Dye-Based Chromoendoscopy in Patients With Lynch Syndrome: An Individual Patient Data Meta-Analysis of Randomized Trials.

INTRODUCTION: The additional diagnostic value of dye-based chromoendosocpy (CE) for surveillance of patients with Lynch syndrome is subject of debate. METHODS: To clarify this debate, we performed an individual patient data meta-analysis of randomized studies that compared CE with WLE for the detection of adenomas in patients with Lynch syndrome. RESULTS: Three randomized studies comprising 533 patients were included. The adenoma detection rate was 74/265 (28%) in patients randomized to WLE compared with 83/266 (31%) in patients randomized to CE (odds ratio 1.17; 95% confidence interval 0.81-1.70). DISCUSSION: Based on low-quality evidence, CE showed no apparent increase in adenoma detection compared to WLE during surveillance of patients with Lynch syndrome.

Palliative treatment of colorectal cancer with secondary metastasis resection in Germany - impact of the multidisciplinary treatment approach on prognosis and cost: the Northern Bavaria IVOPAK I Project.

PURPOSE: The aim of this study was to evaluate the quality of care and interdisciplinary cooperation in the palliative treatment of colorectal cancer (CRC), including the associated costs. PATIENTS AND METHODS: 103 patients were enrolled from 13 institutions to reflect the existing clinical treatment reality and costs of palliative CRC treatment. We present the clinical outcome of the patients and compare the results obtained in the 3 centers with double-figure recruitment numbers (centers A, B, and C). RESULTS: First-line treatment with 5-fluorouracil monotherapy was applied in exceptional cases. The regular treatment method comprised either an irinotecan- (30%) or an oxaliplatin-based regimen (32%). Biological agents were added to the treatment of 33 patients (32%). The median overall survival (OS) of the total patient collective was 25 months. The OS differed significantly in 2 out of the 3 centers, ranging between 27 and 11 months. Secondary metastasis resections were performed in 26% of the total patient collective. The center with the most favorable outcome results also had the lowest costs for palliative treatment and care, including the lowest drug costs. CONCLUSION: A combined chemotherapy treatment was the rule. Concerning biological agents, a significant lack of their application in first-line treatment and the quality of interdisciplinary cooperation have to be addressed.

Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under "Real World" Conditions?

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients' characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471-0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245-4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.

Arylamine N-acetyltransferase type 2 and glutathione S-transferases M1 and T1 polymorphisms in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) exhibits a variable phenotype even in carriers of the same adenomatous polyposis coli germline mutation. Xenobiotic-metabolizing enzymes such as N-acetyltransferases (NATs) and glutathione S-transferases (GSTs) were reported to modify the individual risk for colorectal cancer. We examined whether the polymorphisms of the NAT2, GSTM1, and GSTT1 enzymes affect age at diagnosis of first colorectal adenomas or extracolonic manifestations in 411 FAP patients. Neither age at diagnosis of colorectal adenomas nor occurrence of extra-intestinal tumors differed significantly between genotypes at the NAT2 and GSTM1 loci, whereas GSTT1 polymorphism showed an uncertain association with extra-intestinal manifestations. Combinations of supposed at risk genotypes of the three enzymes showed no significant differences either. Thus, NAT2, GSTM1, or GSTT1 are unlikely to modify the disease phenotype in FAP patients.

Palliative treatment of colorectal cancer in Germany: cost of care and quality of life.

INTRODUCTION: To estimate the costs of palliative care for colorectal cancer (CRC) from the perspective of German statutory health insurance and to measure the patients' quality of life (QoL) for a 2-year time period. METHODS: A prospective observational multicentre study was carried out to estimate the direct costs of care over a 2-year period. Case report forms, medical records, and claims data were all applied to document medical and resource usage data in real-world settings. QoL was measured by using the Short Form-12 Health Survey. RESULTS: In total 101 patients (mean age 67.09 ± 11.13 years, 68 % male) from 12 different settings were included. The mean costs per patient during the 1st and 2nd years were calculated to be 42,361€ and 32,023€, respectively. Highest mean costs were calculated for the second quarter, which reached an amount of 12,900€ (95 % CI: 11,127€-14,673€). Mean physical summary scores and mean mental summary scores were 41.8 and 49.7, respectively. DISCUSSION: This is the first study assessing the costs of palliative care and the quality of life of patients with CRC in real-world health-care delivery in Germany. It could be shown that CRC treatment represents an enormous economic burden to the German health-care system. Increased efforts in promoting effective and efficient treatment options, or performance-based medication reimbursement schemes, might be helpful in reducing the costs.

