Surgical quality assessment for the prospective study of oncologic outcomes after laparoscopic modified complete mesocolic excision for nonmetastatic right colon cancer (PIONEER study).

BACKGROUND: The modified complete mesocolic excision (mCME) procedure for right-sided colon cancer is a tailored approach based on the original complete mesocolic excision (CME) methodology. Limited studies evaluated the safety and feasibility of laparoscopic mCME using objective surgical quality assessments in patients with right colon cancer. The objectives of the PIONEER study were to evaluate oncologic outcomes after laparoscopic mCME and to identify optimal clinically relevant endpoints and values for standardizing laparoscopic right colon cancer surgery based on short-term outcomes of procedures performed by expert laparoscopic surgeons. MATERIALS AND METHODS: This is an ongoing prospective, multi-institutional, single-arm study conducted at five tertiary colorectal cancer centers in South Korea. Study registrants included 250 patients scheduled for laparoscopic mCME with right-sided colon adenocarcinoma (from the appendix to the proximal half of the transverse colon). The primary endpoint was 3-year disease-free survival. Secondary outcomes included 3-year overall survival, incidence of morbidity in the first 4 weeks postoperatively, completeness of mCME, central radicality, and distribution of metastatic lymph nodes. Survival data will be available after the final follow-up date (June 2024). RESULTS: The postoperative complication rate was 12.9%, with a major complication rate of 2.7%. In 87% of patients, central radicality was achieved with dissection at or beyond the level of complete exposure of the superior mesenteric vein. Mesocolic plane resection with an intact mesocolon was achieved in 75.9% of patients, as assessed through photographs. Metastatic lymph node distribution varied by tumor location and extent. Seven optimal clinically relevant endpoints and values were identified based on the analysis of complications in low-risk patients. CONCLUSIONS: Laparoscopic mCME for right-sided colon cancer produced favorable short-term postoperative outcomes. The identified optimal clinically relevant endpoints and values can serve as a reference for evaluating surgical performance of this procedure.

Long-term bowel functional outcomes following anal sphincter-preserving surgery for upper and middle rectal cancer: a single-center longitudinal study.

PURPOSE: Despite advances in neoadjuvant chemoradiotherapy and anal sphincter-preserving surgery for rectal cancer, bowel dysfunction is still unavoidable and negatively affects patients' quality of life. In this longitudinal study, we aimed to investigate the changes in bowel function with follow-up time and the effect of neoadjuvant chemoradiotherapy on bowel function following low anterior resection for rectal cancer. METHODS: In this study, 171 patients with upper or middle rectal cancer who underwent low anterior resection between 2012 and 2018 were included. Bowel function was assessed longitudinally with Memorial Sloan Kettering Cancer Center Bowel Function Instrument and Wexner scores every 6 months after restoration of bowel continuity. Patients with at least 2 follow-up visits were included. RESULTS: Overall, 100 patients received neoadjuvant chemoradiotherapy. Urgency, soilage, and fecal incontinence were noted within 24 months in the patients treated with neoadjuvant chemoradiotherapy. After 2 years of follow-up, significant bowel dysfunction and fecal incontinence were observed in the neoadjuvant chemoradiotherapy group. Low tumor level and neoadjuvant chemoradiotherapy were associated with delayed bowel dysfunction. CONCLUSION: Neoadjuvant chemoradiotherapy in combination with low tumor level was significantly associated with delayed bowel dysfunction even after 2 years of follow-up. Therefore, careful selection and discussion with patients are paramount.

Pretreatment MRI-detected extramural venous invasion as a prognostic and predictive biomarker for neoadjuvant chemoradiotherapy in non-metastatic rectal cancer: a propensity score matched analysis.

