Association of Collagen Changes in Distal Anastomotic Margin and Anastomotic Stenosis after Neoadjuvant Chemoradiotherapy for Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy(nCRT) for rectal cancer can lead to structural changes in collagen in the tumor microenvironment and increase the risk of postoperative anastomotic stenosis (AS). However, the quantitative relationship between AS and collagen has not been defined. This study is to quantitatively analyze the collagen features in rectal cancer and explore the relationship between the changes of collagen and postoperative anastomotic stenosis after nCRT. STUDY DESIGN: This study is a retrospective study. A total of 371 patients with rectal cancer were included. Collagen features in the resection margin of rectal cancer anastomosis was extracted by multi-photon imaging. LASSO-logistic regression was performed to select features related to AS and the collagen score (CS) was constructed. Area under the receiver operating curve (AUROC) and decision curve analysis was performed to evaluate the discrimination and clinical benefit of the nomogram. RESULTS: The probability of AS was 23% in the training cohort and 15.9% in the validation cohort. In the training cohort, the distance between tumor and resection margin, anastomotic leakage and CS were independent risk factors for postoperative AS in univariate and multivariate analyses. A nomogram was constructed based on the above results. The prediction nomogram showed good discrimination (AUROC, 0.864;95% CI, 0.776 to 0.952) and was validated in the validation cohort (AUROC, 0.918;95% CI, 0.851 to 0.985). CONCLUSIONS: CS is an independent risk factor for AS in rectal cancer after nCRT. The predictive model based on CS can predict the occurrence of postoperative AS.

A Clinicopathological Feature-Based Nomogram for Predicting the Likelihood of D3 Lymph Node Metastasis in Right-Sided Colon Cancer Patients.

