FDG metabolic parameter-based models for predicting recurrence after upfront surgery in synchronous colorectal cancer liver metastasis.

OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: • In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. • The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. • The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.

International standardization and optimization group for intersphincteric resection (ISOG-ISR): modified Delphi consensus on anatomy, definition, indication, surgical technique, specimen description and functional outcome.

AIM: Intersphincteric resection (ISR) is an oncologically complex operation for very low-lying rectal cancers. Yet, definition, anatomical description, operative indications and operative approaches to ISR are not standardized. The aim of this study was to standardize the definition of ISR by reaching international consensus from the experts in the field. This standardization will allow meaningful comparison in the literature in the future. METHOD: A modified Delphi approach with three rounds of questionnaire was adopted. A total of 29 international experts from 11 countries were recruited for this study. Six domains with a total of 37 statements were examined, including anatomical definition; definition of intersphincteric dissection, intersphincteric resection (ISR) and ultra-low anterior resection (uLAR); indication for ISR; surgical technique of ISR; specimen description of ISR; and functional outcome assessment protocol. RESULTS: Three rounds of questionnaire were performed (response rate 100%, 89.6%, 89.6%). Agreement (≥80%) reached standardization on 36 statements. CONCLUSION: This study provides an international expert consensus-based definition and standardization of ISR. This is the first study standardizing terminology and definition of deep pelvis/anal canal anatomy from a surgical point of view. Intersphincteric dissection, ISR and uLAR were specifically defined for precise surgical description. Indication for ISR was determined by the rectal tumour's maximal radial infiltration (T stage) below the levator ani. A new surgical definition of T3isp was reached by consensus to define T3 low rectal tumours infiltrating the intersphincteric plane. A practical flowchart for surgical indication for uLAR/ISR/abdominoperineal resection was developed. A standardized ISR surgical technique and functional outcome assessment protocol was defined.

Clinical Implication of Perineural and Lymphovascular Invasion in Rectal Cancer Patients Who Underwent Surgery After Preoperative Chemoradiotherapy.

