Is Robotic Surgery Beneficial for Rectal Cancer Patients with Unfavorable Characteristic After Neoadjuvant Chemoradiotherapy?

BACKGROUND: The objective of this study was to compare long-term oncologic outcomes of robot and laparoscopic surgeries for patients with advanced rectal cancer who underwent neoadjuvant chemoradiotherapy (nCRT) followed by radical resection. METHODS: This study analyzed 3240 rectal cancer patients who underwent radical surgery from 2008 to 2019. Among them, 1204 patients who received nCRT (robotic, n = 316; laparoscopic, n = 888) were analyzed. The oncological outcome according to the number of unfavorable factors (male, body mass index ≥ 25, receiving CCRT) present in patients also was analyzed. We used 1:1 propensity score matching (PSM) to adjust for potential baseline confounders between groups. RESULTS: After PSM, two groups showed similar demographics and pathological results. After PSM analysis, the robotic group showed higher 5-year disease-free survival (DFS) and local recurrence-free survival rates than the laparoscopic group, whereas 5-year overall survival and distant recurrence-free survival rates were similar between the two groups. In addition, by comparing survival rates for each yp stage, it was found 5-year DFS and local recurrence-free survival of the robotic group in yp stage III were significantly higher than those of the laparoscopic group. Five-year DFS was conducted according to the number of unfavorable factors (male, body mass index ≥ 25 kg/m2, and undergoing nCRT) as a subgroup analysis. In patients with all three unfavorable factors, the robotic group showed significantly higher DFS than the laparoscopic group. CONCLUSIONS: Robotic approach for rectal cancer after nCRT, especially for patients with yp stage III and unfavorable factors, have the advantage of improving oncologic outcomes even for surgeons specializing in colorectal cancer.

Pulmonary Metastasis as the First Site of Metastasis After Curative Surgery for Colon Cancer: Incidence and Risk Factors According to the TNM Stage.

BACKGROUND: The lungs are one of the most common sites for colon cancer metastasis. A few studies reported that approximately 2% to 10% of patients with colon cancer developed pulmonary metastasis. However, among these studies, patient characteristics were heterogeneous, and information on pulmonary metastasis incidence by the TNM stage was scarce. OBJECTIVE: This study evaluated the incidence of pulmonary metastasis in colon cancer without synchronous metastasis treated with radical surgery and identified risk factors for pulmonary metastasis according to the TNM stage. DESIGN AND SETTINGS: This retrospective study included all patients with colon cancer without metastasis who underwent radical surgery for primary tumor at Samsung Medical Center between January 2007 and December 2016. PATIENTS: A total of 4889 patients who underwent radical surgery for stage I and III colon cancer were included. MAIN OUTCOME MEASURES: The main outcome measures were the incidence of pulmonary metastasis and overall survival. RESULTS: A total of 156 patients (3.2%) were diagnosed with pulmonary metastasis after a median of 16 months from the time of radical surgery for colon cancer to detection of pulmonary metastasis. The pulmonary metastasis incidence rate by the TNM stage was 0.5% in stage I, 1.6% in stage II, and 6% in stage III. Risk factors for pulmonary metastasis were preoperative CEA >5 ng/mL, cancer obstruction, N stage, vascular invasion, perineural invasion, and adjuvant chemotherapy for primary colon cancer in multivariable analysis. LIMITATION: This was a retrospective single-center study. CONCLUSIONS: Preoperative CEA >5 ng/mL, cancer obstruction, pN stage, vascular invasion, perineural invasion, and receiving adjuvant chemotherapy for primary colon cancer were risk factors for pulmonary metastasis in colon cancer. Therefore, patients with risk factors for pulmonary metastasis should be recommended for intensive follow-up to detect lung metastases. See Video Abstract . METSTASIS PULMONAR EN EL PRIMER SITIO TRAS CIRUGA CURATIVA DEL CNCER DE COLON INCIDENCIA Y FACTORES DE RIESGO SEGN ESTADIO TNM: ANTECEDENTES:Los pulmones son uno de los sitios más comunes de metástasis del cáncer de colon. Algunos estudios informaron que aproximadamente entre el 2% y el 10% de los pacientes con cáncer de colon desarrollaron metástasis pulmonar. Sin embargo, entre estos estudios, las características de los pacientes fueron heterogéneas y la información sobre la incidencia de metástasis pulmonares según el estadio TNM fue escasa.OBJETIVO:Este estudio evaluó la incidencia de metástasis pulmonar en cáncer de colon sin metástasis sincrónica tratada con cirugía radical e identificó factores de riesgo para metástasis pulmonar según el estadio TNM.DISEÑO Y AJUSTES:Este estudio retrospectivo incluyó a todos los pacientes con cáncer de colon sin metástasis que se sometieron a cirugía radical por tumor primario en el Samsung Medical Center entre enero de 2007 y diciembre de 2016.PACIENTES:Se incluyó un total de 4.889 pacientes sometidos a cirugía radical por cáncer de colon en estadio I-III.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas de resultado fueron la incidencia de metástasis pulmonar y la supervivencia general.RESULTADOS:Un total de 156 pacientes (3,2%) fueron diagnosticados con metástasis pulmonar con una duración media de 16 meses desde el momento de la cirugía radical por cáncer de colon hasta la detección de la metástasis pulmonar. La tasa de incidencia de metástasis pulmonares por estadio TNM fue del 0,5% en el estadio I, del 1,6% en el estadio II y del 6% en el estadio III. Los factores de riesgo de metástasis pulmonar fueron CEA preoperatorio superior a 5 ng/ml, obstrucción por cáncer, estadio N, invasión vascular, invasión perineural y quimioterapia adyuvante para el cáncer de colon primario en un análisis multivariable.LIMITACIÓN:Este fue un estudio retrospectivo de un solo centro.CONCLUSIÓN:CEA preoperatorio superior a 5 ng/ml, obstrucción por cáncer, estadio pN, invasión vascular, invasión perineural y recibir quimioterapia adyuvante para el cáncer de colon primario fueron factores de riesgo de metástasis pulmonar en el cáncer de colon. Por lo tanto, se debe recomendar un seguimiento intensivo a los pacientes con factores de riesgo de metástasis pulmonares para detectar metástasis pulmonares. (Traducción-Dr Yolanda Colorado ).

