Transcriptomic analysis of GITR and GITR ligand reveals cancer immune heterogeneity with implications for GITR targeting.

Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a transmembrane protein expressed mostly on CD25+CD4+ regulatory T-cells (Tregs) and upregulated on all T-cells upon activation. It is a T-cell co-stimulatory receptor and has demonstrated promising anti-tumor activity in pre-clinical studies. To date, however, the efficacy of GITR agonism has been discouraging in clinical trials. This study explores GITR and GITR ligand (GITR-L) ribonucleic acid (RNA) expression in solid tumors in an attempt to delineate causes for variable responses to GITR agonists. RNA expression levels of 514 patients with a variety of cancer types were normalized to internal housekeeping gene profiles and ranked as percentiles. 99/514 patients (19.3%) had high GITR expression (defined as ≥ 75th percentile). Breast and lung cancer had the highest proportion of patients with high GITR expression (39% and 35%, respectively). The expression of concomitant high GITR and low-moderate GITR-L expression (defined as <75th percentile) was present in 31% and 30% of patients with breast and lung cancer respectively. High GITR expression also showed a significant independent association with high RNA expression of other immune modulator proteins, namely, PD-L1 immunohistochemistry (IHC) ≥1 (odds ratio (OR) 2.15, P=0.008), CTLA4 (OR=2.17, P=0.05) and OX40 high RNA expression (OR=2.64, P=0.001). Overall, these results suggest that breast and lung cancer have a high proportion of patients with a GITR and GITR-L RNA expression profile that merits further investigation in GITR agonism studies. The association of high GITR expression with high CTLA4 and OX40 RNA expression, as well as positive PD-L1 IHC, provides a rationale for a combination approach targeting these specific immune modulator proteins in patients whose tumors show such co-expression.

Clinical and Biologic Correlates of ADORA2A Transcriptomic Expression in Cancer.

ADORA2A (adenosine A2a receptor) and ADORA2B propagate immunoregulatory signals, including restricting both innate and adaptive immunity, though recent data also suggest a tumor suppressor effect in certain settings. We evaluated the RNA expression from 514 tumors in a clinical-grade laboratory; 489 patients with advanced/metastatic disease had clinical outcome correlates. Transcript expression was standardized to internal housekeeping genes and ranked (0-100 scale) relative to 735 specimens from 35 different cancer types. Transcript abundance rank values were defined as "low/moderate" (0-74) or "high" (75-100) percentile RNA expression ranks. Overall, 20.8% of tumors had high ADORA2A (≥75 percentile RNA rank). The greatest proportion of high ADORA2A expressors was found in neuroendocrine and breast cancers and sarcomas, whereas the lowest was found in colorectal and ovarian cancers, albeit with patient-to-patient variability. In multivariable logistic regression analysis, there was a significant positive correlation between high ADORA2A RNA expression and a high expression of the immune checkpoint-related molecules PD-1 (p = 0.015), VISTA (p ≤ 0.001), CD38 (p = 0.031), and CD39 (p ≤ 0.001). In 217 immunotherapy-treated patients, high ADORA2A did not correlate significantly with progression-free (p = 0.51) or overall survival (OS) (p = 0.09) from the initiation of the checkpoint blockade. However, high versus not-high ADORA2A transcript expression correlated with longer OS from the time of advanced/metastatic disease (N = 489 patients; (HR 0.69 (95% CI 0.51-0.95) (p = 0.02)). Therefore, high ADORA2A transcript levels may be a favorable prognostic factor, unrelated to immunotherapy. Importantly, ascertaining co-expression patterns of ADORA2A with PD-1 and VISTA in individual tumors as a basis for the precision co-targeting of ADORA2A and these other checkpoint-related molecules warrants investigation in clinical trials.

High indoleamine 2,3-dioxygenase transcript levels predict better outcome after front-line cancer immunotherapy.

Indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is a potential target to unlock the immunosuppressive tumor microenvironment. Correlations between IDO1 and immune checkpoint inhibitor (ICI) efficacy remain unclear. Herein, we investigated IDO1 transcript expression across cancers and clinical outcome correlations. High IDO1 transcripts were more frequent in uterine (54.2%) and ovarian cancer (37.2%) but varied between and within malignancies. High IDO1 RNA expression was associated with high expression of PD-L1 (immune checkpoint ligand), CXCL10 (an effector T cell recruitment chemokine), and STAT1 (a component of the JAK-STAT pathway) (all multivariable p < 0.05). PIK3CA and CTCF alterations were more frequent in the high IDO1 group. High IDO1 expression was an independent predictor of progression-free survival (adjusted HR = 0.44, 95% CI 0.20-0.99, p = 0.049) and overall survival (adjusted HR = 0.31, 95% CI 0.11-0.87, p = 0.026) after front-line ICIs. IDO1 expression warrants further exploration as a predictive biomarker for immunotherapy. Moreover, co-expressed immunoregulatory molecules merit exploration for co-targeting.

OX40/OX40 ligand and its role in precision immune oncology.

