Targeted surgery combined with postoperative medical therapy for residual disease for severe and multifocal Crohn disease.

BACKGROUND: In patients with multifocal intestinal Crohn disease requiring surgery for complication or uncontrolled disease, resection of all the lesions may lead to diarrhea and malnutrition. METHODS: This is a single-center retrospective review of all patients undergoing targeted surgery for multifocal Crohn disease with at least one residual Crohn disease location left behind. The primary endpoint was the rate of insufficient control of residual Crohn disease lesions requiring redo-surgery targeting these lesions. The rate of clinical remission defined by Harvey-Bradshaw index <4 was studied over time. RESULTS: From January 2012 to August 2022, among 320 patients undergoing surgery for intestinal Crohn disease, 30 met all criteria. Before surgery, patients had received a mean of 3 medical treatment lines; 83% (n = 25) had a clinically active Crohn disease (Harvey-Bradshaw index ≥4). Surgery consisted in ileocolonic (n = 14;47%), small bowel (n = 5;17%) or colonic resection (n = 12;40%) and strictureplasty (n = 4;13%). Operative mortality was nil. Overall postoperative and severe morbidity rates were 15 of 30 (50%) and 3 of 30. Residual lesions were in the small bowel (n = 15;50%), the colon (n = 16;53%), and/or the rectum (n = 16;53%). Twenty-five patients (83%) had postoperative medical therapy. Median follow-up was 65. Six patients (20%) required reoperation for insufficient control of residual lesions at index surgery after a mean of 98 ± 8 months. The clinical remission rate increased from 17% before surgery to 59% at 6-12 months and 71% at 24 months. CONCLUSION: In patients with multifocal Crohn disease, surgery targeted to severe and complicated lesions combined with postoperative medical treatment is a safe and effective strategy.

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease.

BACKGROUND: E-cadherin, a major actor of cell adhesion in the intestinal barrier, is encoded by the CDH1 gene associated with susceptibility to Crohn Disease (CD) and colorectal cancer. Since epigenetic mechanisms are suspected to contribute to the multifactorial pathogenesis of CD, we studied CpG methylation at the CDH1 locus. The methylation of the CpG island (CGI) and of the 1st enhancer, two critical regulatory positions, was quantified in surgical specimens of inflamed ileal mucosa and in peripheral blood mononuclear cells (PBMC) of 21 CD patients. Sixteen patients operated on for a non-inflammatory bowel disease, although not normal controls, provided a macroscopically normal ileal mucosa and PBMC for comparison. RESULTS: In ileal mucosa, 19/21 (90%) CD patients vs 8/16 control patients (50%) (p < 0.01) had a methylated CDH1 promoter CGI. In PBMC, CD patients with methylated CGI were 11/21 (52%) vs 7/16 controls (44%), respectively. Methylation in the 1st enhancer of CDH1 was also higher in the CD group for each of the studied CpGs and for their average value (45 ± 17% in CD patients vs 36 ± 17% in controls; p < 0.001). Again, methylation was comparable in PBMC. Methylation of CGI and 1st enhancer were not correlated in mucosa or PBMC. CONCLUSIONS: Methylation of several CpGs at the CDH1 locus was increased in the inflamed ileal mucosa, not in the PBMC, of CD patients, suggesting the association of CDH1 methylation with ileal inflammation. Longitudinal studies will explore if this increased methylation is a risk marker for colorectal cancer.

Computer-assisted Individualized Hemodynamic Management Reduces Intraoperative Hypotension in Intermediate- and High-risk Surgery: A Randomized Controlled Trial.