BACKGROUND: Despite advancements in treating right-sided colon cancer patients, the ideal scope of lymphadenectomy remains controversial. OBJECTIVE: Our objective was to investigate the likelihood of D3 lymph node metastasis in right-sided colon cancer patients and develop a clinicopathological feature-based nomogram for D3 lymphadenectomy. DESIGN: We retrospectively analyzed 286 right-sided colon cancer patients who underwent D3 lymphadenectomy. The patients were divided into 2 groups based on whether D3 lymph node metastasis was positive. Then, univariable and multivariable logistic regression analyses were performed to obtain independent risk factors for predicting D3 lymph node metastasis. Moreover, we performed receiver operating characteristic curve analyses to evaluate the predictive power of the model. SETTING: This study was conducted at Nanfang Hospital of Southern Medical University in China. PATIENTS: A total of 286 consecutive patients who underwent right hemicolectomy and D3 lymphadenectomy as a primary treatment for right-sided colon cancer between January 2016 and December 2019 were enrolled in this study. MAIN OUTCOME MEASURES: The primary measures were independent risk factors for predicting D3 lymph node metastasis in right-sided colon cancer. RESULTS: The D3 lymph node metastasis rate in right-sided colon cancer patients was 16.1% (46/286). D3 lymphadenectasis on CT, lymphatic invasion, and T4 tumors were filtered out as independent risk factors for D3 lymph node metastasis according to the multivariable logistic regression analysis. We established a nomogram that predicted D3 lymph node metastasis of right-sided colon cancer on the combination of the 3 factors with an area under the curve of 0.717 (95% CI, 0.629-0.806). LIMITATIONS: This was a retrospective study from a single center. CONCLUSIONS: We developed a valuable clinicopathological feature-based nomogram to predict the incidence of D3 lymph node metastasis in right-sided colon cancer patients. Patients with D3 lymphadenectasis on CT, preoperative T4 tumors, and lymphatic invasion should undergo D3 lymphadenectomy. See Video Abstract at http://links.lww.com/DCR/B852 . UN NOMOGRAMA BASADO EN CARACTERSTICAS CLNICOPATOLGICAS PARA PREDECIR LA PROBABILIDAD DE METSTASIS EN GANGLIOS LINFTICOS D EN PACIENTES CON CNCER DE COLON DERECHO: ANTECEDENTES:A pesar de los avances en el tratamiento de pacientes con cáncer de colon derecho, el ámbito ideal de la linfadenectomía sigue siendo controvertido.OBJETIVO:Investigar la probabilidad de metástasis en los ganglios linfáticos D3 en pacientes con cáncer de colon derecho y desarrollar un nomograma basado en características clínico-patológicas basado para la linfadenectomía D3.DISEÑO:Analizamos retrospectivamente a 286 pacientes con cáncer de colon derecho que se sometieron a linfadenectomía D3. Los pacientes se dividieron en dos grupos en función de si eran positivos para metástasis en los ganglios linfáticos D3. Luego, se realizaron análisis de regresión logística univariable y multivariable para obtener factores de riesgo independientes para predecir metástasis en los ganglios linfáticos D3. Además, realizamos análisis de las curvas de características operatorias del receptor para evaluar el poder predictivo del modelo.SEDE:Este estudio se realizó en el Hospital Nanfang de la Universidad Médica del Sur en China.PACIENTES:Un total de 286 pacientes consecutivos que se sometieron a hemicolectomía derecha y linfadenectomía D3 como tratamiento primario para el cáncer de colon derecho entre enero de 2016 y diciembre de 2019 se inscribieron en este estudio.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas primarias fueron factores de riesgo independientes para predecir las metástasis en ganglios linfáticos D3 en el cáncer de colon derecho.RESULTADOS:La tasa de metástasis en los ganglios linfáticos D3 en pacientes con cáncer de colon del lado derecho fue del 16,1% (46/286). El aumento de tamaño de ganglios D3 en la TC, la invasión linfática y los tumores T4 se filtraron como factores de riesgo independientes de metástasis en los ganglios linfáticos D3 de acuerdo con el análisis de regresión logística multivariable. Establecimos un nomograma que predijo metástasis en los ganglios linfáticos D3 del cáncer de colon derecho en la combinación de los tres factores con un área bajo la curva de 0,717 (IC del 95%, 0,629-0,806).LIMITACIONES:Este fue un estudio retrospectivo de un solo centro.CONCLUSIONES:Desarrollamos un valioso nomograma basado en características clínico-patológicas para predecir la incidencia de metástasis en los ganglios linfáticos D3 en pacientes con cáncer de colon derecho. Los pacientes con crecimiento de ganglios D3 en TC, tumores con clasificación preoperatoria T4 e invasión linfática, deben ser sometidos a linfadenectomía D3. Consulte Video Resumen en http://links.lww.com/DCR/B852 . (Traducción-Dr. Juan Carlos Reyes ).

Indocyanine green for radical lymph node dissection in patients with sigmoid and rectal cancer: randomized clinical trial.

BACKGROUND: D3 lymph node dissection is recommended for patients with advanced sigmoid and rectal cancer in Japan. This trial aimed to investigate the feasibility of indocyanine green (ICG) as a tracer to increase the nodal harvest during D3 lymph node dissection in patients with sigmoid and rectal cancer. METHODS: This prospective randomized clinical trial was performed between May 2021 and April 2022. The inclusion criteria were patients with stage I-III sigmoid or rectal cancer eligible for laparoscopic resection. Patients were 1: 1 randomized to either the ICG group (endoscopic ICG injection at the tumour site and intraoperative imaging to guide dissection) or the control group (routine laparoscopic white-light imaging). All patients were treated with D3 dissection, and the primary outcome was the number of harvested lymph nodes at the D3 level. RESULTS: Out of 210 patients screened, a total of 66 patients were enrolled and randomized. Patients in the two groups presented similar ages and clinical stages (ICG group versus control group, median age of 58.0 versus 58.5 years; stage III 36.4 per cent versus 36.4 per cent, whereas the rate of rectal cancer was 27.3 per cent versus 48.5 per cent respectively). ICG imaging was helpful for completely dissecting D3 lymph nodes and could identify a median of more than 2 (range 1-6) D3 lymph nodes neglected by routine laparoscopic white-light imaging during surgery. The median number of D3 lymph nodes harvested in the ICG group was significantly higher than that in the control group (7.0 versus 5.0, P = 0.003); however, there was no significant difference in the median numbers of positive D1, D2, and D3 lymph nodes between the two groups. CONCLUSION: ICG is safe and feasible to guide D3 lymph node dissection and can increase the number of harvested D3 lymph nodes in patients with sigmoid and rectal cancer. Registration number: NCT04848311 (http://www.clinicaltrials.gov).

