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Background: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization., Methods/design: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate., Discussion: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 )., (© 2022. The Author(s).)

Background: Complete endoscopic resection and accurate histological evaluation for T1 colorectal cancer (CRC) are critical in determining subsequent treatment. Endoscopic full-thickness resection (eFTR) is a new treatment option for T1 CRC < 2 cm. We aimed to report clinical outcomes and short-term results., Methods: Consecutive eFTR procedures for T1 CRC, prospectively recorded in our national registry between November 2015 and April 2020, were retrospectively analyzed. Primary outcomes were technical success and R0 resection. Secondary outcomes were histological risk assessment, curative resection, adverse events, and short-term outcomes., Results: We included 330 procedures: 132 primary resections and 198 secondary scar resections after incomplete T1 CRC resection. Overall technical success, R0 resection, and curative resection rates were 87.0 % (95 % confidence interval [CI] 82.7 %-90.3 %), 85.6 % (95 %CI 81.2 %-89.2 %), and 60.3 % (95 %CI 54.7 %-65.7 %). Curative resection rate was 23.7 % (95 %CI 15.9 %-33.6 %) for primary resection of T1 CRC and 60.8 % (95 %CI 50.4 %-70.4 %) after excluding deep submucosal invasion as a risk factor. Risk stratification was possible in 99.3 %. The severe adverse event rate was 2.2 %. Additional oncological surgery was performed in 49/320 (15.3 %), with residual cancer in 11/49 (22.4 %). Endoscopic follow-up was available in 200/242 (82.6 %), with a median of 4 months and residual cancer in 1 (0.5 %) following an incomplete resection., Conclusions: eFTR is relatively safe and effective for resection of small T1 CRC, both as primary and secondary treatment. eFTR can expand endoscopic treatment options for T1 CRC and could help to reduce surgical overtreatment. Future studies should focus on long-term outcomes., Competing Interests: Prof. dr. Fockens reports personal fees from Cook, Ethicon and Olympus, research support from Boston Scientific, outside the submitted work. Prof. dr. Dekker has endoscopic equipment on loan of FujiFilm, received a research grant from FujiFilm, received a honorarium for consultancy from FujiFilm, Olympus, Tillots, GI Supply and CPP-FAP and a speakers' fee from Olympus, Roche and GI Supply. Prof. dr. Weusten received research support from Pentax Medical Inc and Aqua Medical, outside the submitted work. Dr. Bastiaansen received a speakers’ fee from Olympus, Tillotts Pharma AG and Ovesco Endoscopy AG. All other authors have nothing to disclose., (Thieme. All rights reserved.)