BACKGROUND: Individualized hemodynamic management during surgery relies on accurate titration of vasopressors and fluids. In this context, computer systems have been developed to assist anesthesia providers in delivering these interventions. This study tested the hypothesis that computer-assisted individualized hemodynamic management could reduce intraoperative hypotension in patients undergoing intermediate- to high-risk surgery. METHODS: This single-center, parallel, two-arm, prospective randomized controlled single blinded superiority study included 38 patients undergoing abdominal or orthopedic surgery. All included patients had a radial arterial catheter inserted after anesthesia induction and connected to an uncalibrated pulse contour monitoring device. In the manually adjusted goal-directed therapy group (N = 19), the individualized hemodynamic management consisted of manual titration of norepinephrine infusion to maintain mean arterial pressure within 10% of the patient's baseline value, and mini-fluid challenges to maximize the stroke volume index. In the computer-assisted group (N = 19), the same approach was applied using a closed-loop system for norepinephrine adjustments and a decision-support system for the infusion of mini-fluid challenges (100 ml). The primary outcome was intraoperative hypotension defined as the percentage of intraoperative case time patients spent with a mean arterial pressure of less than 90% of the patient's baseline value, measured during the preoperative screening. Secondary outcome was the incidence of minor postoperative complications. RESULTS: All patients were included in the analysis. Intraoperative hypotension was 1.2% [0.4 to 2.0%] (median [25th to 75th] percentiles) in the computer-assisted group compared to 21.5% [14.5 to 31.8%] in the manually adjusted goal-directed therapy group (difference, -21.1 [95% CI, -15.9 to -27.6%]; P < 0.001). The incidence of minor postoperative complications was not different between groups (42 vs. 58%; P = 0.330). Mean stroke volume index and cardiac index were both significantly higher in the computer-assisted group than in the manually adjusted goal-directed therapy group (P < 0.001). CONCLUSIONS: In patients having intermediate- to high-risk surgery, computer-assisted individualized hemodynamic management significantly reduces intraoperative hypotension compared to a manually controlled goal-directed approach.

Impact of the COVID-19 pandemic on oncological and functional robotic-assisted surgical procedures.

The COVID-19 pandemic led to a decrease in surgical activity to avoid nosocomial contamination. Robotic-assisted surgery safety is uncertain, since viral dissemination could be facilitated by gas environment. We assessed the impact and safety of the COVID-19 pandemic on robotic-assisted surgery. Data were collected prospectively during lockdown (March 16th-April 30th 2020) in 10 academic centres with robotic surgical activity and was compared to a reference period of similar length. After surgery, patients with suspected COVID-19 were tested by RT-PCR. During the COVID-19 lockdown we evidenced a 60% decrease in activity and a 49% decrease in oncological procedures. However, the overall proportion of oncological surgeries was significantly higher during the pandemic (p < 0.001). Thirteen (7.2%) patients had suspected COVID-19 contamination, but only three (1.6%) were confirmed by RT-PCR. The COVID-19 pandemic resulted in a significant decrease in robotic-assisted surgery. Robotic approach was safe with a low rate of postoperative COVID-19 contamination.

What is the Best Therapeutic Strategy for Metachronous Resectable Colorectal Liver Metastases After Adjuvant Oxaliplatin-Based Chemotherapy? A Multidisciplinary Inter-Group Survey.

BACKGROUND: To report the current clinical practice of French physicians for metachronous resectable liver metastasis (LM) occurring after a FOLFOX adjuvant chemotherapy for primary cancer. METHODS: Twenty four clinical situations were proposed to a panel of experts via 4 learned societies. Clinical situations varied according time of recurrence (early between 6 and 12 month or > 12 month), extension of LM (limited ≤ 2 or extended > 2 lesions), presence of a neuropathy or not, and of a RAS or BRAF mutation. RESULTS: A total of 157 physicians participated in this study. A consensus was reached in 17 (71%) clinical situations. For an early limited recurrence, whatever presence of neuropathy, the preferred therapeutic approach (45%) was upfront surgery. For an early extended recurrence, whatever presence of neuropathy, there was a consensus (64%) for a preoperative chemotherapy by FOLFIRI + biologic agent. For a late recurrence without neuropathy, there was a consensus (50%) for a preoperative FOLFOX chemotherapy, whatever the extension of LM. For a late recurrence with neuropathy, upfront surgery was chosen (52%) for limited LM, and preoperative chemotherapy by FOLFIRI + biologic agent (73%) for extended LM. No response was influenced by the RAS mutation status. There was a strong consensus for intensified preoperative chemotherapy in all clinical situations for BRAF-mutated LM. CONCLUSIONS: This national survey provides an overview of the practice patterns in the treatment of LM occurring after adjuvant FOLFOX for primary. It could be a basis to establish expert's recommendations for the clinical practice.