Immune checkpoint inhibitors have changed the treatment landscape for various malignancies; however, their benefit is limited to a subset of patients. The immune machinery includes both mediators of suppression/immune evasion, such as PD-1, PD-L1, CTLA-4, and LAG-3, all of which can be inhibited by specific antibodies, and immune-stimulatory molecules, such as T-cell co-stimulatory receptors that belong to the tumor necrosis factor receptor superfamily (TNFRSF), including OX40 receptor (CD134; TNFRSF4), 4-1BB (CD137; TNFRSF9), and glucocorticoid-induced TNFR-related (GITR) protein (CD357; TNFRSF18). In particular, OX40 and its binding ligand OX40L (CD134L; TNFSF4; CD252) are critical for immunoregulation. When OX40 on activated T cells binds OX40L on antigen-presenting cells, T-cell activation and immune stimulation are initiated via enhanced T-cell survival, proliferation and cytotoxicity, memory T-cell formation, and abrogation of regulatory T cell (Treg) immunosuppressive functions. OX40 agonists are in clinical trials both as monotherapy and in combination with other immunotherapy agents, in particular specific checkpoint inhibitors, for cancer treatment. To date, however, only a minority of patients respond. Transcriptomic profiling reveals that OX40 and OX40L expression vary between and within tumor types, and that only ~ 17% of cancer patients have high OX40 and low OX40L, one of the expression patterns that might be theoretically amenable to OX40 agonist enhancement. Taken together, the data suggest that the OX40/OX40L machinery is a critical part of the immune stimulatory system and that understanding endogenous expression patterns of these molecules and co-existing checkpoints merits further investigation in the context of a precision immunotherapy strategy for cancer therapy.

LAG-3 transcriptomic expression correlates linearly with other checkpoints, but not with clinical outcomes.

Immune checkpoint inhibitors have revolutionized the treatment landscape for patients with cancer. Multi-omics, including next-generation DNA and RNA sequencing, have enabled the identification of exploitable targets and the evaluation of immune mediator expression. There is one FDA-approved LAG-3 inhibitor and multiple in clinical trials for numerous cancers. We analyzed LAG-3 transcriptomic expression among 514 patients with diverse cancers, including 489 patients with clinical annotation for their advanced malignancies. Transcriptomic LAG-3 expression was highly variable between histologies/cancer types and within the same histology/cancer type. LAG-3 RNA levels correlated linearly, albeit weakly, with high RNA levels of other checkpoints, including PD-L1 (Pearson's R2 = 0.21 (P < 0.001)), PD-1 (R2 = 0.24 (P < 0.001)) and CTLA-4 (R2 = 0.19 (P < 0.001)); when examined for Spearman correlation, significance did not change. LAG-3 expression (dichotomized at ≥ 75th (high) versus < 75th (moderate/low) RNA percentile level) was not a prognostic factor for overall survival (OS) in 272 immunotherapy-naïve patients with advanced/metastatic disease (Kaplan Meier analysis; P = 0.54). High LAG-3 levels correlated with longer OS after anti-PD-1/PD-L1-based checkpoint blockade (univariate (P = 0.003), but not multivariate analysis (hazard ratio, 95% confidence interval = 0.80 (0.46-1.40) (P = 0.44))); correlation with longer progression-free survival showed a weak univariate trend (P = 0.13). Taken together, these results suggest that high LAG-3 levels in and of themselves do not predict resistance to anti-PD-1/PD-L1 checkpoint blockade. Even so, since LAG-3 is often co-expressed with PD-1, PD-L1 and/or CTLA-4, selecting patients for combinations of checkpoint blockade based on immunomic co-expression patterns is a strategy that merits exploration.

Targeted Therapies, Biologics, and Immunotherapy in the Neoadjuvant and Adjuvant Settings: Perioperative Risks.

Cancer therapeutics has been revolutionized by the introduction of molecularly targeted therapies and immune checkpoint inhibitors (ICIs). The paradigm of neoadjuvant therapy is commonly employed across multiple solid tumors, exhibiting significant clinical benefit as exemplified with ICIs in melanoma and non-small-cell lung cancer. However, neoadjuvant therapy can be associated with treatment-related adverse events. As the incorporation of these novel therapies in the preoperative space expands, it is crucial for surgical oncologists to understand the potential perioperative implications of these treatments. This article focuses on surgical considerations tied to these treatments, highlighting potential drug-surgery interactions and complications.

High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome.