Revised Nodal Staging Integrating Tumor Deposit Counts With Positive Lymph Nodes in Patients With Stage III Colon Cancer.

OBJECTIVE: We evaluated the prognostic value of tumor deposit (TD) counts and incorporated them with the number of positive lymph nodes to develop a revised nodal staging. SUMMARY BACKGROUND DATA: The current American Joint Committee on Cancer (AJCC) staging on colon cancer includes the TDs only for nodenegative patients, as N1c, and their counts are not considered. METHODS: We included consecutive patients with stage III colorectal cancer who underwent curative resections between January 2010 and December 2019. The patients were grouped as TD 0, TD 1, TD 2, or TD ≥3 based on their TD counts. Disease-free survival and overall survival were compared. RESULTS: Of 2446 eligible stage III patients, 658 (26.9%) had TDs. Among them, 500 (76.0%) patients concurrently had positive lymph nodes (LNs). TD counts were significantly related to worse disease-free survival (DFS) and overall survival regardless of pT stages or the number of positive LNs. The patients were restaged based on the integrated number of TD counts and positive LNs. The N3 stage, which had ≥10 integrated TDs and positive LNs, was newly classified. Among the patients who completed 6 months of adjuvant chemotherapy, those upstaged to N2 from an initial stage of N1 experienced significantly worse DFS than those confirmed as N1 in the revised N staging. The newly N3-staged patients showed significantly worse DFS than the patients initially staged as N2. CONCLUSIONS: Revised N staging using the integrated number of TD counts and positive LNs could predict DFS more accurately than current staging. It would also draw greater attention to the patients with high-risk stage III colon cancer staged as N3.

Association Between Distress at Diagnosis and Disease-free Survival Among Patients With Resectable Colon Cancer: A Large Cohort Study.

OBJECTIVE: This study aimed to evaluate the association between distress at initial diagnosis and disease-free survival in patients with resectable colon cancer. SUMMARY BACKGROUND DATA: Considerable research has examined the psychological impact of having a confirmed diagnosis of cancer, but relatively limited research has examined the impact of distress during the diagnostic phase on oncological outcomes. METHODS: This is a retrospective cohort study. We included newly diagnosed colon cancer patients who had resectable surgery and underwent distress screening between July 2014 and July 2021 (N=1,362). The Korean versions of the Distress Thermometer were used to assess distress and related problems. Patients were categorized into 3 groups based on distress score: low (<4), moderate (4-7), and severe (≥8). The primary outcome was disease-free survival. RESULTS: The mean distress was 5.1 (SD=2.4) and 61%, and 15% of patients had moderate and severe distress at diagnosis, respectively. The severe distress group was more likely to report fear, sadness, and concerns regarding insurance/finance, work, and childcare than the low distress group. Compared with the low distress group, the severe distress group had worse disease-free survival (Hazard Ratio=1.84, 95% CI=1.03, 3.29). The association was more evident in patients with stage IV disease (Hazard Ratio=2.53, 95% CI=1.02, 6.25). CONCLUSIONS: A substantial number of patients with colon cancer experience distress at diagnosis, and severe distress has a negative impact on oncologic outcomes. Active monitoring and appropriate management of distress at diagnosis should be adopted at clinical settings.

Transcriptomes of the tumor-adjacent normal tissues are more informative than tumors in predicting recurrence in colorectal cancer patients.

BACKGROUND: Previous investigations of transcriptomic signatures of cancer patient survival and post-therapy relapse have focused on tumor tissue. In contrast, here we show that in colorectal cancer (CRC) transcriptomes derived from normal tissues adjacent to tumors (NATs) are better predictors of relapse. RESULTS: Using the transcriptomes of paired tumor and NAT specimens from 80 Korean CRC patients retrospectively determined to be in recurrence or nonrecurrence states, we found that, when comparing recurrent with nonrecurrent samples, NATs exhibit a greater number of differentially expressed genes (DEGs) than tumors. Training two prognostic elastic net-based machine learning models-NAT-based and tumor-based in our Samsung Medical Center (SMC) cohort, we found that NAT-based model performed better in predicting the survival when the model was applied to the tumor-derived transcriptomes of an independent cohort of 450 COAD patients in TCGA. Furthermore, compositions of tumor-infiltrating immune cells in NATs were found to have better prognostic capability than in tumors. We also confirmed through Cox regression analysis that in both SMC-CRC as well as in TCGA-COAD cohorts, a greater proportion of genes exhibited significant hazard ratio when NAT-derived transcriptome was used compared to when tumor-derived transcriptome was used. CONCLUSIONS: Taken together, our results strongly suggest that NAT-derived transcriptomes and immune cell composition of CRC are better predictors of patient survival and tumor recurrence than the primary tumor.