What are the risk factors of failure of enhanced recovery after right colectomy? Results of a prospective study on 140 consecutive cases.

PURPOSE: Nausea and vomiting is the main cause of failure of enhanced recovery protocol (ERP) after right hemicolectomy. METHODS: From January 2013 to January 2018, all patients undergoing right hemicolectomy were prospectively included. Patients undergoing emergency surgery, additional complex procedure or temporary stoma, nasogastric tube (NGT) maintenance, or abdominal drainage were excluded. Failure of ERP was defined as nausea/vomiting precluding oral feeding after POD3 and/or the occurrence of postoperative ileus requiring NGT and/or length of stay (LOS) ≥ 8 days except for patients awaiting admission in rehabilitation unit. Risk factors of failure of ERP were identified using univariate and multivariate analysis. RESULTS: Among 306 patients undergoing right hemicolectomy, 140 fulfilled the inclusion criteria. Postoperative morbidity was 31%, and the mortality rate was nil. The mean postoperative hospital stay was 7 days (range 2-30). Successful ERP was achieved in 83 patients (59%). Causes of failure were major nausea/vomiting precluding oral feeding after POD3 in 36, postoperative ileus requiring NGT in 16 and LOS ≥ 8 days in 36. On multivariate analysis, preoperative anemia (OR 5.2; CI 95%, 1.3-21.1, p = 0.02) and platelet anti-aggregant/anti-coagulant (OR 4.5; CI 95%, 1.7-12.1, p = 0.003) were associated with the risk of failure of ERP. CONCLUSION: This study shows that anemia and medication with antiplatelet/anticoagulation therapy increase the risk of failure of ERP after right hemicolectomy that translates most of the time by nausea/vomiting and postoperative ileus. The presence of these factors should lead to adapt the strategy to improve outcome rather than be considered as contraindication to ERP.

What is the Prognostic Value of a Discordant Radiologic and Pathologic Response in Patients Undergoing Resection of Colorectal Liver Metastases After Preoperative Chemotherapy?

BACKGROUND: The clinical significance of discordant radiological and pathological response to preoperative chemotherapy of colorectal liver metastases (CLM) is unknown. METHODS: From 2011 to 2016, all eligible patients undergoing resection for CLM after preoperative chemotherapy were included at two centres. Patients were categorized according to radiologic response using RECIST as Rad-responders (complete/partial response) or Rad-non responders (stable disease) and according to Blazer et al. pathologic response grade as Path-responders (complete/major response) or Path-non responders (minor response). Survival outcome was analysed according to radiologic and pathologic response. RESULTS: Among 413 patients undergoing resection of CLM, 119 fulfilled the inclusion criteria. Among these, 52 (44%) had discordant radiologic and pathologic response including 27 Rad-non responders/path responders and 25 Rad-responders/Path-non responders. Rad-non responders/path responders and Rad-responders/Path-non responders had similar characteristics except for the proportion receiving more than 6 cycles of preoperative chemotherapy (7/27 vs 16/25; P = 0.017). Median disease-free survival was not different in patients with or without discordant radiologic and pathologic responses (P = 0.195) but the type of discordance had an impact on oncologic outcome as median disease-free survival was 13.9 months (95% CI 5.7-22.2 months) in Rad-non responders/Path responders and 8.6 (6.2 - 10.9 months) in Rad-responders/Path-non responders (P = 0.034). Univariate and multivariate analysis showed that major pathologic response was associated with improved disease-free survival (OR 0.583, 95% CI 0.36-0.95, P = 0.031). CONCLUSION: A discordant radiologic and pathologic response is common after preoperative chemotherapy for CLM. In these patients, pathologic response drives oncologic outcome.