Background: CTLA-4 impedes the immune system's antitumor response. There are two Food and Drug Administration-approved anti-CTLA-4 agents - ipilimumab and tremelimumab - both used together with anti-PD-1/PD-L1 agents. Objective: To assess the prognostic implications and immunologic correlates of high CTLA-4 in tumors of patients on immunotherapy and those on non-immunotherapy treatments. Design/methods: We evaluated RNA expression levels in a clinical-grade laboratory and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors, including 489 patients with advanced/metastatic cancers and full outcome annotation. A reference population (735 tumors; 35 histologies) was used to normalize and rank transcript abundance (0-100 percentile) to internal housekeeping gene profiles. Results: The most common tumor types were colorectal (140/514, 27%), pancreatic (55/514, 11%), breast (49/514, 10%), and ovarian cancers (43/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (⩾75th percentile rank). Cancers with the largest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). High CTLA-4 RNA independently/significantly correlated with high PD-1, PD- L2, and LAG3 RNA levels (and with high PD-L1 in univariate analysis). High CTLA-4 RNA expression was not correlated with survival from the time of metastatic disease [N = 272 patients who never received immune checkpoint inhibitors (ICIs)]. However, in 217 patients treated with ICIs (mostly anti-PD-1/anti-PD- L1), progression-free survival (PFS) and overall survival (OS) were significantly longer among patients with high versus non-high CTLA-4 expression [hazard ratio, 95% confidence interval: 0.6 (0.4-0.9) p = 0.008; and 0.5 (0.3-0.8) p = 0.002, respectively]; results were unchanged when 18 patients who received anti-CTLA-4 were omitted. Patients whose tumors had high CTLA-4 and high PD-L1 did best; those with high PD-L1 but non-high CTLA-4 and/or other expression patterns had poorer outcomes for PFS (p = 0.004) and OS (p = 0.009) after immunotherapy. Conclusion: High CTLA-4, especially when combined with high PD-L1 transcript expression, was a significant positive predictive biomarker for better outcomes (PFS and OS) in patients on immunotherapy.

High CTLA-4 expression and immunotherapy outcome High CTLA-4 expression was not a prognostic factor for survival in patients not receiving ICIs but was a significant positive predictive biomarker for better outcome (PFS and OS) in patients on immunotherapy, perhaps because it correlated with expression of other checkpoints such as PD-1 and PD-L2.

Pan-cancer analysis of TIM-3 transcriptomic expression reveals high levels in pancreatic cancer and interpatient heterogeneity.

BACKGROUND: T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor, dampens immune function. TIM-3 antagonists have entered the clinic. METHODS: We analyzed TIM-3 transcriptomic expression in 514 diverse cancers. Transcript abundance was normalized to internal housekeeping genes and ranked (0-100 percentile) to a reference population (735 tumors; 35 histologies [high≥75 percentile rank]). Ninety tumors (17.5%) demonstrated high TIM-3 expression. RESULTS: TIM-3 expression varied between and within tumor types. However, high TIM-3 expression was more common in pancreatic cancer (20/55 tumors, 36.4%; odds ratio, 95% confidence interval (pancreatic vs. other tumors) = 3.176 (1.733-5.818; p < 0.001, multivariate]). High TIM-3 also significantly and independently correlated with high PD-L1 (p = 0.014) and high CTLA-4 (p < 0.001) transcriptomic expression (multivariate). CONCLUSIONS: These observations indicate that TIM-3 RNA expression is heterogeneous, but more common in pancreatic cancer and in tumors exploiting PD-L1 and CTLA-4 checkpoints. Clinical trials with patient selection for matched immune-targeted combinations may be warranted.

Employment Status of Patients With Colorectal Cancer After Surgery: A Multicenter Prospective Cohort Study in Japan.

BACKGROUND: Because of improved survival rates, patients with colorectal cancer may try to return to work. Many countries, however, have limited knowledge of the employment status of these patients. OBJECTIVE: To explore the employment status of patients with colorectal cancer after surgery in Japan and the risk factors affecting the same. DESIGN: This is a prospective multicenter cohort study that used self-administered questionnaires. Patients were recruited from June 2019 to August 2020 and were followed up for 12 months after surgery. SETTING: Six community hospitals and 1 university hospital in Japan. PATIENTS: Patients with clinical stages I to III colorectal cancer, employed at the time of diagnosis. INTERVENTIONS: Patients who underwent surgical resection between June 2019 and August 2020. MAIN OUTCOME MEASUREMENTS: The time it takes patients to return to work after surgery and the proportion of working patients 12 months after surgery were collected using self-administered questionnaires. RESULTS: A total of 129 patients were included in the analyses. The median time to return-to-work was 1.1 months, and the proportion of working patients at 12 months after surgery was 79%. Risk factors for delayed return-to-work after surgery were an advanced tumor stage, stoma, severe postoperative complications, shorter years of service at the workplace, and lower willingness to return-to-work. Risk factors for not working 12 months after surgery were stoma, lower willingness to return-to-work, nonregular employee status, lower income, national health insurance, and no private medical insurance. LIMITATIONS: This study is limited by its short-term follow-up and small sample size. CONCLUSIONS: This study revealed that Japanese patients with stages I to III colorectal cancer found favorable employment outcomes in the 12 months after surgery. These results may help health care providers better understand the employment status of patients with colorectal cancer and encourage them to consider returning to work after surgery. SITUACIN LABORAL DE LOS PACIENTES CON CNCER COLORRECTAL DESPUS DE LA CIRUGA UN ESTUDIO DE COHORTE PROSPECTIVO MULTICNTRICO EN JAPN: ANTECEDENTES:Debido a las mejores tasas de supervivencia, los pacientes con cáncer colorrectal pueden intentar volver al trabajo. Muchos países, sin embargo, tienen un conocimiento limitado de su situación laboral.OBJETIVO:Explorar la situación laboral de los pacientes con cáncer colorrectal después de la cirugía en Japón y los factores de riesgo que afectan a la misma.DISEÑO:Este es un estudio prospectivo de cohortes multicéntrico que utiliza cuestionarios autoadministrados. Los pacientes fueron reclutados desde junio de 2019 hasta agosto de 2020 y fueron seguidos durante 12 meses después de la cirugía.ENTORNO CLINICO:Seis hospitales comunitarios y un hospital universitario en Japón.PACIENTES:Pacientes con estadios clínicos I-III de cáncer colorrectal, trabajando en el momento del diagnóstico.INTERVENCIONES:Pacientes que recibieron resección quirúrgica desde junio de 2019 hasta agosto de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El tiempo que tardan los pacientes en volver al trabajo después de la cirugía y la proporción de pacientes que trabajan 12 meses después de la cirugía se recogieron mediante cuestionarios autoadministrados.RESULTADOS:Un total de 129 pacientes fueron incluidos en los análisis. La mediana de tiempo de reincorporación al trabajo fue de 1,1 meses y la proporción de pacientes que trabajaban a los 12 meses de la cirugía fue del 79%. Los factores de riesgo para el retraso en el regreso al trabajo después de la cirugía fueron un estadio avanzado del tumor, estoma, complicaciones postoperatorias graves, menos años de servicio en el lugar de trabajo y menor disposición para volver al trabajo. Los factores de riesgo para no trabajar 12 meses después de la cirugía fueron estoma, menor voluntad de volver al trabajo, condición de empleado no regular, ingresos más bajos, seguro nacional de salud y la falta de seguro médico privado.LIMITACIONES:Este estudio está limitado por su seguimiento a corto plazo y tamaño de muestra pequeño.CONCLUSIONES:Este estudio reveló que los pacientes japoneses con cáncer colorrectal en estadios I-III obtuvieron resultados laborales favorables en los 12 meses posteriores a la cirugía. Estos resultados pueden ayudar a los proveedores de atención médica a comprender mejor la situación laboral de los pacientes con cáncer colorrectal y alentarlos a considerar regresar al trabajo después de la cirugía. (Traducción- Dr. Francisco M. Abarca-Rendon ).

