Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study.

BACKGROUND: Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown. OBJECTIVE: The study aims to analyze the innate immunity microenvironment in ileal mucosa according to the duration of Crohn's disease. DESIGN: A prospective cohort study. SETTINGS: Tertiary referral center for IBD surgery. PATIENTS: A total of 88 consecutive patients with Crohn's disease undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public data set were analyzed as an external validation cohort. MAIN OUTCOME MEASURES: Neutrophil infiltration was evaluated by histological asessment and macrophage subpopulation was assessed by immunohistochemistry. Expressions of TLR2 , TLR4 , TLR5 , DEFB1 , DEFB4A , DEFB103 , DEFA5 , and DEFA6 were quantified by real-time quantitative polymerase chain reaction. Concentrations of BDNF, CCL-11, ICAM-1, IL-1A, IL-1ß, IL-1RN, IL-12p40, IL-12p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, and VEGFA were determined with an immunometric assay. RESULTS: Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease ( p = 0.07). A higher number of macrophages expressed CD163 at low intensity in late-stage Crohn's disease ( p = 0.04). The concentration of IL-15 ( p = 0.02) and IL-23A ( p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expressions of DEFB1 ( p = 0.03), DEFB4A ( p = 0.01), IL-2 ( p = 0.04), and IL-3 ( p = 0.03) increased in patients with late-stage Crohn's disease. LIMITATIONS: A relatively small number of patients, especially in the newly diagnosed group. CONCLUSIONS: In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in the healthy mucosa of patients with late-stage Crohn's disease, suggesting that reparative and profibrotic processes are predominant in the long term, and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract . ACTIVACIN DE LA INMUNIDAD INNATA EN LA RECIENTEMENTE DIAGNOSTICADA ENFERMEDAD DE CROHN ILEOCLICA UN ESTUDIO DE COHORTE: ANTECEDENTES:Estudios recientes demostraron que la cirugía temprana para la enfermedad de Crohn (EC) conduce a una menor tasa de recurrencia. Sin embargo, se desconoce el mecanismo subyacente.OBJETIVO:El estudio tiene como objetivo analizar el microambiente de la inmunidad innata en la mucosa ileal según la duración de la EC.DISEÑO:Un estudio de cohorte prospectivo.AJUSTES:Centro terciario de referencia para cirugía de EII.PACIENTES:Fueron registrados de manera prospectiva y consecutiva 88 pacientes con EC sometidos a resección ileocolónica. Se obtuvieron muestras de mucosa ileal, tanto del íleon sano como del íleon inflamado. Los datos se analizaron como una cohorte de validación externa.PRINCIPALES MEDIDAS DE RESULTADO:Fueron evaluados la infiltración de neutrófilos por histología y la subpoblación de macrófagos por inmunohistoquímica. La expresión de TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 y DEFA6 fueron cuantificados mediante qPCR en tiempo real. Las concentraciones de BDNF, CCL-11, ICAM-1, IL-1A, IL-1B, IL-1RN, IL-12 p40, IL-12 p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, VEGFA se determinaron con ensayo inmunométrico.RESULTADOS:La infiltración de neutrófilos se correlaciona inversamente con la duración de la enfermedad. La expresión del ARNm de DEFB4A mostro una tendencia a ser mayor en la EC en etapa tardía ( p = 0,07). Un mayor número de macrófagos expresaron CD163 a baja intensidad en la etapa tardía ( p = 0,04). La concentración de IL15 ( p = 0,02) e IL23A ( p = 0,05) fue mayor en la mucosa ileal sana de pacientes en estadio temprano. En la cohorte externa, la expresión de DEFB1 ( p = 0,03) y DEFB4A ( p = 0,01), IL2 ( p = 0,04) e IL3 ( p = 0,03) aumentó en pacientes en etapa tardía.LIMITACIONES:Un número relativamente pequeño de pacientes, especialmente en el grupo recién diagnosticado.CONCLUSIONES:En la EC recién diagnosticada, los altos niveles de IL-15 e IL-23 en la mucosa sana sugieren que la inmunidad innata es el promotor de la inflamación aguda. Además, los macrófagos M2 aumentan en la mucosa sana de pacientes con EC en etapa tardía, lo que sugiere que los procesos reparadores y profibróticos son predominantes a largo plazo y en esta fase, la terapia antiinflamatoria puede ser menos eficiente. (Traducción-Dr. Osvaldo Gauto ).

Completion total mesorectal excision after neoadjuvant radiochemotherapy and local excision for rectal cancer.

