Knowledge transfer as a tool towards improvement of cancer care in low- and middle-income countries. 6th European Roundtable Meeting (ERTM), June 14th, 2019, Berlin, Germany.

PURPOSE: To identify key factors for the best practice of knowledge transfer from high-income settings to low- and middle-income settings. RESULTS: Interactive sessions led to the identification of European learnings that can and should be shared beyond Europe. Furthermore, methods were characterised which may lead to successful knowledge transfer with subsequent quality improvement. CONCLUSION: To ensure successful implementation of knowledge and new methods, political support is extremely important. A strong focus should be an improvement of collaboration and network development. Rehabilitation, early and late pallative care, cost effectiveness and long-term follow-up are priorities. Limitations are budget constraints which limit the execution of NCCPs.

Raman fiber-optical method for colon cancer detection: Cross-validation and outlier identification approach.

Endoscopy plays a major role in early recognition of cancer which is not externally accessible and therewith in increasing the survival rate. Raman spectroscopic fiber-optical approaches can help to decrease the impact on the patient, increase objectivity in tissue characterization, reduce expenses and provide a significant time advantage in endoscopy. In gastroenterology an early recognition of malign and precursor lesions is relevant. Instantaneous and precise differentiation between adenomas as precursor lesions for cancer and hyperplastic polyps on the one hand and between high and low-risk alterations on the other hand is important. Raman fiber-optical measurements of colon biopsy samples taken during colonoscopy were carried out during a clinical study, and samples of adenocarcinoma (22), tubular adenomas (141), hyperplastic polyps (79) and normal tissue (101) from 151 patients were analyzed. This allows us to focus on the bioinformatic analysis and to set stage for Raman endoscopic measurements. Since spectral differences between normal and cancerous biopsy samples are small, special care has to be taken in data analysis. Using a leave-one-patient-out cross-validation scheme, three different outlier identification methods were investigated to decrease the influence of systematic errors, like a residual risk in misplacement of the sample and spectral dilution of marker bands (esp. cancerous tissue) and therewith optimize the experimental design. Furthermore other validations methods like leave-one-sample-out and leave-one-spectrum-out cross-validation schemes were compared with leave-one-patient-out cross-validation. High-risk lesions were differentiated from low-risk lesions with a sensitivity of 79%, specificity of 74% and an accuracy of 77%, cancer and normal tissue with a sensitivity of 79%, specificity of 83% and an accuracy of 81%. Additionally applied outlier identification enabled us to improve the recognition of neoplastic biopsy samples.

The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona.

BACKGROUND AND SCOPE: The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. METHODOLOGY: Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. RESULTS: Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. CONCLUSION: GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.

Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia.

The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca(2+) influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca(2+) increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group.

BACKGROUND: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy. PATIENTS AND METHODS: A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models. RESULTS: In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02-1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17-1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59-3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10-4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25-4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96-2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86-1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87-1.86), P = 0.57] did not have significant impact on OS. CONCLUSION: Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.

Feasibility of a colon capsule overnight procedure followed by colonoscopy.

BACKGROUND AND AIM: Due to limited acceptance of colonoscopy as diagnostic and screening test alternatives are warranted. Colon capsule endoscopy (CCE) has been shown to be a possible filter test, but because of logistical issues a second bowel preparation is usually required, if consecutive colonoscopy is needed. We therefore evaluated the feasibility of a single bowel preparation for both overnight CCE and (therapeutical) colonoscopy thereafter. METHODS: Patients from two university hospitals referred to undergo colonoscopy were prospectively included in a dual centre feasibility study. A polyethylene glycol (PEG) based bowel preparation-schedule with ingestion of a colon capsule endoscopy (CCE) at 10pm and subsequent colonoscopy at about 12am on the next day was investigated. The first generation PillCam colon capsule was used with 4 different preparation protocols containing several prokinetics in different compositions (i. e. metoclopramide, erythromycin, sennosoides). The main endpoint was the proportion of patients who completed both CCE and colonoscopy; secondary endpoints were capsule transit times, amount of colon seen on CCE, bowel cleanliness, sensitivity and specifity of CCE and patients' acceptance. RESULTS: 50 patients between 18 and 75 years were included. The sequence of overnight colon capsule endoscopy and colonoscopy was successfully completed in all but one (one refused colonoscopy). The capsule was excreted during recording time in 86 % of examinations, visualization of the complete colon was possible in 60 %, but adequate colon preparation was achieved in only 45 % irrespective of the regimen used. The preparation regimen consisting of a PEG-solution, erythromycin as prokinetic drug followed by PEG-solution as boost showed the largest proportion of adequate preparations. Overall sensitivity and specificity of CCE for polyps of any size were 65 % and 76 %, respectively. 26 of 30 patients (86.7 %) returned the subjective assessment questionnaire. 23 patients (88 %) reported mild to no discomfort or embarrassment during CCE, whereas 15 patients (58 %) did during the preparation procedure. Drinking the purgative solution was the most inconvenient step in 84 % of cases, drinking the boosts during CCE the second inconvenient step (60 %). CONCLUSION: Overnight CCE-procedure followed by direct capsule-reading is feasible and safe and might avoid repetitive bowel preparation for subsequent colonoscopy. The bowel preparation needs to be improved.