Star Shaped Quivers in Four Dimensions.

We discuss 4D Lagrangian descriptions, across dimensions IR duals, of compactifications of the 6D (D, D) minimal conformal matter theory on a sphere with arbitrary number of punctures and a particular value of flux as a gauge theory with a simple gauge group. The Lagrangian has the form of a "star shaped quiver" with the rank of the central node depending on the 6D theory and the number and type of punctures. Using this Lagrangian one can construct across dimensions duals for arbitrary compactifications (any, genus, any number and type of USp punctures, and any flux) of the (D, D) minimal conformal matter gauging only symmetries which are manifest in the ultraviolet.

Effectiveness of personalized treatment stage-adjusted digital therapeutics in colorectal cancer: a randomized controlled trial.

BACKGROUND: Colorectal cancer survivors often experience decline in physical performance and poor quality of life after surgery and during adjuvant therapies. In these patients, preserving skeletal muscle mass and high-quality nourishment are essential to reduce postoperative complications and improve quality of life and cancer-specific survival. Digital therapeutics have emerged as an encouraging tool for cancer survivors. However, to the best of our knowledge, randomized clinical trials applying personalized mobile application and smart bands as a supportive tool to several colorectal patients remain to be conducted, intervening immediately after the surgical treatment. METHODS: This study is a prospective, multi-center, single-blinded, two-armed, randomized controlled trial. The study aims to recruit 324 patients from three hospitals. Patients will be randomly allocated to two groups for one year of rehabilitation, starting immediately after the operation: a digital healthcare system rehabilitation (intervention) group and a conventional education-based rehabilitation (control) group. The primary objective of this protocol is to clarify the effect of digital healthcare system rehabilitation on skeletal muscle mass increment in patients with colorectal cancer. The secondary outcomes would be the improvement in quality of life measured by EORTC QLQ C30 and CR29, enhanced physical fitness level measured by grip strength test, 30-sec chair stand test and 2-min walk test, increased physical activity measured by IPAQ-SF, alleviated pain intensity, decreased severity of the LARS, weight, and fat mass. These measurements will be held on enrollment and at 1, 3, 6 and 12 months thereafter. DISCUSSION: This study will compare the effect of personalized treatment stage-adjusted digital health interventions on immediate postoperative rehabilitation with that of conventional education-based rehabilitation in patients with colorectal cancer. This will be the first randomized clinical trial performing immediate postoperative rehabilitation in a large number of patients with colorectal cancer with a tailored digital health intervention, modified according to the treatment phase and patient condition. The study will add foundations for the application of comprehensive digital healthcare programs focusing on individuality in postoperative rehabilitation of patients with cancer. TRIAL REGISTRATION: NCT05046756. Registered on 11 May 2021.

Prognostic Impact of Lymphatic Invasion, Venous Invasion, Perineural Invasion, and Tumor Budding in Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy Followed by Total Mesorectal Excision.