Background: Endoscopic full-thickness resection (eFTR) is a minimally invasive resection technique that allows definite diagnosis and treatment for complex colorectal lesions ≤ 30 mm unsuitable for conventional endoscopic resection. This study reports clinical outcomes from the Dutch colorectal eFTR registry., Methods: Consecutive patients undergoing eFTR in 20 hospitals were prospectively included. The primary outcome was technical success, defined as macroscopic complete en bloc resection. Secondary outcomes were: clinical success, defined as tumor-free resection margins (R0 resection); full-thickness resection rate; and adverse events. RESULTS : Between July 2015 and October 2018, 367 procedures were included. Indications were difficult polyps (non-lifting sign and/or difficult location; n = 133), primary resection of suspected T1 colorectal cancer (CRC; n = 71), re-resection after incomplete resection of T1 CRC (n = 150), and subepithelial tumors (n = 13). Technical success was achieved in 308 procedures (83.9 %). In 21 procedures (5.7 %), eFTR was not performed because the lesion could not be reached or retracted into the cap. In the remaining 346 procedures, R0 resection was achieved in 285 (82.4 %) and full-thickness resection in 288 (83.2 %). The median diameter of resected specimens was 23 mm. Overall adverse event rate was 9.3 % (n = 34/367): 10 patients (2.7 %) required emergency surgery for five delayed and two immediate perforations and three cases of appendicitis. CONCLUSION : eFTR is an effective and relatively safe en bloc resection technique for complex colorectal lesions with the potential to avoid surgery. Further studies assessing the role of eFTR in early CRC treatment with long-term outcomes are needed., Competing Interests: P. Fockens receives personal fees from Cook, Ethicon, and Olympus, and research support from Boston Scientific outside the submitted work. E. Dekker has endoscopic equipment on loan from FujiFilm, and has received a research grant from FujiFilm, consultancy fees from FujiFilm, Olympus, Tillotts, GI Supply, and CPP-FAP, and speaker’s fees from Olympus, Roche, and GI Supply. B. Bastiaansen has received speaker’s fees from Olympus, Tillotts Pharma AG, and Ovesco Endoscopy AG. The remaining authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: Colonoscopic surveillance is recommended for individuals with familial colorectal cancer (CRC). However, the appropriate screening interval has not yet been determined. The aim of this randomized trial was to compare a 3-year with a 6-year screening interval., Patients and Methods: Individuals between ages 45 and 65 years with one first-degree relative with CRC age < 50 years or two first-degree relatives with CRC were selected. Patients with zero to two adenomas at baseline were randomly assigned to one of two groups: group A (colonoscopy at 6 years) or group B (colonoscopy at 3 and 6 years). The primary outcome measure was advanced adenomatous polyps (AAPs). Risk factors studied included sex, age, type of family history, and baseline endoscopic findings., Results: A total of 528 patients were randomly assigned (group A, n = 262; group B, n = 266). Intention-to-treat analysis showed no significant difference in the proportion of patients with AAPs at the first follow-up examination at 6 years in group A (6.9%) versus 3 years in group B (3.5%). Also, the proportion of patients with AAPs at the final follow-up examination at 6 years in group A (6.9%) versus 6 years in group B (3.4%) was not significantly different. Only AAPs at baseline was a significant predictor for the presence of AAPs at first follow-up. After correction for the difference in AAPs at baseline, differences between the groups in the rate of AAPs at first follow-up and at the final examination were statistically significant., Conclusion: In view of the relatively low rate of AAPs at 6 years and the absence of CRC in group A, we consider a 6-year surveillance interval appropriate. A surveillance interval of 3 years might be considered in patients with AAPs and patients with ≥ three adenomas., (© 2015 by American Society of Clinical Oncology.)

Introduction: Inflammatory bowel disease (IBD) is likely to have an impact on sexual function because of its symptoms, like diarrhea, fatigue, and abdominal pain. Depression is commonly reported in IBD and is also related to impaired sexual function. This study aimed to evaluate sexual function and its association with depression among patients with IBD compared with controls., Methods: IBD patients registered at two hospitals participated. The control group consisted of a general practitioner practice population. The web-based questionnaire included the Female Sexual Function Index (FSFI) for women and the International Index of Erectile Function (IIEF) for men. Other variables evaluated were depression, disease activity, IBD-related quality of life, body image, and fatigue., Results: In total, 168 female and 119 male patients were available for analysis (response rate 24%). Overall, patients with IBD did not significantly differ in prevalence of sexual dysfunctions from controls: female patients 52%, female controls 44%, male patients and male controls both 25%. However, men and women with an active disease scored significantly lower than patients in remission and controls, indicating impaired sexual functioning during disease activity. Significant associations were found between active disease, fatigue, depressive mood, quality of life, and sexual function for both male and female patients. The association between disease activity and sexual function was totally mediated by depression., Conclusion: Male and female IBD patients with an active disease show impaired sexual function relative to patients in remission and controls. Depression is the most important determinant for impaired sexual function in IBD., (© 2015 International Society for Sexual Medicine.)