Equal detection rate of cervical heterotopic gastric mucosa in standard white light, high definition and narrow band imaging endoscopy.

BACKGROUND AND AIM: The prevalence of cervical heterotopic gastric mucosa (HGM) of the proximal oesophagus differs widely between studies, perhaps due to examination conditions during endoscopy. In this study we aimed to determine whether narrow band imaging (NBI) or high definition (HD) imaging improves detection of HGM. Possible factors of influence for HGM detection, in particular setting (position, timing, in-/out-patient), examination time and sedation parameters, were analysed. METHODS: Retrospective analysis of 641 consecutive patients who underwent an oesophagogastroduodenoscopy (EGD) by the same, substantially experienced endoscopist between June 2011 and August 2013. The type of endoscope was randomly assigned to patients. RESULTS: A total of 85 patients showed HGM with an overall prevalence of 13.3 %. The detection rate in the HD-NBI group was 18/127 (14.2 %) and in the HD white light (HDWL) group, 15/104 (14.4 %, p = 0.957). The detection rate between standard definition white light (SDWL) endoscopy (52/410, 12.7 %) and HD endoscopy did not differ significantly (33/231, 14.3 %, p = 0.566). Setting, sedation dosage and examination times were equally distributed between study groups. The indication of dysphagia (11.8 % vs. 2.4 % with p = 0.000, respectively) and dyspepsia (19.1 % vs. 10.8 %, p = 0.047, respectively) occurred significantly more often in HGM patients than in the control group. There was no difference in the detection rate depending on HGM size. CONCLUSIONS: The prevalence of HGM in the upper EGD is high and does not differ significantly between the study groups of SDWL, HDWL and HD-NBI under equivalent conditions.

Prognostic value of microsatellite instability and p53 expression in metastatic colorectal cancer treated with oxaliplatin and fluoropyrimidine-based chemotherapy.

PURPOSE: The aim of this study was to evaluate the prognostic value of MSI-H and p53 overexpression in metastatic colorectal cancer (mCRC) treated with oxaliplatin and fluoropyrimidine-based first line chemotherapy. METHODS: Tumour samples were retrospectively obtained from 229 patients from a prospective randomised phase III trial of the AIO colorectal study group, comparing CAPOX and FUFOX in mCRC. Immunohistochemistry of p53 and MMR proteins as well as microsatellite analysis were performed. RESULTS: The incidence of MSI-H and p53 overexpression was 7.9 % and 65.4 %, respectively. MSI-H status was not correlated with ORR, PFS and OS. We observed a trend to lower DCR for MSI-H tumours (65 % vs. 85 %, p = 0.055). p53 overexpression was not correlated with DCR, ORR and PFS. The median OS of patients with tumors with p53 overexpression was significantly longer compared to tumors withhout p53 overexpression (19.6 vs. 15.8 months; p = 0.05). The post-progression survival (PPS) of p53-positive patients undergoing 2nd and/or 3rd line chemotherapy with irinotecan and/or cetuximab was significantly longer compared to p53-negative patients. CONCLUSION: MSI-H tumours tend to have lower disease control rates when treated with an oxaliplatin/fluoropyrmidin combination. mCRC patients with p53 overexpression undergoing an irinotecan containing second- or third-line chemotherapy after oxaliplatin failure have a significantly longer post-progression survival compared to patients without p53 overexpression. To validate the clinical impact of p53 in patients with mCRC treated with irinotecan- and/or cetuximab further studies are needed.

Prognostic factors for 60-day mortality in first-line treatment of metastatic colorectal cancer (mCRC): individual patient analysis of four randomised, controlled trials by the AIO colorectal cancer study group.

BACKGROUND: The 60 day mortality is an established parameter for chemotherapy-related safety in randomised trials for metastatic colorectal cancer (mCRC). Prognostic factors associated with 60-day mortality would be helpful to identify high-risk patients in advance. PATIENTS AND METHODS: Individual baseline patient data from four randomised, controlled trials from the Arbeitsgemeinschaft Internistische Onkologie (AIO) study group were retrospectively analysed. Chemotherapy consisted of fluoropyrimidine (5-FU/capecitabine), irinotecan, oxaliplatin with or without bevacizumab or cetuximab. Prognostic factors were identified by univariate and multivariate logistic regression models in two cohorts: one limited to ECOG PS 0 and 1 and one including ECOG PS 2 patients. RESULTS: A total of 1377 patients were evaluated. The analysis of ECOG PS 0, 1 and 2 patients consisted of 898 patients where a total of 33 deaths within the first 60 days of treatment (3.7%) occurred. In multivariate analysis, 60-day mortality was significantly associated with ECOG PS 2 and high leucocyte count (white blood cell, WBC). Odds ratio was 6.28 for WBC and 12.92 for ECOG PS 2. Exclusion of ECOG PS 2 patients but inclusion of one trial limited to ECOG PS 0 and 1 patients resulted in 1302 assessable patients and 44 early deaths (3.4%). In both cohorts, around 50% of deaths were disease related. WBC was confirmed as a significant risk factor for early death (OR 7.60). A combined score using ECOG PS 2 and WBC ≥8.000/µl is able to identify high-risk patients with a sensitivity of 18% and specificity of 98%. CONCLUSIONS: In this large retrospective analysis of individual patient data, around 50% of early deaths were disease related. Elevated WBC was found strongly associated with increased 60-day mortality in first-line treatment of mCRC. The proposed AIO-60-Day-Mortality score serves as an additional trial exclusion criterion.

