Development and Validation of a Post-Radiotherapy Prediction Model for Bowel Dysfunction After Rectal Cancer Resection.

BACKGROUND & AIMS: The benefit of radiotherapy for rectal cancer is based largely on a balance between a decrease in local recurrence and an increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features. METHODS: Eligible patients more than 1 year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score at 3 national hospitals in China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by means of logistic regression on the basis of key factors with proportional weighs. The accuracy of the model for major LARS prediction was internally and externally validated. RESULTS: A total of 868 patients reported a mean LARS score of 28.4 after an average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathologic nodal stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835; 95% CI, 0.800-0.870, n = 521) and external dataset (0.884; 95% CI, 0.848-0.921, n = 347). The model achieved both sensitivity and specificity >0.83 in the external validation. In addition, PORTLARS outperformed the preoperative LARS score for prediction of major events. CONCLUSIONS: PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to identify patients who need additional support for long-term dysfunction in the early stage. CLINICALTRIALS: gov, number NCT05129215.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Intentional Watch and Wait or Organ Preservation Surgery Following Neoadjuvant Chemoradiotherapy Plus Consolidation CAPEOX for MRI-defined Low-risk Rectal Cancer: Findings From a Prospective Phase 2 Trial (PKUCH-R01 Trial, NCT02860234).

OBJECTIVE: To assess the efficacy and safety of intentional watch and wait (W&W) and organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX in magnetic resonance imaging (MRI)-defined low-risk rectal cancer. BACKGROUND: Clinical T2/early T3 rectal cancers can achieve high yield pathological complete response (ypCR) rates after chemoradiotherapy; thus, an intentional W&W or organ preservation strategy for good clinical responders in these subgroups can be further tested. METHODS: This prospective, single-arm, phase 2 trial enrolled patients with low-risk MRI prestaged rectal cancers, who concurrently received chemoradiation, followed by four 3-weekly cycles of CAPEOX regimen. Following reassessment, clinical complete response (cCR) or near-cCR patients underwent W&W/organ preservation surgery; the primary endpoint was a 3-year organ preservation rate. RESULTS: Of the 64 participants, 58 completed treatment, with 6.4% and 33.9% grade 3 to 4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median 39.5-month follow-up. Initial cCR, and non-cCR occurred in 33, 13, and 18 patients, respectively. Of the 31 cCR and 7 near-cCR cases managed by W&W, local regrowth occurred in 7; of these, 6 received salvage surgery. The estimated 2-year local regrowth rates were 12.9% [95% confidence interval (CI): 1.1%-24.7%] in cCR and 42.9% (95% CI: 6.2%-79.6%) in near-cCR cases, respectively. Eight patients received local excision, including 2 with regrowth salvage. Lung metastases occurred in 3 patients and multiple metastasis occurred in 1 patient; no local recurrence occurred. The estimated 3-year organ preservation rate was 67.2% (95% CI: 55.6%-78.8%). The estimated 3-year cancer-specific survival, non-regrowth disease-free survival, and stoma-free survival were 96.6% (95% CI: 92.1%-100%), 92.2% (95% CI: 85.5%-98.9%), and 82.7% (95% CI: 73.5%-91.9%), respectively. CONCLUSIONS: Chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer can lead to high rates of organ preservation through intentional W&W or local excision. The oncologic safety of this strategy should be further tested.

Survival outcomes of stage I colorectal cancer: development and validation of the ACEPLY model using two prospective cohorts.

BACKGROUND: Approximately 10% of stage I colorectal cancer (CRC) patients experience unfavorable clinical outcomes after surgery. However, little is known about the subset of stage I patients who are predisposed to high risk of recurrence or death. Previous evidence was limited by small sample sizes and lack of validation. METHODS: We aimed to identify early indicators and develop a risk stratification model to inform prognosis of stage I patients by employing two large prospective cohorts. Prognostic factors for stage II tumors, including T stage, number of nodes examined, preoperative carcinoma embryonic antigen (CEA), lymphovascular invasion, perineural invasion (PNI), and tumor grade were investigated in the discovery cohort, and significant findings were further validated in the other cohort. We adopted disease-free survival (DFS) as the primary outcome for maximum statistical power and recurrence rate and overall survival (OS) as secondary outcomes. Hazard ratios (HRs) were estimated from Cox proportional hazard models, which were subsequently utilized to develop a multivariable model to predict DFS. Predictive performance was assessed in relation to discrimination, calibration and net benefit. RESULTS: A total of 728 and 413 patients were included for discovery and validation. Overall, 6.7% and 4.1% of the patients developed recurrences during follow-up. We identified consistent significant effects of PNI and higher preoperative CEA on inferior DFS in both the discovery (PNI: HR = 4.26, 95% CI: 1.70-10.67, p = 0.002; CEA: HR = 1.46, 95% CI: 1.13-1.87, p = 0.003) and the validation analysis (PNI: HR = 3.31, 95% CI: 1.01-10.89, p = 0.049; CEA: HR = 1.58, 95% CI: 1.10-2.28, p = 0.014). They were also significantly associated with recurrence rate. Age at diagnosis was a prominent determinant of OS. A prediction model on DFS using Age at diagnosis, CEA, PNI, and number of LYmph nodes examined (ACEPLY) showed significant discriminative performance (C-index: 0.69, 95% CI:0.60-0.77) in the external validation cohort. Decision curve analysis demonstrated added clinical benefit of applying the model for risk stratification. CONCLUSIONS: PNI and preoperative CEA are useful indicators for inferior survival outcomes of stage I CRC. Identification of stage I patients at high risk of recurrence is feasible using the ACEPLY model, although the predictive performance is yet to be improved.