Purpose: Chimerism in transplantation medicine refers to the coexistence of cells of donor and recipient origin. Their existence in relation to possible pathological mechanisms remains largely unknown. We used donor-recipient mismatches for matrix metalloproteinases (MMP) gene polymorphisms in liver biopsies and in blood as a marker for chimerism after orthotopic liver transplantation (OLT). The second aim of this study was to evaluate these polymorphisms in relation to clinical outcome such as ischemia-reperfusion injury (IRI) and acute cellular rejection (ACR)., Methods: MMP-2 and MMP-9 promoter polymorphism donor-recipient mismatches were determined in 147 OLT patients. The relationship between these MMP polymorphism mismatches in donor and recipient DNA with the development of IRI and ACR after OLT was evaluated. Liver biopsy specimens and peripheral blood samples were subsequently evaluated for the presence of chimerism, also in relation to these complications., Results: MMP polymorphism donor-recipient mismatches were found in 53.7% (MMP-2) and 35.5% (MMP-9) of the OLT patients but no relation was observed with IRI or ACR. Chimerism in liver biopsy specimens was found to be present in 28.8% (MMP-2) and 16.2% (MMP-9) of the cases. Liver chimerism in MMP-2 was found to be significantly associated with ACR after OLT (χ(2) 6.4, P = .01). Multivariate analysis revealed MMP-2 chimerism to be an independent risk factor for ACR after OLT even adjusted for Model for End-stage Liver Disease score (hazard ratio = 3.83, P = .03). In addition, evidence of donor chimerism was found in peripheral blood samples of the recipients in some cases., Conclusion: Chimerism after OLT can be found in liver biopsy specimens and in peripheral blood. MMP donor-recipient polymorphism mismatches are good markers for assessing chimerism after OLT. In the multivariate analysis, liver chimerism in MMP-2 was found to be significantly associated with the development of ACR after OLT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT., Aim: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS., Methods: MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra- or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures., Results: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype (P=0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P=0.02) and MMP-2 CT genotype (hazard ratio 3.5, P=0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs., Conclusion: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT., (© 2011 John Wiley & Sons A/S.)

Background and Aims: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas., Patients and Methods: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded., Results: A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09)., Conclusion: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.

Unlabelled: Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN2+6359T, and MASP2+371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P = 0.002), an observation confirmed in the second cohort (P = 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio = 4.52; P = 8.1 x 10(-6)) and the donor-recipient (mis)match genotype (hazard ratio = 6.41; P = 1.9 x 10(-7)), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P = 0.9 x 10(-8)), of which 80% was infection-related., Conclusion: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT.

Unlabelled: Blood stem cells can mature into elements of many different lineages. We investigated the presence and nature of donor-derived (chimeric) cells within the liver after allogeneic stem cell transplantation., Methods: Liver biopsy autopsy specimens were examined from nine female patients who had undergone allogeneic bone marrow (n = 6) or peripheral stem cell (n = 3) transplantation from a male donor. To identify the male origin of cells within the liver, in-situ hybridization for Y-chromosomes was performed in conjunction with CD45 staining to identify leucocytes., Results: Hematopoietic stem cell engraftment was confirmed in all nine recipients. Histologic examination of the liver tissue sections revealed 5.6-fold more Y-chromosome-positive than CD45-positive staining cells (P < .02), indicative of considerable nonleucocytic chimerism. This was particularly observed in patients who had developed graft-versus-host disease., Conclusions: Donor-derived cells can be found in liver tissue specimens after allogeneic stem cell transplantation. A considerable fraction of chimeric (donor-derived) cells appeared to be of nonlymphohematopoietic origin. This finding supports the theory of blood stem cells developing into liver cells of mesenchymal origin.

After orthotopic liver transplantation (OLT) many patients use emulsified cyclosporine. Recent data showed that blood levels 2 hours after dosing (C-2) better reflect systemic exposure to the drug (area under the blood concentration time curve) than trough levels (C-0) do. We investigated difference in dosage, creatinine clearance (CrCl), blood pressure (BP), freedom from rejection, and relation of C-2, C-0, and AUC while switching 31 stable patients more than 6 months after OLT from C-0 to C-2 monitoring. With C-0 between 90 and 150 ng/mL we collected 24-hour urine, while blood samples were taken at t = 0, 1, 2, 3, 4, 6, and 8 hours after dosing to measure cyclosporine, creatinine, liver tests, and blood pressure and calculated AUC and CrCl. Target AUC was calculated based on C-0. Then the dose was adjusted to two subsequent C-2 values of 600 ng/mL +/- 15%, the above was repeated, and the differences were assessed. Cyclosporine dose was reduced in 21/31 patients (68%) and remained unchanged in 10/31 patients (32%) after conversion. Mean lowering was 69 mg daily (26.9 %, P < 0.0001). After dose reduction the mean increase of CrCl was 7.93 ml/min (11.6%, P = 0.016). Only systolic and mean morning BP decreased slightly but significantly. C-2 correlated better with AUC0-12 (r2 = 0.75) than C-0 (r2 = 0.64). However, 13/21 patients had a second AUC below target AUC and 2 of these 13 patients developed rejection after conversion to C-2 levels. In conclusion, while C-0 monitoring frequently results in overdosing and more renal dysfunction, C-2 monitoring may lead to episodes of underdosing and rejection. Therefore better ways of monitoring cyclosporine dosing need to be devised.