Metastatic colorectal cancer (mCRC): French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

INTRODUCTION: This document is a summary of the French intergroup guidelines regarding the management of metastatic colorectal cancer (mCRC) published in January 2019, and available on the French Society of Gastroenterology website (SNFGE) (www.tncd.org). METHODS: This collaborative work was realized by all French medical and surgical societies involved in the management of mCRC. Recommendations are graded in three categories (A, B and C), according to the level of evidence found in the literature, up until December 2018. RESULTS: The management of metastatic colorectal cancer has become complex because of increasing available medical, radiological and surgical treatments alone or in combination. The therapeutic strategy should be defined before the first-line treatment, mostly depending on the presentation of the disease (resectability of the metastases, symptomatic and/or threatening disease), of the patient's condition (ECOG PS, comorbidities), and tumor biology (RAS, BRAF, MSI). The sequence of targeted therapies also seems to have an impact on the outcome (angiogenesis inhibition beyond progression). Surgical resection of metastases was the only curative intent treatment to date, joined recently by percutaneous tumor ablation tools (radiofrequency, microwave). Localized therapies such as hepatic intra-arterial infusion, radioembolization and hyperthermic intraperitoneal chemotherapy, also have seen their indications specified (liver-dominant disease and resectable peritoneal carcinomatosis). New treatments have been developed in heavily pretreated patients, increasing overall survival and preserving quality of life (regorafenib and trifluridine/tipiracil). Finally, immune checkpoint inhibitors have demonstrated high efficacy in MSI mCRC. CONCLUSION: French guidelines for mCRC management are put together to help offer the best personalized therapeutic strategy in daily clinical practice, as the mCRC therapeutic landscape is complexifying. These recommendations are permanently being reviewed and updated. Each individual case must be discussed within a multidisciplinary team (MDT).

The small height of an anastomotic colonic doughnut is an independent risk factor of anastomotic leakage following colorectal resection: results of a prospective study on 154 consecutive cases.

PURPOSE: The aim of this prospective study was to assess the influence of morphological characteristics of anastomotic doughnuts on the risk of anastomotic leakage (AL) after double-stapled colorectal anastomosis. METHODS: This single-center prospective study enrolled all patients undergoing double-stapled colorectal anastomosis between December 2012 and December 2015. Maximal diameter and minimal and maximal heights and widths of both colonic and rectal doughnuts were measured by surgeons in the operating room. Their influence on the risk of AL was analyzed on uni- and multivariate models. RESULTS: One hundred fifty-four patients were included; 92 (59.7%) were operated on for malignancy. Colorectal anastomoses > and <10 cm above the anal verge were performed in 96 (62.3%) and 58 (37.7%) patients, respectively. AL occurred in 17 (11.0%). The minimal height of the colonic doughnut (CD) was the only measurement significantly associated with an increased risk of AL (p = 0.026). A cutoff value of 4.5 mm for the CD determined on the ROC curve (AUC 0.685, p = 0.013) yielded the best sensitivity (61.4%) and specificity (82.4%) to predict AL. On multivariate analysis, a height of the CD <4.5 mm (OR 5.743, 95% IC 1.476-22.346, p = 0.012), malignant disease (OR 8.821, 95% IC 1.051-74.006, p = 0.045), and American Society of Anesthesiologists score >2 (OR 3.408, 95% IC 1.017-11.418, p = 0.047) were the only independent risk factors of AL. CONCLUSION: The CD's minimal height influences the risk of AL. Its routine measurement during operation, along with other risk factors, could help to decide which patients could benefit from a diverting stoma or the creation of a new anastomosis.

Prognostic Value of Sterilized Lymph Nodes After Preoperative Chemoradiotherapy for Patients with ypN0 Rectal Cancer.