What can surgeons do to prevent job leave soon after cancer diagnosis? A brief report on colorectal cancer survivors in Japan.

PURPOSE: Colorectal cancer is one of the most diagnosed cancers in Japan and the number of cancer survivors has increased. Work-related issues of cancer survivors have been investigated in relation to occupational health, and sufficient evidence in clinical practice is needed to support this. This study aimed to obtain the relevant information, intending to support the employment of patients with colorectal cancer for clinical settings. METHODS: We conducted a prospective, multicenter cohort study, which included patients who underwent surgery with clinical stage I-III colorectal cancer. An electronic survey was used at the time of hospital admission to collect the patients' occupational information, including job resignation soon after cancer diagnosis. A cross-sectional analysis was performed to evaluate the patients' employment situations. RESULTS: Of 129 eligible patients, 46 (36%) were female. Thirty-nine (30%) were self-employed and 72 (56%) worked at small-sized workplaces, which are not obliged to have occupational physicians. Most patients (89%) expressed their desire to return to work, but eight patients (6%) left their jobs soon after being diagnosed with colorectal cancer before undergoing surgery for several reasons stemming from worries about future treatment and its consequences. Multivariable analyses indicated that nonregular employees and the self-employed might be at a disadvantage in keeping their job at diagnosis. CONCLUSION: Surgeons should address work-related issues for survivorship, which begins at cancer diagnosis and, when available, collaborate with occupational physicians while being mindful that patients working at smaller companies do not have immediate access to occupational physicians.

LAG-3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics.

BACKGROUND: Lymphocyte activation gene 3 (LAG-3) or CD223 is a transmembrane protein that serves as an immune checkpoint which attenuates T-cell activation. Many clinical trials of LAG-3 inhibitors have had modest effects, but recent data indicate that the LAG-3 antibody relatlimab, together with nivolumab (anti-PD-1), provided greater benefit than nivolumab alone in patients with melanoma. METHODS: In this study, the RNA expression levels of 397 genes were assessed in 514 diverse cancers at a clinical-grade laboratory (OmniSeq: https://www.omniseq.com/). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) using a reference population (735 tumors; 35 histologies). RESULTS: A total of 116 of 514 tumors (22.6%) had high LAG-3 transcript expression (≥75 percentile rank). Cancers with the greatest proportion of high LAG-3 transcripts were neuroendocrine (47% of patients) and uterine (42%); colorectal had among the lowest proportion of high LAG-3 expression (15% of patients) (all p < 0.05 multivariate); 50% of melanomas were high LAG-3 expressors. There was significant independent association between high LAG-3 expression and high expression of other checkpoints, including programmed death-ligand 1 (PD-L1), PD-1, and CTLA-4, as well as high tumor mutational burden (TMB) ≥10 mutations/megabase, a marker for immunotherapy response (all p < 0.05 multivariate). However, within all tumor types, there was inter-patient variability in LAG-3 expression level. CONCLUSIONS: Prospective studies are therefore needed to determine if high levels of the LAG-3 checkpoint are responsible for resistance to anti-PD-1/PD-L1 or anti-CTLA-4 antibodies. Furthermore, a precision/personalized immunotherapy approach may require interrogating individual tumor immunograms to match patients to the right combination of immunotherapeutic agents for their malignancy.