Immuno-PET of colorectal cancer with a CEA-targeted [68 Ga]Ga-nanobody: from bench to bedside.

PURPOSE: An accurate diagnosis of colorectal carcinoma (CRC) can assist physicians in developing reasonable therapeutic regimens, thereby significantly improving the patient's prognosis. Carcinoembryonic antigen (CEA)-targeted PET imaging shows great potential for this purpose. Despite showing remarkable abilities to detect primary and metastatic CRC, previously reported CEA-specific antibody radiotracers or pretargeted imaging are not suitable for clinical use due to poor pharmacokinetics and complicated imaging procedures. In contrast, radiolabeled nanobodies exhibit ideal characteristics for PET imaging, for instance, rapid clearance rates and excellent distribution profiles, allowing same-day imaging with sufficient contrast. In this study, we developed a novel CEA-targeted nanobody radiotracer, [68 Ga]Ga-HNI01, and assessed its tumor imaging ability and biodistribution profile in preclinical xenografts and patients with primary and metastatic CRC. METHODS: The novel nanobody HNI01 was acquired by immunizing the llama with CEA proteins. [68 Ga]Ga-HNI01 was synthesized by site-specifically conjugating [68 Ga]Ga with tris(hydroxypyridinone) (THP). Small-animal PET imaging and biodistribution studies were performed in CEA-overexpressed LS174T and CEA-low-expressed HT-29 tumor models. Following successful preclinical assessment, a phase I study was conducted on 9 patients with primary and metastatic CRC. Study participants received 151.21 ± 25.25 MBq of intravenous [68 Ga]Ga-HNI01 and underwent PET/CT scans at 1 h and 2 h post injection. Patients 01-03 also underwent whole-body dynamic PET imaging within 0-40 min p.i. All patients underwent [18F]F-FDG PET/CT imaging within 1 week after [68 Ga]Ga-HNI01 imaging. Tracer distribution, pharmacokinetics, and radiation dosimetry were calculated. RESULTS: [68 Ga]Ga-HNI01 was successfully synthesized within 10 min under mild conditions, and the radiochemical purity was more than 98% without purification. Micro-PET imaging with [68 Ga]Ga-HNI01 revealed clear visualization of LS174T tumors, while signals from HT-29 tumors were significantly lower. Biodistribution studies indicated that uptake of [68 Ga]Ga-HNI01 in LS174T and HT-29 was 8.83 ± 3.02%ID/g and 1.81 ± 0.87%ID/g, respectively, at 2 h p.i. No adverse events occurred in all clinical participants after the injection of [68 Ga]Ga-HNI01. A fast blood clearance and low background uptake were observed, and CRC lesions could be visualized with high contrast as early as 30 min after injection. [68 Ga]Ga-HNI01 PET could clearly detect metastatic lesions in the liver, lung, and pancreas and showed superior ability in detecting small metastases. A significant accumulation of radioactivity was observed in the kidney, and normal tissues physiologically expressing CEA receptors showed slight uptakes of [68 Ga]Ga-HNI01. An interesting finding was that strong uptake of [68 Ga]Ga-HNI01 was found in non-malignant colorectal tissues adjacent to the primary tumor in some patients, suggesting abnormal CEA expression in these healthy tissues. CONCLUSION: [68 Ga]Ga-HNI01 is a novel CEA-targeted PET imaging radiotracer with excellent pharmacokinetics and favorable dosimetry profiles. [68 Ga]Ga-HNI01 PET is an effective and convenient imaging tool for detecting CRC lesions, particularly for identifying small metastases. Furthermore, its high specificity for CEA in vivo makes it an ideal tool for selecting patients for anti-CEA therapy.

Intracorporeal Anastomosis Versus Extracorporeal Anastomosis in Laparoscopic Right Colectomy: An Observational Cohort Study.