BACKGROUND: Lymphovascular and perineural invasion are well-known negative prognostic indicators in rectal cancer, but previous studies on their significance are not consistent. OBJECTIVE: This study assessed the prognostic value of lymphovascular and perineural invasion in rectal cancer patients who received preoperative chemoradiotherapy followed by curative resection. DESIGN: This is a retrospective analysis. SETTING: This study was performed at a tertiary cancer center. PATIENTS: Rectal cancer patients who underwent curative resection after preoperative chemoradiotherapy between January 2000 and December 2010. MAIN OUTCOME MEASURES: The primary outcomes were disease-free survival and overall survival. The survival rates were estimated using Kaplan-Meier analysis, and group comparisons were conducted using a log-rank test. RESULTS: Of the 1156 included patients, 109 (9.4%) presented with lymphovascular invasion and 137 (11.9%) presented with perineural invasion. Lymphovascular and perineural invasion were associated with T and N downstaging after preoperative chemoradiotherapy ( p < 0.001). In the ypN0 patients, the 5-year disease-free survival rates were 70.8% and 78.5% ( p = 0.150) for the lymphovascular invasion and absent groups, respectively. In the perineural invasion group, the 5-year disease-free survival rate was 59.0% compared to 80.2% in the absent group ( p = 0.001). Among the ypN+ patients, the 5-year disease-free survival rates were 36.9% and 44.4% for the lymphovascular invasion and absent groups, respectively ( p = 0.211). The perineural invasion group had a poorer 5-year disease-free survival rate compared to the absent group (29.7% vs 46.7%; p = 0.011). By multivariable analyses, perineural invasion correlated with a poor disease-free survival (HR 1.412, 95% CI 1.082-1.843; p = 0.011) and also in ypN0 subgroup analysis (HR 1.717, 95% CI 1.093-2.697; p = 0.019). LIMITATIONS: This study was a retrospective study conducted at a single center. CONCLUSIONS: Perineural invasion is a reliable independent predictor of recurrence in rectal cancer patients treated with preoperative chemoradiotherapy. Patients with perineural invasion should be considered for closer surveillance even with ypN0 status. See Video Abstract at http://links.lww.com/DCR/B833 .IMPLICACIÓN CLÍNICA DE LA INVASIÓN PERINEURAL Y LINFOVASCULAR EN PACIENTES CON CÁNCER DE RECTO SOMETIDOS A CIRUGÍA DESPUÉS DE QUIMIORRADIOTERAPIA PREOPERATORIA. ANTECEDENTES: La invasión linfovascular y perineural en cancer de recto, son indicadores pronósticos negativos bien conocidos, pero estudios previos sobre su significancia, no son consistentes. OBJETIVO: El estudio evaluó el valor pronóstico de la invasión linfovascular y perineural en pacientes con cáncer de recto sometidos a quimiorradioterapia preoperatoria seguida de resección curativa. DISEO: Es un análisis retrospectivo. ENTORNO CLINICO: El estudio se realizó en un centro oncológico terciario. PACIENTES: Pacientes con cáncer de recto sometidos a resección curativa después de quimiorradioterapia preoperatoria entre enero de 2000 y diciembre de 2010. PRINCIPALES MEDIDAS DE VALORACION: Los resultados primarios fueron la supervivencia libre de enfermedad y la supervivencia general. Las tasas de supervivencia se estimaron mediante el análisis de Kaplan-Meier y las comparaciones de grupos se realizaron mediante una prueba de rango logarítmico. RESULTADOS: De los 1156 pacientes incluidos, 109 (9,4%) presentaron invasión linfovascular y 137 (11,9%) invasión perineural. La invasión linfovascular y perineural se asoció con reducción del estadio de T y N después de la quimiorradioterapia preoperatoria ( p < 0,001). En los pacientes ypN0, las tasas de supervivencia libre de enfermedad a 5 años fueron del 70,8% y el 78,5% ( p = 0,150) para los grupos con y sin invasión linfovascular, respectivamente. En el grupo de invasión perineural, la tasa de supervivencia libre de enfermedad a 5 años fue del 59,0%, en comparación con el 80,2% en el grupo ausente ( p = 0,001). Entre los pacientes ypN +, las tasas de supervivencia sin enfermedad a 5 años fueron del 36,9% y 44,4% para los grupos con y sin invasión linfovascular, respectivamente ( p = 0,211). El grupo de invasión perineural mostró una tasa de supervivencia libre de enfermedad a 5 años menor, en comparación con el grupo ausente (29,7% versus 46,7%, p = 0,011). Mediante análisis multivariable, la invasión perineural se correlacionó con una pobre tasa de supervivencia de enfermedad (índice de riesgo 1,412; intervalo de confianza del 95%: 1,082-1,843; p = 0,011) y también en el análisis de subgrupos ypN0 (índice de riesgo 1,717; intervalo de confianza del 95%: 1,093-2,697; p = 0,019). LIMITACIONES: Estudio retrospectivo realizado en un solo centro. CONCLUSIONES: La invasión perineural es un predictor independiente y confiable de recurrencia en pacientes con cáncer de recto tratados con quimiorradioterapia preoperatoria. Los pacientes con invasión perineural deben considerarse para una vigilancia más estrecha incluso con estadio ypN0. Consulte Video Resumen en http://links.lww.com/DCR/B833 . (Traducción-Dr. Fidel Ruiz Healy ).

Involvement of tissue changes induced by neoadjuvant treatment in total mesorectal excision (TME): novel suggestions for determining TME quality.

BACKGROUND: Few studies to date have investigated morphological changes after neoadjuvant treatment (NAT) and their implications in total mesorectal excision (TME). This study was primarily designed to evaluate whether tissue changes associated with NAT affected the quality of TME and additionally to suggest a more objective method evaluating TME quality. METHODS: This study enrolled 1322 consecutive patients who underwent curative robot-assisted surgery for rectal cancer. Patients who did and did not receive NAT were subjected to propensity-score matching, yielding 402 patients in each group. RESULTS: NAT independently reduced complete achievement of TME [odds ratio (OR) = 2.056, p = 0.017]. Intraoperative evaluation identified seven tissue changes significantly associated with NAT, including tumor perforation, mucin pool, necrosis, fibrosis, fat degeneration, and rectal or perirectal edema NAT (p < 0.001-0.05). Tumor perforation (OR = 5.299, p = 0.001) and mucin pool (OR = 14.053, p = 0.002) were independently associated with inappropriate (near-complete + incomplete) TME. Complete TME resulted in significantly reduced local recurrence (4.3% vs 15.3%, p = 0.003) and increased 5-year DFS rate (80.6% vs 67.6%, p = 0.047) compared with inappropriate one. By contrast, two tiers of complete and near-complete TMEs vs incomplete TME did not. Notably, among patients with complete TME, those who received NAT had a lower 5-year DFS than those who did not (77.8% vs 83.3%, p = 0.048). CONCLUSIONS: NAT-associated tissue changes, somewhat interrupting complete TME, may provide unsolved clue to the relative inability of NAT to improve overall survival. The conventional three-tier grading of TME seems to be simplified into two tiers as complete and inappropriate.

