Limited wedge resection for T1 colon cancer (LIMERIC-II trial) - rationale and study protocol of a prospective multicenter clinical trial.

BACKGROUND: The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs. METHODS: In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR's technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated. DISCUSSION: CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR. TRIAL REGISTRATION: CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022).

Long-term Outcome of Radical Excision Versus Phenolization of the Sinus Tract in Primary Sacrococcygeal Pilonidal Sinus Disease: A Randomized Controlled Trial.

BACKGROUND: Phenolization of pilonidal sinus disease has been shown to have advantages over radical excision with regard to short-term outcome; however, long-term outcomes are essentially lacking. OBJECTIVE: The aim of this randomized controlled trial was to compare the long-term outcome of pit excision and phenolization of the sinus tracts vs radical excision with primary wound closure in pilonidal sinus disease. DESIGN: Single-center, randomized controlled trial. SETTINGS: A primary teaching hospital in the Netherlands. PATIENTS: The study population included patients with primary pilonidal sinus disease presented between 2013 and 2017. INTERVENTIONS: Patients were randomly assigned to either pit excision with phenolization of the sinus tract(s) or excision with primary off-midline wound closure. MAIN OUTCOME MEASURES: The main outcomes included recurrence, quality of life (Short-Form 36), and patient's satisfaction. RESULTS: A total of 100 patients were randomized. Seventy-four patients (77.1%) were available for long-term follow-up. The mean (±SD) time to follow-up was 48.4 (±12.8) months for the phenolization group and 47.8 (±13.5) months for the excision group. No significant difference was found between both groups regarding quality of life. Two patients in the phenolization group (5.6%) and 1 in the excision group (2.6%) developed a recurrence ( p = 0.604). The impact of the whole treatment was significantly less after phenolization ( p = 0.010). LIMITATIONS: The response rate was almost 80% in this young patient population, patients and assessors were not blinded for the type of surgery, and the results are only applicable to primary pilonidal sinus disease. CONCLUSIONS: Because of the previously shown favorable short-term results and the currently reported comparable long-term recurrence rate and quality of life between phenolization and excision, phenolization should be considered the primary treatment option in patients with pilonidal sinus disease. See Video Abstract at http://links.lww.com/DCR/C27 . DUTCH TRIAL REGISTER ID: NTR4043. RESULTADO A LARGO PLAZO DE LA ESCISIN RADICAL FRENTE AL TRATAMIENTO CON FENOL DEL TRACTO SINUSAL EN LA ENFERMEDAD DEL SENO PILONIDAL SACRO COCCGEO PRIMARIO UN ENSAYO ALEATORIO CONTROLADO: ANTECEDENTES:El tratamiento con fenol de la enfermedad del seno pilonidal ha demostrado tener ventajas sobre la escisión radical con respecto al resultado a corto plazo; sin embargo, los resultados a largo plazo aún se encuentran escasos.OBJETIVO:El objetivo de este ensayo aleatorio controlado fue comparar el resultado a largo plazo de la escisión de la fosa del quiste y el tratamiento con fenol de los trayectos sinusales frente a la escisión radical con cierre primario de la herida en la enfermedad del seno pilonidal.DISEÑO:Ensayo aleatorio controlado de un solo centro.AJUSTES:Hospital de enseñanza primaria en los Países Bajos.PACIENTES:Pacientes con enfermedad primaria del seno pilonidal presentados entre 2013 y 2017.INTERVENCIONES:Los pacientes fueron asignados de manera aleatoria a la escisión de la fosa del quiste y posterior administración de fenol de los tractos sinusales o a la escisión con cierre primario de la herida fuera de la línea media.PRINCIPALES MEDIDAS DE RESULTADO:Recurrencia, calidad de vida (Short-Form 36) y satisfacción del paciente.RESULTADOS:Un total de 100 pacientes con enfermedad primaria del seno pilonidal fueron aleatorizados; 50 pacientes fueron sometidos al tratamiento con fenol y 50 a la escisión radical. Eventualmente, 74 pacientes (77,1%) estuvieron disponibles para seguimiento a largo plazo; 36 pacientes después del uso del fenol y 38 después de la escisión. El tiempo medio (± desviación estándar) de seguimiento fue de 48,4 (± 12,8) y 47,8 (± 13,5) meses, respectivamente. No hubo diferencia significativa entre ambos grupos con respecto a la calidad de vida. En el grupo tratado con fenal, dos pacientes (5,6%) desarrollaron recurrencia y un paciente (2,6%) en el grupo de escisión ( p = 0,604). El impacto de todo el tratamiento fue significativamente menor después del uso del fenol (p = 0,010).LIMITACIONES:La tasa de respuesta fue de casi el 80% en esta población de pacientes jóvenes, los pacientes y los evaluadores no estaban cegados por el tipo de cirugía, los resultados son solo aplicables a la enfermedad primaria del seno pilonidal.CONCLUSIONES:Debido a los resultados favorables a corto plazo descritos y a la tasa de recurrencia a largo plazo y la calidad de vida comparables actualmente informadas entre la administración de fenol y la escisión con cierre primario de la herida para la enfermedad primaria del seno pilonidal, la administración de fenol del tracto sinusal debe considerarse como opción de tratamiento primario en pacientes con enfermedad del seno pilonidal. Consulte Video Resumen en http://links.lww.com/DCR/C27 . (Traducción-Dr. Osvaldo Gauto )Registro de prueba holandés-ID:NTR4043.

