José M. Enríquez-Navascués

MSH6 and MUTYH Deficiency Is a Frequent Event in Early-Onset Colorectal Cancer

Purpose: Early-onset colorectal cancer (CRC) is suggestive of a hereditary predisposition. Lynch syndrome is the most frequent CRC hereditary cause. The MUTYH gene has also been related to hereditary CRC. A systematic characterization of these two diseases has not been reported previously in this population. Experimental Design: We studied a retrospectively collected series of 140 patients ≤50 years old diagnosed with nonpolyposis CRC. Demographic, clinical, and familial features were obtained. Mismatch repair (MMR) deficiency was determined by microsatellite instability (MSI) analysis, and immunostaining for MLH1, MSH2, MSH6, and PMS2 proteins. Germline MMR mutations were evaluated in all MMR-deficient cases. Tumor samples with loss of MLH1 or MSH2 protein expression were analyzed for somatic methylation. Germline MUTYH mutations were evaluated in all cases. BRAF V600E and KRAS somatic mutational status was also determined. Results: Fifteen tumors (11.4%) were MSI, and 20 (14.3%) showed loss of protein expression (7 for MLH1/PMS2, 2 for isolated MLH1, 3 for MSH2/MSH6, 7 for isolated MSH6, and 1 for MSH6/PMS2). We identified 11 (7.8%) germline MMR mutations, 4 in MLH1, 1 in MSH2, and 6 in MSH6. Methylation analysis revealed one case with somatic MLH1 methylation. Biallelic MUTYH mutations were detected in four (2.8%) cases. KRAS and BRAF V600E mutations were present in 39 (27.9%) and 5 (3.6%) cases, respectively. Conclusions: Loss of MSH6 expression is the predominant cause of MMR deficiency in early-onset CRC. Our findings prompt the inclusion of MSH6 and MUTYH screening as part of the genetic counseling of these patients and their relatives. Clin Cancer Res; 16(22); 5402–13. ©2010 AACR.

Patterns of local recurrence in rectal cancer after a multidisciplinary approach

Improvements in surgery and the application of combined approaches to fight rectal cancer have succeeded in reducing the local recurrence (LR) rate and when there is LR it tends to appear later and less often in isolation. Moreover, a subtle change in the distribution of LRs with respect to the pelvis has been observed. In general terms, prior to total mesorectal excision the most common LRs were central types (perianastomotic and anterior) while lateral and posterior forms (presacral) have become more common since the growth in the use of combined treatments. No differences have been reported in the current pattern of LRs as a function of the type of approach used, that is, neo-adjuvant therapies (short-term or long-course radiotherapy, or chemoradiotherapy versus extended lymphadenectomy, though there is a trend towards posterior or presacral LR in patients in the Western world and lateral LR in Asia. Nevertheless, both may arise from the same mechanism. Moreover, as well as the mode of treatment, the type of LR is related to the height of the initial tumor. Nowadays most LRs are related to the advanced nature of the disease. Involvement of the circumferential radial margin and spillage of residual tumor cells from lymphatic leakage in the pelvic side wall are two plausible mechanisms for the genesis of LR. The patterns of pelvic recurrence itself (pelvic subsites) also have important implications for prognosis and are related to the potential success of salvage curative approach. The re-operability for cure and prognosis are generally better for anastomotic and anterior types than for presacral and lateral recurrences. Overall survival after LR diagnosis is lower with radio or chemoradiotherapy plus optimal surgery approaches, compared to optimal surgery alone.

Meta-analysis of randomized controlled trials comparing different techniques with primary closure for chronic pilonidal sinus.