Comparative survival risks in patients undergoing abdominoperineal resection and sphincter-saving operation for rectal cancer: a 10-year cohort analysis using propensity score matching.

PURPOSE: Abdominoperineal resection (APR) has been considered to have a higher risk of local recurrence and poorer survival outcome than sphincter-saving operation (SSO) in patients with rectal cancer. This study compared long-term oncologic outcomes and prognostic parameters in propensity score-matched patients who underwent APR and SSO. METHODS: This study analyzed 958 consecutive patients with lower rectal cancer who underwent preoperative chemoradiotherapy followed by APR or SSO between 2005 and 2015. Propensity score matching analysis was performed to adjust baseline characteristics, including clinical stage, tumor distance from the anal verge, and tumor size. RESULTS: In the entire cohort, the APR group had larger and lower tumors and showed significantly shorter 5-year disease-free survival (DFS) than the SSO group (64.5% vs. 75.8%, p = 0.01). After propensity score matching, there were no significant between-group differences in local (9.5% vs. 8.0%, p = 0.59) and systemic (27.9% vs. 23.4%, p = 0.3) recurrence rates, and 5-year DFS (67.5% vs. 69.9%, p = 0.49) and overall survival (80.8% vs. 82.9%, p = 0.65) rates. A lower number of lymph nodes retrieved was independently associated with recurrence and survival outcomes in the APR group, whereas poorly differentiated histology was an independent associated parameter in the SSO group. Advanced stage and perineural invasion were identified as independent prognostic parameters in both groups. CONCLUSIONS: This study indicated that the long-term oncologic outcomes of APR were comparable to those of SSO. Because prognostic parameters associated with oncologic outcomes differed between the respective procedures, correctable parameters could be ameliorated through complete total mesorectal excision and personalized systemic treatment.

Oncological outcomes according to the treatment modality based on the size of rectal neuroendocrine tumors: a single-center retrospective study.

BACKGROUND: Owing to an increased number of colonoscopy screenings, the incidence of diagnosed rectal neuroendocrine tumors (NETs) has also increased. Tumor size is one of the most frequently regarded factors when selecting treatment; however, it may not be the determinant prognostic variable. We aimed to evaluate oncological outcomes according to the treatment modality based on the size of rectal NETs. METHODS: A retrospective analysis was performed on patients who were treated for rectal NETs between March 2000 and January 2016 at the Asan Medical Center, Seoul, Korea. Patients who underwent endoscopic removal, local surgical excision, and radical resection were included. The primary outcome was recurrence-free survival (RFS). Data were specified and analyzed following the 2019 World Health Organization classification (WHO). RESULTS: A total of 644 patients were categorized under three groups according to the treatment modality used: endoscopic removal (n = 567), surgical local excision (n = 56), and radical resection (n = 21). Of a total of 35 recurrences, 27 were local, whereas eight were distant. The RFS rate did not differ significantly between the treatment groups in the same tumor-size group ([Formula: see text]1 cm group: P = .636, 1-2 cm group: P = .160). For T1 tumors, RFS rate was not different between local excision and radical resection ([Formula: see text]1 cm group: P = .452, 1-2 cm group: P = .700). Depth of invasion, a high Ki-67 index, and margin involvement were confirmed as independent risk factors for recurrence. Among patients treated with endoscopic removal, endoscopic biopsy was a significant factor for worse RFS (P < .001), while tumor size did not affect the RFS. CONCLUSION: The current guideline recommends treatment options according to tumor size. However, more oncologically important prognostic factors include muscularis propria invasion and a higher Ki-67 index.

Depletion of HNRNPA1 induces peroxisomal autophagy by regulating PEX1 expression.

Peroxisomes play an essential role in cellular homeostasis by regulating lipid metabolism and the conversion of reactive oxygen species (ROS). Several peroxisomal proteins, known as peroxins (PEXs), control peroxisome biogenesis and degradation. Various mutations in the PEX genes are genetic causes for the development of inheritable peroxisomal-biogenesis disorders, such as Zellweger syndrome. Among the peroxins, PEX1 defects are the most common mutations in Zellweger syndrome. PEX1 is an AAA-ATPase that regulates the recycling of PEX5, which is essential for importing peroxisome matrix proteins. However, the post-transcriptional regulation of PEX1 is largely unknown. Here, we showed that heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) controls PEX1 expression. In addition, we found that depletion of HNRNPA1 induces autophagic degradation of peroxisome, which is blocked in ATG5-knockout cells. In addition, depletion of HNRNPA1 increased peroxisomal ROS levels. Inhibition of the generation of peroxisomal ROS by treatment with NAC significantly suppressed pexophagy in HNRNPA1-deficient cells. Taken together, our results suggest that depletion of HNRNPA1 increases peroxisomal ROS and pexophagy by downregulating PEX1 expression.