Colonoscopic-Assisted Laparoscopic Wedge Resection for Colonic Lesions: A Prospective Multicenter Cohort Study (LIMERIC-Study).

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of a modified CAL-WR. SUMMARY BACKGROUND DATA: The use of segmental colectomy in patients with endoscopically unresectable colonic lesions results in significant morbidity and mortality. CAL-WR is an alternative procedure that may reduce morbidity. METHODS: This prospective multicenter study was performed in 13 Dutch hospitals between January 2017 and December 2019. Inclusion criteria were (1) colonic lesions inaccessible using current endoscopic resection techniques (judged by an expert panel), (2) non-lifting residual/recurrent adenomatous tissue after previous polypectomy or (3) an undetermined resection margin after endoscopic removal of a low-risk pathological T1 (pT1) colon carcinoma. Thirty-day morbidity, technical success rate and radicality were evaluated. RESULTS: Of the 118 patients included (56% male, mean age 66 years, standard deviation ± 8 years), 66 (56%) had complex lesions unsuitable for endoscopic removal, 34 (29%) had non-lifting residual/recurrent adenoma after previous polypectomy and 18 (15%) had uncertain resection margins after polypectomy of a pT1 colon carcinoma. CAL-WR was technically successful in 93% and R0 resection was achieved in 91% of patients. Minor complications (Clavien-Dindo i-ii) were noted in 7 patients (6%) and an additional oncologic segmental resection was performed in 12 cases (11%). Residual tissue at the scar was observed in 5% of patients during endoscopic follow-up. CONCLUSIONS: CAL-WR is an effective, organ-preserving approach that results in minor complications and circumvents the need for major surgery. CAL-WR, therefore, deserves consideration when endoscopic excision of circumscribed lesions is impossible or incomplete.

Single-cell derived tumor organoids display diversity in HLA class I peptide presentation.

Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15-25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.

Phenolisation of the Sinus Tract in Recurrent Sacrococcygeal Pilonidal Sinus Disease: A Prospective Cohort Study.

