Argon Plasma Coagulation of Gastric Inlet Patches of the Cervical Esophagus Relieves Vocal and Respiratory Symptoms in Selected Patients.

OBJECTIVES: Argon plasma coagulation (APC) of gastric inlet patches of the cervical esophagus (GIP) has been shown to relieve the globus sensation. This study aimed to investigate the long-term effects of APC therapy on a variety of laryngopharyngeal symptoms. METHODS: Patients with laryngopharyngeal symptoms who had undergone endoscopic GIP eradication via APC therapy were eligible for a retrospective observational cohort study. Symptom relief was assessed by a five-grade scale during a structured interview. Statistical analysis included ANOVA, the chi-squared and t-test. RESULTS: A total of 45 patients (61.0 (52.0; 69.0) years, 26 (57.8%) female) were included after a follow-up time of 85.0 (55.3; 111.0) months. Symptoms included dysphagia (56.0%), dysphonia (51.0%), hoarseness (76.0%), the necessity of throat clearing (73.0%), globus sensation (56.0%) and heartburn (71.0%). Complete GIP eradication was achieved after one session in 25 (55.6%), repetitive sessions were needed in the remaining cases. Fourteen patients (31.1%) reported a very strong, 11 (24.4%) a strong and 8 patients (17.8%) an intermediate improvement; five patients did not benefit. The most apparent improvement was seen regarding hoarseness (from 2.6 ± 1.7 to 1.2 ± 1.3), the necessity of throat clearing (from 2.6 ± 1.7 to 1.1 ± 1.3), globus sensation (from 2.0 ± 1.9 to 0.9 ± 1.3) and heartburn (from 2.5 ± 1.8 to 1.4 ± 1.6). Adverse events included post-endoscopic pain (n = 6, 13.3%) and purulent pharyngitis (n = 2, 4.4%). CONCLUSIONS: The APC therapy of GIP is safe and leads to long-term relief of laryngopharyngeal symptoms in carefully selected patients.

Minor microbial alterations after faecal diversion do not affect the healing process of anus-near pressure injuries in patients with spinal cord injury - results of a matched case-control study.

STUDY DESIGN: Retrospective matched case-control study including patients with spinal cord injury who presented with an anus-near pressure injury. Two groups were formed based on the presence of a diverting stoma. OBJECTIVES: To evaluate the primary microbial colonisation and secondary infection of anus-near pressure injuries depending on the presence of a pre-existing diverting stoma and to investigate the effect on the wound healing. SETTING: University hospital with a spinal cord injury unit. METHODS: A total of 120 patients who had undergone surgery of an anus-near decubitus stage 3 or 4 were included in a matched-pair cohort study. Matching was realised according to age, gender, body mass index and general condition. RESULTS: The most common species in both groups was Staphylococcus spp.(45.0%). The only significantly different primary colonisation affected Escherichia coli, that was found in the stoma patients less often (18.3 and 43.3%, p < 0.01). A secondary microbial colonisation occurred in 15.8% and was equally distributed, except for Enterococcus spp. that was present in the stoma group only (6.7%, p < 0.05). The time to complete cure took longer in the stoma group (78.5 versus 57.0 days, p < 0.05) and was associated with a larger ulcer size (25 versus 16 cm2, p < 0.01). After correction for the ulcers' size, there was no association to outcome parameters such as overall success, healing time or adverse events. CONCLUSIONS: The presence of a diverting stoma alters the microbial flora of an anus-near decubitus slightly without impact on the healing process.

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

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.

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.

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

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.

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

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.

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.

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/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 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.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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

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.

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

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.

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

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.

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

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.

Acute myeloid leukemia with central diabetes insipidus.

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.

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

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.

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

Background/aims: 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. Methods: 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. Results: A total of 211 patients with DiC were included (97 males, age 62.1 ± 16.1 years, BMI 25.9 ± 6.1 kg m-2). 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 (p<.05). The severity of DiC was mostly mild (85.7%). Conclusions: 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.

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

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/ ].

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.

BACKGROUND: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) 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 path_MMR 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. Path_MMR 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 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 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 (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 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 path_MMR 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 path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

[Current recommendations for surveillance, risk reduction and therapy in Lynch syndrome patients]. / Empfehlungen zur Früherkennung, Risikoreduktion, Überwachung und Therapie bei Patienten mit Lynch-Syndrom.

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 (MLH1, MSH2, MSH6, PMS2, and EPCAM). 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.

Risk of Malignancy in Adenomas Detected During Screening Colonoscopy.

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.

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

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.