Long-term oncological outcomes after local excision of T1 rectal cancer.

BACKGROUND: A growing proportion of patients with early rectal cancer is treated by local excision only. The aim of this study was to evaluate long-term oncological outcomes and the impact of local recurrence on overall survival for surgical local excision in pT1 rectal cancer. METHODS: Patients who only underwent local excision for pT1 rectal cancer between 1997 and 2014 in two Dutch tertiary referral hospitals were included in this retrospective cohort study. The primary outcome was the local recurrence rate. Secondary outcomes were distant recurrence, overall survival and the impact of local recurrence on overall survival. RESULTS: A total of 150 patients (mean age 68.5 ± 10.7 years, 57.3% males) were included in the study. Median length of follow-up was 58.9 months (range 6-176 months). Local recurrence occurred in 22.7% (n = 34) of the patients, with a median time to local recurrence of 11.1 months (range 2.3-82.6 months). The vast majority of local recurrences were located in the lumen. Five-year overall survival was 82.0%, and landmark analyses showed that local recurrence significantly impacted overall survival at 6 and 36 months of follow-up (6 months, p = 0.034, 36 months, p = 0.036). CONCLUSIONS: Local recurrence rates after local excision of early rectal cancer can be substantial and may impact overall survival. Therefore, clinical decision-making should be based on patient- and tumour characteristics and should incorporate patient preferences.

Efficacy and safety of autologous adipose-derived stromal vascular fraction enriched with platelet-rich plasma in flap repair of transsphincteric cryptoglandular fistulas.

BACKGROUND: Transanal advancement flap repair of transsphincteric fistulas is a sphincter-preserving procedure, which frequently fails, probably due to ongoing inflammation in the remaining fistula tract. Adipose-derived stromal vascular fraction (SVF) has immunomodulatory properties promoting wound healing and suppressing inflammation. Platelet-rich plasma (PRP) reinforces this biological effect. The aim of this study was to evaluate the efficacy and safety of autologous adipose-derived SVF enriched with PRP in flap repair of transsphincteric cryptoglandular fistulas. METHODS: A prospective cohort study was conducted including consecutive patients with transsphincteric cryptoglandular fistula in a tertiary referral center. During flap repair, SVF was obtained by lipoharvesting and mechanical fractionation of adipose tissue and combined with PRP was injected around the internal opening and into the fistulous wall. Endpoints were fistula healing at clinical examination and fistula closure on postoperative magnetic resonance imaging (MRI). Adverse events were documented. RESULTS: Forty-five patients with transsphincteric cryptoglandular fistula were included (29 males, median age 44 years [range 36-53 years]). In the total study population, primary fistula healing was observed in 38 patients (84%). Among the 42 patients with intestinal continuity at time of surgery, primary fistula healing was observed in 35 patients (84%). In one patient, the fistula recurred, resulting in a long-term healing rate of 82%. MRI, performed in 37 patients, revealed complete closure of the fistula tract in 33 (89.2%). In the other patients, the tract was almost completely obliterated by scar tissue. During follow-up, none of these patients showed clinical signs of recurrence. The postoperative course was uneventful, except for three cases; venous thromboembolism in one patient and bleeding under the flap, necessitating intervention in two patients. CONCLUSIONS: Addition of autologous SVF enriched with PRP during flap repair is feasible, safe and might improve outcomes in patients with a transsphincteric cryptoglandular fistula. TRIAL REGISTRATION: Dutch Trial Register, Trial Number: NL8416, https://www.trialregister.nl/.

Local recurrence after local excision of early rectal cancer: a meta-analysis of completion TME, adjuvant (chemo)radiation, or no additional treatment.