AIM: Local excision (LE) in selected cases after neoadjuvant radiochemotherapy (RCT) for locally advanced rectal cancer in clinically complete or major responders has been recently reported as an alternative to standard radical resection. Completion total mesorectal excision (cTME) is generally performed when high-risk pathological features are found in LE surgical specimens. The aim of this study was to evaluate the incidence of residual tumour and lymph node metastases after cTME in patients previously treated by RCT + LE. The secondary aims were to quantify the rate of postoperative morbidity and mortality and to evaluate the long-term oncological outcome of this group of patients. METHODS: All patients treated from 2007 to 2020 by LE for locally advanced rectal cancer with a clinically complete or major response to RCT who had a subsequent cTME for high-risk pathological factors (ypT >1 and/or TRG >2 and/or positive margins) were included in this multicentre retrospective study. Pathological data, postoperative short-term morbidity (classified according to Clavien-Dindo) and mortality and oncological long-term outcome after cTME were recorded in a database. Statistical analysis was performed using Wizard for iOS version 1.9.31. RESULTS: A total of 47 patients were included in the study. The rate of R0 resection was 95.7%, and a sphincter-saving procedure was performed in 37 patients (78.7%), with a protective stoma rate of 78.4%. In 28 cases (59.6%), it was possible to perform a minimally invasive approach. A residual tumour (pT and/or pN) on cTME specimens was found in 21 cases (44.7%). The rate of lymph node metastases was 12.8%. The overall short-term (within 30 days) postoperative morbidity was 34%, but grade >2 postoperative complications occurred in only nine patients (19.1%), with a reoperation rate of 6.4%. No short-term postoperative deaths occurred. At a median follow-up of 57 months (range: 21-174), the long-term stoma-free rate was 70.2%, and the actuarial 5-year overall survival (OS), disease-free survival (DFS) and local control (LC) were 86.7%, 88.9% and 95.7%, respectively. CONCLUSION: When patients exhibit high-risk pathological factors after RCT + LE, cTME should be suggested due to the high risk of residual tumour or lymph node involvement (44.7%). The results after cTME in terms of the rate of R0 resection, sphincter-saving procedure, postoperative morbidity and mortality and long-term oncological outcome seem to be acceptable and do not represent a contraindication to use LE as a first-step treatment in patients with major or complete clinical response after RCT.

An integrated multiomics analysis of rectal cancer patients identified POU2F3 as a putative druggable target and entinostat as a cytotoxic enhancer of 5-fluorouracil.

Rectal cancer (RC) accounts for one-third of colorectal cancers (CRC), and 40% of these are locally advanced rectal cancers (LARC). The use of neoadjuvant chemoradiotherapy (nCRT) significantly reduces the rate of local recurrence compared to adjuvant therapy or surgery alone. However, after nCRT, up to 40%-60% of patients show a poor pathological response, while only about 20% achieve a pathological complete response. In this scenario, the identification of novel predictors of tumor response to nCRT is urgently needed to reduce LARC mortality and to spare poorly responding patients from unnecessary treatments. Therefore, by combining gene and microRNA expression datasets with proteomic data from LARC patients, we developed an integrated network centered on seven hub-genes putatively involved in the response to nCRT. In an independent validation cohort of LARC patients, we confirmed that differential expression of NFKB1, TRAF6 and STAT3 is correlated with the response to nCRT. In addition, the functional enrichment analysis also revealed that these genes are strongly related to hallmarks of cancer and inflammation, whose dysfunction may causatively affect LARC patient's response to nCRT. Furthermore, by constructing the transcription factor-module network, we hypothesized a protective role of POU2F3 gene, which could be used as a new drug target in LARC patients. Finally, we identified and tested in vitro entinostat, a histone deacetylase inhibitor, as a chemical compound that could be combined with a classical therapeutic regimen in order to design more efficient therapeutic strategies in LARC management.

Prognostic value of major pathological response following neoadjuvant therapy for non resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The aim of this study is to evaluate the impact of major pathological response on overall survival (OS) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma following neoadjuvant treatment, and to identify predictors of major pathological response. METHODS: Patients surgically resected following neoadjuvant treatment between 2010 and 2020 at the Pederzoli Hospital were retrospectively analyzed. Pathologic response was assessed using the College of American Pathologists (CAP) score, and major pathological response was defined as CAP 0-1. OS was estimated and compared using the Kaplan-Meier method and log-rank test. A logistic and Cox regression model were performed to identify predictors of major pathologic response and OS. RESULTS: Overall, 200 patients were included in the study. A major and complete pathological response were observed in 52(26.0%) and 15(7.3%) patients respectively. The 1-, 3-, 5-year OS was 92.7, 67.2, and 41.7%, and 71.0, 37.4, and 20.8% in patients with or without major pathologic response respectively (log-rank test p < 0.001). Major pathologic response was confirmed as independent predictor of OS (OR 0.50 95%CI 0.29-0.88, p = 0.01). Post-treatment CA19-9 normalization (OR 4.20 95%CI 1.14-10.35, p = 0.02) and radiological post-treatment tumor residual size<25 mm (OR 2.71 95%CI 1.27-5.79, p = 0.01) were found to be independent predictors of major pathologic response. CONCLUSION: Patients experienced a major pathological response after neoadjuvant treatment have an increased survival, and major pathologic response is an independent predictor of OS. A normal CA19-9 value and radiological tumor size at restaging are confirmed to be independent predictors of major pathologic response.