BackgroundThere are different open healing and primary closure approaches for chronic pilonidal sinus (CPD) that differ in principles and extension.Aims To compare the results of different closure surgical techniques, we performed a meta-analysis of randomized controlled trials (RCT) comparing: (1) open wide excision versus open limited excision (sinusectomy) or unroofing (sinotomy); (2) midline closure (conventional and tension-free) versus off-midline; (3) advancing versus rotation flaps; and (4) sinusectomy/sinotomy versus primary closure.Methods Data extraction and risk of bias assessment were conducted independently by the authors using the Cochrane Collaboration’s tool. Data were pooled using fixed and random-effects models. Primary outcomes were rate of healing, recurrence, wound infection and dehiscence. Twenty-five trials (2,949 patients) were included.Results Four trials compared limited versus radical open healing. Although recurrence rate did not differ, all other outcomes favored the limited approach. Ten studies compared midline versus off-midline primary closure; wound infection and dehiscence were significantly higher after midline closure. Six RCT compared Karydakis/Bascom versus Limberg. No difference was found in recurrence or wound complications rate. Six RCT compared sinusectomy/sinotomy versus primary closure. Recurrence rate was significantly lower after sinusectomy/sinotomy; no significant differences were found in other outcomes.Conclusion Our meta-analysis suggest that some of the questions of which is the best surgical technique for CPD have now been answered: open radical excision and primary midline closure should be abandoned. Sinusotomy/sinectomy or en bloc resection with off midline primary closure are the preferred approaches.

Susceptibility genetic variants associated with early-onset colorectal cancer.

Colorectal cancer (CRC) is the second most common cancer in Western countries. Hereditary forms only correspond to 5% of CRC burden. Recently, genome-wide association studies have identified common low-penetrant CRC genetic susceptibility loci. Early-onset CRC (CRC<50 years old) is especially suggestive of hereditary predisposition although 85-90% of heritability still remains unidentified. CRC<50 patients (n = 191) were compared with a late-onset CRC group (CRC>65 years old) (n = 1264). CRC susceptibility variants at 8q23.3 (rs16892766), 8q24.21 (rs6983267), 10p14 (rs10795668), 11q23.1 (rs3802842), 15q13.3 (rs4779584), 18q21 (rs4939827), 14q22.2 (rs4444235), 16q22.1 (rs9929218), 19q13.1 (rs10411210) and 20p12.3 (rs961253) were genotyped in all DNA samples. A genotype-phenotype correlation with clinical and pathological characteristics in both groups was performed. Risk allele carriers for rs3802842 [Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.05, P = 0.0096, dominant model) and rs4779584 (OR = 1.39, 95% CI 1.02-1.9, P = 0.0396, dominant model) were more frequent in the CRC<50 group, whereas homozygotes for rs10795668 risk allele were also more frequent in the early-onset CRC (P = 0.02, codominant model). Regarding early-onset cases, 14q22 (rs4444235), 11q23 (rs3802842) and 20p12 (rs961253) variants were more associated with family history of CRC or tumors of the Lynch syndrome spectrum excluding CRC. In our entire cohort, sum of risk alleles was significantly higher in patients with a CRC family history (OR = 1.40, 95% CI 1.06-1.85, P = 0.01). In conclusion, variants at 10p14 (rs10795668), 11q23.1 (rs3802842) and 15q13.3 (rs4779584) may have a predominant role in predisposition to early-onset CRC. Association of CRC susceptibility variants with some patients familiar and personal features could be relevant for screening and surveillance strategies in this high-risk group and it should be explored in further studies.

Evaluation of Alpha 1-Antitrypsin and the Levels of mRNA Expression of Matrix Metalloproteinase 7, Urokinase Type Plasminogen Activator Receptor and COX-2 for the Diagnosis of Colorectal Cancer

Background Colorectal cancer (CRC) is the second most common cause of death from cancer in both men and women in the majority of developed countries. Molecular tests of blood could potentially provide this ideal screening tool. Aim Our objective was to assess the usefulness of serum markers and mRNA expression levels in the diagnosis of CRC. Methods In a prospective study, we measured mRNA expression levels of 13 markers (carbonic anhydrase, guanylyl cyclase C, plasminogen activator inhibitor, matrix metalloproteinase 7 (MMP7), urokinase-type plasminogen activator receptor (uPAR), urokinase-type plasminogen activator, survivin, tetranectin, vascular endothelial growth factor (VEGF), cytokeratin 20, thymidylate synthase, cyclooxygenase 2 (COX-2), and CD44) and three proteins in serum (alpha 1 antitrypsin, carcinoembryonic antigen (CEA) and activated C3 in 42 patients with CRC and 33 with normal colonoscopy results. Results Alpha 1-antitrypsin was the serum marker that was most useful for CRC diagnosis (1.79±0.25 in the CRC group vs 1.27±0.25 in the control group, P<0.0005). The area under the ROC curve for alpha 1-antitrypsin was 0.88 (0.79–0.96). The mRNA expression levels of five markers were statistically different between CRC cases and controls: those for which the ROC area was over 75% were MMP7 (0.81) and tetranectin (0.80), COX-2 (0.78), uPAR (0.78) and carbonic anhydrase (0.77). The markers which identified early stage CRC (Stages I and II) were alpha 1-antitrypsin, uPAR, COX-2 and MMP7. Conclusions Serum alpha 1-antitrypsin and the levels of mRNA expression of MMP7, COX-2 and uPAR have good diagnostic accuracy for CRC, even in the early stages.