Distribution pattern of tumor infiltrating lymphocytes and tumor microenvironment composition as prognostic indicators in anorectal malignant melanoma.

Anorectal malignant melanoma (ARMM) is a rare disease with poor prognosis. Determining ARMM prognosis precisely is difficult due to the lack of proper assessment techniques. Immunotherapy has proven effective against cutaneous malignant melanoma and may show efficacy in ARMM. Herein, we assessed the immune profile of ARMM to identify possible prognostic biomarkers. Twenty-two ARMM formalin-fixed and paraffin-embedded samples were evaluated using an nCounter® PanCancer Immune Profiling Panel. Validation was performed through immunohistochemical staining for CD3, CD8, Foxp3, CD68, CD163, and PD-L1. RNA analysis revealed significantly decreased scores for pathways involved in cell regulation and function, as well as chemokines, in recurrent patients compared to nonrecurrent patients. In cell-type profiling, the recurrent cases displayed significantly low tumor infiltrating lymphocyte (TIL) scores. Recurrence/death prediction models were defined using logistic regression and showed significantly lower scores in recurrent and deceased patients (all, P < 0.001) compared to those in nonrecurrent and surviving patients. The high total TIL and tumor-associated macrophage (TAM) groups had significantly better overall survival outcomes compared to the low total TIL and TAM groups (P = 0.007 and P = 0.035, respectively). In addition, the presence of CD3 + TILs in the invasion front was an independent favorable prognostic indicator (P = 0.003, hazard ratio = 0.21, 95% confidential interval, 0.01-0.41). Patients with inflamed or brisk-infiltration type tumors also had a significantly better overall survival than that of patients with immune-desert/excluded and absent/non-brisk type tumors (P = 0.03 and P = 0.0023, respectively). In conclusion, TILs have a strong prognostic value in ARMM, and the quantification of TILs and an analysis of the TIL phenotype and infiltration pattern during pathological diagnosis are essential to guide treatment strategies and accurate prognosis in ARMM.

Comparison of long-term recurrence-free survival between primary surgery and endoscopic resection followed by secondary surgery in T1 colorectal cancer.

BACKGROUND AND AIMS: We aimed to investigate whether endoscopic resection of T1 colorectal cancer (CRC) before surgery (secondary surgery) unfavorably affects long-term recurrence-free survival (RFS) compared with surgery without prior endoscopic resection (primary surgery). METHODS: We reviewed the medical records of patients who underwent radical surgery for T1 CRC with high-risk histologic features at a tertiary referral hospital in Korea between 2011 and 2016. The primary outcome was RFS. We performed 2 types of propensity score (PS) analyses to control for confounders. RESULTS: Of 852 patients, 388 underwent primary surgery and 464 secondary surgery. During the median follow-up period of 57.0 months (range, 41.0-63.0), cancer recurred in 18 patients (2.1%). The 5-year RFS rates did not differ between the primary and secondary surgery groups (97.0 vs 98.5%, P = .194). Further analyses of RFS rates according to nodal stages and number of high-risk histologic features showed no difference between groups. Moreover, RFS rates were not different between the groups after PS matching. In multivariable Cox proportional regression analysis, baseline serum carcinoembryonic antigen level was an independent risk factor for cancer recurrence (hazard ratio, 1.464; 95% confidence interval, 1.242-1.725; P < .001) but prior endoscopic resection of T1 CRC was not (P = .201). Both PS analyses consistently showed no increase in cancer recurrence risk in the secondary surgery group. CONCLUSIONS: Our data showed no additional cancer recurrence risk by endoscopic resection before surgery of T1 CRC with high-risk histologic features.

Re-evaluation of controversial issues in the treatment of cT3N0-2 rectal cancer: a 10-year cohort analysis using propensity-score matching.