Diagnostic accuracy of state-of-the-art rectal MRI sequences for the diagnosis of extramural vascular invasion in locally advanced rectal cancer after preoperative chemoradiotherapy: dos or maybes?

OBJECTIVES: The aim of this study was to determine the accuracy of three state-of-the-art MRI sequences for the detection of extramural venous invasion (EMVI) in locally advanced rectal cancer (LARC) patients after preoperative chemoradiotherapy (pCRT). METHODS: This retrospective study included 103 patients (median age 66 years old [43-84]) surgically treated with pCRT for LARC and submitted to preoperative contrast-enhanced pelvic MRI after pCRT. T2-weighted, DWI, and contrast-enhanced sequences were evaluated by two radiologists with expertise in abdominal imaging, blinded to clinical and histopathological data. Patients were scored according to the probability of EMVI presence on each sequence using a grading score ranging from 0 (no evidence of EMVI) to 4 (strong evidence of EMVI). Results from 0 to 2 were ranked as EMVI negative and from 3 to 4 as EMVI positive. ROC curves were drawn for each technique, using histopathological results as reference standard. RESULTS: T2-weighted, DWI, and contrast-enhanced sequences demonstrated an area under the ROC curve (AUC) respectively of 0.610 (95% CI: 0.509-0.704), 0.729 (95% CI: 0.633-0.812), and 0.624 (95% CI: 0.523-0.718). The AUC of DWI sequence was significantly higher than that of T2-weighted (p = 0.0494) and contrast-enhanced (p = 0.0315) sequences. CONCLUSIONS: DWI is more accurate than T2-weighted and contrast-enhanced sequences for the identification of EMVI following pCRT in LARC patients. CLINICAL RELEVANCE STATEMENT: MRI protocol for restaging locally advanced rectal cancer after preoperative chemoradiotherapy should routinely include DWI due to its higher accuracy for the diagnosis of extramural venous invasion compared to high-resolution T2-weighted and contrast-enhanced T1-weighted sequences. KEY POINTS: • MRI has a moderately high accuracy for the diagnosis of extramural venous invasion in locally advanced rectal cancer after preoperative chemoradiotherapy. • DWI is more accurate than T2-weighted and contrast-enhanced T1-weighted sequences in the detection of extramural venous invasion after preoperative chemoradiotherapy of locally advanced rectal cancer. • DWI should be routinely included in the MRI protocol for restaging locally advanced rectal cancer after preoperative chemoradiotherapy.

Nodal staging with MRI after neoadjuvant chemo-radiotherapy for locally advanced rectal cancer: a fast and reliable method.

OBJECTIVES: In patients with locally advanced rectal carcinoma (LARC), negative nodal status after neoadjuvant chemoradiotherapy (nCRT) may allow for rectum-sparing protocols rather than total mesorectal excision; however, current MRI criteria for nodal staging have suboptimal accuracy. The aim of this study was to compare the diagnostic accuracy of different MRI dimensional criteria for nodal staging after nCRT in patients with LARC. MATERIALS AND METHODS: Patients who underwent MRI after nCRT for LARC followed by surgery were retrospectively included and divided into a training and a validation cohort of 100 and 39 patients, respectively. Short-, long-, and cranial-caudal axes and volume of the largest mesorectal node and nodal status based on European Society of Gastrointestinal Radiology consensus guidelines (i.e., ESGAR method) were assessed by two radiologists independently. Inter-reader agreement was assessed in the training cohort. Histopathology was the reference standard. ROC curves and the best cut-off were calculated, and accuracies compared with the McNemar test. RESULTS: The study population included 139 patients (median age 62 years [IQR 55-72], 94 men). Inter-reader agreement was high for long axis (κ = 0.81), volume (κ = 0.85), and ESGAR method (κ = 0.88) and low for short axis (κ = 0.11). Accuracy was similar (p > 0.05) for long axis, volume, and ESGAR method both in the training (71%, 74%, and 65%, respectively) and in the validation (83%, 78%, and 75%, respectively) cohorts. CONCLUSION: Accuracy of the measurement of long axis and volume of the largest lymph node is not inferior to the ESGAR method for nodal staging after nCRT in LARC. CLINICAL RELEVANCE STATEMENT: In MRI restaging of rectal cancer, measurement of the long axis or volume of largest mesorectal lymph node after preoperative chemoradiotherapy is a faster and reliable alternative to ESGAR criteria for nodal staging. KEY POINTS: • Current MRI criteria for nodal staging in locally advanced rectal cancer after chemo-radiotherapy have suboptimal accuracy and are time-consuming. • Measurement of long axis or volume of the largest mesorectal lymph node on MRI showed good accuracy for assessment of loco-regional nodal status in locally advanced rectal cancer. • MRI measurement of the long axis and volume of largest mesorectal lymph node after chemo-radiotherapy could be a faster and reliable alternative to ESGAR criteria for nodal staging.