OBJECTIVES: This study evaluated pretreatment magnetic resonance imaging (MRI)-detected extramural venous invasion (pmrEMVI) as a predictor of survival after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Medical records of 1184 patients with rectal adenocarcinoma who underwent TME between January 2011 and December 2016 were reviewed. MRI data were collected from a computerized radiologic database. Cox proportional hazards analysis was used to assess local, systemic recurrence, and disease-free survival risk based on pretreatment MRI-assessed tumor characteristics. After propensity score matching (PSM) for pretreatment MRI features, nCRT therapeutic outcomes according to pmrEMVI status were evaluated. Cox proportional hazards analysis was used to identify risk factors for early recurrence in patients receiving nCRT. RESULTS: Median follow-up was 62.8 months. Among all patients, the presence of pmrEMVI was significantly associated with worse disease-free survival (DFS; HR 1.827, 95% CI 1.285-2.597, p = 0.001) and systemic recurrence (HR 2.080, 95% CI 1.400-3.090, p < 0.001) but not local recurrence. Among patients with pmrEMVI, nCRT provided no benefit for oncological outcomes before or after PSM. Furthermore, pmrEMVI( +) was the only factor associated with early recurrence on multivariate analysis in patients receiving nCRT. CONCLUSIONS: pmrEMVI is a poor prognostic factor for DFS and SR in patients with non-metastatic rectal cancer and also serves as a predictive biomarker of poor DFS and SR following nCRT in LARC. Therefore, for patients who are positive for pmrEMVI, consideration of alternative treatment strategies may be warranted. CLINICAL RELEVANCE STATEMENT: This study demonstrated the usefulness of pmrEMVI as a predictive biomarker for nCRT, which may assist in initial treatment decision-making in patients with non-metastatic rectal cancer. KEY POINTS: • Pretreatment MRI-detected extramural venous invasion (pmrEMVI) was significantly associated with worse disease-free survival and systemic recurrence in patients with non-metastatic rectal cancer. • pmrEMVI is a predictive biomarker of poor DFS following nCRT in patients with LARC. • The presence of pmrEMVI was the only factor associated with early recurrence on multivariate analysis in patients receiving nCRT.

Postchemoradiation magnetic resonance imaging circumferential resection margin predicts treatment failure after multidisciplinary directed sphincter preservation in low rectal cancer.

BACKGROUND: This study aimed to review the magnetic resonance imaging (MRI) features of patients with low rectal cancer (LRC) undergoing preoperative chemoradiotherapy (CRT) and investigate the risk factors for treatment failure after sphincter preserving surgery following preoperative CRT based on multidisciplinary approach. OBJECTIVES: Patients who underwent standard CRT and sphincter preserving radical surgery for LRC between January 2000 and December 2011 were retrospectively reviewed. Sphincter preservation failure (SPF) was defined as any one of the following: positive pathologic circumferential resection margin, local recurrence, failure to repair ileostomy, or permanent stoma formation due to anastomotic complications. RESULTS: Among the 191 patients, there were no overall significant differences between sphincter preservation success (n = 161) and SPF (n = 30) groups. SPF group showed a higher MRI circumferential resection margins (mrCRM) positive rate before and after CRT (before CRT: 33.3% vs. 16.1%, p = 0.027; after CRT: 23.3% vs. 6.2%, p = 0.002). Multivariate analysis showed that only mrCRM after CRT was associated with SPF (hazard ratio = 4.596, p = 0.005). SPF group showed worse 5-year cancer-specific survival (51% vs. 92.7%, p < 0.001). CONCLUSIONS: MRI-based assessment of the tumor after CRT plays a crucial role in predicting the success and feasibility of sphincter preservation as well as oncological outcomes in patients with LRC.

Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol.

BACKGROUND: Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis. METHODS: This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate. DISCUSSION: This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.

Neoadjuvant chemotherapy versus upfront surgery as the initial treatment for patients with resectable, synchronous colorectal cancer liver metastases.

BACKGROUND: Although perioperative chemotherapy has been the standard treatment for colorectal cancer with resectable liver metastases (CRLM), studies that have compared neoadjuvant chemotherapy (NAC) and upfront surgery, especially in the setting of synchronous metastases are rare. METHODS: We compared perioperative outcomes, overall survival (OS) and overall survival after recurrence (rOS) in a retrospective study of 281 total and 104 propensity score-matched (PSM) patients who underwent curative resection, with or without NAC, for synchronous CRLM, from 2006 to 2017. A Cox regression model was developed for OS. RESULTS: After PSM, 52 NAC and 52 upfront surgery patients with similar baseline characteristics were compared. Postoperative morbidity, mortality, and 5-year OS rate (NAC: 78.9%, surgery: 64.0%; p = 0.102) were similar between groups; however, the NAC group had better rOS (NAC: 67.3%, surgery: 31.5%; p = 0.049). Initial cancer stage (T4, N1-2), poorly differentiated histology, and >1 hepatic metastases were independent predictors of worse OS. Based on these factors, patients were divided into low-risk (≤1 risk factor, n = 115) and high-risk (≥2 risk factors, n = 166) groups. For high-risk patients, NAC yielded better OS than upfront surgery (NAC: 74.5%, surgery: 53.2%; p = 0.024). CONCLUSIONS: Although NAC and upfront surgery-treated patients had similar perioperative outcomes and OS, better postrecurrence survival was shown in patients with NAC. In addition, NAC may benefit patients with worse prognoses; therefore, physicians should consider patient disease risk before initiating treatment to identify patients who are most likely to benefit from chemotherapy.