BACKGROUND: Although neoadjuvant treatment is thought to provide optimal local control for stage II and III rectal cancers, many patients have been reported cured by total mesorectal excision (TME), alone or with additional chemotherapy (CTX). METHODS: This study retrospectively evaluated outcomes in 2643 patients with cT3N0-2 rectal cancers undergoing curative TME during 2005-2015. Recurrence and survival outcomes were measured in three propensity-score matched groups, consisting of patients who underwent preoperative chemoradiotherapy (CRT) with postoperative CTX (NAPOC), postoperative CRT (POCRT), and exclusively postoperative CTX (EPOCT). RESULTS: Near-complete or complete TME was conducted in more than 95.9% of patients and 80% of scheduled dose of postoperative CTX was completed in 99%. Except for higher SR rate in the POCRT group than the NAPOC group (p = 0.008), 5-year cumulative local and systemic recurrence (LR and SR) rates were 4.9% and 15.2% for cT3N0, and 4.2% and 21% for cT3N1-2 patients (LR, p = 0.703; SR, 0.065), respectively, with no significant differences associated with treatment exposure (p = 0.11-1). The 5-year cumulative disease-free (75.6% vs 65.7%, p = 0.018) and overall survival (87.1% vs 79.4%, p = 0.018 each) rates were higher in the NAPOC group than the POCRT group with cT3N1-2. However, any significant survival differences were not identified between the NAPOC and EPOCT groups according to tumor sub-stages or locations (p = 0.395-0.971). CONCLUSIONS: We found any treatment modalities including competent TME and postoperative adjuvant CTX efficiently reducing LR generating robust survival outcome in the propensity-matched cohorts, demanding further randomized controlled trials by clinical sub-stages II-III.

Study protocol for an International Prospective Observational Cohort Study for Optimal Bowel Resection Extent and Central Radicality for Colon Cancer (T-REX study).

This is a prospective observational cohort study aiming to include 4000 patients with stages I to III colon cancer treated at 35 specialist institutions in Japan, South Korea, Germany, Russia, Lithuania and Taiwan. The anatomical distribution of lymph nodes and feeding arteries are investigated using surgical specimens according to pre-specified categorizing methods using intraoperative anatomical markings. Primary analyses are performed to identify the general principles of metastatic lymph node distribution in terms of its relation to the location of the primary tumor and feeding arteries. Secondary analyses will be used to estimate prognostic outcomes according to bowel resection length and central radicality and will be used to evaluate the quality of resected surgical specimens. Through in-depth lymph node mapping, standardized criteria for the definite area of 'regional' lymph node resection in routine surgical procedures can be identified, which is expected to contribute to international standardization in colon cancer surgery (ClinicalTrials.gov NCT02938481).

Re-evaluation of possible vulnerable sites in the lateral pelvic cavity to local recurrence during robot-assisted total mesorectal excision.

BACKGROUND: Despite mechanical and technical improvements in laparoscopic and robot-assisted (LAR) rectal cancer procedures, the absence of prognostic disparities among various approaches cannot improve the quality of TME. The present study re-evaluated robot-assisted total mesorectal excision (TME) procedures to determine whether these procedures may reveal technical faults that may increase the rate of local recurrence (LR). METHODS: This study enrolled 886 consecutive patients with rectal cancer, who underwent curative robot-assisted LAR at Asan Medical Center (Seoul, Korea) between July 2010 and August 2017 (the first vs second period; n = 399 vs 487). The quality of TME and lateral pelvic mesorectal excision (LPME) were analyzed, as were LR rates and survival outcomes. RESULTS: Complete TME and LPME were achieved in 89.2% and 80.1% of these patients, respectively, with ≤ 1% having incomplete TME excluding intramesorectal excision. LR rates were 13.5 and 14.5 times higher in patients with incomplete TME and LPME, respectively, than in patients with complete TME and LPME (14.8% vs 1.1% and 8.7% vs 0.6%; p < 0.001 each by univariate analyses). Multivariate analyses showed that defective LPME was independently associated with incomplete TME and vice versa (p < 0.001). Cox regression analysis showed that defective LPME was independently correlated with reduced 5-year disease-free survival rate (hazard ratio, 1.563; 95% confidence interval, 1.052-2.323; p = 0.027). CONCLUSIONS: LR in rectal cancer patients was largely due to incomplete LPME, which was significantly associated with incomplete TME. Complete LPME may enhance the likelihood of complete TME, reducing LR rates.

Characteristics and Prognosis of Colorectal Cancer after Liver or Kidney Transplantation.