BACKGROUND: Current studies did not draw definitive conclusions on comparison of intracorporeal anastomosis (ICA) with extracorporeal anastomosis (ECA) in laparoscopic right colectomy. Whether the intraperitoneal contamination induced by ICA can result in higher risk of postoperative abdominal infection remains unclear. This study was aimed to compare the short-term outcomes, especially the risk of abdominal infection after ICA versus ECA. METHODS: This was an observational cohort study as a secondary analysis of a randomized controlled trial (RCT)-RELARC trial (NCT02619942). The patients enrolled in the RELARC trial were diagnosed with primary colon adenocarcinoma without distant metastasis and underwent radical laparoscopic right colectomy between Jan 2016 and Dec 2019. In our study the patients who converted to open surgery in RELARC trial were excluded. The short-term outcomes were compared between ICA and ECA. The primary endpoint was abdominal infection. The inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) was used for adjusting the potential confounders. RESULTS: This study enrolled 975 patients with 119 patients undergoing ICA and 856 patients undergoing ECA. The incidence of abdominal infection was higher in ICA group (9.2% versus 1.5%, RR from IPTW = 5.7 (95%CI: 2.6-12.6), P < 0.001) as well as the incidence of wound infection (14.3% vs 3.3%, RR from IPTW = 5.0 (95%CI: 2.9-8.6), P < 0.001). ICA was associated with higher incidence of Clavien-Dindo (CD) grade I and II complications (CD-I: 15.1% versus 6.8%, RR from IPTW = 2.4 (95%CI: 1.5-3.9), P < 0.001; CD-II: 26.9% versus 8.2%, RR from IPTW = 3.6 (95%CI: 2.5-5.1), P < 0.001) but similar incidence of CD-III ~ IV complications compared to ECA (3.4% vs 2.1%, RR from IPTW = 1.2 (95%CI: 0.4-4.0), P = 0.73). In ICA group, choosing another incision rather than lengthening main port site decreased the incidence of wound infection although without statistical significance (17.3% (14/81) versus 7.9% (3/38), crude RR = 2.2 (95%CI: 0.7-7.2), P = 0.17). CONCLUSION: ICA is likely to be associated with higher risk of abdominal infection and CD-I ~ II complications.

17ß-Estradiol Mediates Staphylococcus aureus Adhesion in Vaginal Epithelial Cells via Estrogen Receptor α-Associated Signaling Pathway.

Staphylococcus aureus, a major opportunistic pathogen in aerobic vaginitis (AV), can potentially invade the host and occasionally cause infections. Estrogen is associated with an altered immune response of vaginal epithelial cells and prevention of certain vaginal infectious diseases. However, the molecular mechanisms involving estrogen and S. aureus adhesion to vaginal epithelial cells remain unclear. Thus, here, VK2/E6E7 vaginal epithelial cells were infected with S. aureus, and the role of the estrogen receptor α-associated signaling pathway (ERα/FAK/Src/iNOS axis) in S. aureus adhesion was evaluated. The estrogen-associated phosphorylation status of ERα, FAK, and Src and the protein level of iNOS were assessed by western blotting. We used a specific ERα inhibitor to validate the involvement of the ERα-associated signaling pathway. The results showed that with exposure to 1 nM estrogen for 24 h, transient ERα-associated pathway activation was observed, and the protein expression upregulation was accompanied by a dose-dependent increase in 17-ß-estradiol (E2) content and increased S. aureus adherence to vaginal epithelial cells. Estrogen-induced activation of the ERα/FAK/Src/iNOS axis was notably inhibited by the specific ERα inhibitor (ICI 182780). Simultaneously, a significant decrease in the number of adherent S. aureus was observed. However, this inhibitory effect diminished after inhibitor treatment for 24 h. Our findings suggested that the ERα-associated signaling pathway might be involved in S. aureus adherence to vaginal epithelial cells, which appeared to be linked to enhanced cell adhesion leading to AV.

Organ Preservation in MSS Rectal Cancer.

Rectal cancer is a heterogeneous disease with complex genetic and molecular subtypes. Emerging progress of neoadjuvant therapy has led to increased pathological and clinical complete response (cCR) rates for microsatellite stable (MSS) rectal cancer, which responds poorly to immune checkpoint inhibitor alone. As a result, organ preservation of MSS rectal cancer as an alternative to radical surgery has gradually become a feasible option. For patients with cCR or near-cCR after neoadjuvant treatment, organ preservation can be implemented safely with less morbidity. Patient selection can be done either before the neoadjuvant treatment for higher probability or after with careful assessment for a favorable outcome. Those patients who achieved a good clinical response are managed with nonoperative management, organ preservation surgery, or radiation therapy alone followed by strict surveillance. The oncological outcomes of patients with careful selection and organ preservation seem to be noninferior compared with those of radical surgery, with lower postoperative morbidity. However, more studies should be done to seek better regression of tumor and maximize the possibility of organ preservation in MSS rectal cancer.

Nonoperative management of gastrointestinal malignancies in era of neoadjuvant treatment.