BACKGROUND: The diagnostic implications of lymphatic invasion, venous invasion, perineural invasion, and tumor budding in rectal cancer treated with neoadjuvant chemoradiotherapy are unknown. OBJECTIVE: This study aimed to identify the prognostic impact of lymphatic invasion, venous invasion, perineural invasion, and tumor budding in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at the Samsung Medical Center. Grouping was performed on the basis of lymphatic invasion, venous invasion, perineural invasion, and tumor budding status: no-risk group with 0 factor (n = 299), low-risk group with any 1 factor (n = 131), intermediate-risk group with any 2 factors (n = 75), and high-risk group with 3 or 4 risk factors (n = 32). PATIENTS: Patients who underwent neoadjuvant chemoradiotherapy, followed by radical operation for locally advanced rectal cancer, from January 2010 to December 2015 were included. MAIN OUTCOME MEASURES: The main outcome measures were disease-free and overall survival. RESULTS: Disease-free and overall survival varied significantly between the groups in stage III ( p < 0.001 and p < 0.001). Disease-free survival in stage I differed between the no-risk group and the intermediate-risk group ( p = 0.026). In stage II, disease-free and overall survival differed between the no-risk group and the intermediate-risk group ( p = 0.010 and p = 0.045). In multivariable analysis, risk grouping was an independent prognostic factor for both disease-free (p <0.001) and overall survival ( p < 0.001). LIMITATIONS: The inherent limitations are associated with the retrospective single-center study design. CONCLUSIONS: Lymphatic invasion, venous invasion, perineural invasion, and tumor budding are strong prognostic factors for disease-free and overall survival in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Therefore, adjuvant chemotherapy is strongly recommended in patients with positive lymphatic invasion, venous invasion, perineural invasion, and tumor budding. See Video Abstract at http://links.lww.com/DCR/B919 . IMPACTO PRONSTICO DE LA INVASIN LINFTICA, LA INVASIN VENOSA, LA INVASIN PERINEURAL Y LA GEMACIN TUMORAL EN EL CNCER DE RECTO TRATADO CON QUIMIORRADIOTERAPIA NEOADYUVANTE SEGUIDA DE ESCISIN TOTAL DEL MESORRECTO: ANTECEDENTES:Se desconocen las implicaciones diagnósticas de la invasión linfática, la invasión venosa, la invasión perineural y el crecimiento tumoral en el cáncer de recto tratado con quimiorradioterapia neoadyuvante.OBJETIVO:Este estudio fue diseñado para identificar el impacto pronóstico de la invasión linfática, la invasión venosa, la invasión perineural y la gemación tumoral en el cáncer de recto localmente avanzado tratado con quimiorradioterapia neoadyuvante.DISEÑO:Este estudio fue un estudio de cohorte retrospectivo.AJUSTES:Este estudio se realizó en el Centro Médico Samsung. La agrupación se realizó en función de la invasión linfática, la invasión venosa, la invasión perineural y el estado de crecimiento del tumor: grupo sin riesgo con 0 factores (n = 299), grupo de bajo riesgo con cualquier factor 1 (n = 131), grupo de riesgo intermedio con 2 factores cualquiera (n = 75), y un grupo de alto riesgo con 3 o 4 factores de riesgo (n = 32).PACIENTES:Se incluyeron un total de 537 pacientes que se sometieron a quimiorradioterapia neoadyuvante seguida de operación radical por cáncer de recto localmente avanzado desde enero de 2010 hasta diciembre de 2015.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas de resultado fueron la supervivencia libre de enfermedad y la supervivencia general.RESULTADOS:La mediana del período de seguimiento fue de 77 meses, y la supervivencia libre de enfermedad a los 5 años y la supervivencia general a los 5 años variaron significativamente entre los grupos en el estadio III (p < 0,001, p < 0,001). La supervivencia libre de enfermedad a los 5 años en el estadio I difirió entre el grupo sin riesgo y el grupo de riesgo intermedio (p = 0,026). En el estadio II, la supervivencia libre de enfermedad a 5 años y la supervivencia global a 5 años difirieron entre el grupo sin riesgo y el grupo de riesgo intermedio p = 0,010, p = 0,045). En el análisis multivariable, la agrupación de riesgo fue un factor pronóstico independiente tanto para la supervivencia libre de enfermedad (p < 0,001) como para la supervivencia global (p < 0,001).LIMITACIÓN:Las limitaciones inherentes están asociadas con el diseño de estudio retrospectivo de un solo centro..CONCLUSIÓN:La invasión linfática, la invasión venosa, la invasión perineural y la gemación tumoral son fuertes factores pronósticos para la supervivencia libre de enfermedad y la supervivencia general en el cáncer de recto localmente avanzado tratado con quimiorradioterapia neoadyuvante. Por lo tanto, se recomienda fuertemente la quimioterapia adyuvante en pacientes con invasión linfática positiva, invasión venosa, invasión perineural y tumor en en formacion. Consulte Video Resumen en http://links.lww.com/DCR/B919 . (Traducción-Dr Yolanda Colorado ).

Prognostic Impact of Mucinous Adenocarcinoma in Stage II and III Colon Cancer.

BACKGROUND: Mucinous adenocarcinoma is a rare histologic feature of colorectal cancer and is characterized by oncologic features that are different from those of adenocarcinoma. However, there are conflicting views regarding the prognostic impact of mucinous adenocarcinoma on colon cancer. OBJECTIVE: This study aimed to evaluate the prognostic impact of mucinous adenocarcinoma in stage II and III colon cancer. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted between January 2010 and December 2015. Patients were divided into the mucinous adenocarcinoma and nonmucinous adenocarcinoma groups. Disease-free survival and overall survival were assessed using propensity score matching. PATIENTS: Overall, 2532 patients who underwent radical surgery for stage II and III colon cancer were included in the study. MAIN OUTCOME MEASURES: The main outcome measures were disease-free survival and overall survival. RESULTS: The median follow-up duration was 86 months. The disease-free survival and overall survival were significantly lower in the mucinous adenocarcinoma group than in the nonmucinous adenocarcinoma group. In subgroup analysis, there was no significant difference in the disease-free survival and overall survival between patients with and without mucinous adenocarcinoma with stage II colon cancer. In stage III colon cancer, the disease-free survival and overall survival were significantly lower in patients with mucinous adenocarcinoma than in those without mucinous adenocarcinoma. Multivariable analysis showed that mucinous adenocarcinoma was a poor prognostic factor for disease-free survival and overall survival. LIMITATION: The study's limitations include those that are inherently associated with retrospective single-center studies. CONCLUSIONS: Mucinous adenocarcinoma is a poor prognostic factor in stage III but not in stage II colon cancer. Therefore, mucinous adenocarcinoma might not be regarded as an independent risk factor requiring chemotherapy for favorable oncologic outcomes. However, for stage III colon cancer, patients with mucinous adenocarcinoma require close observation. IMPACTO PRONSTICO DEL ADENOCARCINOMA MUCINOSO EN LAS ETAPAS II Y III DE CNCER DE CLON: ANTECEDENTES:El adenocarcinoma mucinoso es una característica histológica rara del cáncer colorrectal, se caracteriza por propiedades oncológicas que son diferentes a las del adenocarcinoma. Sin embargo, existen puntos de vista contradictorios con respecto al impacto pronóstico del adenocarcinoma mucinoso en el cáncer de colon.OBJETIVO:Este estudio tuvo como objetivo evaluar el impacto pronóstico del adenocarcinoma mucinoso en las etapas II y III de cáncer de cólon.DISEÑO Y CONFIGURACIONES:Este estudio de cohorte retrospectivo se realizó entre enero de 2010 y diciembre de 2015. Los pacientes se dividieron entre grupos de adenocarcinoma mucinoso y adenocarcinoma no mucinoso. La supervivencia libre de enfermedad y la supervivencia global se evaluaron utilizando emparejamiento por puntuación de propensión.PACIENTES:En general, 2,532 pacientes que se sometieron a cirugía radical para etapa II y III de cáncer de colon se incluyeron en el estudio.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas de resultado fueron la supervivencia libre de enfermedad y la supervivencia general.RESULTADOS:La mediana de duración del seguimiento fue de 86 meses. La supervivencia libre de enfermedad y la supervivencia global fueron significativamente menores en el grupo de adenocarcinoma mucinoso que en el grupo de adenocarcinoma no mucinoso. En el análisis de subgrupos, no hubo diferencias significativas en la supervivencia libre de enfermedad y la supervivencia global entre los pacientes con o sin adenocarcinoma mucinoso con cáncer de cólon etapa II. En el cáncer de colon etapa III, la supervivencia libre de enfermedad y la supervivencia global fueron significativamente más bajas en pacientes con adenocarcinoma mucinoso que en aquellos sin adenocarcinoma mucinoso. El análisis multivariable mostró que el adenocarcinoma mucinoso era un factor de mal pronóstico para la supervivencia libre de enfermedad y la supervivencia global.LIMITACIONES:Las limitaciones del estudio incluyen aquellas que están inherentemente asociadas con estudios retrospectivos de un solo centro.CONCLUSIONES:El adenocarcinoma mucinoso es un factor de mal pronóstico en el cáncer de colon etapa III pero no en etapa II. Por lo tanto, el adenocarcinoma mucinoso podría no considerarse un factor de riesgo independiente que requiera quimioterapia para obtener resultados oncológicos favorables. Sin embargo, para el cáncer de colon etapa III, los pacientes con adenocarcinoma mucinoso requieren observación cercana. (Traducción-Dr. Aurian Garcia Gonzalez ).