Post-operative anastomotic leakage and collagen changes in patients with rectal cancer undergoing neoadjuvant chemotherapy vs chemoradiotherapy.

Background: A significant difference in the anastomotic leakage (AL) rate has been observed between patients with locally advanced rectal cancer who have undergone preoperative chemotherapy and those undergoing preoperative chemoradiotherapy. This study aimed to quantitatively analyse collagen structural changes caused by preoperative chemoradiotherapy and illuminate the relationship between collagen changes and AL. Methods: Anastomotic distal and proximal "doughnut" specimens from the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were quantitatively assessed for collagen structural changes between patients with and without preoperative radiotherapy using multiphoton imaging. Then, patients treated with preoperative chemoradiotherapy were used as a training cohort to construct an AL-SVM classifier by the Mann-Whitney U test and support vector machine (SVM). An independent test cohort from the Fujian Province Cancer Hospital (Fuzhou, China) was used to validate the AL-SVM classifier. Results: A total of 207 patients were included from the Sixth Affiliated Hospital of Sun Yat-sen University. The AL rate in the preoperative chemoradiotherapy group (n = 107) was significantly higher than that in the preoperative chemotherapy group (n = 100) (21.5% vs 7.0%, P = 0.003). A fully quantitative analysis showed notable morphological and spatial distribution feature changes in collagen in the preoperative chemoradiotherapy group. Then, the patients who received preoperative chemoradiotherapy were used as a training cohort to construct the AL-SVM classifier based on five collagen features and the tumor distance from the anus. The AL-SVM classifier showed satisfactory discrimination and calibration with areas under the curve of 0.907 and 0.856 in the training and test cohorts, respectively. Conclusions: The collagen structure may be notably altered by preoperative radiotherapy. The AL-SVM classifier was useful for the individualized prediction of AL in rectal cancer patients undergoing preoperative chemoradiotherapy.

Association of the collagen signature with pathological complete response in rectal cancer patients.

Collagen in the tumor microenvironment is recognized as a potential biomarker for predicting treatment response. This study investigated whether the collagen features are associated with pathological complete response (pCR) in locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (nCRT) and develop and validate a prediction model for individualized prediction of pCR. The prediction model was developed in a primary cohort (353 consecutive patients). In total, 142 collagen features were extracted from the multiphoton image of pretreatment biopsy, and the least absolute shrinkage and selection operator (Lasso) regression was applied for feature selection and collagen signature building. A nomogram was developed using multivariable analysis. The performance of the nomogram was assessed with respect to its discrimination, calibration, and clinical utility. An independent cohort (163 consecutive patients) was used to validate the model. The collagen signature comprised four collagen features significantly associated with pCR both in the primary and validation cohorts (p < 0.001). Predictors in the individualized prediction nomogram included the collagen signature and clinicopathological predictors. The nomogram showed good discrimination with area under the ROC curve (AUC) of 0.891 in the primary cohort and good calibration. Application of the nomogram in the validation cohort still gave good discrimination (AUC = 0.908) and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. In conclusion, the collagen signature in the tumor microenvironment of pretreatment biopsy is significantly associated with pCR. The nomogram based on the collagen signature and clinicopathological predictors could be used for individualized prediction of pCR in LARC patients before nCRT.

In vivo real-time assessment of the anastomotic blood supply in colorectal surgery using confocal laser endomicroscopy in an anastomotic model.