Fusobacterium nucleatum induces a tumor microenvironment with diminished adaptive immunity against colorectal cancers.

Background & Aims: Fusobacterium nucleatum (FN) plays a pivotal role in the development and progression of colorectal cancer by modulating antitumor immune responses. However, the impact of FN on immune regulation in the tumor microenvironment has not been fully elucidated. Methods: The abundance of FN was measured in 99 stage III CRC tumor tissues using quantitative polymerase chain reaction. Gene expression profiles were assessed and annotated using consensus molecular subtypes (CMS), Gene Ontology (GO) analysis, and deconvolution of individual immune cell types in the context of FN abundance. Immune profiling for tumor infiltrating T cells isolated from human tumor tissues was analyzed using flow cytometry. Ex vivo tumor-infiltrating T cells were stimulated in the presence or absence of FN to determine the direct effects of FN on immune cell phenotypes. Results: Gene expression profiles, CMS composition, abundance of immune cell subtypes, and survival outcomes differed depending on FN infection. We found that FN infection was associated with poorer disease-free survival and overall survival in stage III CRC patients. FN infection was associated with T cell depletion and enrichment of exhausted CD8+ and FoxP3+ regulatory T cells in the tumor microenvironment. The presence of FN in tumors was correlated with a suppressive tumor microenvironment in a T cell-dependent manner. Conclusion: FN enhanced the suppressive immune microenvironment with high depletion of CD8+ T cells and enrichment of FoxP3+ regulatory T cells in human colorectal cancer cases. Our findings suggest a potential association for FN in adaptive immunity, with biological and prognostic implications.

Comparison of Laparoscopic Versus Robot-Assisted Surgery for Rectal Cancers: The COLRAR Randomized Controlled Trial.

OBJECTIVE: To evaluate whether robotic for middle or low rectal cancer produces an improvement in surgical outcomes compared with laparoscopic surgery in a randomized controlled trial (RCT). BACKGROUND: There is a lack of proven clinical benefit of robotic total mesorectal excision (TME) compared with a laparoscopic approach in the setting of multicenter RCTs. METHODS: Between July 2011 and February 2016, patients diagnosed with an adenocarcinoma located <10 cm from the anal verge and clinically rated T1-4aNxM0 were enrolled. The primary outcome was the completeness of TME assessed by a surgeon and a pathologist. RESULTS: The RCT was terminated prematurely because of poor accrual of data. In all, 295 patients were assigned randomly to a robot-assisted TME group (151 in R-TME) or a laparoscopy-assisted TME group (144 in L-TME). The rates of complete TME were not different between groups (80.7% in R-TME, 77.1% in L-TME). Pathologic outcomes including the circumferential resection margin and the numbers of retrieved lymph nodes were not different between groups. In a subanalysis, the positive circumferential resection margin rate was lower in the R-TME group (0% vs 6.1% for L-TME; P =0.031). Among the recovery parameters, the length of opioid use was shorter in the R-TME group ( P =0.028). There was no difference in the postoperative complication rate between the groups (12.0% for R-TME vs 8.3% for L-TME). CONCLUSIONS: In patients with middle or low rectal cancer, robotic-assisted surgery did not significantly improve the TME quality compared with conventional laparoscopic surgery (ClinicalTrial.gov ID: NCT01042743).

Palliative surgery as a bridge to systemic treatment for malignant bowel obstruction due to peritoneal metastases: A retrospective, case-control study.