The Prognostic Value of Micropapillary Pattern in Colon Cancer and Its Role as a High-Risk Feature in Patients With Stage II Disease.

BACKGROUND: The association of a micropapillary pattern with oncologic outcomes has not been fully studied in patients with colon cancer. OBJECTIVE: We evaluated the prognostic value of a micropapillary pattern, especially for patients with stage II colon cancer. DESIGN: A retrospective comparative cohort study using propensity score matching. SETTING: This study was conducted at a single tertiary center. PATIENTS: Patients with primary colon cancer undergoing curative resection from October 2013 to December 2017 were enrolled. Patients were grouped into micropapillary pattern positive or micropapillary pattern negative. MAIN OUTCOME MEASUREMENTS: Disease-free survival and overall survival. RESULTS: Of the eligible 2192 patients, 334 (15.2%) were with micropapillary pattern (+). After 1:2 propensity score matching, 668 patients with micropapillary pattern-negative status were selected. The micropapillary pattern-positive group showed significantly worse 3-year disease-free survival (77.6% vs 85.1%, p = 0.007). Three-year overall survival of micropapillary pattern-positive and micropapillary pattern-negative patients did not show a statistically significant difference (88.9% vs 90.4%, p = 0.480). In multivariable analysis, micropapillary pattern-positive was an independent risk factor for poor disease-free survival (HR 1.547, p = 0.008). In the subgroup analysis for 828 patients with stage II disease, 3-year disease-free survival deteriorated significantly in micropapillary pattern-positive patients (82.6% vs 93.0, p < 0.001). Three-year overall survival was 90.1% and 93.9% in patients positive and negative for micropapillary pattern, respectively ( p = 0.082). In the multivariable analysis for patients with stage II disease, micropapillary pattern-positive status was an independent risk factor for poor disease-free survival (HR 2.003, p = 0.031). LIMITATIONS: Selection bias due to the retrospective nature of the study. CONCLUSIONS: Micropapillary pattern-positive status may serve as an independent prognostic factor for colon cancer, especially for patients with stage II disease. VALOR PRONSTICO DEL PATRN MICROPAPILAR Y SU PAPEL COMO CARACTERSTICA DE ALTO RIESGO EN PACIENTES CON CNCER DE COLON EN ESTADO II: ANTECEDENTES:La asociación del patrón micropapilar con los resultados oncológicos no ha sido completamente estudiada en pacientes con cáncer de colon.OBJETIVO:Evaluamos el valor pronóstico del patrón micropapilar, especialmente en pacientes con cáncer de colon en estadio II.DISEÑO:Estudio de cohortes comparativo y retrospectivo que utilize el emparejamiento por puntuación de propensiones.AJUSTE:Estudio realizado en un solo centro terciario.PACIENTES:Se incluyeron los pacientes con cáncer de colon primario sometidos a resección curativa desde octubre de 2013 hasta diciembre de 2017. Los pacientes se agruparon en patrón micropapilar positivo ( + ) o patrón micropapilar negativo ( - ).PRINCIPALES MEDIDAS DE RESULTADO:Sobrevida libre de enfermedad y la sobrevida global.RESULTADOS:De los 2192 pacientes elegibles, 334 (15,2%) tenían patrón micropapilar (+). Después de emparejar el puntaje de propensión 1:2, se seleccionaron 668 pacientes con patrón micropapilar (-). El grupo con patrón micropapilar (+) mostró una sobrevida libre de enfermedad significativamente inferior a los tres años (77,6% frente a 85,1%, p = 0,007). La sobrevida global a los tres años del patrón micropapilar (+) y del patrón micropapilar (-) no mostró una diferencia estadísticamente significativa (88,9 % frente a 90,4%, p = 0,480). En el análisis multivariable, el patrón micropapilar (+) fue un factor de riesgo independiente para una deficiente sobrevida libre de enfermedad (índice de riesgo 1,547, p = 0,008). En el análisis de subgrupos de 828 pacientes con enfermedad en estadio II, la sobrevida libre de enfermedad a los tres años se deterioró significativamente en los pacientes con patrón micropapilar (+) (82,6% frente a 93,0, p < 0,001). La sobrevida global a los tres años fué del 90,1% y del 93,9% en el patrón micropapilar (+) y el patrón micropapilar (-), respectivamente ( p = 0,082). En el análisis multivariable de los pacientes con enfermedad en estadio II, el patrón micropapilar (+) fue un factor de riesgo independiente para una sobrevida libre de enfermedad deficiente (índice de riesgo 2,003, p = 0,031).LIMITACIONES:Sesgo de selección debido a la naturaleza retrospectiva del estudio.CONCLUSIONES:El patrón micropapilar (+) sirve como factor pronóstico independiente para el cáncer de colon, especialmente para pacientes con enfermedad en estadio II. (Traducción-Dr. Xavier Delgadillo ).