Massive hypercoagulable state despite full-dose anticoagulant treatment in a patient with occult malignancy: considerations concerning chemotherapy without definitive diagnosis.

A 55-year-old female patient presented with recurrent deep venous thrombosis and pulmonary embolism while on oral anticoagulant treatment using the vitamin K antagonist phenprocoumon. Hypercoagulable state was regarded to be paraneoplastic, but no underlying malignancy could be identified despite extensive screening for cancer, including gastroscopy and colonoscopy, a bone marrow biopsy, thoracoabdominal CT scans with subsequent biopsies of possibly malignant findings, octreotide scintigraphy, skeletal scintigraphy and gynaecological screening. In the course of her hospital stay she developed progressive right cardiac insufficiency due to the formation of new thromboses despite aggressive anticoagulant treatment and died of right-sided heart failure. The autopsy showed a poorly differentiated adenocarcinoma in the middle lobe of the right lung. In addition, pulmonary lymphangiosis carcinomatosa, pleural and pericardial carcinosis, and lymph node metastases and osteoblastic vertebral body metastases were shown.

Contribution of common monoallelic MUTYH gene variants in German patients with familial colorectal cancer.

UNLABELLED: Mutations of the base excision repair gene MUTYH have been reported as underlying genetic defects in autosomal-recessive familial adenomatous polyposis (FAP). Our aim was to determine the frequency of the most common mutations (p.Tyr165Cys and p.Gly382Asp) in patients with strong evidence for familial colorectal cancer (fCRC). METHODS: We recruited 93 patients with fCRC but no indication for monogenic CRC syndromes (FAP, hereditary non-polyposis colorectal cancer). Tumors showed regular expression of MLH1 and MSH2, and microsatellite instability was excluded. Sporadic CRC patients (n=93) and 'hyper-normal' controls without any adenomas in screening colonoscopies (n=93) were studied for comparison. RESULTS: In the fCRC group, two patients carried biallelic mutations (p.Tyr165Cys/p.Tyr165Cys, p.Tyr165Cys/p.Gly382Asp), while four patients displayed a heterozygous genotype (3 x p.Tyr165Cys/wt, 1 x p.Gly382Asp/wt). In contrast, only two p.Gly382Asp/wt patients were detected in the sporadic CRC group and one p.Gly382Asp carrier was observed in 'hyper-normal' controls, and the p.Tyr165Cys risk allele was absent in both control groups. Association tests demonstrated an increased odds ratio (OR) for CRC in carriers of the p.Tyr165Cys risk allele among fCRC patients, as compared to sporadic CRC patients and controls (OR 2.38; p=0.03). CONCLUSIONS: In our cohort the prevalence of pathogenic MUTYH mutations was increased among fCRC patients compared to sporadic CRC and controls. The association of the p.Tyr165Cys mutation with fCRC indicates that this variant represents a susceptibility factor in a defined subgroup of CRC patients with a positive family history.

Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes.

Hereditary nonpolyposis colorectal cancer (HNPCC) is often caused by a deficiency in DNA mismatch repair. By using conventional methods of mutation analysis, point mutations in the DNA mismatch repair genes MSH2 and MLH1 have been detected in up to 64% of patients suspected of HNPCC. However, large genomic deletions cannot be detected by these methods. In our study, we applied a semiquantitative multiplex PCR to detect the proportion of large deletions in patients meeting the Bethesda criteria whose tumours exhibited microsatellite instability (MSI). Of 368 unrelated patients, 180 exhibited MSI. In these patients, 68 disease-causing point mutations (38%) had previously been detected in the MSH2 and MLH1 genes by SSCP, heteroduplex analysis or DHPLC followed by direct sequencing. The remaining 112 patients (including 24 patients with rare missense or other unclarified variants) were examined for large deletions. We identified deletions in 19 patients (10.6%); 11/19 (58%) deletions were located in MSH2 and 8/19 (42%) in MLH1, respectively. The size of deletions ranged from 1 exon to a deletion of a whole gene. Five breakpoints of deletions were sequenced; Alu-repetitive elements were involved in all of them. In patients meeting the Amsterdam criteria the proportion of large deletions was 12.6%. A similar proportion of deletions was found in the group of patients with a positive family history for colorectal cancer and MSI tumours, not meeting the Amsterdam criteria. The results of our study suggest that large genomic deletions in both MSH2 and MLH1 genes play a considerable role in the pathogenesis of HNPCC and should be part of the routine HNPCC mutation detection protocols.