BACKGROUND: The risks of local recurrence and treatment-related morbidity need to be balanced after local excision of early rectal cancer. The aim of this meta-analysis was to determine oncological outcomes after local excision of pT1-2 rectal cancer followed by no additional treatment (NAT), completion total mesorectal excision (cTME) or adjuvant (chemo)radiotherapy (aCRT). METHODS: A systematic search was conducted in PubMed, Embase and the Cochrane Library. The primary outcome was local recurrence. Statistical analysis included calculation of the weighted average of proportions. RESULTS: Some 73 studies comprising 4674 patients were included in the analysis. Sixty-two evaluated NAT, 13 cTME and 28 aCRT. The local recurrence rate for NAT among low-risk pT1 tumours was 6·7 (95 per cent c.i. 4·8 to 9·3) per cent. There were no local recurrences of low-risk pT1 tumours after cTME or aCRT. The local recurrence rate for high-risk pT1 tumours was 13·6 (8·0 to 22·0) per cent for local excision only, 4·1 (1·7 to 9·4) per cent for cTME and 3·9 (2·0 to 7·5) per cent for aCRT. Local recurrence rates for pT2 tumours were 28·9 (22·3 to 36·4) per cent with NAT, 4 (1 to 13) per cent after cTME and 14·7 (11·2 to 19·0) per cent after aCRT. CONCLUSION: There is a substantial risk of local recurrence in patients who receive no additional treatment after local excision, especially those with high-risk pT1 and pT2 rectal cancer. The lowest recurrence risk is provided by cTME; aCRT has outcomes comparable to those of cTME for high-risk pT1 tumours, but shows a higher risk for pT2 tumours.

ANTECEDENTES: Tras una resección temprana de un cáncer de recto localizado, hay que considerar el equilibrio entre el riesgo de recidiva local y la morbilidad relacionada con el tratamiento. El objetivo de este metaanálisis era determinar los resultados oncológicos tras la resección de un cáncer de recto pT1-T2 seguida de ningún tratamiento adicional (no additional treatment, NAT), escisión total del mesorrecto (completion total mesorectal excision, cTME) o quimiorradioterapia adyuvante (adjuvant chemoradiotherapy, aCRT). METHODS: Se llevó a cabo una búsqueda sistemática en PubMed, Embase y biblioteca Cochrane. La variable principal de resultado era la recidiva local (local recurrence, LR). En el análisis estadístico se calcularon las medias ponderadas de proporciones. RESULTADOS: Se incluyeron en el análisis 76 estudios con un total de 4.793 pacientes. NAT fue evaluada en 72 estudios, cTME en 13 y aCRT en 28. La tasa de LR para NAT en tumores pT1 de bajo riesgo era de 6,7% (i.c. del 95% 4,8-9,3). No se observaron casos de LR en tumores pT1 de bajo riesgo tras cTME o aCRT. La tasa de LR para tumores pT1 de alto riesgo fue de 13,6% (i.c. del 95% 8,0-22,0) para la resección local como único tratamiento, 4,1% (i.c. del 95% 1,7-9,4) para cTME y 3,9% (i.c. del 95% 2,0-7,5) para aCRT. La tasa de LR para tumores pT2 fue de 28,9% (i.c. del 95% 22,3-36,4) para NAT, 4,3% (i.c. del 95% 1,4-12,5) para cTME y 14,7% (i.c. del 95% 11,2-19,0) para aCRT. CONCLUSIÓN: Tras la resección local de cáncer pT1 de alto riesgo y pT2, existe un riesgo sustancial de recidiva local en ausencia de tratamiento adicional. La escisión total del mesorrecto se asocia con el menor riesgo de recidiva. La quimiorradioterapia adyuvante ofrece resultados similares a la escisión total del mesorrecto en tumores pT1 de alto riesgo, pero presenta un mayor riesgo en tumores pT2.

Structured training pathway and proctoring; multicenter results of the implementation of transanal total mesorectal excision (TaTME) in the Netherlands.