Purpose Phenolisation is a minimally invasive treatment option in patients with primary pilonidal disease. However, most studies focus on patients with primary pilonidal sinus disease, while data of patients with recurrent pilonidal disease are very scarce. The purpose of this study was to evaluate phenolisation of the sinus tract in patients with recurrent pilonidal sinus disease after previous surgery for SPSD. Methods This single-center prospective cohort study included 60 patients with recurrent pilonidal disease. Loss of days of normal daily activities, surgical site infection, wound epithelization, quality of life, and complaints related to pilonidal disease were postoperatively assessed. Results A total of 57 patients (95%) were treated with phenolisation and the median loss of days of normal daily activities was 5.0 (1.0 - 12.0) days. Fifty-one patients (89.5%) resumed normal daily activities after two weeks. Surgical site infection occurred in five patients (8.8%). Compared to preoperative scores, quality of life was significantly higher 12 weeks postoperatively (p=0.014) and pain and itch scores were lower after six and 12 weeks (p ≤ 0.005). Wounds were completely healed in 45 of 51 patients (89.8%) who were available after 12 weeks of follow-up. Conclusion Phenolisation for recurrent pilonidal disease is safe with a median complete return to daily activities within five days and complete wound healing after three months in 90%. Therefore, phenolisation should be considered as a treatment option in patients with recurrent pilonidal sinus disease.

Sexual Function in Patients Suffering from Sacrococcygeal Pilonidal Sinus Disease.

Introduction Sexual function is one of the aspects upon which quality of life (QoL) is based. Although previous studies have evaluated the influence of sacrococcygeal pilonidal sinus disease (SPSD) on QoL, no data are available on the influence of SPSD on sexual function in a highly active sexual population based on the age range. The aim of this prospective study was to evaluate whether SPSD has a negative impact on sexual function and whether this is influenced by the surgical treatment of SPSD. Methods  Sexual function was pre- and postoperatively assessed by the Sexual Self-Consciousness Scale (SSCS; score range 0-48), subdivided into the sexual embarrassment (SE; score range 0-24) and sexual self-focus subscale (SFF; score range 0-24). The higher the score, the higher is the sexual dysfunction. Patients were also asked whether SPSD influenced their sexual functioning. Results  A total of 88 male patients who underwent surgical treatment for SPSD were included in the study. The mean (±SD) preoperative SSCS score was 14.5±9.1 and 13.9±8.4 two weeks postoperatively (p=0.394). Six and twelve weeks after surgery, there was a significant reduction to 12.2±9.0 (p=0.002) and 12.3±8.8 (p=0.013), respectively. SE decreased from 5.5±5.1 preoperatively to 5.1±4.6 (p=0.258), 4.2±4.7 (p=0.004) and 4.0±4.6 (p=0.013) two, six, and twelve weeks after surgery. For SFF, there was a decrease from 9.0±5.0 to 8.9±4.9 (p=0.717), 7.8±5.2 (p=0.004) and 8.2±5.3 (p=0.168), respectively. Preoperatively, 70% of the patients totally or partially disagreed that SPSD influenced their sexual functioning, and this increased to 80% of the patients 12 weeks after surgery. Conclusion  This prospective study showed a significant decrease in sexual dysfunction, both six and twelve weeks after surgery, compared to preoperatively in patients suffering from SPSD.

[Chronic pilonidal sinus disease: overview of treatment options]. / Chronische sinus pilonidalis.

Chronic pilonidal sinus disease: overview of treatment options Pilonidal sinus disease is a common disease in predominantly young men; this condition can have a significant socio-economic impact. Although excision with primary or secondary wound healing is often applied, there is no consensus on the treatment of first choice for pilonidal sinus disease. Minimally invasive techniques, such as phenolisation, laser, and endoscopic treatments are increasingly applied, since these are associated with less pain, faster wound healing and facilitating a more rapid return to work for patients. Skin advancement flap techniques, considering they cause morbidity and large wounds, should only be considered in case of recurrent pilonidal sinus disease. Laser hair removal at the natal cleft after surgical treatment appears to reduce the risk of recurrence.

Intra-tumour diversification in colorectal cancer at the single-cell level.

Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

Long-term Results of a Randomized Double-blinded Prospective Trial of a Lightweight (Ultrapro) Versus a Heavyweight Mesh (Prolene) in Laparoscopic Total Extraperitoneal Inguinal Hernia Repair (TULP-trial).