Ventral rectal sacropexy (colpo-perineal) in the treatment of rectal and rectogenital prolapse

Abstract Introduction Ventral sacral-rectopexy with mesh corrects rectal prolapse and minimises rectal dissection. Subsequent colpopexy corrects apical and posterior prolapses of the vagina. The combination of both procedures can lead to the simultaneous correction of pelvic organ prolapses (POP). Objective To present the results of a patient series with several types of POP treated using the same approach and operation. Material and method A total of 57 patients diagnosed with any type of POP were operated on between January 2005 and August 2008 using ventral rectal-colpo-sacropexy, who were grouped into 3 types: A, total rectal prolapse isolated or combined with a hysterocele or colpocele (11 patients); B, rectoenterocele with internal rectal invagination and/or descending perineum (4 patients); and C, middle and posterior genital compartment prolapse (42 patients). The laparoscopic approach was used in the 15 patients of groups A and B and 11 from group C. A biological mesh was used in 41 patients and a macroporous synthetic one in the rest. Results The mean age of the patients in the series was 66 (19–81) years, with 55 females and 2 males. The median follow up was 25 (4–48) months. There were no major post-surgical complications. A recurrence of prolapse was recorded in one patient in group A (1/11); the 7 patients who suffered from incontinence improved after the surgery, no case of de novo constipation being recorded and an improvement in 8 of the 9 patients from groups A and B with obstructive defecation. There were 9 (21%) recurrences detected in group C, but only 4 (9%) required reintervention. In all the recurrences a biological mesh had been used. Conclusions Laparoscopic ventral rectal-colpo-pexy is an effective technique to correct POP. Although safe and innocuous, the results with biological meshes did not last as long.

Preventing complications in colorectal anastomosis: results of a randomized controlled trial using bioabsorbable staple line reinforcement for circular stapler.

BACKGROUND: Anastomotic complications, including leaks, stenoses, and bleeding, cause considerable mortality and morbidity after colorectal surgery. OBJETIVE: The purpose of this work was to evaluate the effectiveness of bioabsorbable staple line reinforcement in reducing colorectal anastomotic complications. DESIGN: This was a prospective randomized clinical study. SETTINGS: This study was conducted at a university hospital within a specialized colorectal unit. PATIENTS: Patients undergoing left colon resection for a benign or malignant condition were eligible. A total of 302 patients participated, including 154 control subjects and 148 with reinforcement. INTERVENTION: Patients were prospectively randomly assigned to reinforcement of circular stapled anastomosis with a bioabsorbable device versus stapled circular anastomosis without reinforcement. MAIN OUTCOME MEASURES: The primary end point was the rate of pooled incidences of anastomotic complications (leakage, bleeding, or stenosis). Secondary outcomes were the rate of reoperations and the length of hospital stay. RESULTS: Baseline characteristics were similar between both groups. Intention-to-treat analysis revealed that there were no significant differences in the pooled incidences of anastomotic complications (p = 0.821). Regarding individual complications, we did not observe statistical differences between groups, including leakage (6.6% vs 4.8%; p = 0.518), hemorrhage (1.4% vs 1.3%; p = 0.431), or stenosis (2.9% vs 6.8%; p = 0.128). Again, no significant differences were observed in length of stay (7 days; p = 0.242) or rate of reoperation (7.3% vs 9.6%; p = 0.490). A patient (0.3%) in the control group died. LIMITATIONS: Sample size calculation was performed including all 3 of the complications, which may render it underpowered to detect differences regarding a specific complication. Anastomoses located within 5 cm from the anal verge were excluded from the study. CONCLUSIONS: The results obtained show that bioabsorbable staple line reinforcement in a colorectal anastomosis >5 cm from the anal verge does not reduce the rate of pooled anastomotic complications (ie, leaks, bleeding, or stenosis).