BACKGROUND: Transanal total mesorectal excision (TaTME) is a new complex technique with potential to improve the quality of surgical mesorectal excision for patients with mid and low rectal cancer. The procedure is technically challenging and has shown to be associated with a relative long learning curve which might hamper widespread adoption. Therefore, a national structured training pathway for TaTME has been set up in the Netherlands to allow safe implementation. The aim of this study was to monitor safety and efficacy of the training program with 12 centers. METHODS: Short-term outcomes of the first ten TaTME procedures were evaluated in 12 participating centers in the Netherlands within the national structured training pathway. Consecutive patients operated during and after the proctoring program for rectal carcinoma with curative intent were included. Primary outcome was the incidence of intraoperative complications, secondary outcomes included postoperative complications and pathological outcomes. RESULTS: In October 2018, 12 hospitals completed the training program and from each center the first 10 patients were included for evaluation. Intraoperative complications occurred in 4.9% of the cases. The clinicopathological outcome reported 100% for complete or nearly complete specimen, 100% negative distal resection margin, and the circumferential resection margin was positive in 5.0% of patients. Overall postoperative complication rate was 45.0%, with 19.2% Clavien-Dindo ≥ III and an anastomotic leak rate of 17.3%. CONCLUSIONS: This study shows that the nationwide structured training program for TaTME delivers safe implementation of TaTME in terms of intraoperative and pathology outcomes within the first ten consecutive cases in each center. However, postoperative morbidity is substantial even within a structured training pathway and surgeons should be aware of the learning curve of this new technique.

Multicentre study of non-surgical management of diverticulitis with abscess formation.

This multicentre retrospective cohort study included 447 patients with Hinchey Ib and II diverticular abscesses, who were treated with antibiotics, with or without percutaneous drainage. Abscesses of 3 and 5 cm in size were at higher risk of short-term treatment failure and emergency surgery respectively. Initial non-surgical treatment of Hinchey Ib and II diverticular abscesses was comparable between patients treated with antibiotics only and those who underwent percutaneous drainage in combination with antibiotics, with regard to short- and long-term outcomes. Most do not need drainage.

Short-term outcomes of transanal completion total mesorectal excision (cTaTME) for rectal cancer: a case-matched analysis.

BACKGROUND: Local excision of early rectal tumors as a rectal preserving treatment is gaining popularity, especially since bowel cancer screening programs result in a shift towards the diagnosis of early stage rectal cancers. However, unfavorable histological features predicting high risk for recurrence within the "big biopsy" may mandate completion total mesorectal excision (cTME). Completion surgery is associated with higher morbidity, poorer specimen quality, and less favorable oncological outcomes compared to primary TME. Transanal approach potentially improves outcome of completion surgery for rectal cancer. The aim of this study was to compare radical completion surgery after local excision for rectal cancer by the transanal approach (cTaTME) with conventional abdominal approach (cTME). METHODS: All consecutive patients who underwent cTaTME for rectal cancer between 2012 and 2017 were case-matched with cTME patients, according to gender, tumor height, preoperative radiotherapy, and tumor stage. Surgical, pathological, and short-term postoperative outcomes were evaluated. RESULTS: In total, 25 patients underwent completion TaTME and were matched with 25 patients after cTME. Median time from local excision to completion surgery was 9 weeks in both groups. In the cTaTME and cTME groups, perforation of the rectum occurred in 4 and 28% of patients, respectively (p = 0.049), leading to poor specimen quality in these patients. Number of harvested lymph nodes was higher after cTaTME (median 15; range 7-47) than after cTME (median 10; range 0-17). No significant difference was found in end colostomy rate between the two groups. Major 30-day morbidity (Clavien-Dindo≥ III) was 20 and 32%, respectively (p = 0.321). Hospital stay was significantly longer after cTME. CONCLUSION: TaTME after full-thickness excision is a promising technique with a significantly lower risk of perforation of the rectum and better specimen quality compared to conventional completion TME.

Effectiveness of endosponge therapy for the management of presacral abscesses following rectal surgery.

