617736231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987275PMC
May 2018

Gastrointestinal endoscopy under sedation is associated with pneumonia in older inpatients-results of a retrospective case-control study.

United European Gastroenterol J 2018 Apr 27;6(3):382-390. Epub 2017 Sep 27.

Berufsgenossenschaftliches Universitaetsklinikum Bergmannsheil gGmbH, Ruhr-University Bochum, Department of Gastroenterology and Hepatology, Bochum, Germany.

Background And Aims: Apparent aspiration is a notable adverse event during gastrointestinal endoscopy under sedation (GIES), but data about inapparent aspiration are scarce. Generally, particularly older patients are at higher risk of suffering from adverse events.

Objective: The objective of this article is to determine the risk of pneumonia, lower respiratory tract infection (LRI) and systemic inflammatory activation after GIES, especially in patients of at least 65 years.

Methods: The retrospective case-control study included 250 patients undergoing GIES and assigned age-, gender- and time of performance-matched controls without invasive procedure or sedation (ratio 1:1).

Results: On day 3 patients of advanced age presented with both pneumonia and LRI more often (2.6 vs. 0.0%,  = 0.041 and 7.8 vs. 2.5%,  = 0.034, respectively). In general, several inflammatory parameters increased significantly after GIES (i.e. white blood cell count (increase of ≥ 25%) 18.6 vs. 6.9%,  < 0.001), leading to more frequent antibiotic treatment (6.8 vs. 1.6%,  = 0.004). The effects were less pronounced on day 7.

Conclusions: Patients of advanced age carry an increased risk of pneumonia and LRI after GIES. Patients are generally more likely to feature inflammation and to receive antibiotic treatment.
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http://dx.doi.org/10.1177/2050640617735059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949974PMC
April 2018

Significance of Liquid Biopsy for Monitoring and Therapy Decision of Colorectal Cancer.

Transl Oncol 2018 Apr 28;11(2):213-220. Epub 2018 Jan 28.

IMBL Medical Clinic, Ruhr-University of Bochum, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Germany; Department of Medicine, Hematology and Oncology, Ruhr-University of Bochum, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Germany. Electronic address:

Purpose: Despite therapeutic improvements, all patients with nonresectable metastatic colorectal cancer (mCRC) acquire resistance to treatment probably due to the growth of mutated clones. In contrast to tissue-based studies, liquid biopsies have enabled the opportunity to reveal emerging resistance to treatment by detecting mutated clones and noninvasively monitoring clonal dynamics during therapy.

Methods: The courses of three patients with mCRC who were initially RAS wild-type were monitored longitudinally using liquid biopsy with long-term follow-up of up to 20 sequential samples. Detection of fragmented RAS mutated circulating cell-free DNA (cf)DNA in plasma was performed by BEAMing. In addition, plasma digital droplet PCR was used to detect and quantify BRAF and PIK3CA mutated cfDNA. Changes of mutational load were correlated with imaging data.

Results: A combination of liquid biopsy and radiological imaging enabled visualization of the occurrence of clonal redistribution after discontinuation of anti-EGFR mAb therapy, as well as emerging RAS mutations during therapy with anti-EGFR mAb indicating resistance. Furthermore, we found that growth of RAS mutated clones is independent of direct selective pressure by anti-EGFR therapy, which is a significant and new finding of this study.

Conclusions: Our findings demonstrated the whole spectrum of clonal selection and redistribution of mutated cell clones leading to acquired resistance. Given our observation that the growth of RAS mutated clones can evolve even in the absence of anti-EGFR mAb therapy, there is a clear imperative to monitor RAS mutations in serial blood draws in all RAS wild-type patients in general and independent of the therapy.
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http://dx.doi.org/10.1016/j.tranon.2017.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789760PMC
April 2018

MicroRNA-30c as a novel diagnostic biomarker for primary and secondary B-cell lymphoma of the CNS.

J Neurooncol 2018 May 11;137(3):463-468. Epub 2018 Jan 11.

Department of Medicine, Ruhr-University of Bochum, Knappschaftskrankenhaus Bochum-Langendreer, Bochum, Germany.

Primary lymphomas of the central nervous system (PCNSL) are highly aggressive tumors affecting exclusively the CNS, meninges, and eyes. PCNSL must be separated from secondary spread of systemic lymphoma to the CNS (SCNSL), which may occur at diagnosis or relapse of systemic lymphomas. At present, there are no valid methods to distinguish PCNSL from SCNSL based on tumor biopsy because of similar histological presentation. However, SCNSL and PCNSL are different in terms of prognosis and adequate therapy protocols. MicroRNA expression profiles of CSF samples collected from SCNSL and PCNSL patients were compared using microRNA arrays. MiR-30c revealed the largest differential expression and was selected for validation by RT-PCR on 61 CSF samples from patients with PCNSL and 14 samples from SCNSL. MiR-30c was significantly increased in patients with SCNSL compared to PCNSL (p < 0.001). MiR-30c levels in CSF enabled the differentiation of patients with PCNSL from SCNSL with an area under the curve (AUC) of 0.86, with a sensitivity of 90.9% and a specificity of 85.5%. Our data suggest that miR-30c detected in the CSF can serve as biomarker for distinction between PCNSL and SCNSL. The validation in a larger cohort is needed. With respect to its function, miR-30c may facilitate lymphoma cells to engraft into CNS by interaction with CELSR3 gene that controls the function of ependymal cilia and, thus, affects the circulation of CSF.
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http://dx.doi.org/10.1007/s11060-018-2749-0DOI Listing
May 2018