Metástasis pancreáticas por carcinoma renal. Nuestra casuística y revisión de la literatura

OBJECTIVE To analyse the cases of pancreatic metastases due to renal carcinoma operated on in our hospital between the years 2000 and 2011. MATERIAL AND METHODS A retrospective study using the variables of 8 patients who were subjected to surgery of pancreatic metastases due to renal carcinoma, and a comparison of our data with those from the literature. RESULTS The incidence of metastatic disease of the pancreas due to renal carcinoma in our series was 1.2%. All the metastases were metachronous, with both sexes being affected equally. The mean time between resection of the renal tumour and the diagnosis of the metastasis was 12.42 years (range: 1.62-30.13 years). The therapeutic approach to the pancreatic lesions was surgical in all cases. Seven patients are currently still alive. CONCLUSION Metastatic disease of the pancreas due to renal carcinoma is uncommon (1%-2.8%). The interval between the primary resection and the metastasis can be quite long. Pancreatic metastasis must always be suspected in patients who present with a pancreatic mass and a history of renal carcinoma. Aggressive surgical treatment is recommended in selected cases. The surgery in these cases improves survival and the quality of life.

Influencia del volumen quirúrgico en los resultados oncológicos después de estandarizar la cirugía en el Proyecto Español del Cáncer de Recto

UNLABELLED INTRODUCCIóN: The purpose of this prospective multicentre multilevel study was to investigate the influence of hospital caseload on long-term outcomes following standardization of rectal cancer surgery in the Rectal Cancer Project of the Spanish Society of Surgeons. METHODS Data relating to 2910 consecutive patients with rectal cancer treated for cure between March 2006 and March 2010 were recorded in a prospective database. Hospitals were classified according to number of patients treated per year as low-volume, intermediate-volume, or high volume hospitals (12-23, 24-35, or ≥36 procedures per year). RESULTS After a median follow-up of 5 years, cumulative rates of local recurrence, metastatic recurrence and overall survival were 6.6 (CI95% 5.6-7.6), 20.3 (CI95% 18.8-21.9) and 73.0 (CI95% 74.7 - 71.3) respectively. In the multilevel regression analysis overall survival was higher for patients treated at hospitals with an annual caseload of 36 or more patients (HR 0,727 [CI95% 0,556-0,951]; P=.02). The risk of local recurrence and metastases were not related to the caseload. Moreover, there was a statistically significant variation in overall survival (median hazard ratio [MHR] 1.184 [CI95% 1.071-1,333]), local recurrence (MHR 1.308 [CI95% 1.010-1.668]) and metastases (MHR 1.300 [CI95% 1.181; 1.476]) between all hospitals. CONCLUSIONS Overall survival was higher for patients treated at hospitals with an annual caseload of 36 or more patients. However, local recurrence was not influenced by caseload.

Exenteración pélvica total en el tratamiento de las neoplasias avanzadas, primarias o recurrentes, de vísceras pélvicas

INTRODUCTION Complete resection with clear margins in locally advanced pelvic visceral tumors, primary or recurrent, occasionally requires total pelvic exenteration (TPE). METHODS We reviewed the results of EFA in 34 consecutive patients operated on between June 2006 and December 2013. RESULTS Median age was 62 (40-82) years; 24 (70%) were male. The tumor origin most frequent was advanced primary rectal tumor (APRT), with 19 cases (55.9%) and most common type of exenteration was supraelevator (61.8%). R₀ resection was achieved in 24 (70.6%) patients and in 16 (85%) of the APRT. Fifteen (79%) patients had pT₄ APRT, and 4 (20%) pN +. Reconstruction of the bowel and bladder was performed with two stomas in 17 cases (50%), colorectal anastomosis and Bricker in 11 (32.3%) and wet double barreled colostomy in 6 (17.6%). There was no postoperative mortality; 23 (67,5%) patients had complications, and 5 (14.6%) required a postoperative reoperation to solve them. Median follow-up was 23 (13-45) months. Overall survival (OS) and disease free survival (DFS) at 2 years were 67% and 58% respectively, and the median OS and DFS was 59 months (95% CI 26-110) and 39 months (95% CI 14-64), respectively. The DFS of R₀ was significantly better (p=0.003) than R₁. CONCLUSIONS TPE is a potentially curative procedure for advanced pelvic visceral malignancies with similar morbi-mortality than other extended excisional surgery.