BACKGROUND: Patients with ypN0 rectal cancer who have received preoperative chemoradiotherapy can be divided into those who initially were node negative and those whose positive nodes have been sterilized by preoperative therapy. The long-term prognosis for ypN0 patients with sterilized lymph nodes (LNS) is unknown. This study aimed to assess the prognostic value of LNS after preoperative chemoradiotherapy for patients with ypN0 rectal cancer. METHODS: From January 2007 to March 2014, 206 patients with ypN0 tumors of the mid or lower rectum treated by chemoradiotherapy and radical surgery were enrolled in the study. Of these 206 patients, 49 had ypN0 tumors with LNS (LNS+ group), and 157 had ypN0 tumors without LNS (LNS- group). The patients in both groups were comparable in terms of tumor characteristics, type of chemoradiotherapy, type of surgery, R0 resection rate, and postoperative complication rate. RESULTS: The mean follow-up period was 40.5 ± 27 months. The 1- and 3-year OS rates in the LNS+ group were respectively 100 and 95.5% versus 99.4 and 91.6% in the LNS- group (P = 0.549). The 1- and 3-year DFS rates in the LNS+ group were respectively 100 and 94.2% versus 94.7 and 87.1% in the LNS- group (P = 0.117). The multivariate analysis showed that the presence of LNS did not affect OS (P = 0.918) or DFS (P = 0.209). CONCLUSIONS: The prognosis is excellent for patients with ypN0 rectal cancer who have LNS after preoperative chemoradiotherapy. The presence of LNS in ypN0 rectal cancer patients after chemoradiotherapy should not be considered a factor for a poor prognosis.

Preoperative oral polymeric diet enriched with transforming growth factor-beta 2 (Modulen) could decrease postoperative morbidity after surgery for complicated ileocolonic Crohn's disease.

OBJECTIVE: Exclusive polymeric diet enriched with transforming growth factor-beta 2 (ANS-TGF-ß2) has been used for remission induction and maintenance in pediatric Crohn's disease (CD). Its use in the preoperative setting has never been evaluated. The aim of this study was to evaluate preoperative ANS-TGF-ß2 to decrease postoperative complications after surgery for complicated ileocolonic CD. METHODS: From 2011 to 2015, data of all consecutive patients who underwent elective surgery for ileocolonic CD were collected prospectively. Preoperative, exclusive ANS-TGF-ß2 was administered in high-risk patients with complicated CD. Complicated CD was defined by the presence of obstructive symptoms, and/or steroid treatment, and/or preoperative weight loss >10% and/or perforating CD. Outcomes of high-risk patients receiving preoperative ANS-TGF-ß2 were compared to those of low-risk patients with no complicated CD who underwent upfront surgery. RESULTS: Fifty-six patients underwent surgery for ileocolonic CD. Among them, 35 high-risk patients received preoperative ANS-TGF-ß2 and 21 low-risk patients underwent upfront surgery. Preoperative full-dose ANS-TGF-ß2 was feasible in 34/35 high-risk patients. Discontinuation of steroids during preoperative ANS-TGF-ß2 could be achieved in 10/16 patients (62.5%). Postoperative complications rates were 8/35 (23.8%) and 5/21 (22.9%) in high-risk and low-risk patients, respectively (p = 1). Temporary ileocolostomy rates in high-risk patients and in low-risk patients were 4/35 (11%) and 0/21, respectively (p = 0.286) Conclusion: Preoperative ANS-TGF-ß2 is feasible in most high-risk patients with complicated ileocolonic CD and could limit the deleterious effects of risk factors of postoperative morbidity. These results need to be confirmed in a large randomized controlled trial.

Sigmoid resection with primary anastomosis and ileostomy versus laparoscopic lavage in purulent peritonitis from perforated diverticulitis: outcome analysis in a prospective cohort of 40 consecutive patients.