Cancers derived from the gastrointestinal (GI) tract are often treated with radical surgery to achieve a cure. However, recent advances in the management of GI cancers involve the use of a combination of neoadjuvant radiation and chemotherapy followed by surgical intervention to achieve improved local control and cure. Interestingly, a small proportion of patients with highly sensitive tumors achieved a pathological complete response (pCR) (no residual tumor cells in the resected specimen) to neoadjuvant chemoradiation therapy (nCRT). The desire for organ preservation and avoidance of surgical morbidity brings the idea of a nonoperative management (NOM) strategy. Because of the different nature of tumor biology, GI cancers present diverse responses to nCRT, ranging from high sensitivity (anal cancer) to low sensitivity (gastric/esophageal cancer). There is an increasing attention to NOM of localized GI cancers; however, without the use of biomarkers/imaging parameters to select such patients, NOM will remain a challenge. Therefore, this review intends to summarize some of the recent updates from the aspect of current nCRT regimens, criteria for patient selection and active surveillance schedules. We also hope to review significant sequelae of radical surgery and the complications of nCRT to clarify the directions for optimization of nCRT and NOM for oncologic outcomes and quality of life.

Correlation Between the Distance to Mesorectal Fascia and Prognosis of cT3 Rectal Cancer: Results of a Multicenter Study From China.

BACKGROUND: The cT3 substage criteria based on extramural depth of tumor invasion in rectal cancer have several limitations. OBJECTIVE: This study proposed that the distance between the deepest tumor invasion and mesorectal fascia on pretherapy MRI can distinguish the prognosis of patients with cT3 rectal cancer. DESIGN: This is a cohort study. SETTING: This study included a prospective, single-center, observational cohort and a retrospective, multicenter, independent validation cohort. PATIENT: Patients who had cT3 rectal cancer with negative mesorectal fascia undergoing neoadjuvant chemoradiotherapy followed by radical surgery were included in 4 centers in China from January 2013 to September 2014. INTERVENTION: Baseline MRI with the distance between the deepest tumor invasion and mesorectal fascia, extramural depth of tumor invasion, and mesorectum thickness were measured. MAIN OUTCOME MEASURES: The cutoff of the distance between the deepest tumor invasion and mesorectal fascia was determined by time-dependent receiver operating characteristic curves, supported by a 5-year progression rate from the prospective cohort, and was then validated in a retrospective cohort. RESULTS: There were 124 and 274 patients included in the prospective and independent validation cohorts. The distance between the deepest tumor invasion and mesorectal fascia was the only predictor for cancer-specific death (HR, 0.1; 95% CI, 0.0-0.7) and was also a significant predictor for distant recurrence (HR, 0.4; 95% CI, 0.2-0.9). No statistically significant difference was observed in prognosis between patients classified as T3a/b and T3c/d. LIMITATIONS: The sample size is relatively small, and the study focused on cT3 rectal cancers with a negative mesorectal fascia. CONCLUSIONS: A cutoff of 7 mm of the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI can distinguish cT3 rectal cancer from a different prognosis. We recommend using the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI for local and systemic risk assessment and providing a tailored schedule of neoadjuvant treatment. See Video Abstract at http://links.lww.com/DCR/B682.CORRELACIÓN ENTRE LA DISTANCIA DE LA FASCIA MESORRECTAL Y EL PRONÓSTICO DEL CÁNCER DE RECTO cT3: RESULTADOS DE UN ESTUDIO MULTICÉNTRICO DE CHINAANTECEDENTES:Los criterios de subestadificación cT3 basados en la profundidad extramural de invasión tumoral en el cáncer de recto tienen varias limitaciones.OBJETIVO:Este estudio propuso que la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética preterapia puede distinguir el pronóstico de los pacientes con cT3.DISEÑO:Estudio de cohorte.ENTORNO CLINICO:El estudio incluyó una cohorte observacional, prospectiva, unicéntrica, y una cohorte de validación retrospectiva, multicéntrica e independiente.PACIENTE:Se incluyeron pacientes con cáncer de recto cT3 con fascia mesorrectal negativa sometidos a quimio-radioterapia neoadyuvante seguida de cirugía radical en cuatro centros de China desde enero de 2013 hasta septiembre de 2014.INTERVENCIÓN:Imágenes de resonancia magnética de referencia fueron medidas con la distancia entre la invasión tumoral más profunda y la fascia mesorrectal; la profundidad extramural de la invasión tumoral y el grosor del mesorrecto.PRINCIPALES MEDIDAS DE VALORACION:El límite de la distancia entre la invasión tumoral más profunda y la fascia mesorrectal se determinó mediante curvas características operativas del receptor dependientes del tiempo y se apoyó en la tasa de progresión a 5 años de la cohorte prospectiva, y luego se validó en una cohorte retrospectiva.RESULTADOS:Se incluyeron 124 y 274 pacientes en la cohorte de validación prospectiva e independiente, respectivamente. La distancia entre la invasión tumoral más profunda de la fascia mesorrectal fue el único predictor de muerte específica por cáncer (Hazard ratio: 0.1, 95% CI, 0,0-0,7); y también fue un predictor significativo de recurrencia distante Hazard ratio: 0,4, 95% CI, 0,2-0,9). No se observaron diferencias estadísticamente significativas en el pronóstico entre los pacientes clasificados como T3a/b y T3c/d.LIMITACIONES:El tamaño de la muestra es relativamente pequeño y el estudio se centró en los cánceres de recto cT3 con fascia mesorrectal negativa.CONCLUSIONES:Un límite de 7 mm de distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia puede distinguir el cáncer de recto cT3 de diferentes pronósticos. Recomendamos la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia para la evaluación del riesgo local y sistémico, proporcionando un programa personalizado de tratamiento neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B682. (Traducción- Dr. Francisco M. Abarca-Rendon).