Single-incision laparoscopic partial cecectomy for appendiceal mucocele in a patient with porphyria photosensitivity.

Erythropoietic protoporphyria (EPP) is a rare hereditary subtype of cutaneous porphyria characterized by photosensitivity. Increased exposure to light irradiation may precipitate acute liver failure, and surgical light-induced intestinal burns and perforations are known to occur. We report a case of EPP in a patient who underwent laparoscopic partial cecectomy for appendiceal mucocele. A 55-year-old man with EPP was presented for treatment of appendiceal mucocele. A light test using two types of laparoscopes (Companies O and S) was performed preoperatively. Light from the laparoscope manufactured by Company O caused photosensitivity; this effect was not observed with light from the laparoscope manufactured by Company S. Therefore, we performed laparoscopic partial cecectomy through a single umbilical incision using the laparoscope from Company S. Except for the incision site, the patient's skin was completely covered using surgical drapes. No intra- or postoperative complications were observed. Histopathological examination of the resected specimen revealed a low-grade appendiceal mucinous neoplasm.

Identification of high-risk stage I colon and rectal cancer patients: a retrospective analysis of a large Japanese cohort.

PURPOSE: Data regarding risk factors for recurrence in stage I colorectal cancer patients are limited. The aim of this study was to clarify the existence of a high-recurrence-risk population among stage I colorectal cancer patients. METHODS: This analysis included 7,539 stage I colorectal cancer patients treated between 1997 and 2012 at 24 leading hospitals in Japan. Risk factors for time to recurrence were evaluated using a Cox proportional hazards model, and a high-risk group for recurrence was identified. Prognostic outcomes of high-risk stage I colorectal cancer patients were compared with those of low-risk stage I and stage II patients. RESULTS: Multivariable analyses identified left-sided location (hazard ratio [HR]: 1.65, 95% confidence interval [CI]: 1.09-2.58), T2 tumors (HR: 1.80, 95% CI: 1.21-2.66), and lymphatic invasion (HR: 1.55, 95% CI: 1.05-2.28) as risk factors for recurrence in stage I colon cancer, and patients with these three risk factors were classified as high risk. For stage I rectal cancer, patients with poor differentiation (HR: 2.86, 95% CI: 1.21-5.69), T2 tumors (HR: 1.53, 95% CI: 1.07-2.23), and venous invasion (HR: 1.51, 95% CI: 1.08-2.13) were identified as high risk. The Kaplan-Meier analysis of cumulative recurrence rate and recurrence-free survival revealed that the high-risk stage I colorectal cancer patients have poorer clinical outcomes than the low-risk patients. CONCLUSION: Although stage I colorectal cancer patients generally have a favorable prognosis after curative surgery, poorer prognosis was observed in high-risk stage I colorectal cancer patients than in low-risk patients.

Establishment and validation of a nomogram for predicting potential lateral pelvic lymph node metastasis in low rectal cancer.

BACKGROUND: Identifying lateral pelvic lymph node (LPN) metastasis in low rectal cancer is crucial before treatment. Several risk factors and prediction models for LPN metastasis have been reported. However, there is no useful tool to accurately predict LPN metastasis. Therefore, we aimed to construct a nomogram for predicting LPN metastasis in rectal cancer. METHODS: We analyzed the risk factors for potential LPN metastasis by logistic regression analysis in 705 patients who underwent primary resection of low rectal cancer. We included patients at 49 institutes of the Japan Society of Laparoscopic Colorectal Surgery between June 2010 and February 2012. Clinicopathological factors and magnetic resonance imaging findings were evaluated. The nomogram performance was assessed using the c-index and calibration plots, and the nomogram was validated using an external cohort. RESULTS: In the univariable logistic regression analysis, age, sex, carcinoembryonic antigen, tumor location, clinical T stage, tumor size, circumferential resection margin (CRM), extramural vascular invasion (EMVI), and the short and long axes of LPN and perirectal lymph node (PRLN) were nominated as risk factors for potential LPN metastasis. We identified a combination of the short axis of LPN, tumor location, EMVI, and short axis of PRLN as optimal for predicting potential LPN metastasis and developed a nomogram using these factors. This model had a c-index of 0.74 and was moderately calibrated and well-validated. CONCLUSIONS: This is the first study to construct a well-validated nomogram for predicting potential LPN metastasis in rectal cancer, and its performance was high.

Laparoscopic Versus Open Surgery for Locally Advanced Rectal Cancer: Five-Year Survival Outcomes in a Large, Multicenter, Propensity Score-Matched Cohort Study.