BACKGROUND AND STUDY AIMS: Anastomotic ischemia can affect healing and eventually lead to anastomotic leakage, and confocal laser endomicroscopy (CLE) can offer detailed observations at the subcellular level. We aimed to evaluate the anastomotic microcirculation in different anastomotic perfusion models using CLE. METHODS: Anastomotic perfusion models were established using twelve rabbits distributed into two groups: group A (good perfusion, n = 6) and group B (poor perfusion, n = 6). Afterward, intraoperative detection of anastomotic perfusion was carried out using CLE, and quantitative analysis of blood cells was performed. Rabbits that satisfied the criteria underwent a second exploratory operation and specimens were stained by hematoxylin and eosin. RESULTS: Enhanced with fluorescein sodium, capillaries were obviously highlighted in group A, while few capillaries were viewed in group B. Delayed development of fluorescence occurred in group B. The average flow of blood cells was 37.0 ± 5.93 per minute in group A and 6.33 ± 2.16 per minute in group B (p < 0.001). In addition, during the second exploratory surgery, rabbits with inadequate anastomotic perfusion exhibited more serious intestinal adhesion and ischemia. Anastomotic leakage and abdominal infection occurred in all rabbits in group B. CONCLUSION: CLE can realize real-time imaging of the anastomotic microcirculation and is a feasible technique for performing intraoperative evaluation in different anastomotic perfusion situations. This animal experiment provides the groundwork for future in vivo research in humans.

Real-time in vivo distal margin selection using confocal laser endomicroscopy in transanal total mesorectal excision for rectal cancer.

BACKGROUND: Transanal total mesorectal excision (TaTME) allows patients with ultralow rectal cancer to be treated with sphincter-saving surgery. However, accurate delineation of the distal resection margin (DRM), which is essential to achieve R0 resection for low rectal cancer in TaTME, is technically demanding. AIM: To assess the feasibility of optical biopsy using probe-based confocal laser endomicroscopy (pCLE) to select the DRM during TaTME for low rectal cancer. METHODS: A total of 43 consecutive patients who were diagnosed with low rectal cancer and scheduled for TaTME were prospectively enrolled from January 2019 to January 2021. pCLE was used to determine the distal edge of the tumor as well as the DRM during surgery. The final pathological report was used as the gold standard. The diagnostic accuracy of pCLE examination was calculated. RESULTS: A total of 86 pCLE videos of 43 patients were included in the analyses. The sensitivity, specificity and accuracy of real-time pCLE examination were 90.00% [95% confidence interval (CI): 76.34%-97.21%], 86.96% (95%CI: 73.74%-95.06%) and 88.37% (95%CI: 79.65%-94.28%), respectively. The accuracy of blinded pCLE reinterpretation was 86.05% (95%CI: 76.89%-92.58%). Furthermore, our results show satisfactory interobserver agreement (κ = 0.767, standard error = 0.069) for the detection of cancer tissue by pCLE. There were no positive DRMs (≤ 1 mm) in this study. The median DRM was 7 mm [interquartile range (IQR) = 5-10 mm]. The median Wexner score was 5 (IQR = 3-6) at 6 mo after stoma closure. CONCLUSION: Real-time in vivo pCLE examination is feasible and safe for selecting the DRM during TaTME for low rectal cancer (clinical trial registration number: NCT04016948).

Association of Tumor-Associated Collagen Signature With Prognosis and Adjuvant Chemotherapy Benefits in Patients With Gastric Cancer.