PURPOSE: This prospective study aimed to compare outcomes after laparoscopic peritoneal lavage (LPL) and sigmoid resection with primary colorectal anastomosis (RPA). METHODS: From June 2010 to June 2015, 40 patients presenting with Hinchey III peritonitis from perforated diverticulitis underwent LPL or RPA. Patients with Hinchey II or IV peritonitis and patients who underwent an upfront Hartmann procedure were excluded. Primary endpoint was overall 30-day or in-hospital postoperative morbidity after surgical treatment of peritonitis. RESULTS: Twenty-five patients underwent RPA and 15 LPL. Overall postoperative morbidity and mortality rates were not significantly different after RPA and LPL (40 vs 67 %, p = 0.19; 4 vs 6.7 %, p = 1, respectively). Intra-abdominal morbidity and reoperation rates were significantly higher after LPL compared to RPA (53 vs 12 %, p < 0.01; 40 vs 4 %, p = 0.02, respectively). Multivariate analysis showed that LPL (p = 0.028, HR = 18.936, CI 95 % = 1.369-261.886) was associated with an increased risk of postoperative intra-abdominal septic morbidity. Among 6 patients who underwent reoperation after LPL, 4 had a Hartmann procedure. All surviving patients who had a procedure requiring stoma creation underwent stoma reversal after a median delay of 92 days after LPL and 72 days after RPA (p = 0.07). CONCLUSION: LPL for perforated diverticulitis is associated with a high risk of inadequate intra-abdominal sepsis control requiring a Hartmann procedure in up to 25 % of patients. RPA appears to be safer and more effective. It may represent the best option in this context.

Can we predict complete or major response after chemoradiotherapy for rectal cancer by noninvasive methods? Results of a prospective study on 61 patients.

Rectal preservation has been proposed as an alternative to radical resection in patients with presumed complete or major response to chemoradiotherapy (CRT). The aim of this prospective study was to evaluate the accuracy of digital rectal examination (DRE) and magnetic resonance imaging (MRI) to predict major or complete rectal cancer response to CRT. Over 2 years, 61 patients underwent radical resection after CRT for rectal cancer. DRE and MRI were carried out before and 6 to 8 weeks after the end of CRT. Data from DRE and MRI post-CRT were compared with pathological examinations. At pathological examination, major/complete responses were recorded for tumors classified ypT1N0 and ypT0N0, respectively. DRE post-CRT showed major/complete response in 26 cases, of which 14 (54%) were confirmed by pathology. The positive (PPV) and negative (NPV) predictive values of DRE to predict major/complete response were 54 and 88 per cent, respectively. MRI post-CRT showed major/complete response in 12 cases, of which nine (75%) were confirmed by pathology. The PPV and NPV of MRI to predict major/complete response were 75 and 82 per cent, respectively. Data from DRE and RMI post-CRT were concordant in 45 patients. The PPV and NPV of concordant DRE and MRI to predict major/complete response were 82 and 91 per cent, respectively. DRE and MRI do not appear to be sufficiently accurate for safe selection of patients appropriate for a rectum-sparing strategy because the risk of leaving an invasive tumor untreated is 18 per cent.

Management of patients over 80 years of age treated with resection for localised colon cancer: results from a French referral centre.

BACKGROUND: Few data are available on management of very elderly colon cancer patients, especially concerning the parameters of therapeutic decisions and the role of geriatricians. METHODS: We retrospectively reviewed the charts of patients over 80 years of age who underwent surgery for a localised colon cancer in a French academic hospital. RESULTS: A total of 176 patients underwent surgery (postoperative morbidity and mortality rates: 25% and 6.7%). Adjuvant chemotherapy was discussed at a multidisciplinary team meeting for 91% of stage III patients, but only 13.5% of them were treated. Twenty-five patients relapsed: 19 were discussed at the multidisciplinary meeting and 16 were treated (5 had a metastasectomy). Despite their increase with time, geriatric assessments were infrequent, 17% (33% after 2006), and had no impact on postoperative morbi-mortality. Median overall survival and recurrence-free survival were 65.3 months and 65.1 months, respectively. Age, emergency surgery, and Charlson comorbidity index were independent prognostic factors. CONCLUSION: Selected elderly colon cancer patients have significant access to surgery. However, postoperative morbi-mortality rates remain high and adjuvant chemotherapy rarely prescribed. Perioperative geriatric assessment, especially before surgery, should be routinely proposed to these patients to evaluate its impact on postoperative morbi-mortality and prescription of adjuvant treatment.