Limits of Clinical Restaging in Detecting Responders After Neoadjuvant Therapies for Rectal Cancer.

BACKGROUND: Accurate clinical restaging is required to select patients who respond to neoadjuvant chemoradiotherapy for locally advanced rectal cancer and who may benefit from an organ preservation strategy. OBJECTIVE: The purpose of this study was to review our experience with the clinical restaging of rectal cancer after neoadjuvant therapy to assess its accuracy in detecting major and pathological complete response to treatment. DESIGN: This was a retrospective cohort study. SETTING: This study was conducted at 2 high-volume Italian centers for Colorectal Surgery. PATIENTS: Data were included from all consecutive patients who underwent neoadjuvant therapy and surgery for locally advanced rectal cancer from January 2012 to July 2020. Criteria to define clinical response were no palpable mass, a superficial ulcer <2 cm (major response), or no mucosal abnormality (complete response) at endoscopy and no metastatic nodes at MRI. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity, specificity, positive predictive values, and negative predictive values of clinical restaging in detecting pathological complete response (ypT0) or major pathological response (ypT0-1) after neoadjuvant therapy. RESULTS: A total of 333 patients were included; 81 (24.3%) had a complete response whereas 115 (34.5%) had a pathological major response. Accuracy for clinical complete response was 80.8% and for major clinical response was 72.9%. Sensitivity was low for both clinical complete response (37.5%) in detecting ypT0 and clinical major response (59.3%) in detecting ypT0-1. Positive predictive value was 68.2% for ypT0 and 60.4% for ypT0-1. LIMITATIONS: The main limitation of the study its retrospective nature. CONCLUSION: Accuracy of actual clinical criteria to define pathological complete response or pathological major response is poor. Failure to achieve good sensitivity and precision is a major limiting factor in the clinical setting. Current clinical assessments need to be revised to account for indications for rectal preservation after neoadjuvant chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/C63 . LMITES DE LA REESTADIFICACIN CLNICA EN LA DETECCIN DE RESPONDEDORES DESPUS DE TERAPIAS NEOADYUVANTES PARA EL CNCER DE RECTO: ANTECEDENTES:Se requiere una nueva reestadificación clínica precisa para seleccionar pacientes que respondan a la quimiorradioterapia neoadyuvante para el cáncer de recto localmente avanzado y que puedan beneficiarse de una estrategia de preservación de órganos.OBJETIVO:El propósito de este estudio fue revisar nuestra experiencia con la reestadificación clínica del cáncer de recto después de la terapia neoadyuvante para evaluar su precisión en la detección de una respuesta patológica importante y completa al tratamiento.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Este estudio se realizó en dos centros italianos de alto volumen para cirugía colorrectal.PACIENTES:Incluimos datos de todos los pacientes consecutivos que se sometieron a terapia neoadyuvante y cirugía por cáncer de recto localmente avanzado desde enero de 2012 hasta julio de 2020. Los criterios para definir la respuesta clínica fueron ausencia de masa palpable, úlcera superficial <2 cm (respuesta mayor) o ausencia de anomalías en la mucosa. (respuesta completa) en la endoscopia, y sin ganglios metastásicos en la resonancia magnética.PRINCIPALES MEDIDAS DE RESULTADO:Exploramos la sensibilidad, la especificidad, los valores predictivos positivos y negativos de la reestadificación clínica para detectar una respuesta patológica completa (ypT0) o mayor (ypT0-1) después de la terapia neoadyuvante.RESULTADOS:Se incluyeron 333 pacientes; 81 (24,3%) tuvieron una respuesta completa mientras que 115 (34,5%) tuvieron una respuesta patológica mayor. La precisión de la respuesta clínica completa y la respuesta clínica importante fue del 80,8 % y el 72,9 %, respectivamente. La sensibilidad fue baja tanto para la respuesta clínica completa (37,5 %) en la detección de ypT0 como para la respuesta clínica mayor (59,3 %) en la detección de ypT0-1. El valor predictivo positivo fue del 68,2 % para ypT0 y del 60,4 % para ypT0-1.LIMITACIONES:Nuestro estudio tiene como principal limitación su carácter retrospectivo.CONCLUSIÓNES:La precisión de los criterios clínicos reales para definir una respuesta patológica completa o mayor es pobre. El hecho de no lograr una buena sensibilidad y precisión es un factor limitante importante en el entorno clínico. La indicación para la preservación rectal después de la quimiorradioterapia neoadyuvante necesita una mejora de la evaluación clínica actual. Consulte Video Resumen en http://links.lww.com/DCR/C63 . (Traducción-Dr. Mauricio Santamaria ).