OBJECTIVE: The aim of the randomized clinical trial was to compare the 2 years of clinical outcomes of a lightweight (Ultrapro) vs a heavyweight (Prolene) mesh for laparoscopic total extraperitoneal (TEP) inguinal hernia repair. BACKGROUND: Lightweight meshes reduce postoperative pain and stiffness in open anterior inguinal hernia repair. The discussion about a similar benefit for laparoscopic repair is ongoing, but concerns exist about higher recurrence rates. METHODS: Between March 2010 and October 2012, male patients who presented with a primary, reducible unilateral inguinal hernia who underwent day-case TEP repair were eligible. Outcome parameters included chronic pain, recurrence, foreign body feeling, and quality of life scores. RESULTS: During the study period, 950 patients were included. One year postoperatively the presence of relevant pain (Numeric Rating Score 4-10) was significantly higher in the lightweight mesh group (2.9%) compared with the heavyweight mesh group (0.7%) (P = 0.01), and after 2 years this difference remained significant (P = 0.03). There were 4 (0.8%) recurrent hernias in the heavyweight mesh group and 13 (2.7%) in the lightweight group (P = 0.03). No differences in foreign body feeling or quality of life scores were detected. CONCLUSIONS: In TEP hernia surgery, there was no benefit of lightweight over heavyweight meshes observed 2 years postoperatively.

Combined surgery for primary colorectal cancer and synchronous pulmonary metastasis: a pilot experience in two patients.

BACKGROUND: Pulmonary metastasectomy in patients with pulmonary metastases from primary colorectal cancer seems to improve survival in properly selected patients. Therefore, pulmonary metastasectomy has been incorporated widely into the management of colorectal pulmonary metastases. Generally, in patients presenting with primary colorectal cancer and synchronous pulmonary metastases, the primary colorectal cancer is resected first, followed by pulmonary metastasectomy during a second-stage procedure. In the current paper we describe our pilot experience with laparoscopic resection of primary colorectal cancer and thoracoscopic pulmonary metastasectomy during the same operative session. PATIENTS AND METHODS: The results of two patients who underwent laparoscopic resection of primary colorectal cancer and thoracoscopic pulmonary metastasectomy during the same operative session are described. RESULTS: Both patients were healthy women, 60 and 81 years old, respectively, and without severe comorbidities. In both patients, the colorectal resection was performed first by a laparoscopic approach. Subsequently, thoracoscopic resection of a single pulmonary metastasis followed in both patients. The operative procedure and postoperative course were uneventful and the patients could be discharged within 1 week after surgery. Both the primary colorectal cancer and the pulmonary metastasis were radically removed in both patients. Current follow-up, 14 and 8 months after surgery, respectively, showed no signs of disease recurrence on computed tomographic scan of the abdomen and chest in both patients. CONCLUSION: The outcome in these two patients suggests that simultaneous resection of primary colorectal cancer and pulmonary metastasectomy using minimal invasive surgery is safe and might lead to both a decrease in costs and benefit to patients. This simultaneous approach could therefore be considered as an alternative for a two-stage approach in properly selected patients. However, these results should be validated in a larger series.

Enterobius vermicularis infection of the liver in a patient with colorectal carcinoma with suspected liver metastasis.

A 68-year-old man diagnosed with cT3N2 adenocarcinoma of the rectum presented with a synchronous solitary liver metastasis on CT scan. Neoadjuvant chemoradiotherapy was started to downstage the primary tumour. Resection of the rectal tumour followed 3 months after the last radiotherapy session and primary resection of the isolated liver lesion was performed in the intervening period. Histopathological assessment of the liver lesion, however, showed no malignancy, but did reveal a necrotic infection due to Enterobius vermicularis. This parasite is frequently found in the intestines, but only rarely infects the liver. The patient was subsequently treated with the anthelmintic drug mebendazole 100 mg once a week for 2 weeks. Histopathological assessment of the rectal specimen showed complete regression after neoadjuvant chemoradiotherapy without evidence of remaining E. vermicularis, suggesting pinworm eradication. The patient recovered promptly after both surgical procedures.