Response of liver metastases to preoperative radiochemotherapy in patients with locally advanced rectal cancer and resectable synchronous liver metastases.

BACKGROUND: No standard treatment for advanced rectal cancer with synchronous resectable liver metastases (LM) has been defined. Radiochemotherapy prior to simultaneous or staged curative resection of both primary tumor and LM is one of the treatment options available. The response of LM to radiochemotherapy has never been evaluated and, in particular, the risk for progression of LM is unknown. METHODS: Between 2000 and 2011, 20 patients underwent preoperative radiochemotherapy for advanced rectal cancer with synchronous limited but resectable LM. Imaging responses of LM to radiochemotherapy were analyzed on per-patient and per-lesion bases using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Of the patients, 20 had 41 LM; 15 of the 20 patients (75%) had rectal cancer with expected circumferential margins <1 mm on magnetic resonance imaging (MRI), and 50% had a solitary LM before treatment. Of the patients, 13 received oxaliplatin-based chemotherapy, and 7 received fluorouracil (FU)-based chemotherapy in combination with radiation. Of the 41 LM, 7 showed complete response (17%); 7 showed partial response (17%); 20 remained stable (49%); and 7 progressed (17%). Of the 25 LM treated with oxaliplatin-based chemotherapy, only 1 LM (4%) progressed. All 20 patients were suitable for resection of LM with curative intent after the radiochemotherapy. CONCLUSION: In patients with advanced rectal cancer and synchronous limited, but resectable LM, the risk for progression of LM during radiochemotherapy is low, especially if the chemotherapy regimen contains oxaliplatin. This low risk does not compromise a curative surgical approach to LM.

Linear quantification of lymphoid infiltration of the tumor margin: a reproducible method, developed with colorectal cancer tissues, for assessing a highly variable prognostic factor.

BACKGROUND: Lymphoid infiltration is a prognostic marker in solid tumors, such as colorectal, breast and lung carcinomas. However, lymphoid infiltration is heterogeneous and the reproducibility of quantification based on single counts within a tumor is very low. We aimed to develop a reproducible method for evaluating lymphoid infiltration in tumors. METHODS: Virtual slides were obtained from tissue sections from the localized colorectal carcinomas of 117 patients, stained for CD3 and CD45R0. We assessed the variation of lymphoid cell density by automatic counts in 1 mm-wide, 5 µm-long segments of the invasive front, along an axis 4 mm in length running perpendicular to the invasive front of the tumor. RESULTS: We plotted curves of the variation of lymphocyte density across the tumor front. Three distinct patterns emerged from this linear quantification of lymphocyte (LQLI). In pattern 1, there was a high density of lymphocytes within the tumor. In pattern 2, lymphocyte density peaked close to the invasive margin. In pattern 3, lymphocytes were diffusely distributed, at low density. It was possible to classify all the tumors studied, and interobserver reproducibility was excellent (kappa =0.9). By contrast, single counts of CD3+ cells on tissue microarrays were highly variable for a given LQLI pattern, confirming the heterogeneity of lymphoid infiltration within individual tumors. In univariate analysis, all pathologic features (stage, metastatic lymph node ratio (LNR), vascular embolism, perineural invasion), CD3+ cell density, LQLI patterns for CD3+ and CD45R0+ cells) were found to have a significant effect on disease-free survival (DFS). In multivariate analysis, only the LQLI pattern for CD3+ cells (HR: 6.02; 95% CI: 2.74-13.18) and metastatic lymph node ratio (HR: 6.14; 95% CI: 2.32-16.2) were associated with DFS. CONCLUSION: LQLI is an automated, reproducible method for the assessment of lymphoid infiltration. However, validation of its prognostic value in larger series is required before its introduction into routine practice for prognostic evaluation in patients with colorectal carcinomas. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9861460717895880.