[Colorectal cancer - personalized, stage-adjusted tumour therapy]. / Kolorektale Karzinome - personalisierte, stadienadaptierte Tumortherapie.

Colorectal cancer (CRC) is the second leading cause of cancer death in the western world. Every second patient dies of the disease. The introduction of new and effective chemotherapeutic substances and biologics during the past decade has significantly improved the systemic treatment of patients with CRC. In stage III colon cancer combination chemotherapy with oxaliplatin is the standard of care. Primary resection of metastases or resection after combination therapy and downsizing of lesions offers a chance for cure for some patients. In the treatment of rectal carcinoma, multimodality and neoadjuvant treatment concepts have replaced adjuvant chemoradio-therapy for locally advanced rectal cancer. In the palliative setting intensive combination treatment is indicated in colorectal cancer if tumor related symptoms or a rapid progress of the disease occur. The aim of palliative therapy is the prolongation of survival and the improvement of quality of life. The introduction of the mutational status of the KRAS oncogene as the first predictive marker into clinical care is an important step towards the personalization of treatment in CRC.

[S3 guideline--Diagnosis and treatment of colorectal carcinoma: relevance for radiologic imaging and interventions]. / Aktualisierte S3--Leitlinie zur Diagnostik und Therapie des kolorektalen Karzinoms: Bedeutung für die Radiologische Diagnostik und Intervention.

The new German S3 guideline "Colorectal Carcinoma" was created as part of the German Guideline Program in Oncology of the Association of the Scientific Medical Societies in Germany, the German Cancer Society and the German Cancer Aid under the auspices of the German Society for Digestive and Metabolic Diseases and replaces the guideline from 2008. With its evidence-based treatment recommendations, the guideline contains numerous updates and detailed definitions regarding the diagnosis and treatment of colon and rectal cancer. In particular, consensus-based recommendations regarding early detection, preoperative diagnostic method selection, and the use of interventional radiological treatment methods are detailed. The guideline also includes quality indicators so that standardized quality assurance methods can be used to optimize patient-related processes.The present article discusses the significance of the current recommendations for radiological diagnosis and treatment and is intended to enhance the quality of patient information and care by increasing distribution.

[Dyspnea and weight loss in a 70-year-old man]. / Dyspnoe und Gewichtsverlust bei einem 70-jährigen Patienten.

A 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.

Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group.

BACKGROUND: This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m(2)/day 1 plus capecitabine 1000 mg/m(2) bid/days 1-14 or with irinotecan 200 mg/m(2)/day 1 plus capecitabine 800 mg/m(2) bid/days 1-14 both every 21 days. The primary end point was 6 months progression-free survival (PFS). RESULTS: A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx-bevacizumab: n = 127; mCapIri-bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%-84%) and 84% (95% CI, 77%-90%). Median PFS and OS were 10.4 months (95% CI, 9.0-12.0) and 24.4 months (95% CI, 19.3-30.7) with CapOx-bevacizumab, and 12.1 months (95% CI, 10.8-13.2) and 25.5 months (95% CI, 21.0-31.0) with mCapIri-bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx-bevacizumab and in 16% with mCapIri-bevacizumab. CONCLUSIONS: Both, CapOx-bevacizumab and mCapIri-bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.

[83-year-old patient with salmonella bacteremia and infection-associated Sweet's syndrome]. / 83-jähriger Patient mit Salmonellenbakteriämie und Infekt-getriggertem Sweet-Syndrom.

HISTORY AND PHYSICAL EXAMINATION: An 83 year-old man presented with watery diarrhea and a rash. He was hypotensive, febrile and dehydrated. The rash was maculopapular and most pronounced on the dorsal trunk. INVESTIGATIONS: The lab tests showed an acute renal failure with hypokalemia and hyponatremia. Salmonella typhimurium was isolated from the aerobic blood culture, stool cultures were negative. The rash was consistent with an infection-associated Sweet's syndrome. THERAPY AND COURSE OF DISEASE: The patient was admitted and received iv fluids and potassium. An empiric antibiotic treatment with i. v. ciprofloxacin was started and changed to p. o. after 8 days. Antibiotic therapy was given 11 days total. After the administration of steroids the skin rash resolved. CONCLUSION: It is important to draw blood cultures in patients presenting with diarrhea if fever is present. Complications associated with non-typhoidal salmonella bacteremia occur most frequently in elderly patients and include pneumonia, infected aneurysms and bone/soft part infections. In rare cases patients can also present with a skin rash.