BACKGROUND: Anastomotic leak after rectal surgery is reported in 9% (range 3-28%) of patients. The aim of our study was to evaluate the effectiveness of endosponge therapy for anastomotic. Endpoints were the rate of restored continuity and the functional bowel outcome after anastomotic leakage. METHODS: This was a multicenter retrospective observational cohort study. All patients with symptomatic anastomotic leakage after rectal surgery who had endosponge therapy between January 2012 and August 2017 were included. Functional bowel outcome was measured using the low anterior resection syndrome (LARS) score system. RESULTS: Twenty patients were included. Eighteen patients had low anterior resection (90%) for rectal cancer. A diverting ileostomy was performed at primary surgical intervention in 14 patients (70%). Fourteen patients (70%) were treated with neoadjuvant (chemo-)radiotherapy. The median time between primary surgical intervention and first endosponge placement was 21 (5-537) days. The median number of endosponge changes was 9 (2-28). The success rate of the endosponge treatment was 88% and the restored gastrointestinal continuity rate was 73%. A chronic sinus occurred in three patients (15%). All patients developed LARS, of which 77% reported major LARS. CONCLUSIONS: Endosponge therapy is an effective treatment for the closure of presacral cavities with high success rate and leading to restored gastrointestinal continuity in 73%. However, despite endosponge therapy many patients develop major LARS.

Non-operative treatment as a strategy for patients with parastomal hernia: a multicentre, retrospective cohort study.

AIM: Parastomal hernia is the most common complication following stoma construction. Surgical treatment is usually chosen over non-operative treatment, but a clear rationale for the choice of management is often lacking. This study aims to investigate the reasons for non-operative treatment, cross-over rates and postoperative complications. METHOD: A multicentre, retrospective cohort study was conducted. Patients diagnosed with a parastomal hernia between January 2007 and December 2012 were included. Data on baseline characteristics, primary surgery and hernias were collected. For non-operative treatment, reasons for this treatment and cross-over rates were evaluated. For all patients undergoing surgery (surgical treatment and cross-overs), complication and recurrence rates were analysed. RESULTS: Of the 80 patients included, 42 (53%) were in the surgical treatment group and 38 (48%) in the non-operative treatment group. Median follow-up was 46 months (interquartile range 24-72). The reasons for non-operative treatment were absence of symptoms in 12 patients (32%), comorbidities in nine (24%) and patient preference in three (7.9%). In 14 patients (37%) reasons were not documented. Eight patients (21%) crossed over from non-operative treatment to surgical treatment, of whom one needed emergency surgery. In 23 patients (55%), parastomal hernia recurred after the original surgical treatment, of whom 21 (91%) underwent additional repair. CONCLUSION: Parastomal hernia repair is associated with high recurrence and additional repair rates. Non-operative treatment has a relatively low cross-over and emergency surgery rate. Given these data, non-operative treatment might be a better choice for patients without complaints or with comorbidities.

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool.

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.

PURPOSE: Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury. METHODS: We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions. RESULTS: AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%. CONCLUSIONS: After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic. WHAT THIS STUDY ADDS: • For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation. • Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation. • AKI after lung transplantation shows low recovery rates.

A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation.

Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor ß (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.

A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer.

BACKGROUND: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. METHODS/STUDY DESIGN: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. DISCUSSION: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. TRIAL REGISTRATION: NCT02371304 , registration date: February 2015.

Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation.