Pit excision with phenolisation of the sinus tract versus radical excision in sacrococcygeal pilonidal sinus disease: study protocol for a single centre randomized controlled trial.

BACKGROUND: Excision of the pit of the sinus with phenolisation of the sinus tract and surgical excision are two treatment modalities for patients with sacrococcygeal pilonidal sinus disease. Phenolisation seems to have advantages over local sinus excision as it is performed under local anaesthesia with a relatively small surgical procedure, less postoperative pain, minor risk of surgical site infection (8.7%), and only a few days being unable to perform normal activity (mean of 2.3 days). The disadvantage may be the higher risk of recurrence (13%) and the necessity to perform a second phenolisation in a subgroup of patients. Wide surgical excision of sacrococcygeal pilonidal sinus disease has a recurrence rate of 4 to 11%. The disadvantages, however, are postoperative pain, high risk of surgical site infection, and a longer period being unable to perform normal activity (mean of 10 days). The objective of this study is to show that excision of the pit of the sinus of sacrococcygeal pilonidal sinus disease with phenolisation of the sinus tract is a successful first-time treatment modality for sacrococcygeal pilonidal sinus disease accompanied by a quicker return to normal daily activity compared to local excision of the sinus. METHODS/DESIGN: Patients with sacrococcygeal pilonidal sinus disease will be randomly allocated to excision of the pit of the sinus followed by phenol applications of the sinus tract or radical surgical excision of the sinus. Patients are recruited from a single Dutch teaching, non-university hospital. The primary endpoint is loss of days of normal activity/working days. Secondary endpoints are anatomic recurrence rate, symptomatic recurrence rate, quality of life, surgical site infection, time to wound closure, symptoms related to treatment, pain, usage of pain medication and total treatment time. To demonstrate a reduction of return to normal activity from 7.5 days in the excision group to 4 days in the phenolisation group, with 80% power at 5% alpha, a total sample size of 100 is required. DISCUSSION: This study is a randomised controlled trial to provide evidence that phenolisation of the sinus tract compared to radical excision reduces the total number of days unable to perform normal activity. TRIAL REGISTRATION: Dutch trial register NTR4043 , registered on 24 June 2013.

Multidisciplinary decision-making on chemotherapy for colorectal cancer: an age-based comparison.

INTRODUCTION: With the ageing of society, optimising decision-making for older patients with cancer becomes increasingly important. A first step is awareness of current clinical practice. We analysed how treatment decisions regarding chemotherapy for older and younger patients with colorectal cancer are currently being made by the multidisciplinary team, the oncologist and the patient. METHODS: A total of 316 patients with colorectal cancer (median age 68.3 years), discussed at the multidisciplinary gastrointestinal oncology team meetings between 2010 and 2013, were reviewed to select patients for whom guidelines recommended chemotherapy. Multidisciplinary decision-making and subsequent clinical course were extracted from medical files. RESULTS: The multidisciplinary team recommended chemotherapy in 97% of younger patients treated with curative intent, compared to 65% of older patients; 86% of younger patients and 42% of older patients subsequently received chemotherapy. In a palliative setting, the multidisciplinary team recommended chemotherapy in 98% of younger and 69% of older patients and 81% and 45%, respectively, subsequently received this treatment. In addition to comorbidity and the patient's physical condition, chronological age was an important reason for withholding chemotherapy. When older patients did receive chemotherapy, reduced intensity regimens were often effectuated. CONCLUSION: Multidisciplinary decision-making regarding chemotherapy for older patients with colorectal cancer is still frequently based on clinical impressions, preconceptions or chronological age alone. Rather, treatment decisions should be made after thorough evaluation of the patient's health status across multiple domains, either by a geriatrician or within the oncology team itself. Given the preference-sensitive nature of chemotherapy decisions in the elderly, shared decision-making should be strived for whenever possible.

The effect of ultrapro or prolene mesh on postoperative pain and well-being following endoscopic Totally Extraperitoneal (TEP) hernia repair (TULP): study protocol for a randomized controlled trial.