Metaverse in Healthcare Integrated with Explainable AI and Blockchain: Enabling Immersiveness, Ensuring Trust, and Providing Patient Data Security.

Digitization and automation have always had an immense impact on healthcare. It embraces every new and advanced technology. Recently the world has witnessed the prominence of the metaverse which is an emerging technology in digital space. The metaverse has huge potential to provide a plethora of health services seamlessly to patients and medical professionals with an immersive experience. This paper proposes the amalgamation of artificial intelligence and blockchain in the metaverse to provide better, faster, and more secure healthcare facilities in digital space with a realistic experience. Our proposed architecture can be summarized as follows. It consists of three environments, namely the doctor's environment, the patient's environment, and the metaverse environment. The doctors and patients interact in a metaverse environment assisted by blockchain technology which ensures the safety, security, and privacy of data. The metaverse environment is the main part of our proposed architecture. The doctors, patients, and nurses enter this environment by registering on the blockchain and they are represented by avatars in the metaverse environment. All the consultation activities between the doctor and the patient will be recorded and the data, i.e., images, speech, text, videos, clinical data, etc., will be gathered, transferred, and stored on the blockchain. These data are used for disease prediction and diagnosis by explainable artificial intelligence (XAI) models. The GradCAM and LIME approaches of XAI provide logical reasoning for the prediction of diseases and ensure trust, explainability, interpretability, and transparency regarding the diagnosis and prediction of diseases. Blockchain technology provides data security for patients while enabling transparency, traceability, and immutability regarding their data. These features of blockchain ensure trust among the patients regarding their data. Consequently, this proposed architecture ensures transparency and trust regarding both the diagnosis of diseases and the data security of the patient. We also explored the building block technologies of the metaverse. Furthermore, we also investigated the advantages and challenges of a metaverse in healthcare.

Determining Which Patients Require Preoperative Pelvic Radiotherapy Before Curative-Intent Surgery and/or Ablation for Metastatic Rectal Cancer.

BACKGROUND: The aim of this study is to determine the optimal indications for preoperative pelvic radiotherapy (RT) in patients with metastatic rectal cancer who underwent curative-intent surgical resection and/or ablation. METHODS: Between January 2000 and October 2019, 246 patients who met our inclusion criteria were enrolled. Preoperative RT was performed in 22 patients (8.9%). Lower margin below the peritoneal reflection (p < 0.001), mesorectal fascia (MRF) invasion (p = 0.02), and lateral pelvic lymph node (LPLN) involvement (p = 0.005) were more frequent in the preoperative RT group. RESULTS: During the median follow-up period of 13.3 months (interquartile range [IQR]: 6.0-36.3 months), local recurrence (LR) was identified in 60 patients (24.4%). It was the first site of recurrence in 45 of them (18.3%). Among them, three patients were in the preoperative RT group. On multivariable analysis, lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, carcinoembryonic antigen (CEA) level ≥ 10 ng/mL before treatment, and preoperative RT were significant prognostic factors for LR-free survival (LRFS). In the patient group without any risk factors, the 2-year LRFS rate was 94.9% without preoperative RT. In the patient group with one or more risk factors, the 2-year LRFS was 64.4% without and 95.2% with preoperative RT. CONCLUSION: LR developed in about 25% of patients within 2 years. Preoperative RT should be considered, especially in patients with a risk factor for LR, including lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, or CEA ≥ 10 ng/mL before treatment.

Sphincter-saving surgery versus abdominoperineal resection in low rectal cancer following neoadjuvant treatment with propensity score analysis.

BACKGROUND: Sphincter-saving operation is the treatment of choice in patients with lower rectal cancer, although abdominoperineal resection (APR) is necessary in some cases for adequate oncological outcomes. This study compared the oncologic outcomes of patients with low rectal cancer undergoing APR and intersphincteric resection (ISR) after neoadjuvant chemoradiotherapy (nCRT). METHODS: We compared 104 patients who underwent ISR for lower rectal cancer between 2008 and 2014 with 79 patients who underwent APR during the same period. Cases in which tumors involved the levator ani muscle or the external anal sphincter, as well as those in which surgeons were unable to obtain a negative distal margin via sphincter-saving operation were excluded. Fifty-two patients who underwent ISR were matched via propensity scoring with 52 patients who underwent APR. The analyzed variables included patient and tumor characteristics and long-term outcomes before and after 1:1 propensity score matching (PSM). RESULTS: After matching, there were no significant differences between the two groups in clinical stage and tumor distance from anal verge. Short- and long-term outcomes were similar between the two groups. The 5-year disease-free survival rate was 76.3% in the ISR group and 57.8% in the APR group (p = 0.080). The 5-year cancer-specific survival rate was 89.5% in the ISR group and 85.4% in the APR group (p = 0.383). CONCLUSIONS: This reveals that ISR and APR have similar oncologic outcomes following nCRT in patients with advanced low rectal cancer adjusted for background variables.