A 40-year-old woman with type 2 diabetes mellitus, hypertension, central obesity (body mass index: 40 kg/m2) and mixed hyperlipidaemia was treated with oral hypoglycaemic, antihypertensive and hypolipidaemic drugs as well as with intramuscular insulin. She kept gaining weight and developed hiatus hernia with regurgitation. Treatment was changed to a very low caloric diet during 9 months. She lost 18 kg of body weight and all drugs could be discontinued, as she became normoglycaemic, normotensive and normolipidaemic. Obesity is a risk factor for insulin resistance and type 2 diabetes mellitus. To reach euglycaemia in overweight type 2 diabetics is a difficult task. Oral hypoglycaemic agents and insulin are often used in combination with dietary intervention without adequate results. Losing body weight should be first-line treatment. However, compliance with weight-reducing methods is often low. The pathophysiologic importance of significant weight loss in the treatment of (morbid) obesity in type 2 diabetic patients is great.

During June to August 1989, 158 symptomatic outpatients with P. falciparum malaria were randomly treated with either amodiaquine or chloroquine 25 mg/kg, divided over three days. Amodiaquine (Camoquin, Parke-Davis) was significantly more effective in terms of the rate of parasite clearance, 2.4 versus 3.1 days; parasite clearance day 7; 87% versus 41%; and clinical amelioration, 98% versus 68%. Moreover, this study demonstrates the lack of therapeutic toxicity of amodiaquine. Globally, tolerance was better with amodiaquine than with chloroquine; in particular, cutaneous side effects were less frequent with amodiaquine. There was no evidence of granulocyte or gross hepatic toxicity. These results suggest that WHO recommendations concerning amodiaquine should be questioned. In view of its low cost, demonstrated efficacy and lack of proven therapeutic toxicity, amodiaquine should be considered as a viable replacement for chloroquine in areas with high levels of clinical chloroquine failure.

Background: In this study, the anticoagulant response of 12,500 IU heparin s.c. was investigated in patients with myocardial infarction and healthy volunteers to determine variabilities in response and modifying factors., Methods and Results: On the fourth day after thrombolytic therapy, blood samples were taken before and at frequent intervals until 10 hours after the injection of 12,500 IU heparin s.c. Plasma anti-Xa activity, anti-IIa activity, and the activated partial thromboplastin time (APTT) were measured in addition to body weight and thickness of the abdominal subcutaneous fat layer. Contrary to expectations, the increase of anti-Xa activity, anti-IIa activity, and APTT compared with baseline (predrug) levels was very small, with an average maximal APTT of 42.6 seconds (SD, 12.4 seconds; range, 30.4-70.7 seconds). Subsequently, the influence of the length of the injection needle on the anticoagulant effect of 12,500 IU heparin s.c. was studied in 10 healthy volunteers to find a factor that could be responsible for the poor response in the patients. The length of the injection needle did not influence the anticoagulant effect of heparin. Large interindividual and intraindividual variabilities were seen in the volunteers. The majority of volunteers had minimal prolongation of the APTT, but very strong prolongation was also seen (maximal APTT, 163 seconds). There was no correlation between the abdominal skinfold thickness and anti-Xa activity, anti-IIa activity, or APTT (p > 0.05), but in the patient study, there was a correlation between weight and anti-Xa activity and anti-IIa activity (p < 0.05), and in the volunteer study, there was a correlation between weight and anti-Xa activity and APTT (p < 0.05)., Conclusions: Subcutaneous administration of heparin in a fixed dose for prophylactic and therapeutic purposes may be inadequate because of the large interindividual and intraindividual variations in anticoagulant effect.