BACKGROUND: There is a paucity of evidence pertaining to long-term survival outcomes of laparoscopic versus open surgery for locally advanced rectal cancer. OBJECTIVE: This study aimed to evaluate the long-term survival outcomes of laparoscopic surgery for locally advanced rectal cancer and to investigate the recurrence pattern. DESIGN: This was a prospective analysis of a registered cohort. SETTINGS: This study was conducted at 69 institutions across Japan. PATIENTS: A total of 1500 patients with clinical stage II-III rectal cancer located below the peritoneal reflection between January 2010 and December 2011 were included. After propensity score matching, all eligible patients, including the matched patients registered in 2014, were prospectively followed up. MAIN OUTCOME MEASURES: Five-year relapse-free survival was the primary outcome. RESULTS: The median follow-up period was 5.6 years. Among the 964 matched patients, the 5-year relapse-free survival was 65.1% in the open group versus 63.5% in the laparoscopic group (HR 1.04; p = 0.71). Distant recurrences at rare sites, which were more frequently observed in the laparoscopic group, were significantly less salvaged (adjusted OR 0.74; p = 0.045). Postrecurrence 5-year overall survival was significantly better for patients who underwent salvage surgery than for those who did not; 55.3% vs 29.5% for patients with initial local recurrence ( p = 0.03) and 64.4% vs 30.7% for patients with distant recurrence alone ( p < 0.001). LIMITATIONS: Potential heterogeneity and influence of unknown confounding. CONCLUSIONS: Five-year follow-up data demonstrated that laparoscopic surgery for locally advanced rectal cancer was safely performed in terms of long-term prognosis. In addition, salvage surgery for recurrent lesions was associated with prolonged postrecurrence survival, both in patients with local and distant recurrence. However, recurrence at rare sites may require further investigation. See Video Abstract at http://links.lww.com/DCR/B793 . CIRUGA LAPAROSCPICA VERSUS CIRUGA ABIERTA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS DE SUPERVIVENCIA A CINCO AOS EN UN ESTUDIO DE COHORTE DE GRAN MAGNITUD, MULTICNTRICO Y DE PAREAMIENTO POR PUNTAJE DE PROPENSIN: ANTECEDENTES:Existe una escasez de pruebas relacionadas con los resultados de supervivencia a largo plazo de la cirugía laparoscópica versus abierta para el cáncer de recto localmente avanzado.OBJETIVO:Este estudio tuvo como objetivo evaluar los resultados de supervivencia a largo plazo de la cirugía laparoscópica para el cáncer de recto localmente avanzado e investigar el patrón de recurrencia.DISEÑO:Fue un análisis prospectivo de una cohorte registrada.ENTORNO CLÍNICO:El estudio se llevó a cabo en 69 instituciones en todo Japón.PACIENTES:Se incluyó un total de 1500 pacientes con cáncer de recto en estadio clínico II-III ubicados por debajo de la reflección peritoneal, entre enero del 2010 y diciembre del 2011. Después del pareamiento por puntaje de propensión, se realizó un seguimiento prospectivo de todos los pacientes elegibles, incluidos los pacientes emparejados registrados en 2014.PRINCIPALES MEDIDAS DE VALORACIÓN:La supervivencia sin recaídas a cinco años fue el resultado primario.RESULTADOS:El período de seguimiento medio fue de 5,6 años. Entre los 964 pacientes emparejados, la supervivencia libre de recaída a 5 años fue del 65,1% en el grupo abierto frente al 63,5% en el grupo laparoscópico (cociente de riesgo 1,04; p = 0,71). Las recurrencias a distancia en sitios raros, que se observaron con mayor frecuencia en el grupo laparoscópico, tuvieron menor sobrevida (razón de posibilidades ajustada 0,74; p = 0,045). La supervivencia general a los 5 años después de la recidiva fue significativamente menor en los pacientes sometidos a una cirugía de rescate; 55,3% frente al 29,5% para los pacientes con recidiva local inicial ( p = 0,03) y 64,4% frente al 30,7% para los pacientes con recidiva a distancia sola ( p < 0,001).LIMITACIONES:Potencial heterogeneidad e influencia de factores de confusión desconocidos.CONCLUSIONES:El seguimiento a cinco años demostró que la cirugía laparoscópica para el cáncer de recto localmente avanzado es segura en términos de pronóstico a largo plazo. Además, la cirugía de rescate de las lesiones recurrentes se asoció con una mayor supervivencia posrecurrencia, tanto en pacientes con recurrencia local como a distancia. Sin embargo, la recurrencia en sitios raros puede requerir una mayor investigación. Consulte Video Resumen en http://links.lww.com/DCR/B793 . (Traducción- Dr. Ingrid Melo ).