BACKGROUND: High-quality data on palliative surgery in patients with malignant bowel obstruction (MBO) caused by peritoneal metastases (PM) are lacking. We aimed to determine the utility of palliative surgery for such patients. METHODS: We retrospectively analyzed patients considered for surgery for MBO, caused by PM, in our department from January 2019 to October 2020. None of them could tolerate a diet, despite conservative treatment. We investigated the clinical characteristics and perioperative outcomes and calculated overall survival (OS). Kaplan-Meier survival analysis was performed, with the log-rank test to evaluate differences in OS rates. Multivariate Cox regression was performed to determine prognostic factors. RESULTS: Sixty (67%) patients underwent surgery, whereas, 30 (33%) received the best supportive care (BSC) treatment. A better (p = 0.002) median OS was observed in patients undergoing surgery (3.9 months) than in those receiving BSC (2.6 months). Severe complications were observed in 12 (20%) patients, including 30-day mortality (7 patients). Forty-eight (80%) patients in the surgery group could tolerate a diet and the hospital stay (mean ± standard deviation) was 20.0 ± 23.1 days. Re-obstruction was observed in five (8.3%) patients after 78.6 ± 63.3 days. Patients in the postoperative chemotherapy group exhibited a better (p < 0.001) median OS (12.3 months) than did those in the no-postoperative chemotherapy group (3.5 months). Only postoperative chemotherapy (hazard ratio 0.264, 95% confidence interval 0.143-0.487, p < 0.001) was identified as an independent prognostic factor. CONCLUSIONS: Compared with BSC, surgery is associated with a better OS in patients with MBO due to PM. Surgery should be considered as a bridge to systemic treatment for such patients.

Preoperative computed tomography assessment of circumferential resection margin in retroperitonealized colon cancer predicts disease-free survival.

OBJECTIVES: The aim of this retrospective study was to predict circumferential resection margin (CRM) involvement on preoperative CT, and prognostic impact of CRM assessment by CT (ctCRM) in patients with retroperitonealized colon cancer. METHODS: This study included patients who underwent resection for ascending or descending colon cancer between July 2010 and February 2013. Positive ctCRM was defined as tumor distance to the retromesenteric plane of ≤ 1 mm. The origin of positive CRM was divided into primary tumor or other tumor components including lymph nodes, tumor deposits, or extramural venous invasions. Logistic regression analysis was performed to identify preoperative factors to predict pathologic CRM (pCRM). A Cox proportional hazards model was used in multivariable analysis to determine the preoperative factors affecting disease-free survival (DFS). RESULTS: A total of 274 patients (mean age, 64.0 years ± 11.0 [standard deviation]; 157 men) with retroperitonealized colon cancer were evaluated. Of 274 patients, 67 patients (24.5%) had positive CRM on surgical pathology. The accuracy of preoperative CT in predicting pCRM was 79.6% (218/274). Among preoperative factors, only CRM assessment on CT was independently associated with pCRM (p < 0.001). Positive ctCRM by primary tumor was an independent factor for DFS (HR, 3.362 [1.714-6.593]) and systemic recurrence (HR, 3.715 [1.787-7.724], but not for local recurrence on multivariable analyses. CONCLUSIONS: Preoperative CT can accurately predict pCRM, and positive ctCRM by primary tumor is an independent risk factor for DFS and systemic recurrence, but not for local recurrence in retroperitonealized colon cancer. KEY POINTS: • Preoperative CT can predict pathologic circumferential resection margin (CRM) with approximately 80% of accuracy in patients with retroperitonealized colon cancer. • Positive CRM by a primary tumor on preoperative CT is a poor prognostic factor for disease-free survival and systemic recurrence in patients with retroperitonealized colon cancer. • CRM involvement on CT was not associated with local recurrence in patients with retroperitonealized colon cancer.

Impact of neoadjuvant treatment on rectal gastrointestinal stromal tumors.

