Activation of STING by the novel liposomal TLC388 enhances the therapeutic response to anti-PD-1 antibodies in combination with radiotherapy.

Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.

Robotic versus laparoscopic pelvic lateral lymph node dissection in locally advanced rectal cancer: a systemic review and meta-analysis.

BACKGROUND: There are few available studies that compare the feasibility, efficacy, and safety of robotic pelvic lateral lymph node dissection compared to laparoscopic pelvic lateral lymph node dissection (LPLND) in advanced rectal cancer. This meta-analysis aims to compare perioperative outcomes between robotic and LPLND. METHODS: We performed a systemic literature review of PubMed, Embase, and Web of Science databases. Perioperative parameters were extracted and pooled for analysis. This meta-analysis provided an analysis of heterogeneity and prediction intervals. RESULTS: Five studies were included: 567 patients divided between 266 robotic and 301 LPLND. Overall operation time was longer in the robotic group than laparoscopic group (difference in means = 67.11, 95% CI [30.80, 103.42], p < 0.001) but the difference in the pelvic lateral lymph dissection time was not statistically significant (difference in means = - 1.212, 95% CI [ - 11.594, 9.171], p = 0.819). There were fewer overall complications in the robotic than in the laparoscopic group (OR = 1.589, 95% CI [1.009, 2.503], p = 0.046), especially with respect to urinary retention (OR = 2.23, 95% CI [1.277, 3.894], p = 0.005). More pelvic lateral lymph nodes were harvested by robotic surgery than by laparoscopy (differences in means = - 1.992, 95% CI [ - 2.421, 1.563], p < 0.001). CONCLUSIONS: In this meta-analysis, robotic pelvic lateral lymph node dissection was associated with more pelvic lateral lymph nodes harvested and lower overall complications, especially urinary retention when compared to LPLND. Further studies are needed to reinforce these findings.

Acupuncture May Help to Prevent Chemotherapy-Induced Peripheral Neuropathy: A Randomized, Sham-Controlled, Single-Blind Study.

OBJECTIVE: This study investigated the efficacy of acupuncture in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with colorectal cancer (CRC). METHODS: This single center, randomized, controlled, single-blind clinical trial randomly assigned patients with stage 3 CRC attending outpatient clinics in China Medical University Hospital to either verum or sham acupuncture treatment concurrently with chemotherapy. Primary outcomes were nerve conduction velocity (NCV) and touch thresholds of limb terminals. Secondary outcomes were total and subdomain scores on the Functional Assessment of Cancer Therapy-General (FACT-G), and scores on the FACT/GOG-Ntx subscale and the Brief Pain Inventory-Short Form (BPI-SF), at baseline, weeks 12, 36, and follow-up (week 48). RESULTS: Thirty-two patients met the inclusion criteria and received verum acupuncture (N = 16) or sham acupuncture (N = 16). Under the -intent-to-treat principle, 26 participants were analyzed. Significant changes from baseline for questionnaire scores and sensory NCV were observed in both study groups. Sham acupuncture was associated with significant reductions from baseline in motor NCV and sensory touch thresholds; no such changes were observed with verum acupuncture. No serious adverse events were reported. CONCLUSION: Prophylactic acupuncture may exert neuroprotective effects on mechanical or tactile touch thresholds during chemotherapy regimens in patients with CRC, with evidence of this protectiveness persisting at 6 months' follow-up. The lack of change in motor NCV values with verum acupuncture indicates neuroprotective effects. Sensory NCV values and patient-reported outcomes did not differ significantly between the study groups.

Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation.

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084-1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103-1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.

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.

Laparoscopic total pelvic peritonectomy for colorectal cancer pelvic carcinomatosis: a retrospective case series and photographic/videographic step-by-step guide.

BACKGROUND: Cytoreductive surgery (CRS) for colorectal cancer peritoneal carcinomatosis has been shown to prolong survival with acceptable morbidity rates. Total pelvic peritonectomy (TPP), or complete removal of all pelvic peritoneum, constitutes an important and technically challenging component of CRS. Here we report our experience and describe our technique of laparoscopic total pelvic peritonectomy (LTPP), using a photographic/videographic step-by-step guide. METHODS: All patients who underwent LTPP for pelvic carcinomatosis from a colorectal origin were included in the study. Only patients with peritoneal cancer index (PCI) score of ≤ 10 were selected for CRS with LTPP. Patients who had extra-abdominopelvic cavity metastases were excluded. The final decision to proceed with CRS was made following laparoscopic assessment. RESULTS: From January 2017 to December 2020, 15 consecutive patients underwent LTPP for colorectal cancer pelvic carcinomatosis. Median patient age and PCI score was 53 years (range 33-78) and 8 (range 3-10), respectively. Complete cytoreduction was achieved in all patients. Thirteen patients (87%) underwent concomitant hyperthermic intraperitoneal chemotherapy (HIPEC). The median operative duration was 748 min (interquartile range [IQR] 681-850). Median intra-operative blood loss and length of hospital stay was 100 ml (IQR 50-300) and 10 days (IQR 8-12), respectively. Five patients (33%) experienced 30-day post-operative morbidity, with one (6.7%) experiencing a higher grade (Clavien-Dindo IIIa) complication. Median follow-up duration was 13 months (IQR 3-19), during which four (27%) had systemic recurrence and one (6.7%) died after 15 months following peritoneal and systemic recurrences. CONCLUSION: LTPP is a feasible option for low-volume pelvic carcinomatosis from colorectal cancer, offering the benefits of a minimally invasive approach. Strict patient selection is essential, and the procedure should be converted if the PCI score cannot be assessed or complete cytoreduction cannot be achieved. Proficiency at laparoscopic pelvic surgery is mandatory for performing LTPP.