Roux-en-Y versus Billroth-I reconstruction after distal gastrectomy for gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer diagnosed worldwide. Due to improved early detection rates of gastric cancer and technological advances in treatments, a significant improvement in survival rates has been achieved in people with cancer undergoing gastrectomy. Subsequently, there has been increasing emphasis on postgastrectomy syndrome (e.g. fullness, delayed emptying, and cold sweat, amongst others) and quality of life postsurgery. However, it is uncertain which types of reconstruction result in better outcomes postsurgery. OBJECTIVES: To assess the evidence on health-related quality of life and safety outcomes of Roux-en-Y and Billroth-I reconstructions after distal gastrectomy for people with gastric cancer. SEARCH METHODS: We searched the Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase on 4 May 2021. We checked the reference lists of the included studies and contacted manufacturers and professionals in the field. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) allocating participants to Roux-en-Y reconstruction or Billroth-I reconstruction after distal gastrectomy for gastric cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies identified by the search for eligibility and extracted data. The primary outcomes were health-related quality of life after surgery and incidence of anastomotic leakage. The secondary outcomes included body weight loss, incidence of bile reflux, length of hospital stay, and overall morbidity. We used a random-effects model to conduct meta-analyses. We assessed risk of bias of the included studies in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, and the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included eight RCTs (942 participants) in the review. One study included both cancer patients and benign disease patients such as stomach ulcers. Two studies compared Roux-en-Y, Billroth-I, and Billroth-II reconstructions, whilst the other studies compared Roux-en-Y and Billroth-I directly.  For the primary outcomes, the evidence suggests that there may be little to no difference in health-related quality of life between Roux-en-Y and Billroth-I reconstruction (standardised mean difference 0.04, 95% confidence interval (CI) -0.11 to 0.18; I² = 0%; 6 studies; 695 participants; low-certainty evidence due to study limitations and imprecision). The evidence for the effect of Roux-en-Y versus Billroth-I reconstruction on the incidence of anastomotic leakage is very uncertain (risk ratio (RR) 0.63, 95% CI 0.16 to 2.53; I² = 0%; 5 studies; 711 participants; very low-certainty evidence). The incidence of anastomotic leakage was 0.6% and 1.4% in the Roux-en-Y and Billroth-I groups, respectively. For the secondary outcomes, the evidence suggests that Billroth-I reconstruction may result in little to no difference in loss of body weight compared to Roux-en-Y reconstruction (mean difference (MD) 0.41, 95% CI -0.77 to 1.59; I² = 0%; 4 studies; 541 participants; low-certainty evidence). Roux-en-Y reconstruction probably reduces the incidence of bile reflux compared to Billroth-I reconstruction (RR 0.40, 95% CI 0.25 to 0.63; I² = 22%; 4 studies; 399 participants; moderate-certainty evidence). Billroth-I reconstruction may shorten postoperative hospital stay, but the evidence for this outcome is very uncertain (MD 0.96, 95% CI 0.16 to 1.76; I² = 56%; 7 studies; 894 participants; very low-certainty evidence). Billroth-I reconstruction may reduce postoperative overall morbidity compared to Roux-en-Y reconstruction (RR 1.47, 95% CI 1.02 to 2.11; I² = 0%; 7 studies; 891 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence suggests that there is little to no difference between Roux-en-Y and Billroth-I reconstruction for the outcome health-related quality of life. The evidence for the effect of Roux-en-Y versus Billroth-I reconstruction on the incidence of anastomotic leakage is very uncertain as the incidence of this outcome was low. Although the certainty of evidence was low, we found some possibly clinically meaningful differences between Roux-en-Y and Billroth-I reconstruction for short-term outcomes. Roux-en-Y reconstruction probably reduces the incidence of bile reflux into the remnant stomach compared to Billroth-I reconstruction. Billroth-I reconstruction may shorten postoperative hospital stay compared to Roux-en-Y reconstruction, but the evidence is very uncertain. Billroth-I reconstruction may reduce postoperative overall morbidity compared to Roux-en-Y reconstruction. Future trials should include long-term follow-up of health-related quality of life and body weight loss.

Prognostic Impact of Lateral Pelvic Node Dissection on the Survival of Patients in Low Rectal Cancer Subgroups Based on Lymph Node Size.

BACKGROUND: Lateral pelvic node (LPN) dissection (LPND) is considered a promising technique for treating low rectal cancer; however, there is insufficient evidence of its prognostic value. Using centrally reviewed preoperative pelvic magnetic resonance (MR) images, this study aimed to find the patient population who has benefited from LPND. PATIENTS AND METHODS: MR images of patients from 69 institutes with stage II-III low rectal cancer were reviewed by experienced radiologists. Recurrence-free survival (RFS), overall survival (OS), and short-term outcomes were measured. RESULTS: In total, 731 preoperative MR images were reviewed (excluding patients with short-axis LPN ≥ 10 mm). Of these, 322 underwent total mesorectum excision (TME) without LPND (non-LPND group), and 409 underwent TME with LPND (LPND group). Preoperative treatment was performed for 40% and 25% of patients in the non-LPND and LPND groups, respectively. The incidence of postoperative complications was higher in the LPND group (44.5%) than in the non-LPND group (33.2%; P = 0.002). Among patients with LPNs < 5 mm, OS and RFS curves were not significantly different between the groups. Among patients with LPNs ≥ 5 mm, the LPND group had significantly higher 5-year OS and RFS than the non-LPND group (OS: 81.9% versus 67.3%; RFS: 69.4% versus 51.6%). On multivariate analysis of LPN ≥ 5 mm cases, LPND was independently associated with RFS. CONCLUSIONS: Despite the high incidence of postoperative complications, this study showed the prognostic impact of LPND on low rectal cancer patients with LPNs (≥ 5 mm, < 10 mm short axis) measured by experienced radiologists. Trial registration UMIN-ID: UMIN000013919.

Development of a preoperative prediction model for new-onset diabetes mellitus after partial pancreatectomy: A retrospective cohort study.