BACKGROUND: The purpose of this study was to describe the rationale and design of a randomized controlled trial analyzing the effects of mesh type (Ultrapro versus Prolene mesh) on postoperative pain and well-being following an endoscopic Totally Extraperitoneal (TEP) repair for inguinal hernias (short: TULP trial). METHODS AND DESIGN: The TULP trial is a prospective, two arm, double blind, randomized controlled trial to assess chronic postoperative pain and quality of life following implantation of a lightweight (Ultrapro) and heavyweight (Prolene) mesh in endoscopic TEP hernia repair. The setting is a high-volume single center hospital, specializing in TEP hernia repair. All patients are operated on by one of four surgeons. Adult male patients (≥18 years of age) with primary, reducible, unilateral inguinal hernias and no contraindications for TEP repair are eligible for inclusion in the study. The primary outcome is substantial chronic postoperative pain, defined as moderate to severe pain persisting ≥ 3 months postoperatively (Numerical Rating Scale, NRS 4-10). Secondary endpoints are the individual development of pain until three years after the TEP procedure, the quality of life (QoL), recurrence rate, patient satisfaction and complications. DISCUSSION: Large prospective randomized controlled studies with a long follow-up evaluating the incidence of chronic postoperative pain following implantation of lightweight and heavyweight mesh in endoscopic (TEP) hernia repair are limited. By studying the presence of pain and quality of life, but also complications and recurrences in a large patient population, a complete efficiency and feasibility assessment of both mesh types in TEP hernia repair will be performed. TRIAL REGISTRATION: The TULP study is registered in the Dutch Trial Register (NTR2131).

Male infertility after endoscopic Totally Extraperitoneal (Tep) hernia repair (Main): rationale and design of a prospective observational cohort study.

BACKGROUND: To describe the rationale and design of an observational cohort study analyzing the effects of endoscopic Totally Extraperitoneal (TEP) hernia repair on male fertility (MAIN study). METHODS AND DESIGN: The MAIN study is an observational cohort study designed to assess fertility after endoscopic TEP hernia repair. The setting is a high-volume single center hospital, specialized in TEP hernia repair. Male patients of 18-60 years of age, with primary, reducible, bilateral inguinal hernias and no contraindications for endoscopic TEP repair are eligible for inclusion in this study. Patients with an ASA-classification≥III and patients with recurrent and/or scrotal hernias and/or a medical history of pelvic surgery and/or radiotherapy, known fertility problems, diabetes and/or other diseases associated with a risk of fertility problems, will be excluded. The primary outcome is the testicular perfusion before and 6 months after TEP hernia repair (assessed by means of a scrotal ultrasonography). Secondary endpoints are the testicular volume (Ultrasound), semen quality and quantity and the endocrinological status, based on serum levels of the sexual hormones follicle-stimulating hormone (FSH), luteinizing hormone (LSH), testosterone and inhibin B before and 6 months after TEP hernia repair. DISCUSSION: The use of polypropylene mesh is associated with a strong foreign body reaction which could play a role in chronic groin pain development. Since the mesh in (endoscopic) inguinal hernia repair is placed in close contact to the vas deferens and spermatic vessels, the mesh-induced inflammatory reaction could lead to a dysfunction of these structures. Relevant large and prospective clinical studies on the problem are limited. This study will provide a complete assessment of fertility in male patients who undergo simultaneous bilateral endoscopic TEP hernia repair, by analyzing testicular perfusion and volume, semen quantity and quality and endocrinological status before and 6 months after TEP repair. TRIAL REGISTRATION: The MAIN study is registered in the Dutch Trial Register (NTR2208).

Mechanism, assessment, and incidence of male infertility after inguinal hernia surgery: a review of the preclinical and clinical literature.