Molecular Determinants of Peritoneal Dissemination in Gastric Adenocarcinoma.

BACKGROUND: Peritoneal dissemination represents a poor prognostic indicator in gastric cancer. Despite a comprehensive molecular characterization of this disease, no peritoneal dissemination-specific signature has been identified, limiting the tailoring of the surgical and oncological treatments. In this review, we outline the available literature focusing on the role of the different molecular pathways involved in the acquisition of peritoneal metastatic dissemination. SUMMARY: According to our results, several molecular determinants are associated with peritoneal carcinomatosis and are involved in several cellular and molecular carcinogenetic processes. However, a comprehensive understanding of the complex molecular landscape of gastric carcinosis is still lacking. KEY MESSAGES: More efforts should be made toward the integration of molecular and histologic data to perform a risk prediction assessment of peritoneal dissemination based on molecular profiling and histological evaluation.

Minimally invasive vs. open segmental resection of the splenic flexure for cancer: a nationwide study of the Italian Society of Surgical Oncology-Colorectal Cancer Network (SICO-CNN).

BACKGROUND: Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes. METHODS: This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo > 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed ≧12, and proximal and distal free resection margins length ≧ 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate. RESULTS: A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to ∞). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to ∞). CONCLUSIONS: Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection.

Predictors of urinary tract infection after lower gastrointestinal surgery.

BACKGROUND: Urinary tract infections (UTIs) cause postoperative morbidity in patients undergoing lower gastrointestinal (GI) surgery that can prolong postoperative hospital stays. In patients with a fever of unknown origin (FUO), clinicians ignore what to do while waiting for the results of the urine culture test. This study aimed to develop a nomogram predicting UTI in the case of postoperative FUO. METHODS: This observational, retrospective study included all consecutive patients from 1 November 2020 to 1 November 2021 undergoing lower-GI surgery at the Chirurgia Generale 3, University Hospital of Padua, Italy. A nomogram was created and externally validated in 90 consecutive patients undergoing urine culture tests for FUO at the Chirurgia Oncologica Unit, Veneto Institute of Oncology. RESULTS: In the development cohort, 109 (N = 109) patients performed a urine culture test for FUO, and 39 were diagnosed with UTI. In a multivariate analysis of patients who underwent urine culture tests for FUO, UTI was associated with female sex, older age, and duration of catheterization at the date of the urine culture test. We developed a nomogram to predict UTI in surgical patients with a C-index of 0.76. In the validation cohort, 90 consecutive patients, who had lower-GI surgery, underwent a urine culture test for FUO and were tested with this nomogram. In the validation cohort, the C-index of the nomogram for predicting a positive urine culture test was 0.71. CONCLUSIONS AND RELEVANCE: UTIs are a common problem in patients undergoing lower-GI surgery. A nomogram including the major risk factors may help to reduce the inappropriate use of antibiotics during the period awaiting the result of the urine culture test.

Leaving behind a diseased small bowel during surgery for Crohn's disease: Long-term outcomes.

PURPOSES: Stricture is a common complication of Crohn's disease (CD) and may be treated with bowel-sparing procedures. Our study analyzed what happens in terms of intestinal and systemic inflammation when the diseased bowel is left behind following surgery. METHODS: In this retrospective study, we enrolled 42 consecutive patients who underwent strictureplasty (alone or with resection) for stricturing CD. Control patients who underwent complete diseased bowel resection were identified and propensity score-matched for the sex, age, and history of abdominal surgery. Biohumoral values were collected at follow-up examinations at 1, 6, and 12 months after surgery. Magnetic resonance imaging (MRI) was performed before and after strictureplasty in 19 patients. RESULTS: In the strictureplasty group, fecal calprotectin levels were decreased at 12 months (p = 0.03), whereas in the resectiongroup, they were decreased at 6 months (p = 0.02). On MRI, the ADC [apparent diffusion coefficient] (p < 0.001), wall thickness (p = 0.046) and Magnetic Resonance Index of Activity (MaRIA) (p < 0.001) and Clermont (p < 0.001) scores were improved after strictureplasty. Surgical recurrence was more frequent in the strictureplasty group than in the resection group (p = 0.003). CONCLUSIONS: Our retrospective study showed that even if the diseased bowel was left behind after surgery, the intestinal inflammatory activity still decreased. However, the permanence of the diseased bowel still increased the risk of reoperation, probably because of the fibrotic nature of the stenosis and the multifocality of CD.

Prediction of Metachronous Peritoneal Metastases After Radical Surgery for Colon Cancer: A Scoring System Obtained from an International Multicenter Cohort.