Detection of COVID-19 in X-ray Images Using Densely Connected Squeeze Convolutional Neural Network (DCSCNN): Focusing on Interpretability and Explainability of the Black Box Model.

The novel coronavirus (COVID-19), which emerged as a pandemic, has engulfed so many lives and affected millions of people across the world since December 2019. Although this disease is under control nowadays, yet it is still affecting people in many countries. The traditional way of diagnosis is time taking, less efficient, and has a low rate of detection of this disease. Therefore, there is a need for an automatic system that expedites the diagnosis process while retaining its performance and accuracy. Artificial intelligence (AI) technologies such as machine learning (ML) and deep learning (DL) potentially provide powerful solutions to address this problem. In this study, a state-of-the-art CNN model densely connected squeeze convolutional neural network (DCSCNN) has been developed for the classification of X-ray images of COVID-19, pneumonia, normal, and lung opacity patients. Data were collected from different sources. We applied different preprocessing techniques to enhance the quality of images so that our model could learn accurately and give optimal performance. Moreover, the attention regions and decisions of the AI model were visualized using the Grad-CAM and LIME methods. The DCSCNN combines the strength of the Dense and Squeeze networks. In our experiment, seven kinds of classification have been performed, in which six are binary classifications (COVID vs. normal, COVID vs. lung opacity, lung opacity vs. normal, COVID vs. pneumonia, pneumonia vs. lung opacity, pneumonia vs. normal) and one is multiclass classification (COVID vs. pneumonia vs. lung opacity vs. normal). The main contributions of this paper are as follows. First, the development of the DCSNN model which is capable of performing binary classification as well as multiclass classification with excellent classification accuracy. Second, to ensure trust, transparency, and explainability of the model, we applied two popular Explainable AI techniques (XAI). i.e., Grad-CAM and LIME. These techniques helped to address the black-box nature of the model while improving the trust, transparency, and explainability of the model. Our proposed DCSCNN model achieved an accuracy of 98.8% for the classification of COVID-19 vs normal, followed by COVID-19 vs. lung opacity: 98.2%, lung opacity vs. normal: 97.2%, COVID-19 vs. pneumonia: 96.4%, pneumonia vs. lung opacity: 95.8%, pneumonia vs. normal: 97.4%, and lastly for multiclass classification of all the four classes i.e., COVID vs. pneumonia vs. lung opacity vs. normal: 94.7%, respectively. The DCSCNN model provides excellent classification performance consequently, helping doctors to diagnose diseases quickly and efficiently.

The role of PDGFRA as a therapeutic target in young colorectal cancer patients.

BACKGROUND: Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear. METHODS: We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation. RESULTS: Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = - 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients. CONCLUSIONS: Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.

Tumor Budding as a Prognostic Marker in Rectal Cancer Patients on Propensity Score Analysis.

BACKGROUND: Tumor budding is associated with adverse histology. It is a predictor of poor oncologic outcomes in colorectal cancer. However, it remains unclear whether tumor budding is a predictor of poor prognosis for rectal cancer patients regardless of neoadjuvant chemoradiotherapy (nCRT). PATIENTS AND METHODS: This study analyzed 2888 rectal cancer patients who underwent radical surgery from 2007 to 2014. Among these patients, 939 underwent nCRT while 1949 did not receive nCRT. Tumor budding was defined as positive if the number of isolated tumor cells or small clusters of up to five tumor cells at the invasive front of the tumor was five or more. If the number was less than five, it was defined as negative. Patients were categorized according to tumor budding status. We used 1:1 propensity score matching to adjust for potential baseline confounders between the two groups. RESULTS: Among 2888 patients, 939 received nCRT while 1949 did not receive nCRT. A total of 418 patients who received nCRT were matched (209 in each group). A total of 1024 patients without nCRT were also matched (512 in each group). In matched patients, 5-year overall survival (OS) and 5-year disease-free survival (DFS) rates for the positive budding group were significantly lower than those in the negative budding group regardless of nCRT. On multivariate analysis of prognostic factors, positive budding was associated with poorer disease-free survival independent of nCRT. CONCLUSION: Tumor budding positivity is a prognostic indicator of poor outcomes in rectal cancer patients regardless of neoadjuvant chemoradiotherapy.

Effect of lymphadenectomy in colorectal cancer with isolated synchronous para-aortic lymph node metastasis.

AIM: There is controversy about the treatment of para-aortic lymph node (PALN) metastasis and usefulness of surgical removal. We investigated the clinical effects of synchronous isolated PALN dissection in patients with this metastasis. METHODS: Patients with colorectal cancer with isolated PALN metastasis were selected between January 2008 and December 2016 at Samsung Medical Center. Patients who were selected for gross-free PALN dissection were set as the dissection group (DG). Patients who did not undergo PALN dissection or underwent biopsy were set as the non-dissection group (NDG). The oncological and operative outcomes were compared. RESULTS: A total of 73 patients were recruited. The most clinical and pathological characteristics were not significantly different. The incidence of postoperative complications was also similar. The 5-year overall survival of DG patients was 33.9%, that of NDG patients was 10.1%, and the survival curves were significantly different (P = 0.044). Multivariate analysis revealed that location of tumour in the left colon rather than in the right colon was a risk factor affecting survival in sub-analysis. CONCLUSION: PALN dissection did not increase postoperative complications and had a better effect on patient survival. It is suggested that lymphadenectomy be performed more aggressively when PALN metastasis is seen in patients with right colon cancer.