ABSTRACT: Pancreatectomy is an invasive surgery that is sometimes associated with complications. New-onset diabetes mellitus sometimes develops after partial pancreatectomy and severely affects the patient's quality of life. This study aimed to develop a preoperative prediction model of new-onset diabetes mellitus after partial pancreatectomy, which will help patients and surgeons to achieve more easily better common decisions on regarding whether to perform partial pancreatectomy. This retrospective cohort study analyzed medical records of patients who underwent partial pancreatectomy (total pancreatectomy excluded) from April 1, 2008, to February 28, 2016, which were available in the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The predictors were preoperative age, body mass index, hemoglobin A1c level, blood glucose level, and indication for partial pancreatectomy. The outcome was the development of new-onset diabetes mellitus at 1 to 12 months after partial pancreatectomy. We used a logistic regression model and calculated the scores of each predictor. To determine test performance, we assessed discrimination ability using the receiver operating characteristic curve and calibration with a calibration plot and the Hosmer-Lemeshow test. We also performed internal validation using the bootstrap method. Of 681 patients, 125 (18.4%) had new-onset diabetes mellitus after partial pancreatectomy. The developed prediction model had a possible range of 0 to 46 points. The median score was 13, and the interquartile range was 9 to 22. The C-statistics of the receiver operating characteristic curve on the score to predict the outcome was .70 (95% confidence interval [CI], .65-.75). Regarding the test performance, the Hosmer-Lemeshow test was not significant (P = .17), and calibration was good. In the bootstrapped cohorts, the C-statistics was .69 (95% CI, .62-.76). We developed a preoperative prediction model for new-onset diabetes mellitus after partial pancreatectomy. This would provide important information for surgeons and patients when deciding whether to perform partial pancreatectomy.

Nonsurgical Management Following Local Resection for Early Rectal Cancer in Patients with High-risk Factors: A Single-institute Experience.

OBJECTIVE: Additional surgery is considered for patients at high risk for lymph node metastasis (LNM) after local resection for early rectal cancer. Several factors are considered as indications for additional surgery, although there are currently no definitive criteria. This study aimed to clarify the need for additional surgery based on the number of risk factors for LNM and to evaluate the significance of submucosal invasion on recurrence. METHODS: Patients with early rectal cancer harboring risk factors for LNM who underwent local resection between March 2005 and December 2016 were retrospectively analyzed. Associations among the number of risk factors, prognosis, and additional treatment after local resection were investigated. RESULTS: A total of 29 eligible patients were classified into the surgery (n = 10), chemoradiotherapy (n = 7), and no-additional-treatment (NAT, n = 12) groups. Among the 29 patients, 15 patients (52%) with only one risk factor did not relapse. The NAT group harbored fewer risk factors for LNM, and 8 of the 12 patients (67%) had only deep submucosal invasion. Local recurrence occurred in one patient in the chemoradiotherapy group. The estimated 5-year overall survival rates were 88.9%, 75.0%, and 81.5% in the surgery, chemoradiotherapy, and NAT groups, respectively. There were no disease-specific deaths in the overall cohort. CONCLUSIONS: In the present study, no recurrence occurred in patients who did not receive additional surgery with deep submucosal invasion as the only risk factor. A multicenter investigation is necessary to confirm the safety of nonsurgical options.

Qualitative and Quantitative Analysis of Posttreatment Strategy After Endoscopic Resection for Patients with T1 Colorectal Cancer at High Risk of Lymph Node Metastasis.

BACKGROUND: Although endoscopic resection is increasingly performed to treat submucosal invasive colorectal cancer (T1CRC), approximately 10% are at risk of lymph node metastasis. The Japanese Society for Cancer of the Colon and Rectum guideline indicates that the following risk factors should be considered when deciding whether to perform additional surgical resection with lymph node dissection: depth of T1 invasion, lymphovascular invasion, poor histological grade, and budding grade 2/3. However, there is little information about the prognosis of T1CRC patients, or factors to consider when deciding subsequent treatment of high-risk T1CRC. METHODS: This retrospective mixed method study was conducted using electronic medical records at Kyoto University Hospital between February 2005 and February 2015. Participants were T1CRC patients at risk of lymph node metastasis with at least one of the above four risk factors. They were assigned either careful follow-up (FU) or additional surgery (AS) through shared decision-making. To identify factors affecting decision-making in the FU group, we performed qualitative content analysis of electronic medical records. The prognosis of the groups was compared using the Kaplan-Meier method and the log-rank test. RESULTS: Of 161 T1CRC patients, 18 were included in the FU group and 19 in the AS group. The median follow-up time was 39.5 (range 23-126) months for the FU group and 62 (range 22-141) months for the AS group. Factors considered in selecting FU were advanced age, comorbidities, the sole presence of the "depth" risk factor, and lower rectal cancer. For AS, the risk factors cited in the guideline were considered. There was one recurrent case in each group during the research period. There were no significant differences in overall survival, cause-specific survival, or recurrence-free survival between the groups. CONCLUSIONS: Age, comorbidities, and lower-rectal cancer location were considered in deciding posttreatment strategy among high-risk T1CRC patients, alongside with positive vertical margin, depth, lymphovascular invasion, poor histologic grade, and budding. During the research period, there was no prognostic difference between the FU and AS groups.