BACKGROUND: Since novel strategies for prevention and treatment of metachronous peritoneal metastases (mPM) are under study, it appears crucial to identify their risk factors. Our aim is to establish the incidence of mPM after surgery for colon cancer (CC) and to build a statistical model to predict the risk of recurrence. PATIENTS AND METHODS: Retrospective analysis of consecutive pT3-4 CC operated at five referral centers (2014-2018). Patients who developed mPM were compared with patients who were PM-free at follow-up. A scoring system was built on the basis of a logistic regression model. RESULTS: Of the 1423 included patients, 74 (5.2%) developed mPM. Patients in the PM group presented higher preoperative carcinoembryonic antigen (CEA) [median (IQR): 4.5 (2.5-13.0) vs. 2.7 (1.5-5.9), P = 0.001] and CA 19-9 [median (IQR): 17.7 (12.0-37.0) vs. 10.8 (5.0-21.0), P = 0.001], advanced disease (pT4a 42.6% vs. 13.5%; pT4b 16.2% vs. 3.2%; P < 0.001), and negative pathological characteristics. Multivariate logistic regression identified CA 19-9, pT stage, pN stage, extent of lymphadenectomy, and lymphovascular invasion as significant predictors, and individual risk scores were calculated for each patient. The risk of recurrence increased remarkably with score values, and the model demonstrated a high negative predictive value (98.8%) and accuracy (83.9%) for scores below five. CONCLUSIONS: Besides confirming incidence and risk factors for mPM, our study developed a useful clinical tool for prediction of mPM risk. After external validation, this scoring system may guide personalized decision-making for patients with locally advanced CC.

Very Early Recurrence After Curative-Intent Surgery for Gastric Adenocarcinoma.

BACKGROUND: Recurrence after curative-intent surgery can occur in more than 50% of gastric cancer (GC) patients. We sought to identify predictors of very early recurrence (VER) among GC patients who underwent curative-intent surgery. METHODS: A multi-institutional database of GC patients undergoing curative-intent surgery between 2000 and 2020 at 8 major institutions was queried. VER was defined as local or distant tumor recurrence within 6 months from surgery. Univariable Cox proportional hazard models were used to evaluate the predictive value of clinical-pathological features on VER. A regularized Cox regression model was employed to build a predictive model of VER and recurrence within 12 months. The discriminant ability of the Cox regularized models was evaluated by reporting a ROC curve together with the calibration plot, considering 200 runs. RESULTS: Among 1133 patients, 65 (16.0%) patients experienced a VER. Preoperative symptoms (HR 1.198), comorbidities (HR 1.289), tumor grade (HR 1.043), LNR (HR 4.339) and T stage (HR 1.639) were associated with an increased likelihood of VER. Model performance was very good at predicting VER at 6 months (AUC of 0.722) and 12 months (AUC 0.733). Two nomograms to predict 6-month and 12-month VER were built based on the predictive model. A higher nomogram score was associated with worse prognosis. There was good prediction between observed and estimated VER with minimal evidence of overfitting and good performance on internal bootstrapping validation. CONCLUSION: One in 6 patients experienced VER following curative-intent surgery for GC. Nomograms to predict risk of VER performed well on internal validation, and stratified patients into distinct prognostic groups relative to 6- and 12-months recurrence.

Rectal Sparing Approach After Neoadjuvant Therapy in Patients with Rectal Cancer: The Preliminary Results of the ReSARCh Trial.

BACKGROUND: Rectum-preservation for locally advanced rectal cancer has been proposed as an alternative to total mesorectal excision (TME) in patients with major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The purpose of this study was to report on the short-term outcomes of ReSARCh (Rectal Sparing Approach after preoperative Radio- and/or Chemotherapy) trial, which is a prospective, multicenter, observational trial that investigated the role of transanal local excision (LE) and watch-and-wait (WW) as integrated approaches after neoadjuvant therapy for rectal cancer. METHODS: Patients with mid-low rectal cancer who achieved mCR or cCR after neoadjuvant therapy and were fit for major surgery were enrolled. Clinical response was evaluated at 8 and 12 weeks after completion of chemoradiotherapy. Treatment approach, incidence, and reasons for subsequent TME were recorded. RESULTS: From 2016 to 2019, 160 patients were enrolled; mCR or cCR at 12 weeks was achieved in 64 and 96 of patients, respectively. Overall, 98 patients were managed with LE and 62 with WW. In the LE group, Clavien-Dindo 3+ complications occurred in three patients. The rate of cCR increased from 8- to 12-week restaging. Thirty-three (94.3%) of 35 patients with cCR had ypT0-1 tumor. At a median 24 months follow-up, a tumor regrowth was found in 15 (24.2%) patients undergoing WW. CONCLUSIONS: LE for patients achieving cCR or mCR is safe. A 12-week interval from chemoradiotherapy completion to LE is correlated with an increased cCR rate. The risk of ypT > is reduced when LE is performed after cCR.

Development of a Prognostic Nomogram and Nomogram Software Application Tool to Predict Overall Survival and Disease-Free Survival After Curative-Intent Gastrectomy for Gastric Cancer.