Although gastrointestinal stromal tumors (GISTs) are rare disease and rectal GISTs is only 5% of total GISTs, they have the worst prognosis. Due to narrow pelvis, tumor rupture or positive resection margin are common in the management of rectal GISTs. The impact of neoadjuvant treatment on the clinical outcomes of rectal gastrointestinal stromal tumors (GISTs) remains unclear. Thus, we conducted a retrospective study to investigate the impact of neoadjuvant imatinib on rectal GIST. The cohort comprised 33 patients; of them, 10 and 23 belonged to the neoadjuvant (i.e., those who underwent neoadjuvant imatinib treatment) and the control group (i.e., those who underwent surgery without prior imatinib treatment), respectively. Neoadjuvant group was associated with more common levator ani muscle displacement (P = 0.002), and showed significantly larger radiologic tumor size (P = 0.036) than the control group. The mean tumor size was significantly decreased after imatinib treatment (6.8 cm to 4.7cm, P = 0.006). There was no significant difference in resection margin involvement (P >0.999), and sphincter preservation rates (P = 0.627) between the two groups. No difference was observed with respect to morbidities, hospital stay, local recurrence and disease-free survival. Neoadjuvant imatinib treated group had similar propensity with control group after treatment. We thought reduced tumor sized could enhance resectability and provide more chance to preserve sphincter for rectal GIST patients. Considering large tumor size and higher rate of sphincter invasion in the neoadjuvant group, imatinib treatment could be helpful as a conversion strategy to make huge and low-lying rectal GIST operable and achieve better surgical outcomes.

Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling.

Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8+ T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8+ T cells after PD-1 blockade. Lenalidomide redirects the CRL4Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28- T cells.

AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis.

Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.

Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer.

BACKGROUND: We investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced rectal cancer (LARC) and whether modifiable factors in radiotherapy (RT) influenced the NLR. METHODS: Data of 1386 patients who were treated with neoadjuvant RT and concurrent or sequential chemotherapy for LARC between 2006 and 2019 were evaluated. Most patients (97.8%) were treated with long-course RT (LCRT; 50-50.4 Gy in 25-28 fractions) using three-dimensional conformal radiotherapy (3D-CRT) (n = 851) or helical tomotherapy (n = 504), and 30 patients underwent short-course RT (SCRT; 25 Gy in 5 fractions, followed by XELOX administration for 6 weeks). Absolute neutrophil and lymphocyte counts were obtained at initial diagnosis, before and during the preoperative RT course, and after preoperative concurrent chemoradiotherapy. The primary endpoint was distant metastasis-free survival (DMFS). RESULTS: The median follow-up time was 61.3 (4.1-173.7) months; the 5-year DMFS was 80.1% and was significantly associated with the NLR after RT but not before. A post-RT NLR ≥ 4 independently correlated with worse DMFS (hazard ratio, 1.42; 95% confidence interval, 1.12-1.80), along with higher ypT and ypN stages. Post-RT NLR (≥ 4) more frequently increased following LCRT (vs. SCRT, odds ratio [OR] 2.77, p = 0.012) or helical tomotherapy (vs. 3D-CRT, OR 1.29, p < 0.001). CONCLUSIONS: Increased NLR after neoadjuvant RT is associated with increased distant metastasis risk and poor survival outcome in patients with LARC. Moreover, high NLR following RT is directly related to RT fractionation, delivery modality, and tumor characteristics. These results are hypothesis-generating only, and confirmatory studies are required.

Comparison of clinical outcomes between carbon ion radiotherapy and X-ray radiotherapy for reirradiation in locoregional recurrence of rectal cancer.

Carbon ion radiotherapy (CIRT) has garnered interest for the treatment of locoregional rectal cancer recurrence. No study has compared CIRT and X-ray radiotherapy (XRT) for reirradiation (reRT) in such cases. We analyzed and compared the clinical outcomes such as local control, overall survival, and late toxicity rate between CIRT and XRT, for treating locoregional rectal cancer recurrence. Patients with rectal cancer who received reRT to the pelvis by CIRT or XRT from March 2005 to July 2019 were included. The CIRT treatment schedule was 70.4 Gy (relative biological effectiveness) in 16 fractions. For the XRT group, the median reRT dose was 50 Gy (range 25-62.5 Gy) with a median of 25 fractions (range 3-33). Thirty-five and 31 patients received CIRT and XRT, respectively. Tumour and treatment characteristics such as recurrence location and chemotherapy treatment differed between the two groups. CIRT showed better control of local recurrence (adjusted hazard ratio [HR] 0.17; p = 0.002), better overall survival (HR 0.30; p = 0.004), and lower severe late toxicity rate (HR 0.15; p = 0.015) than XRT. CIRT was effective for treating locoregional rectal cancer recurrence, with high rates of local control and survival, and a low late severe toxicity rate.

Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.

BACKGROUND: The genetic test solely based on the clinical features of hereditary colorectal cancer has limitations in clinical practice. OBJECTIVE: This study aimed to analyze the results of comprehensive multigene panel tests based on clinical findings. DESIGN: This was a cross-sectional study based on a prospectively compiled database. SETTING: The study was conducted at a tertiary hospital. PATIENTS: A total of 381 patients with high risk for hereditary colorectal cancer syndromes were enrolled between March 2014 and December 2019. MAIN OUTCOME MEASURES: The primary outcome was to describe the mutational spectrum based on genotype-phenotype concordance and discordance. RESULTS: Germline mutations were identified in 89 patients for polyposis hereditary colorectal cancer genes (76 in APC; 4 in PTEN; 4 in STK11; 3 in BMPR1A; 1 in POLE; 1 in POLD1), 89 patients for nonpolyposis hereditary colorectal cancer genes (41 in MLH1; 40 in MSH2; 6 in MSH6; and 2 in PMS2), and 12 patients for other cancer predisposition genes (1 in ATM; 2 in BRCA1; 1 in BRCA2; 1 in BRIP1; 1 in MLH3; 1 in NBN; 1 in PMS1; 1 in PTCH1; 1 in TP53; and 2 in monoallelic MUTYH). If we had used direct sequencing tests of 1 or 2 major genes based on phenotype, 48 (25.3%) of 190 mutations would not have been detected due to technical differences (12.1%), less frequent genotype (4.2%), unclear phenotype (3.7%), and genotype-phenotype discordance (4.7%). The genotype-phenotype discordance is probably linked to compound heterozygote, less distinctive phenotype, and insufficient information for colorectal cancer risk. LIMITATIONS: This study included a small number of patients with insufficient follow-up duration. CONCLUSIONS: A comprehensive multigene panel is expected to identify more genetic mutations than phenotype-based direct sequencing, with special utility for unclear phenotype or genotype-phenotype discordance. See Video Abstract at http://links.lww.com/DCR/B844. APLICACIN DE PRUEBAS DE PANEL MULTIGNICO EN PACIENTES CON ALTO RIESGO DE CNCER COLORRECTAL HEREDITARIO INFORME DESCRIPTIVO ENFOCADO EN LA CORRELACIN GENOTIPOFENOTIPO: ANTECEDENTES:La prueba genética basada únicamente en la característica clínica del cáncer colorrectal hereditario tiene limitaciones en la práctica clínica.OBJETIVO:Este estudio tuvo como objetivo analizar el resultado de pruebas integrales de panel multigénico basadas en hallazgos clínicos.DISEÑO:Este fue un estudio transversal basado en una base de datos recopilada prospectivamente.AJUSTE:El estudio se realizó en un hospital terciario.PACIENTES:Se inscribió un total de 381 pacientes con alto riesgo de síndromes de cáncer colorrectal hereditario entre marzo del 2014 y diciembre del 2019.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue describir el espectro mutacional basado en la concordancia y discordancia genotipo-fenotipo.RESULTADOS:Se identificaron mutaciones de la línea germinal en 89 pacientes para genes de cáncer colorrectal hereditario con poliposis (76 en APC; 4 en PTEN; 4 en STK11; 3 en BMPR1A; 1 en POLE; 1 en POLD1), 89 pacientes para genes de CCR hereditario sin poliposis (41 en MLH1; 40 en MSH2; 6 en MSH6; y 2 ​​en PMS2) y 12 pacientes por otro gen de predisposición al cáncer (1 en ATM; 2 en BRCA1; 1 en BRCA2; 1 en BRIP1; 1 en MLH3; 1 en NBN; 1 en PMS1; 1 en PTCH1; 1 en TP53; y 2 ​​en MUTYH monoalélico). Si hubiéramos utilizado pruebas de secuenciación directa de uno o dos genes principales basados ​​en el fenotipo, 48 (25,3%) de 190 mutaciones no se habrían detectado debido a diferencias técnicas (12,1%), genotipo menos frecuente (4,2%), fenotipo poco claro (3,7%) y discordancia genotipo-fenotipo (4,7%). La discordancia genotipo-fenotipo probablemente esté relacionada con el heterocigoto compuesto, el fenotipo menos distintivo y la información insuficiente para el riesgo de cáncer colorrectal.LIMITACIONES:Este estudio incluyó una pequeña cantidad de pacientes con una duración de seguimiento insuficiente.CONCLUSIONES:Se espera que un panel multigénico completo identifique más mutaciones genéticas que la secuenciación directa basada en el fenotipo, con especial utilidad para la discordancia de fenotipo o genotipo-fenotipo poco clara. Consulte Video Resumen en http://links.lww.com/DCR/B844. Traducción- Dr. Francisco M. Abarca-Rendon).