BACKGROUND: The purpose of this study was to evaluate the characteristics and prognosis of de novo CRC patients who underwent liver or kidney transplantation. METHODS: We retrospectively reviewed the medical records of 66 de novo CRC patients selected from 8,734 liver transplant (LT) or kidney transplant (KT) recipients. We analyzed characteristics and survival outcomes of de novo CRC patients and sporadic CRC patients who underwent radical surgery with stage I-III in Asan Medical Center between 2005 and 2016. Survival outcomes were analyzed via the 1:4 matching method. RESULTS: The standard incidence ratio (SIR) of de novo CRC in KT recipients is 1.67 in men and 2.54 in women. That in LT recipients is 3.10 in men and 2.25 in women. Compared with sporadic CRC patients, de novo CRC patients had more colon cancer than rectal cancer (p=0.041). In 9 patients (13.6%), CRC was diagnosed within one year after transplantation, 21 patients (31.8%) were diagnosed between 1-5 years, and the remaining 36 patients (54.6%) were diagnosed thereafter. There were no significant differences in recurrence-free survival and overall survival between the two groups (p=0.211 and p=0.324, respectively). CONCLUSIONS: The risk of developing de novo CRC in transplant recipients was higher than in the general population. The survival outcome of de novo CRC was no different compared with the sporadic CRC. Therefore, regular surveillance is essential for timely diagnosis and treatment for transplantation patients. A large prospective study for an intense CRC surveillance program in transplantation patients is needed.

Oncological and anorectal functional outcomes of robot-assisted intersphincteric resection in lower rectal cancer, particularly the extent of sphincter resection and sphincter saving.

BACKGROUND: Few investigations to date assessing the effectiveness of robot-assisted intersphincteric resection (ISR) have included sufficient patients and follow-up period. This study assessed the utility and safety of robot-assisted ISR by comparing groups of patients who underwent low anterior resection (LAR) with or without ISR and ISR extent. METHODS: This study enrolled 897 patients who underwent curative LAR between 2010 and 2017. Patients were divided into those who did (ISR+) and did not (ISR-) undergo ISR, with the former group subdivided by ISR extent (partial, subtotal, and total). Tumor recurrence and survival were compared in the two groups by one-to-one nearest neighbor matching (218 patients each). RESULTS: Robot-assisted ISR was performed via an entirely transabdominal approach in 93% of patients who underwent LAR. The rate of circumferential margin positivity was ≤ 2% in all patients and did not differ in the ISR- and ISR+ groups or in the three ISR+ subgroups. Mean fecal incontinence score and manometric values deteriorated significantly during postoperative until 12-24 months (p < 0.05 to < 0.001), but recovered subsequently. The 5-year cumulative rates of local recurrence in the ISR+ and ISR- groups were 2.5% and 2.9%, respectively (p = 0.731). The 5-year cumulative rates of overall (86.7% vs. 84.2%, p = 0.899) and disease-free (80.7% vs. 78.5%, p = 0.934) survival did not differ significantly in the ISR+ and ISR- groups. CONCLUSIONS: Because ISR involves resection of low-lying tumors and complex pelvic dissection, robot-assisted ISR via a mostly transabdominal procedure may be technically more efficient, providing lasting anorectal function and good oncologic outcomes.

Local excision for ypT2 rectal cancer following preoperative chemoradiation therapy: it should not be justified.

PURPOSE: Among individuals who respond well to preoperative chemoradiation therapy (CRT) for ypT0-1, local excision (LE) could provide acceptable oncological outcomes. However, in ypT2 cases, the oncological safety of LE has not been determined. This study aimed to compare oncological outcomes between LE and total mesorectal excision of ypT2-stage rectal cancer after chemoradiation therapy and investigate the oncological safety of LE in these patients. METHODS: We included 351 patients who exhibited ypT2-stage rectal cancer after CRT followed by LE (n = 16 [5%]) or total mesorectal excision (TME) (n = 335 [95%]) after preoperative CRT between January 2007 and December 2013. After propensity matching, oncological outcomes between LE group and TME group were compared. RESULTS: The median follow-up period was 57 months (range, 12-113 months). In the LE group, local recurrence occurred more frequently (18 vs. 4%; p = 0.034) but not distant metastases (12 vs. 11%; p = 0.690). The 5-year local recurrence-free (76 vs. 96%; p = 0.006), disease-free (64 vs. 84%; p = 0.075), and overall survival (79 vs. 93%; p = 0.045) rates of the LE group were significantly lower than those of the TME group. After propensity matching, 5-year local recurrence-free survival of the LE group was significantly lower than that of the TME group (76 vs. 97%, p = 0.029). CONCLUSION: The high local failure rate and poor oncological outcomes for ypT2-stage rectal cancer patients who undergo CRT followed by LE cannot be justified as an indication for LE. Salvage surgery should be recommended in these patients.

Prognostic and Oncologic Significance of Perineural Invasion in Sporadic Colorectal Cancer.