BACKGROUND: The treatment of inguinal hernia has changed considerably over the past 15 years. We reviewed the preclinical and clinical literature to find out the effect of inguinal hernia surgery on male fertility because it has been suggested that hernia surgery may impair testicular function and male fertility. DATA SOURCES: A search on Embase, MEDLINE, and the Cochrane Library was performed to find related articles. CONCLUSIONS: Animal models show substantial effects of hernia repair on the structures in the spermatic cord, which is more pronounced in mesh repairs. Although the number of studies and the included numbers of patients were limited, clinical studies indicate that these potential adverse effects do not seem to have a clinical impact on male fertility in humans with inguinal hernias. Future clinical studies, preferably with bilateral patients, are necessary to investigate the clinical relevance of the effects of inguinal hernia and hernia surgery on male fertility.

Early laparoscopic cholecystectomy improves outcomes after endoscopic sphincterotomy for choledochocystolithiasis.

BACKGROUND & AIMS: Patients with choledochocystolithiasis generally undergo endoscopic sphincterotomy (ES) followed by laparoscopic cholecystectomy (LC). However, many patients receive this surgery 6-8 weeks after ES. There is a high conversion rate of elective LC after ES, and patients can develop recurrent biliary events during the waiting period. We investigated whether the timing of surgery influences outcome. METHODS: We performed a randomized trial of patients with choledochocystolithiasis who underwent successful ES. Patients were randomly assigned to groups that received early LC (within 72 hours after ES, n = 49) or delayed LC (after 6-8 weeks, n = 47), based on an expected difference in conversion rate of 25% vs 5%, respectively. Conversion rate, biliary events during follow-up, duration and difficulty of surgeries, postoperative morbidity, and hospital stay were scored. Intention-to-treat analyses were performed. RESULTS: Groups were comparable in age, sex, and comorbidity. There was no difference between groups in conversion rate (4.3% in early vs 8.7% in delayed group) nor were there differences in operating times and/or difficulties or hospital stays. During the waiting period for LC, 17 patients in the delayed group (36.2%) developed recurrent biliary events compared with 1 patient in the early group (P < .001). CONCLUSIONS: In a randomized trial to evaluate timing of LC after ES, recurrent biliary events occurred in 36.2% of patients whose LC was delayed for 6-8 weeks. Early LC (within 72 hours) appears to be safe and might prevent the majority of biliary events in this period following sphincterotomy.

Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells.

BACKGROUND & AIMS: Death receptors expressed on tumor cells can prevent metastasis formation by inducing apoptosis, but they also can promote migration and invasion. The determinants of death receptor signaling output are poorly defined. Here we investigated the role of oncogenic K-Ras in determining death receptor function and metastatic potential. METHODS: Isogenic human and mouse colorectal cancer cell lines differing only in the presence or absence of the K-Ras oncogene were tested in apoptosis and invasion assays using CD95 ligand and tumor necrois factor-related apoptosis-inducing ligand (TRAIL) as stimuli. Metastatic potential was assessed by intrasplenic injections of green fluorescent protein- or luciferase-expressing tumor cells, followed by intravital fluorescence microscopy or bioluminescence imaging, and confocal microscopy and immunohistochemistry. Ras-effector pathway control of CD95 output was assessed by an RNA-interference and inhibitor-based approach. RESULTS: CD95 ligand and TRAIL stimulated invasion of colorectal tumor cells and liver metastases in a K-Ras-dependent fashion. Loss of mutant K-Ras switched CD95 and TRAIL receptors back into apoptosis mode and abrogated metastatic potential. Raf1 was essential for the switch in CD95 function, for tumor cell survival in the liver, and for K-Ras-driven formation of liver metastases. K-Ras and Raf1 suppressed Rho kinase (ROCK)/LIM kinase-mediated phosphorylation of the actin-severing protein cofilin. Overexpression of ROCK or LIM kinase allowed CD95L to induce apoptosis in K-Ras-proficient cells and prevented metastasis formation, whereas their suppression protected K-Ras-deficient cells against apoptosis. CONCLUSIONS: Oncogenic K-Ras and its effector Raf1 convert death receptors into invasion-inducing receptors by suppressing the ROCK/LIM kinase pathway, and this is essential for K-Ras/Raf1-driven metastasis formation.