Importance: The current TNM staging system provides limited information for prognosis prediction and adjuvant chemotherapy benefits for patients with gastric cancer (GC). Objective: To develop a tumor-associated collagen signature of GC (TACSGC) in the tumor microenvironment to predict prognosis and adjuvant chemotherapy benefits in patients with GC. Design, Setting, and Participants: This retrospective cohort study included a training cohort of 294 consecutive patients treated between January 1, 2012, and December 31, 2013, from Nanfang Hospital, Southern Medical University, People's Republic of China, and a validation cohort of 225 consecutive patients treated between October 1, 2010, and December 31, 2012, from Fujian Provincial Cancer Hospital, Fujian Medical University, People's Republic of China. In total, 146 collagen features in the tumor microenvironment were extracted with multiphoton imaging. A TACSGC was then constructed using the least absolute shrinkage and selection operator Cox proportional hazards regression model in the training cohort. Data analysis was conducted from October 1, 2020, to April 30, 2021. Main Outcomes and Measures: The association of TACSGC with disease-free survival (DFS) and overall survival (OS) was assessed. An independent external cohort was included to validate the results. Interactions between TACSGC and adjuvant chemotherapy were calculated. Results: This study included 519 patients (median age, 57 years [IQR, 49-65 years]; 360 [69.4%] male). A 9 feature-based TACSGC was built. A higher TACSGC level was significantly associated with worse DFS and OS in both the training (DFS: hazard ratio [HR], 3.57 [95% CI, 2.45-5.20]; OS: HR, 3.54 [95% CI, 2.41-5.20]) and validation (DFS: HR, 3.10 [95% CI, 2.26-4.27]; OS: HR, 3.24 [95% CI, 2.33-4.50]) cohorts (continuous variable, P < .001 for all comparisons). Multivariable analyses found that carbohydrate antigen 19-9, depth of invasion, lymph node metastasis, distant metastasis, and TACSGC were independent prognostic predictors of GC, and 2 integrated nomograms that included the 5 predictors were established for predicting DFS and OS. Compared with clinicopathological models that included only the 4 clinicopathological predictors, the integrated nomograms yielded an improved discrimination for prognosis prediction in a C index comparison (training cohort: DFS, 0.80 [95% CI, 0.73-0.88] vs 0.78 [95% CI, 0.71-0.85], P = .03; OS, 0.81 [95% CI, 0.75-0.88] vs 0.80 [95% CI, 0.73-0.86], P = .03; validation cohort: DFS, 0.78 [95% CI, 0.70-0.87] vs 0.76 [95% CI, 0.67-0.84], P = .006; OS, 0.78 [95% CI, 0.69-0.86] vs 0.75 [95% CI, 0.67-0.84], P = .002). Patients with stage II and III GC and low TACSGC levels rather than high TACSGC levels had a favorable response to adjuvant chemotherapy (DFS: HR, 0.65 [95% CI, 0.43-0.96]; P = .03; OS: HR, 0.55 [95% CI, 0.36-0.82]; P = .004; dichotomized variable, P < .001 for interaction for both comparisons). Conclusions and Relevance: The findings suggest that TACSGC provides additional prognostic information for patients with GC and may distinguish patients with stage II and III disease who are more likely to derive benefits from adjuvant chemotherapy.

A Nomogram Based on a Collagen Feature Support Vector Machine for Predicting the Treatment Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer Patients.

BACKGROUND: The relationship between collagen features (CFs) in the tumor microenvironment and the treatment response to neoadjuvant chemoradiotherapy (nCRT) is still unknown. This study aimed to develop and validate a perdition model based on the CFs and clinicopathological characteristics to predict the treatment response to nCRT among locally advanced rectal cancer (LARC) patients. METHODS: In this multicenter, retrospective analysis, 428 patients were included and randomly divided into a training cohort (299 patients) and validation cohort (129 patients) [7:3 ratio]. A total of 11 CFs were extracted from a multiphoton image of pretreatment biopsy, and a support vector machine (SVM) was then used to construct a CFs-SVM classifier. A prediction model was developed and presented with a nomogram using multivariable analysis. Further validation of the nomogram was performed in the validation cohort. RESULTS: The CFs-SVM classifier, which integrated collagen area, straightness, and crosslink density, was significantly associated with treatment response. Predictors contained in the nomogram included the CFs-SVM classifier and clinicopathological characteristics by multivariable analysis. The CFs nomogram demonstrated good discrimination, with area under the receiver operating characteristic curves (AUROCs) of 0.834 in the training cohort and 0.854 in the validation cohort. Decision curve analysis indicated that the CFs nomogram was clinically useful. Moreover, compared with the traditional clinicopathological model, the CFs nomogram showed more powerful discrimination in determining the response to nCRT. CONCLUSIONS: The CFs-SVM classifier based on CFs in the tumor microenvironment is associated with treatment response, and the CFs nomogram integrating the CFs-SVM classifier and clinicopathological characteristics is useful for individualized prediction of the treatment response to nCRT among LARC patients.