Comparison of transanal total mesorectal excision and robotic total mesorectal excision for low rectal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: To improve the quality of surgery for rectal cancer, both transanal total mesorectal excision (taTME) and robotic total mesorectal excision (R-TME) can be performed. However, few studies have compared outcomes of taTME and R-TME, especially for patients with low rectal cancer after undergoing neoadjuvant chemoradiation (nCRT). Thus, the objective of this study was to compare outcomes of taTME and R-TME for patients with low rectal cancer after undergoing nCRT. METHODS: A total of 306 consecutive patients with low rectal cancer who underwent taTME or R-TME after nCRT between 2008 and 2018 were analyzed retrospectively. Patients were classified into two groups: 1) taTME surgery group (n = 94); and 2) R-TME surgery group (n = 212). RESULTS: Clinicopathologic variables were comparable between the two groups. There was no significant difference in circumference margin involvement (1.1% in taTME vs. 2.8% in R-TME, p = 0.680) or distal resection margin (2.3 cm in taTME vs. 2.4 cm in R-TME, p = 0.629). Total operation time (239 min in taTME vs. 243 min in R-TME, p = 0.675) and major complications (including anastomosis site leakage, surgical site infection, and voiding difficulty) showed no significant difference between the two groups either. CONCLUSIONS: Transanal and robotic TMEs have similar short-term outcomes for patients with rectal cancer after undergoing nCRT. High quality TME can be equally achieved with both transanal and robotic approaches.

A Comprehensive Analysis of Symmetric Arginine Dimethylation in Colorectal Cancer Tissues Using Immunoaffinity Enrichment and Mass Spectrometry.

Protein arginine methyltransferase 5 (PRMT5) is a major enzyme responsible for generating monomethyl and symmetric dimethyl arginine in proteins. PRMT5 is essential for cell viability and development, and its overexpression is observed in a variety of cancers. In the present study, it is found that levels of PRMT5 protein and symmetric arginine dimethylation in colorectal cancer (CRC) tissues are increased compared to those in adjacent noncancerous tissues. Using immunoaffinity enrichment of methylated peptides combined with high-resolution mass spectrometry, a total of 147 symmetric dimethyl-arginine (SDMA) sites in 94 proteins are identified, many of which are RNA binding proteins and enzymes. Quantitative analysis comparing CRC and normal tissues reveals significant increase in the symmetric dimethylation of 70 arginine sites in 46 proteins and a decrease in that of four arginine sites in four proteins. Among the 94 proteins identified in this study, it is confirmed that KH-type splicing regulatory protein is a target of PRMT5 and highly expressed in CRC tissues compared to noncancerous tissues. This study is the first comprehensive analysis of symmetric arginine dimethylation using clinical samples and extends the number of known in vivo SDMA sites. The data obtained are available via ProteomeXchange with the identifier PXD015653.

Proteome-wide identification of arginine methylation in colorectal cancer tissues from patients.

BACKGROUND: Protein arginine methylation reaction is catalyzed by protein arginine methyltransferase (PRMT) and the modification is implicated in various diseases including cancer. Currently, thousands of arginine methylation sites have been identified using high-resolution mass spectrometry-based proteomics technology. However, identification of arginine methylation using clinical samples at proteome level has not been reported yet. The objective of the present study was to identify, monomethyl-arginine (MMA) and asymmetric dimethyl-arginine (ADMA) sites in colorectal cancer (CRC) tissues at proteome level. METHODS: Pooled CRC tissue samples from 10 patients with stage II and III were digested by trypsin and these digests were further processed and lyophilized. Using monomethyl- or asymmetric dimethyl arginine (MMA or ADMA, respectively) motif kits, methylarginine-containing peptides were enriched and subsequently analyzed by high-resolution LC-MS/MS. DLD1 and HCT116 colon cancer cells were treated with type I PRMTs inhibitor (MS023) alone or combined with SN-38, and the effect of the drugs on CRC cell proliferation and apoptosis was measured by water-soluble tetrazolium salt (WST-1) assay and FACS analysis, respectively. RESULTS: In the present study, 455 MMA sites of 272 proteins and 314 ADMA sites of 155 proteins were identified from CRC tissues acquired from patients. In addition, 216 methylation sites and 75 substrates for PRMTs were newly identified. These results reveal the significant presence of MMA and ADMA sites on nucleic acid binding proteins and protein complexes involved in transcription. To investigate the effect of protein arginine methylation in CRC proliferation and apoptosis, MS023 was treated to two CRC cell lines. After 48 h treatment with various concentrations of MS023, CRC cell proliferation was significantly suppressed, with concomitant apoptosis induction. Furthermore, MS023 treatment significantly enhanced the inhibitory effect of SN-38 on CRC cell proliferation. CONCLUSION: This work reports the first comprehensive analysis of arginine methylation with clinical sample and suggests that type I PRMTs are potential therapeutic targets for drug discovery in CRC.