Colorectal neuroendocrine carcinomas and adenocarcinomas share oncogenic pathways. A clinico-pathologic study of 12 cases.

OBJECTIVE: Neuroendocrine carcinomas (NECs) are rare neoplasms with an increasing incidence. Oncogenetic pathways of colorectal NEC are still poorly understood, and no treatment standards are available for these rare tumors. METHODS: We analyzed retrospectively the clinical records and histology of 12 patients with colorectal NEC. KRAS and BRAF mutations were investigated after the dissection of exoendocrine and neuroendocrine components. ALK alterations and EML4-ALK transcripts were detected by in-situ hybridization and determination of fusion transcripts, respectively. RESULTS: At the time of diagnosis, the mean age of the patients was 60 years (40-79) and 10 patients had synchronous metastases. A transient response occurred in two patients and one patient treated with cisplatin-etoposide or fluoropyrimidine-oxaliplatin, respectively. Tumor progression-related death occurred in 11 of 12 patients. Ten tumors contained an exocrine component, accounting for 5-70% of the tumor, and the other two contained an amphicrine component. BRAF/KRAS mutations were found in six of 10 tumors, corresponding to BRAF(V600E) (n=2) or KRAS(G12D) (n=2), KRAS(G12V) or KRAS(G13D). DNA was obtained from both exocrine and endocrine components in seven cases, and the BRAF/KRAS status was identical in all cases. Split of the ALK locus was detected in a minority of tumor cells in two of eight cases, but EML4-ALK transcripts were absent. CONCLUSION: The association of an exocrine component in all cases and the similar profile of BRAF/KRAS mutations indicate that colorectal NEC may correspond to a high-grade transformation of colorectal carcinoma. New chemotherapy regimens using targeted therapies should be assessed in these tumors.

Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma.

BACKGROUND & AIMS: Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery. METHODS: Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time. RESULTS: The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [P < .0001] and 0.57 [P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant (P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine. CONCLUSIONS: High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine.

Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome.

The optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome-causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI-positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In our dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in our series of consecutive CRC. Our results support systematic screening for MMR deficiency in all new CRC cases.

Preservation of genital innervation in women during total mesorectal excision: which anterior plane?

BACKGROUND: Erectile dysfunction, principally related to injury of the autonomic nerve fibers in men, is a major cause of postoperative morbidity after anterolateral dissection during total mesorectal excision (TME) for rectal adenocarcinoma. However, the autonomic innervation of erectile bodies is less known in women, and the anterolateral plane of dissection during TME remains unclear. The existence of the rectovaginal septum(RVS) is controversial. The purpose of the present study was to identify the RVS in the human fetus and adult female by dissection, immunohistochemistry, and three-dimensional reconstruction, and to define its relationship with erectile nerve fibers so as to determine the anterolateral plane of dissection during TME, which could reduce postoperative sexual dysfunction in women. METHOD: Macroscopic dissection, histologic studies, and immunohistochemistry examination with 3D reconstruction were performed in six fresh female adult cadavers and six female fetuses. RESULTS: The RVS was clearly definable in all adult specimens. It was composed of multiple connective tissue, with smooth muscle fibers originating from the uterus and the vagina. It is closely applied to the vagina and has a relationship with the neurovascular bundles (NVBs) that contain erectile fibers intended for the clitoris. The NVBs are situated anteriorly to the posterior extension of rectovaginal septum. This posterior extension protects the NVBs during the anterior and anterolateral dissection for removal of rectal cancer. CONCLUSIONS: To reduce the risk of postoperative sexual dysfunction in women undergoing TME for rectal cancer, we recommend careful dissection to the anterior mesorectum to develop a plane of dissection behind the posterior extension of the RVS if oncologically reasonable.