BACKGROUND: The presence of perineural invasion (PNI) in colorectal cancer (CRC) indicates a more aggressive phenotype, resulting in a poor prognosis. The aims of this study were to evaluate the oncologic outcome of PNI+ tumors and to investigate whether PNI status affects patient survival. METHODS: The study retrospectively enrolled 3807 patients from a single institution who underwent surgery for colorectal adenocarcinoma between January 2006 and December 2010. The patients were classified into two groups based on PNI status: PNI+ and PNI-. RESULTS: The PNI+ group included 565 patients (14.8 %) and had significantly more involved circumferential resection margins (p = 0.001) and a more advanced TNM stage (p = 0.001) than the PNI- group. Compared with the PNI- group, the PNI+ group had worse 5-year overall survival (65 vs. 88 %; p = 0.001) and 5-year disease-free survival (63 vs. 85 %; p = 0.001). Among PNI+ patients with stage IIA disease, those who received adjuvant therapy had significantly greater 5-year overall survival than those who did not (89.3 vs. 50.8 %; p = 0.001). In multivariate analyses, PNI+ was an independent negative prognostic factor for 5-year overall survival (hazard ratio [HR] 1.518, 95 % confidence interval [CI] 1.175-1.961; p = 0.001) and 5-year disease-free survival (HR 1.495, 95 % CI 1.237-1.806; p = 0.001). CONCLUSIONS: PNI positivity is an independent predictor of aggressive behavior and unfavorable prognosis in CRC. Further evaluation is needed to confirm the impact of PNI status on survival in stage IIA CRC.

Microsatellite Instability was not Associated with Survival in Stage III Colon Cancer Treated with Adjuvant Chemotherapy of Oxaliplatin and Infusional 5-Fluorouracil and Leucovorin (FOLFOX).

BACKGROUND: The impact of microsatellite instability (MSI) on survival in stage III colon cancer treated with adjuvant 5-fluorouracil-oxaliplatin combination (FOLFOX) chemotherapy is not clear. We evaluated the association between MSI and survival in this population. METHODS: We analyzed 598 patients with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification; tumors were classified as high MSI (MSI-H, ≥2 unstable markers), low MSI (MSI-L, 1 unstable marker), or microsatellite stable (MSS, no unstable marker). RESULTS: Of 598 patients, 8.4% showed MSI-H. Tumors classified as MSI-H were more commonly located in the ascending colon (54.0 vs. 27.7%, p < 0.0001) and had poorly differentiated features (32.0 vs. 8.0%, p < 0.0001). After the median follow-up of 52.8 months, 5-year disease-free (DFS) and overall survival (OS) rates were 77.0 and 85.9%, respectively. In univariate analysis, pathologic T4 (pT4) and pathologic N2 (pN2) was associated with reduced DFS (p < 0.0001 and p < 0.0001, respectively) and OS (p = 0.002 and p = 0.001, respectively), whereas MSI status did not affect either DFS (p = 0.114) or OS (p = 0.525). In patients with pN2 tumors; however, MSI-H was associated with better survival compared with MSS/MSI-L; DFS and OS in patients with MSI-H/pN2 were comparable to those in patients with pN1 tumors. CONCLUSIONS: In patients with stage III colon cancer treated with adjuvant FOLFOX, pT4 and pN2 was associated with reduced survival, but MSI status alone did not affect survival.

Interpretative Guidelines and Possible Indications for Indocyanine Green Fluorescence Imaging in Robot-Assisted Sphincter-Saving Operations.

BACKGROUND: Since the introduction of indocyanine green angiography more than 25 years ago, few studies have presented interpretative guidelines for indocyanine green fluorescent imaging. OBJECTIVE: We aimed to provide interpretative guidelines for indocyanine green fluorescent imaging through quantitative analysis and to suggest possible indications for indocyanine green fluorescent imaging during robot-assisted sphincter-saving operations. DESIGN: This is a retrospective observational study. SETTINGS: This study was conducted at a single center. PATIENTS: A cohort of 657 patients with rectal cancer who consecutively underwent curative robot-assisted sphincter-saving operations was enrolled between 2010 and 2016, including 310 patients with indocyanine green imaging (indocyanine green fluorescent imaging+ group) and 347 patients without indocyanine green imaging (indocyanine green fluorescent imaging- group). MAIN OUTCOME MEASURES: We tried to quantitatively define the indocyanine green fluorescent imaging findings based on perfusion (mesocolic and colic) time and perfusion intensity (5 grades) to provide probable indications. RESULTS: The anastomotic leakage rate was significantly lower in the indocyanine green fluorescent imaging+ group than in the indocyanine green fluorescent imaging- group (0.6% vs 5.2%) (OR, 0.123; 95% CI, 0.028-0.544; p = 0.006). Anastomotic stricture was closely correlated with anastomotic leakage (p = 0.002) and a short descending mesocolon (p = 0.003). Delayed perfusion (>60 s) and low perfusion intensity (1-2) were more frequently detected in patients with anastomotic stricture and marginal artery defects than in those without these factors (p ≤ 0.001). In addition, perfusion times greater than the mean were more frequently observed in patients aged >58 years, whereas low perfusion intensity was seen more in patients with short descending mesocolon and high ASA classes (≥3). LIMITATIONS: The 300 patients in the indocyanine green fluorescent imaging- group underwent operations 3 years before indocyanine green fluorescent imaging. CONCLUSIONS: Quantitative analysis of indocyanine green fluorescent imaging may help prevent anastomotic complications during robot-assisted sphincter-saving operations, and may be of particular value in high-class ASA patients, older patients, and patients with a short descending mesocolon.