BACKGROUND: We sought to derive and validate a prediction model of survival and recurrence among Western patients undergoing resection of gastric cancer. METHODS: Patients who underwent curative-intent surgery for gastric cancer at seven US institutions and a major Italian center from 2000 to 2020 were included. Variables included in the multivariable Cox models were identified using an automated model selection procedure based on an algorithm. Best models were selected using the Bayesian information criterion (BIC). The performance of the models was internally cross-validated via the bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index and accuracy was evaluated using calibration plots. Nomograms were made available as online tools. RESULTS: Overall, 895 patients met inclusion criteria. Age (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.17-1.84), presence of preoperative comorbidities (HR 1.66, 95% CI 1.14-2.41), lymph node ratio (LNR; HR 1.72, 95% CI 1.42-2.01), and lymphovascular invasion (HR 1.81, 95% CI 1.33-2.45) were associated with overall survival (OS; all p < 0.01), whereas tumor location (HR 1.93, 95% CI 1.23-3.02), T category (Tis-T1 vs. T3: HR 0.31, 95% CI 0.14-0.66), LNR (HR 1.82, 95% CI 1.45-2.28), and lymphovascular invasion (HR 1.49; 95% CI 1.01-2.22) were associated with disease-free survival (DFS; all p < 0.05) The models demonstrated good discrimination on internal validation relative to OS (C-index 0.70) and DFS (C-index 0.74). CONCLUSIONS: A web-based nomograms to predict OS and DFS among gastric cancer patients following resection demonstrated good accuracy and discrimination and good performance on internal validation.

Surgical treatment of gastric adenocarcinoma: Are we achieving textbook oncologic outcomes for our patients?

BACKGROUND AND OBJECTIVES: Composite measures are increasingly used to assess quality of care in surgical oncology. We sought to define the incidence of "textbook oncologic outcome" (TOO) following resection of gastric adenocarcinoma among a large, international cohort of patients. METHODS: Gastric adenocarcinoma patients undergoing resection between 2000 and 2020 were identified from an international database. TOO was defined as margin-negative resection, examination of ≥16 lymph nodes, no prolonged length-of-stay (LOS), no 30-day mortality, and stage-appropriate receipt of chemotherapy. RESULTS: Among a total of 910 patients, 321 patients (35.3%) achieved a postoperative TOO. While failure to evaluate ≥16 lymph nodes (n = 591, 65.0%) and receipt of chemotherapy (n = 651, 71.5%) had the greatest negative impact on the ability to obtain a TOO, no 30-day mortality (n = 880, 96.7%), margin-negative resection (n = 831, 91.3%), and no extended LOS (n = 706, 77.6%) were more commonly achieved. No postoperative complications (OR: 0.44; 95% CI: 0.31-0.63) and T1a/T1b-stage disease (OR: 2.87; 95% CI: 1.59-5.18) were independently associated with achieving a TOO (p < 0.05). The odds of achieving a TOO improved over time (p-trend < 0.05), which was largely attributable to improved odds of evaluating ≥16 lymph nodes (2010-2014 vs. 2000-2004: OR, 5.21; 95% CI: 3.22-8.45). CONCLUSIONS: Only about one in three patients achieved a TOO following resection of gastric adenocarcinoma. Odds of TOO increased over time, largely due to improved lymph node evaluation.

Prognostic significance of pathological sub-classification of pT3 rectal cancer.

PURPOSE: Patients with pT3 rectal cancer represent a heterogeneous prognostic group. A more accurate histological sub-classification of pT status has been suggested as an improvement of the TNM staging system. The aim of the study was to evaluate the prognostic implication of a histopathologic sub-classification of pT3 rectal cancer. METHODS: In this retrospective single-center study, pT3 rectal cancer patients who underwent surgery from January 2000 to December 2018 were evaluated. The maximum depth of tumor invasion beyond the muscularis propria was recorded. A ROC curve identified the best prognostic cutoff value to classify patients in two prognostic groups. Survival curves were estimated by the Kaplan-Meier method, and univariate and multivariate analyses with the Cox regression model were used to find independent factors influencing survival. RESULTS: Overall, 203 patients were included. Four millimeters was identified as the best cutoff value: 82 patients showed a depth of invasion < 4 mm (group A) and 121 ≥ 4 mm (group B). Both the estimated 5-year OS and DFS were statistically better in group A than in group B (OS: 83.9% vs 62.2%, p < 0.01; DFS: 78.3% vs 40.6%, p < 0.01). The depth of tumor invasion was an independent risk factor for OS (HR 2.25, 95% CI 1.26-3.99, p = 0.006) and DFS (HR 2.30, 95% CI 1.40-3.78, p = 0.001). CONCLUSION: Our findings suggest that a sub-classification of pT3 rectal cancer, based on the depth of tumor invasion, should be considered to be introduced in the TNM staging system.

The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial.