MRI measurements predict major low anterior resection syndrome in rectal cancer patients.

PURPOSE: Current low anterior resection syndrome (LARS) score is lagging behind and only based on clinical symptoms patient described. Preoperative imaging indicators which can be used to predict LARS is unknown. We proposed preoperative MRI parameters for identifying major LARS. METHODS: Patients receiving curative restorative anterior resection from Sept. 2007 to Sept. 2015 were collected to complete LARS score (median 75.7 months since surgery). MRI measurements associated with LARS were tested, and a multivariate logistic model was conducted for predicting LARS. Receiver operating characteristic curve was used to evaluate the model. RESULTS: Two hundred fifty-five patients undergoing neoadjuvant chemoradiotherapy and 72 patients undergoing direct surgery were enrolled. The incidence of major LARS in NCRT group was significantly higher (53.3% vs.34.7%, P = 0.005). In patients with neoadjuvant chemoradiotherapy, the thickness of ARJ (TARJ), the distance between the tumor's lower edge and anal rectal joint (DTA), and sex were independent factors for predicting major LARS; ORs were 0.382 (95% CI, 0.198-0.740), 0.653 (95% CI, 0.565-0.756), and 0.935 (95% CI, 0.915-0.955). The AUC of the multivariable model was 0.842 (95% CI, 0.794-0.890). In patients with direct surgery, only DTA was the independent factor for predicting major LARS; OR was 0.958 (95% CI, 0.930-0.988). The AUC was 0.777 (95% CI: 0.630-0.925). CONCLUSIONS: Baseline MRI measurements have the potential to predict major LARS in rectal cancer, which will benefit the decision-making and improve patients' life quality.

BMI and pelvimetry help to predict the duration of laparoscopic resection for low and middle rectal cancer.

BACKGROUND: In rectal cancer surgery, recent studies have found associations between clinical factors, especially pelvic parameters, and surgical difficulty; however, their findings are inconsistent because the studies use different criteria. This study aimed to evaluate common clinical factors that influence the operative time for the laparoscopic anterior resection of low and middle rectal cancer. METHODS: Patients who underwent laparoscopic radical resection of low and middle rectal cancer from January 2018 to December 2020 were retrospectively analyzed and classified according to the operative time. Preoperative clinical and magnetic resonance imaging (MRI)-related parameters were collected. Logistic regression analysis was used to identify factors for predicting the operative time. RESULTS: In total, 214 patients with a mean age of 60.3 ± 8.9 years were divided into two groups: the long operative time group (n = 105) and the short operative time group (n = 109). Univariate analysis revealed that the male sex, a higher body mass index (BMI, ≥ 24.0 kg/m2), preoperative treatment, a smaller pelvic inlet (< 11.0 cm), a deeper pelvic depth (≥ 10.7 cm) and a shorter intertuberous distance (< 10.1 cm) were significantly correlated with a longer operative time (P < 0.05). However, only BMI (OR 1.893, 95% CI 1.064-3.367, P = 0.030) and pelvic inlet (OR 0.439, 95% CI 0.240-0.804, P = 0.008) were independent predictors of operative time. Moreover, the rate of anastomotic leakage was higher in the long operative time group (P < 0.05). CONCLUSION: Laparoscopic rectal resection is expected to take longer to perform in patients with a higher BMI or smaller pelvic inlet.

Predictors of pathologic complete response in patients with residual flat mucosal lesions after neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Objective: The accurate prediction of tumor response to neoadjuvant chemoradiotherapy (nCRT) remains challenging. Few studies have investigated pathologic complete response (ypCR) prediction in patients with residual flat mucosal lesions after treatment. This study aimed to identify variables for predicting ypCR in patients with residual flat mucosal lesions after nCRT for locally advanced rectal cancer (LARC). Methods: Data of patients with residual flat mucosal lesions after nCRT who underwent radical resection between 2009 and 2015 were retrospectively collected from the LARC database at Peking University Cancer Hospital. Univariate and multivariate analyses of the association between clinicopathological factors and ypCR were performed, and a nomogram was constructed by incorporating the significant predictors. Results: Of the 246 patients with residual flat mucosal lesions included in the final analysis, 56 (22.8%) had ypCR. Univariate and multivariate analyses showed that pretreatment cT stage (pre-cT) ≤T2 (P=0.016), magnetic resonance tumor regression grade (MR-TRG) 1-3 (P=0.001) and residual mucosal lesion depth =0 mm (P<0.001) were associated with a higher rate of ypCR. A nomogram was developed with a concordance index (C-index) of 0.759 and the calibration curve showed that the nomogram model had good predictive consistency. The follow-up time ranged from 3.0 to 113.3 months, with a median follow-up time of 63.77 months. The multivariate Cox regression model showed that the four variables in the nomogram model were not risk factors for disease-free survival (DFS) or overall survival (OS). Conclusions: Completely flat mucosa, early cT stage and good MR-TRG were predictive factors for ypCR instead of DFS or OS in patients with LARC with residual flat mucosal lesions after nCRT. Endoscopic mucosal re-evaluation before surgery is important, as it may contribute to decision-making and facilitate nonoperative management or organ preservation.