Annually, about 8000 heart and lung transplantations are successfully performed worldwide. However, morbidity and mortality still pose a major concern. Renal failure in heart and lung transplant recipients is an essential adverse cause of morbidity and mortality, often originating in the early postoperative phase. At this time of clinical instability, the kidneys are exposed to numerous nephrotoxic stimuli. Among these, tacrolimus toxicity plays an important role, and its pharmacokinetics may be significantly altered in this critical phase by fluctuating drug absorption, changed protein metabolism, anemia and (multi-) organ failure. Limited understanding of tacrolimus pharmacokinetics in these circumstances is hampering daily practice. Tacrolimus dose adjustments are generally based on whole blood trough levels, which widely vary early after transplantation. Moreover, whole blood trough levels are difficult to predict and are poorly related to the area under the concentration-time curve. Even within the therapeutic range, toxicity may occur. These shortcomings of tacrolimus monitoring may not hold for the unbound tacrolimus plasma concentrations, which may better reflect tacrolimus toxicity. This review focuses on posttransplant tacrolimus pharmacokinetics, discusses relevant factors influencing the unbound tacrolimus concentrations and tacrolimus (nephro-) toxicity in heart and lung transplantation patients.

Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (CARTS study).

BACKGROUND: This prospective multicentre study was performed to quantify the number of patients with minimal residual disease (ypT0-1) after neoadjuvant chemoradiotherapy and transanal endoscopic microsurgery (TEM) for rectal cancer. METHODS: Patients with clinically staged T1-3 N0 distal rectal cancer were treated with long-course chemoradiotherapy. Clinical response was evaluated 6-8 weeks later and TEM performed. Total mesorectal excision was advocated in patients with residual disease (ypT2 or more). RESULTS: The clinical stage was cT1 N0 in ten patients, cT2 N0 in 29 and cT3 N0 in 16 patients. Chemoradiotherapy-related complications of at least grade 3 occurred in 23 of 55 patients, with two deaths from toxicity, and two patients did not have TEM or major surgery. Among 47 patients who had TEM, ypT0-1 disease was found in 30, ypT0 N1 in one, ypT2 in 15 and ypT3 in one. Local recurrence developed in three of the nine patients with ypT2 tumours who declined further surgery. Postoperative complications grade I-IIIb occurred in 13 of 47 patients after TEM and in five of 12 after (completion) surgery. After a median follow-up of 17 months, four local recurrences had developed overall, three in patients with ypT2 and one with ypT1 disease. CONCLUSION: TEM after chemoradiotherapy enabled organ preservation in one-half of the patients with rectal cancer.

Predictors of treatment dropout in self-guided web-based interventions for depression: an 'individual patient data' meta-analysis.

BACKGROUND: It is well known that web-based interventions can be effective treatments for depression. However, dropout rates in web-based interventions are typically high, especially in self-guided web-based interventions. Rigorous empirical evidence regarding factors influencing dropout in self-guided web-based interventions is lacking due to small study sample sizes. In this paper we examined predictors of dropout in an individual patient data meta-analysis to gain a better understanding of who may benefit from these interventions. METHOD: A comprehensive literature search for all randomized controlled trials (RCTs) of psychotherapy for adults with depression from 2006 to January 2013 was conducted. Next, we approached authors to collect the primary data of the selected studies. Predictors of dropout, such as socio-demographic, clinical, and intervention characteristics were examined. RESULTS: Data from 2705 participants across ten RCTs of self-guided web-based interventions for depression were analysed. The multivariate analysis indicated that male gender [relative risk (RR) 1.08], lower educational level (primary education, RR 1.26) and co-morbid anxiety symptoms (RR 1.18) significantly increased the risk of dropping out, while for every additional 4 years of age, the risk of dropping out significantly decreased (RR 0.94). CONCLUSIONS: Dropout can be predicted by several variables and is not randomly distributed. This knowledge may inform tailoring of online self-help interventions to prevent dropout in identified groups at risk.

YKL-40 and matrix metalloproteinases as potential biomarkers of inflammation and fibrosis in the development of bronchiolitis obliterans syndrome.