PURPOSE: The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection. METHODS: This is an extension of a multicentre RCT (NCT01110798). Kaplan-Meier method and the log-rank test were used to estimate and compare the 3-, 5-, and 10-year OS and DFS, and local and distant recurrence in patients with and without AL. Predictors of OS and DFS were evaluated using the Cox regression analysis as secondary aim. RESULTS: Follow-up was available for 311 patients. Of them, 252 (81.0%) underwent neoadjuvant chemoradiotherapy and 138 (44.3%) adjuvant therapy. AL occurred in 63 (20.3%) patients. At a mean follow-up of 69.5 ± 31.9 months, 23 (7.4%) patients experienced local recurrence and 49 (15.8%) distant recurrence. The 3-, 5-, and 10-year OS and DFS were 89.2%, 85.3%, and 70.2%; and 80.7%, 75.1%, and 63.5% in patients with AL, and 88.9%, 79.8% and 72.3%; and 83.7, 74.2 and 62.8%, respectively in patients without (p = 0.89 and p = 0.84, respectively). At multivariable analysis, AL was not an independent predictor of OS (HR 0.65, 95%CI 0.34-1.28) and DFS (HR 0.70, 95%CI 0.39-1.25), whereas positive circumferential resection margins and pathological stage impaired both. CONCLUSIONS: In the context of modern multimodal rectal cancer treatment, AL does not affect long-term OS, DFS, and local and distant recurrence in patients with mid-low rectal cancer.

Crohn's Disease-Related Stoma Complications and Their Impact on Postsurgical Course.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. The diversion through a colostomy or an ileostomy is sometimes required for disease control. In these patients, common stoma-related complications sum up with CD-related complications and often require revisional surgery. METHODS: The aim of the study was to assess stoma morbidity after surgery for CD and to identify the burden of CD-related or CD-associated complications. Thus, details of past medical history, surgery, and follow-up of 54 consecutive patients operated on for CD with any sort of stoma were retrieved from the stoma therapist prospectively maintained database. RESULTS: In our series, 23 patients had a colostomy, and 31 patients had an ileostomy. Complications occurred after stoma creation in 38 patients (70%) at a median of 1.3 months (interquartile range 0.6-7.2). CD-related complications arose in 8 patients (including pyoderma gangrenosum in 3 patients, peristomal fistulae in 2, granulomas in 2, and peristomal abscess in 1). Patients with CD-related complications tended to have a shorter disease duration (p = 0.07) and higher occurrence of CD-related complications was associated with end-stoma (p = 0.006). In this cohort, 11 cases had to be surgically treated for peristomal fistulae or abscess, parastomal hernia, prolapse, pyoderma gangrenosum, and recurrent CD. DISCUSSION/CONCLUSIONS: In patients with CD, stoma creation is burdened by a high rate of postoperative complication and a relevant rate is specifically related to CD. Often these patients are required to be reoperated on to redo the stoma. Moreover, end-stoma configuration and aggressive CD phenotype are associated to a higher rate of complications.

Prognostic significance of additional histologic features for subclassification of pathological T3 colon cancer.

BACKGROUND: Additional histologic features of T3 colon cancer, such as tumour depth invasion beyond muscularis propria and elastic lamina invasion (ELI), have taken interest for a more accurate staging. METHODS: Patients with pT3 and pT4a (control group) colon adenocarcinoma were retrospectively collected from our institutional database. The study group was divided according to depth of tumour invasion < 5 mm and ≥ 5 mm, and into ELI - and ELI + . Chi-square test was used to compare the clinicopathological characteristics. OS and DFS were estimated using Kaplan-Meier method and compared with the log-rank test. Univariable and multivariable Cox proportional hazard models were employed to assess the effect on OS and DFS. RESULTS: Out of 290 pT3 tumours, 168 (58%) had a depth of tumour invasion < 5 mm and 122 (42%) ≥ 5 mm. The 5-year OS and DFS were 85.2, 68.7 and 60.9%, and 81.4, 73.9 and 60.1% in pT3 < 5 mm, pT3 ≥ 5 mm, and pT4a respectively (p = 0.001, p = 0.072). Considering ELI - (n = 157, 54%) and ELI + (n = 133, 46%), the 5-year OS and DFS were 78.9, 76.7, and 60.9%, and 75.5, 81.5, and 60.1% in ELI - , ELI + and pT4a respectively (p = 0.955, p = 0.462). At multivariable analysis, the depth of invasion was found to be an independent predictive factor for OS (HR 2.04, 95%CI 1.28-3.24, p = 0.003) and DFS (HR 1.98, 95%CI 1.24-3.18, p = 0.004), while ELI did not result a prognostic factor for OS nor DFS. CONCLUSION: In pT3 colon cancer, depth of tumour invasion ≥ 5 mm is an independent risk factor for OS and DFS, whereas ELI did not result a prognostic factor affecting OS nor DFS.