Single-incision laparoscopic surgery compared to conventional laparoscopic surgery for appendiceal mucocele: a series of 116 patients.

BACKGROUND: Although the safety and feasibility of conventional laparoscopic surgery (CLS) for appendiceal mucocele (AM) has been reported, studies on single-incision laparoscopic surgery (SILS) for AM have not been reported. Here, we aimed to compare the perioperative and short-term outcomes between SILS and CLS for AM and to evaluate the oncological safety of SILS. METHODS: We retrospectively analyzed the medical records of patients, diagnosed based on computed tomography findings, who underwent laparoscopic surgery for AM between 2010 and 2018 at one institution. We excluded patients strongly suspected of having malignant lesions and those with preoperative appendiceal perforation. Patients were divided into two groups-CLS and SILS. Pathological outcomes and long-term results were investigated. The median follow-up period was 43.7 (range: 12.3-118.5) months. RESULTS: Ultimately, 116 patients (CLS = 68, SILS = 48) were enrolled. Patient demographic characteristics did not differ between the groups. The preoperative mucocele diameter was greater in the CLS than in the SILS group (3.2 ± 2.9 cm vs. 2.3 ± 1.4 cm, P = 0.029). More extensive surgery (right hemicolectomies and ileocecectomies) was performed in the CLS than in the SILS group (P = 0.014). Intraoperative perforation developed in only one patient per group. For appendectomies and cecectomies, the CLS group exhibited a longer operation time than the SILS group (63.3 ± 24.5 min vs. 52.4 ± 17.3 min, P = 0.014); the same was noted for length of postoperative hospital stay (2.9 ± 1.8 days vs. 1.7 ± 0.6 days, P < 0.001). The most common AM etiology was low-grade appendiceal mucinous neoplasm (71/116 [61.2%] patients); none of the patients exhibited mucinous cystadenocarcinoma. Among these 71 patients, there were 8 patients with microscopic appendiceal perforation or positive resection margins. No recurrence was detected. CONCLUSIONS: SILS for AM is feasible and safe perioperatively and in the short-term and yields favorable oncological outcomes. Despite the retrospective nature of the study, SILS may be suitable after careful selection of AM patients.

Interaction between CD36 and FABP4 modulates adipocyte-induced fatty acid import and metabolism in breast cancer.

Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.

Multi-layered proteogenomic analysis unravels cancer metastasis directed by MMP-2 and focal adhesion kinase signaling.

The role of matrix metalloproteinase-2 (MMP-2) in tumor cell migration has been widely studied, however, the characteristics and effects of MMP-2 in clinical sample of metastatic colorectal cancer (CRC) remain poorly understood. Here, in order to unveil the perturbed proteomic signal during MMP-2 induced cancer progression, we analyzed plasma proteome of CRC patients according to disease progression, HCT116 cancer secretome upon MMP-2 knockdown, and publicly available CRC tissue proteome data. Collectively, the integrative analysis of multi-layered proteomes revealed that a protein cluster containing EMT (Epithelial-to-Mesenchymal Transition)-associated proteins such as CD9-integrin as well as MMP-2. The proteins of the cluster were regulated by MMP-2 perturbation and exhibited significantly increased expressions in tissue and plasma as disease progressed from TNM (Tumor, Node, and Metastasis) stage I to II. Furthermore, we also identified a plausible association between MMP-2 up-regulation and activation of focal adhesion kinase signaling in the proteogenomic analysis of CRC patient tissues. Based on these comparative and integrative analyses, we suggest that the high invasiveness in the metastatic CRC resulted from increased secretion of MMP-2 and CD9-integrin complex mediated by FAK signaling activation.