Association of the collagen score with anastomotic leakage in rectal cancer patients after neoadjuvant chemoradiotherapy.

BACKGROUND: Collagen changes in the extracellular matrix caused by neoadjuvant chemoradiotherapy are a potential mechanism of anastomotic leakage. We aimed to construct a fully quantitative collagen score to describe collagen structure changes in the extracellular matrix and then develop and validate a prediction model to identify patients who are at a high risk of postoperative anastomotic leakage. METHODS: This is a retrospective study in which 372 patients were enrolled, and their baseline clinicopathological characteristics were collected. Anastomotic distal and proximal "doughnut" specimens underwent second harmonic generation imaging, and collagen features were extracted. A LASSO regression was used to select significant predictors, and the collagen score was constructed. A prediction model based on collagen score was developed and internally and externally validated. RESULTS: The primary cohort included 214 consecutive patients, and the anastomotic leakage rate was 8.9%. The validation cohort comprised 158 consecutive patients, and the anastomotic leakage rate was 10.1%. The collagen score was significantly related to anastomotic leakage in both cohorts (P < .001). Multivariate analysis revealed that tumor location, preoperative albumin, and collagen score were independent predictors of anastomotic leakage. These 3 predictors were incorporated into the prediction model, and a nomogram was established. The model showed good discrimination in the primary (area under the curve: 0.954) and validation (area under the curve: 0.928) cohorts. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: The collagen score is associated with anastomotic leakage, and the collagen nomogram based on the collagen score is useful for individualized prediction of anastomotic leakage in rectal cancer patients with neoadjuvant chemoradiotherapy after surgery.

Laparoscopic resection is better than endoscopic dissection for gastric gastrointestinal stromal tumor between 2 and 5 cm in size: a case-matched study in a gastrointestinal center.

BACKGROUND: The feasibility of endoscopic dissection for gastric gastrointestinal stromal tumor (gGIST) between 2 and 5 cm in size has been demonstrated. However, its impact on short-term and long-term outcomes, compared with laparoscopic resection, is unknown. The purpose of this study was to compare short-term and long-term outcomes between laparoscopic resection and endoscopic dissection for 2-5-cm gGIST. METHODS: A case-matched study was performed using the propensity score. To overcome selection bias, we performed a 1:1 match using six covariates, including age, sex, BMI, ASA score, tumor size, and tumor location. Short-term and long-term outcomes between laparoscopic resection and endoscopic dissection were compared. RESULTS: A total of 210 patients with 2-5-cm gGIST were enrolled between 2006 and 2017 in our gastrointestinal center. According to the intention-to-treat approach, 165 patients underwent laparoscopic resection, and 45 patients underwent endoscopic dissection. After the propensity score, 45 pairs were balanced and analyzed. There was no significant difference in the baseline characteristics between the laparoscopic and endoscopic groups after matching. The rate of complications was significantly higher in the endoscopic group compared with the laparoscopic group (P < 0.001). Perforations occurred in 16 patients in the endoscopic group (16/45, 35.6%). The postoperative hospital stay was significantly longer in the endoscopic group compared with the laparoscopic group (P < 0.001). There was no significant difference between the two groups in disease-free survival or overall survival. CONCLUSION: Laparoscopic resection is better than endoscopic dissection for 2-5-cm gGIST because of the lower complication rate and shorter hospital stay.