Short-term outcomes of complete mesocolic excision versus D2 dissection in patients undergoing laparoscopic colectomy for right colon cancer (RELARC): a randomised, controlled, phase 3, superiority trial.

BACKGROUND: Whether extended lymphadenectomy for right colon cancer leads to increased perioperative complications or improves survival is still controversial. This trial aimed to compare the efficacy and safety of complete mesocolic excision (CME) versus D2 dissection in laparoscopic right hemicolectomy for patients with right colon cancer. This article reports the early safety results from the trial. METHODS: This randomised, controlled, phase 3, superiority, trial was done at 17 hospitals in nine provinces of China. Eligible patients were aged 18-75 years with histologically confirmed primary adenocarcinoma located between the caecum and the right third of the transverse colon, without evidence of distant metastases. Central randomisation was done by means of the Clinical Information Management-Central Randomisation System via block randomisation (block size of four). Patients were randomly assigned (1:1) to CME or D2 dissection during laparoscopic right colectomy. Central lymph nodes were dissected in the CME but not in the D2 procedure. Neither investigators nor patients were masked to their group assignment but the quality control committee were masked to group assignment. The primary endpoint was 3-year disease-free survival, but the data for this endpoint are not yet mature; thus, only the secondary outcomes-intraoperative surgical complications and postoperative complications within 30 days of surgery, graded according to the Clavien-Dindo classification, mortality (death from any cause within 30 days of surgery), and central lymph node metastasis rate in the CME group only-are reported in this Article. This early analysis of safety was preplanned. The outcomes were analysed according to a modified intention-to-treat principle (excluding patients who no longer met inclusion criteria after surgery or who did not have surgery). This study is registered with ClinicalTrials.gov, NCT02619942. Study recruitment is complete, and follow-up is ongoing. FINDINGS: Between Jan 11, 2016, and Dec 26, 2019, 1072 patients were enrolled and randomly assigned. After exclusion of 77 patients, 995 patients were included in the modified intention-to-treat population (495 in the CME group and 500 in the D2 dissection group). The postoperative surgical complication rate was 20% (97 of 495 patients) in the CME group versus 22% (109 of 500 patients) in the D2 group (difference, -2·2% [95% CI -7·2 to 2·8]; p=0·39); the frequency of Clavien-Dindo grade I-II complications were similar between groups (91 [18%] vs 92 [18%], difference, -0·0% [95% CI -4·8 to 4·8]; p=1·0) but Clavien-Dindo grade III-IV complications were significantly less frequent in the CME group than in the D2 group (six [1%] vs 17 [3%], -2·2% [-4·1 to -0·3]; p=0·022); no deaths occurred in either group. Of the intraoperative complications, vascular injury was significantly more common in the CME group than in the D2 group (15 [3%] vs six [1%], difference, 1·8 [95% CI 0·04 to 3·6]; p=0·045). Metastases in the central lymph nodes were detected in 13 (3%) of 394 patients who underwent central lymph node biopsy in the CME group; no patient had isolated metastases to central lymph nodes. INTERPRETATION: Although the CME procedure might increase the risk of intraoperative vascular injury, it generally seems to be safe and feasible for experienced surgeons. FUNDING: The Capital Characteristic Clinical Project of Beijing and the Chinese Academy of Medical Sciences.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Prognostic and predictive value of mismatch repair deficiency in gastric and gastroesophageal junction adenocarcinoma patients receiving neoadjuvant or adjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: Evidence is inconclusive regarding the prognostic significance of deficient DNA mismatch repair (dMMR) in gastric and gastroesophageal junction (GEJ) adenocarcinoma patients receiving chemotherapy. We aim to explore such associations with a large cohort. METHODS: We retrospectively identified a consecutive cohort of patients who had histology proven gastric or GEJ adenocarcinoma and received neoadjuvant chemotherapy plus surgery or upfront surgery plus adjuvant chemotherapy. MMR status was assessed by immunohistochemistry staining on surgical specimen. The association of MMR status with tumor regression grade (TRG), overall survival (OS), and disease-free survival (DFS) were analyzed. RESULTS: In total, 1568 patients received neoadjuvant or adjuvant chemotherapy, of which 128 (8.2%) had dMMR tumors. No significant difference was found in the frequencies of TRG categories between proficient MMR (pMMR) and dMMR tumors (p = .62). Among patients receiving neoadjuvant chemotherapy, dMMR status was associated with better OS (log-rank p = .044) and DFS (log-rank p = .022) in the univariate analysis; this association became nonsignificant after adjusting for pathologic stages and other prognostic factors. Similar results were found for patients receiving adjuvant chemotherapy. CONCLUSIONS: dMMR status was not significantly associated with OS and DFS among gastric and GEJ adenocarcinoma patients with neoadjuvant and adjuvant platinum and fluorouracil-based chemotherapy.