Robot-assisted intersphincteric resection facilitates an efficient sphincter-saving in patients with low rectal cancer.

PURPOSE: Few investigations of robot-assisted intersphincteric resection (ISR) are presently available to support this procedure as a safe and efficient procedure. We aimed to evaluate the utility of robot-assisted ISR by comparison between ISR and abdominoperineal resection (APR) using both robot-assisted and open approaches. METHODS: The 558 patients with lower rectal cancer (LRC) who underwent curative operation was enrolled between July 2010 and June 2015 to perform either by robot-assisted (ISR vs. APR = 310 vs. 34) or open approaches (144 vs. 70). Perioperative and functional outcomes including urogenital and anorectal dysfunctions were measured. Recurrence and survival were examined in 216 patients in which >3 years had elapsed after the operation. RESULTS: The robot-assisted approach was the most significant parameter to determine ISR achievement among potent parameters (OR = 3.467, 95% CI = 2.095-5.738, p < 0.001). Early surgical complications occurred more frequently in the open ISR group (16 vs. 7.7%, p = 0.01). The voiding and male sexual dysfunctions were significantly more frequent in the open ISR (p < 0.05). The fecal incontinence and lifestyle alteration score was greater in the open ISR than in the robot-assisted ISR at 12 and 24 months, respectively (p < 0.05). However, the 3-year cumulative rates of local recurrence and survival did not differ between the two groups. CONCLUSIONS: The current procedure of robot-assisted ISR replaced a significant portion of APR to achieve successful SSO via mostly transabdominal approach and double-stapled anastomosis. The robot-assisted ISR with minimal invasiveness might be a help to reduce anorectal and urogenital dysfunctions.

Factors affecting the postoperative morbidity and survival of patients with liver cirrhosis following colorectal cancer surgery.

PURPOSE: Data are lacking on the appropriate risk stratification of patients undergoing surgery for colorectal cancer (CRC). This study aimed to evaluate the predictive factors for perioperative morbidity and oncological outcomes in CRC patients with liver cirrhosis (LC). METHODS: A retrospective analysis of prospectively collected data was conducted. A total of 161 LC patients who underwent surgery for CRC were identified between January 2001 and December 2010. RESULTS: The mean patient age was 60 ± 10 years, and the median follow-up period was 54.0 months (range 0.5-170.0). The proportions of patients with Child-Pugh classifications for LC were as follows: A (n = 118; 73.3%), B (n = 39; 24.2%), and C (n = 4; 2.5%). The median model for end-stage liver disease (MELD) score was 8 (range 6-21). The postoperative morbidity rate was 37.3% (60/161). Hyperbilirubinemia (p = 0.002), prothrombin time (PT) prolongation (p = 0.020), and intraoperative transfusion (p = 0.003) were the significant factors for postoperative morbidity in multivariate analysis. The postoperative mortality rate was 3.1% (5/161), and the 5-year cancer-specific and 5-year overall survival rates were 86.1 and 59.9%, respectively. The significant clinical risk factors by multivariate analysis that influenced overall survival were the TNM stage of CRC (p = 0.035), MELD score (>8 points) (p < 0.001), and the coexistence of hepatocellular carcinoma (HCC) (p = 0.012). CONCLUSIONS: Hyperbilirubinemia, PT prolongation, and intraoperative transfusion are significant risk factors for postoperative morbidity in LC patients who undergo surgery for CRC. Additionally, not only advanced TNM stage but also a high MELD score and the coexistence of HCC are associated with poor overall survival in CRC patients with LC.