BACKGROUND AND OBJECTIVE: The development of bronchiolitis obliterans syndrome (BOS) after lung transplantation is characterized by inflammation, remodeling and fibrosis. Both YKL-40 and matrix metalloproteinase (MMP)-9 have shown to be involved in these processes. We measured serial YKL-40 and MMP-9 serum levels in lung transplant recipients and assessed their usefulness as biomarker for BOS. Furthermore, we investigate the relationship between these two potential biomarkers of BOS and MMP-7. DESIGN: Ten patients with BOS (BOS(pos)) and 10 matched patients without BOS (BOS(neg)) were included. Serial serum samples were collected after lung transplantation and prior to BOS. YKL-40, MMP-9 and MMP-7 serum levels were determined by ELISA. RESULTS: The median concentrations of YKL-40 did not differ between BOS(pos) and BOS(neg) patients (p > 0.05). The median concentration of MMP-9 in BOS(pos) patients was significantly higher than in BOS(neg) patients (p < 0.0001). For MMP-9 as possible risk factor for BOS, a cut off value of 145 ng/ml has a sensitivity of 90% and a negative predictive value of 83%. Longitudinal analysis of YKL-40 and MMP-9 serum levels from the early post-transplant period onwards did not reveal a significant trend in time in both serum levels preceding BOS. In BOS(neg) patients MMP-9 showed an inverse relationship with MMP-7, that was absent in BOS(pos) patients. CONCLUSIONS: From the moment of transplantation onwards, patients who eventually developed BOS had significantly increased MMP-9 serum levels in comparison with patients who did not develop BOS. Therefore, increased MMP-9 serum levels might be useful as risk factor for BOS.

The effect of endoscopic mucosal resection and transanal endoscopic microsurgery on anorectal function.

AIM: The study assessed the impact on anorectal function of endoscopic mucosal resection (EMR) and transanal endoscopic microsurgery (TEM) of large rectal adenomas. METHOD: Patients with a large (≥ 3 cm) rectal adenoma undergoing EMR or TEM were included. Self-reported faecal incontinence was assessed using the Colorectal Functional Outcome (COREFO) questionnaire and the Wexner Incontinence Grading Scale. Anorectal manometry was performed before and at 6 months after treatment to measure anal resting (ARP) and squeeze pressure (SP), squeeze endurance (SE), the rectoanal inhibitory reflex (RAIR), rectal volumetry of first sensation (FS), first urge (FU), maximum tolerable volume (MTV) and rectal compliance (RC). RESULTS: Twenty-four patients were included in the study, of whom 11 underwent EMR and 13 underwent TEM. The mean adenoma size was 51 ± 19 mm and the median distance from the anal verge was 3 cm (interquartile range 1-10 cm). Follow-up data were available from 20 patients; one patient had died and three had undergone total mesorectal excision. Incontinence for liquid stool and Wexner score decreased significantly after treatment. In contrast, none of the measured parameters of anorectal motility (ARP, SP, SE, RAIR, RC) and perception (FS, FU, MTV) was affected by adenoma resection. No differences were found in baseline and follow-up incontinence and functional parameters between intervention groups, except for postprocedural ARP, which was lower after TEM than after EMR. CONCLUSION: Continence in patients with a large rectal adenoma improved after EMR or TEM, probably due to decreased rectal mucus production. Anal sphincter pressure, rectoanal reflexes, rectal sensation and compliance were not affected by adenoma resection.

Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.

AIMS: The aims of the study are to investigate the prevalence of diabetes in patients with cystic fibrosis compared with patients without cystic fibrosis, and its impact on the outcome after lung transplantation. METHODS: Data were reviewed from 77 lung transplantation recipients in our centre between 2001 and 2010; 43 patients had cystic fibrosis and 34 patients had other lung diseases (no cystic fibrosis). To define diabetes, we used the American Diabetes Association definition. RESULTS: Before lung transplantation, diabetes was diagnosed in 63% of patients with cystic fibrosis and 6% of patients without cystic fibrosis (P<0.001). In both groups, approximately 60% of the patients at risk developed new-onset diabetes after transplantation. The mortality in patients with cystic fibrosis was higher in patients with diabetes diagnosed before lung transplantation compared with those without (44 vs. 6%, P=0.04). Diabetes remained an independent factor in multivariate analyses. CONCLUSIONS: Diabetes diagnosed before lung transplantation has a negative effect on survival after lung transplantation in patients with cystic fibrosis. Pre-existing diabetes is common in patients with cystic fibrosis, in contrast to patients without cystic fibrosis. Development of new-onset diabetes after transplantation is similar in both groups.