Prognostic value of nucleotyping, DNA ploidy and stroma in high-risk stage II colon cancer.

BACKGROUND: Heterogeneity with respect to recurrence and survival in high-risk stage II colon cancer patients still exists, and further classification is urgently required. This study aimed to ascertain the prognostic value of DNA ploidy, stroma-tumour fraction and nucleotyping in the prognosis of high-risk stage II colon cancer. METHODS: A total of 188 high-risk stage II colon cancer patients received radical surgery in Peking University Cancer Hospital, from 2009 to 2015. Status of mismatch repair proteins in tumours was analysed using immunohistochemistry. DNA ploidy, stroma-tumour fraction and nucleotyping were estimated by automated digital imaging systems. RESULTS: Nucleotyping and DNA ploidy were significant prognostic factors, while stroma-tumour fraction were not significantly prognostic in the univariate analysis. In the multivariable model, the dominant contributory factor of disease-free survival was chromatin heterogeneous vs. chromatin homogeneous [HR 3.309 (95% CI: 1.668-6.564), P = 0.001]. CONCLUSIONS: Our study indicates that nucleotyping is an independent prognostic factor in high-risk stage II colon cancer. Therefore, it may help subdivide patients into different subgroups and give them different strategies for follow-up and treatment in the future.

Clinical Decision Support for High-Risk Stage II Colon Cancer: A Real-World Study of Treatment Concordance and Survival.

BACKGROUND: Prognostic and pathologic risk factors typically guide clinicians and patients in their choice of surveillance or adjuvant chemotherapy when managing high-risk stage II colon cancer. However, variations in treatment and outcomes in patients with stage II colon cancer remain. OBJECTIVE: This study aimed to assess the survival benefits of treatments concordant with suggested therapeutic options from Watson for Oncology, a clinical decision support system. DESIGN: This is a retrospective observational study of concordance between actual treatment and Watson for Oncology therapeutic options. SETTING: This study was conducted at a top-tier cancer center in China. PATIENTS: Postoperative treatment data were retrieved from the electronic health records of 306 patients with high-risk stage II colon adenocarcinoma. MAIN OUTCOME MEASURES: The primary outcomes measured were the treatment patterns plus 3- and 5-year overall and disease-free survival for concordant and nonconcordant cases. RESULTS: Overall concordance was 90%. Most nonconcordant care resulted from adjuvant chemotherapy use (rather than surveillance) in patients with high-level microsatellite instability and ≥70 years old. No difference in overall survival (p = 0.56) or disease-free survival (p = 0.19) was observed between concordance groups. Patients receiving adjuvant chemotherapy had significantly higher 5-year overall survival than those undergoing surveillance (94% vs 84%, p = 0.01). LIMITATIONS: This study was limited by the use of retrospective cases drawn from patients presenting for surgery, the lack of complete follow-up data for 58% of patients who could not be included in the analysis, and a survival analysis that assumes no unmeasured correlation between survival and censoring. CONCLUSIONS: Watson for Oncology produced therapeutic options highly concordant with human decisions at a top-tier cancer center in China. Treatment patterns suggest that Watson for Oncology may be able to guide clinicians to minimize overtreatment of patients with high-risk stage II colon cancer with chemotherapy. Survival analyses suggest the need for further investigation to specifically assess the association between surveillance, single-agent and multiagent chemotherapy, and survival outcomes in this population. See Video Abstract at http://links.lww.com/DCR/B291. APOYO A LA DECISIÓN CLÍNICA DEL CÁNCER DE COLON EN ESTADIO II DE ALTO RIESGO: UN ESTUDIO DEL MUNDO REAL SOBRE LA CONCORDANCIA DEL TRATAMIENTO Y LA SUPERVIVENCIA: Los factores de riesgo pronósticos y patológicos generalmente guían a los médicos y pacientes en su elección de vigilancia o quimioterapia adyuvante cuando se trata el cáncer de colon en estadio II de alto riesgo. Sin embargo, las variaciones en el tratamiento y los resultados en pacientes con cáncer de colon en estadio II permanecen.Evaluar los beneficios de supervivencia de los tratamientos concordantes con las opciones terapéuticas sugeridas por "Watson for Oncology" (Watson para la oncología), un sistema de apoyo a la decisión clínica.Estudio observacional retrospectivo de concordancia entre el tratamiento real y las opciones terapéuticas de Watson para oncología.Un centro oncológico de primer nivel en China.Datos de tratamiento postoperatorio de registros de salud electrónicos de 306 pacientes con adenocarcinoma de colon en estadio II de alto riesgo.Patrones de tratamiento más supervivencia global y libre de enfermedad a 3 y 5 años para casos concordantes y no concordantes.La concordancia general fue del 90%. La mayoría de la atención no concordante resultó del uso de quimioterapia adyuvante (en lugar de vigilancia) en pacientes de alto nivel con inestabilidad de microsatélites y pacientes ≥70 años. No se observaron diferencias en la supervivencia global (p = 0,56) o la supervivencia libre de enfermedad (p = 0,19) entre los grupos de concordancia. Los pacientes que recibieron quimioterapia adyuvante tuvieron una supervivencia global a los 5 años significativamente más alta que los que fueron sometidos a vigilancia (94% frente a 84%, p = 0,01).Uso de casos retrospectivos extraídos de pacientes que se presentan para cirugía, falta de datos de seguimiento completos para el 58% de los pacientes que no pudieron ser incluidos en el análisis, y análisis de supervivencia que asume que no exite una correlación no medida entre supervivencia y censura.Watson para Oncología produjo opciones terapéuticas altamente concordantes con las decisiones humanas en un centro oncológico de primer nivel en China. Los patrones de tratamiento sugieren que Watson para Oncología puede guiar a los médicos para minimizar el sobretratamiento de pacientes con cáncer de colon en estadio II de alto riesgo con quimioterapia. Los análisis de supervivencia sugieren la necesidad de realizar mas investigaciónes para evaluar específicamente la asociación entre la vigilancia, la quimioterapia con uno solo o múltiples agentes y los resultados de supervivencia en esta población. Consulte Video Resumen en http://links.lww.com/DCR/B291. (Traducción-Dr. Gonzalo Hagerman).

Impact of postoperative major complications on long-term survival after radical resection of gastric cancer.

BACKGROUND: This study was designed to evaluate the impact of postoperative major complications on long-term survival following curative gastrectomy. METHODS: This retrospective study included 239 patients with gastric cancer undergoing gastrectomy at the Beijing Cancer Hospital from February 2012 to January 2013. Survival curves were compared between patients with major complications (mC group) and those without major complications (NmC group). Multivariate analysis was conducted to identify independent prognostic factors. RESULTS: Postoperative complication and mortality rates were 24.7 and 0.8%, respectively. The severity of complications was graded in accordance with the Clavien-Dindo classification. The incidence of minor complications (grades I-II) and major complications (grades III-V) was 9.2 and 15.5%, respectively. The 3-year overall survival (OS) and disease-free survival (DFS) rates were better in the NmC group than in the mC group (p = 0.014, p = 0.013). Multivariate analysis identified major complications as an independent prognostic factor for OS and DFS. After stratification by pathological stage, this trend was also observed in stage II patients. CONCLUSIONS: Postoperative major complications adversely affect OS and DFS. The prevention and early diagnosis of complications are essential to minimize the negative effects of complications on surgical safety and long-term patient survival.

MRI of Extramural Venous Invasion in Locally Advanced Rectal Cancer: Relationship to Tumor Recurrence and Overall Survival.

Purpose To study the relationship between MRI-defined extramural venous invasion (EMVI) prior to treatment and prognosis in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy-radiation therapy followed by surgery. Materials and Methods This retrospective study included 517 patients with locally advanced rectal cancer evaluated from August 2008 to December 2014. Baseline and posttherapy MRI and follow-up data were retrieved for all patients. After training by using 328 cases with pathologic evaluation of EMVI after therapy, radiologists evaluated baseline MRI for EMVI status in addition to tumor size and characteristics, nodal status, and invasion of the mesorectal fascia. Reader reproducibility was determined by using κ coefficient. Kaplan-Meier curves and adjusted Cox models were used to determine the relationship of baseline MRI parameters to overall survival, metastasis-free survival, and local relapse-free survival. Results Among 517 patients, 335 (64.8%) were men; the mean age was 55.6 years ± 11.5 (standard deviation). At baseline, radiologists identified 259 of 517 (50%) patients with EMVI by using MRI. In adjusted analysis, EMVI and mesorectal fascial invasion at baseline MRI were predictors of metastasis-free survival (hazard ratio, 0.3 and 0.6; P ˂ .01 and P ˂ .02, respectively) and overall survival (hazard ratio, 0.5 and 0.5; P = .01 and P = .02, respectively). EMVI was the only factor associated with local relapse-free survival (hazard ratio, 0.3; P ˂ .01). The κ coefficient for determination of EMVI was 0.80. Conclusion Extramural venous invasion (EMVI) can be reliably evaluated with MRI. The presence of EMVI was associated with greater risk of local and distant tumor recurrence and overall death in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy-radiation therapy. © RSNA, 2018 Online supplemental material is available for this article.