Endoscopic mucosal resection vs transanal endoscopic microsurgery for the treatment of large rectal adenomas.

AIM: Large (> 2 cm) rectal adenomas are currently treated by transanal endoscopic microsurgery (TEM) or piecemeal endoscopic mucosal resection (EMR). The potential lower morbidity of EMR becomes irrelevant if it is less effective. We aimed to compare the safety and effectiveness of EMR and TEM for large rectal adenomas. METHOD: Data from patients undergoing TEM or EMR for a rectal adenoma > 2 cm in eight hospitals were retrospectively collected. Patient- and procedure-related characteristics, complications and recurrences were recorded. As EMR may require several attempts to achieve complete resection, early (after a single intervention) and late (permitting re-treatment for residual adenoma within 6 months) recurrence rates were determined. RESULTS: Two hundred and ninety-two (292) patients (49% male; mean age 67 years) were included; 219 were treated by TEM and 73 by EMR. Adenomas treated by EMR were smaller (median 30 vs 40 mm; P = 0.007). Perioperative complication rates were 2% for TEM and 6% for EMR (P = 0.171). Postoperative complications occurred in 24% of TEM patients and in 13% of EMR patients (P = 0.038). Median hospitalization after TEM was 3 days vs 0 days after EMR (P < 0.001). Median follow-up was 12.6 months (0-47 months); Early recurrence rates were 10.2% in TEM patients and 31.0% in EMR patients (P < 0.001); late recurrence rates were 9.6% and 13.8%, respectively (P = 0.386). CONCLUSION: After a single intervention, EMR of large rectal adenomas seems less effective, but safer than TEM. When allowing re-treatment of residual adenoma within 6 months, EMR and TEM seem equally effective. A prospective randomized comparison seems to be necessary.

Treatment of clinical T1 rectal cancer in the Netherlands; a population-based overview of clinical practice.

INTRODUCTION: Local excision is increasingly used as an alternative treatment for radical surgery in patients with early stage clinical T1 (cT1) rectal cancer. This study provides an overview of incidence, staging accuracy and treatment strategies in patients with cT1 rectal cancer in the Netherlands. MATERIALS AND METHODS: Patients with cT1 rectal cancer diagnosed between 2005 and 2018 were included from the Netherlands Cancer Registry. An overview per time period (2005-2009, 2010-2014 and 2015-2018) of the incidence and various treatment strategies used, e.g. local excision (LE) or major resection, with/without neoadjuvant treatment (NAT), were given and trends over time were analysed using the Chi Square for Trend test. In addition, accuracy of tumour staging was described, compared and analysed over time. RESULTS: In total, 3033 patients with cT1 rectal cancer were diagnosed. The incidence of cT1 increased from 540 patients in 2005-2009 to 1643 patients in 2015-2018. There was a significant increased use of LE. In cT1N0/X patients, 9.2% received NAT, 25.5% were treated by total mesorectal excision (TME) and 11.4% received a completion TME (cTME) following prior LE. Overall accuracy in tumour staging (cT1 = pT1) was 77.3%, yet significantly worse in cN1/2 patients, as compared to cN0 patients (44.8% vs 77.9%, respectively, p < 0.001). CONCLUSION: Over time, there was an increase in the incidence of cT1 tumours. Both the use of neoadjuvant therapy and TME surgery in clinically node negative patients decreased significantly. Clinical accuracy in T1 tumour staging improved over time, but remained significantly worse in clinical node positive patients.