Peritoneal contamination and associated post-operative infectious complications after natural orifice specimen extraction for laparoscopic colorectal surgery.

BACKGROUND: Peritoneal contamination is a major concern during natural orifice specimen extraction after laparoscopic colorectal resection (LCR-NOSE), but few data are available. We explored the prevalence, risk factors, and association between clinical outcomes and infectious complications in patients with positive peritoneal drain fluid culture (PDFC) after LCR-NOSE. METHOD: We retrospectively analyzed patient records in our prospectively maintained registry database who underwent LCR-NOSE between 2011and 2020. Peritoneal drain fluid was collected within 12 h post-operative and cultures for microorganisms were obtained. The relationships between PDFC, clinical variables, and infectious complications were examined by univariate and multivariable analysis. RESULTS: Of 241 consecutive patients who underwent LCR-NOSE and drainage fluid culture, 59 (24.5%) had PDFC. Anterior resection (Odds ratio OR 2.40) was identified as an independent predictor for PDFC. Twenty-eight patients (11.6%) developed infectious complications. Multivariable analysis identified low anterior resection (OR 2.74), prolonged operative time (OR 3.20), and PDFC (OR 5.14) as independent risk factors. Pseudomonas aeruginosa was the most frequently found microorganism (OR 5.19) responsible for infectious complications. CONCLUSIONS: Microorganisms are commonly present in the peritoneum after LCR-NOSE and play a critical role in the development of infectious complications and related morbidity. Specific caution is warranted in patients contaminated with specific types of microorganisms.

Natural orifice versus conventional mini-laparotomy for specimen extraction after reduced-port laparoscopic surgery for colorectal cancer: propensity score-matched comparative study.

BACKGROUND: Although reduced port laparoscopic surgery (RPLS), defined as laparoscopic surgery performed with the minimum possible number of ports and/or small-sized ports, is less invasive than conventional laparoscopic surgery by reducing the number of surgical wounds, an extension of the incision is still needed for specimen extraction, which can undermine the merits of RPLS. OBJECTIVE: To determine the impact of natural orifice specimen extraction (NOSE) in patients undergoing RPLS for colorectal cancer. The endpoints were perioperative outcome and oncologic safety at 3 years. SETTING: Single-center experience (2013-2019). PATIENTS: We retrospectively analyzed our prospectively collected patient records (American Joint Committee on Cancer (AJCC) stage I-III sigmoid or upper rectal cancer (tumor diameter ≤ 5 cm) who underwent curative anterior resection via RPLS. We excluded patients who did not undergo intestinal anastomosis. INTERVENTIONS: Perioperative and oncologic outcomes were compared between patients undergoing natural orifice (RPLS-NOSE) or conventional (mini-laparotomy) specimen extraction (RPLS-CSE). Patients were matched by propensity scores 1:1 for tumor diameter, AJCC stage, American Society of Anesthesiologists score and tumor location. RESULTS: Of 119 eligible patients, 104 were matched (52 RPLS-NOSE; 52 RPLS-CSE) by propensity scores. Compared with RPLS-CSE, RPLS-NOSE was associated with longer operative time (223.9 vs. 188.7 min; p = 0.003), decreased use of analgesics (morphine dose 33.9 vs. 43.4 mg; p = 0.011) and duration of hospital stay (4.2 vs. 5.1 days; p = 0.001). No statistically significant difference was found in morbidity or wound-related complication rates between the two groups. After a median follow-up of 34.3 months, no local recurrence was observed in RPLS-NOSE. The 3-year disease-free survival did not differ statistically significantly between groups (90.9 vs. 90.5%; p = 0.610). CONCLUSION: NOSE enhances the advantages of RPLS by avoiding the need for abdominal wall specimen extraction in patients with tumor diameter ≤ 5 cm. Surgical and oncologic safety are comparable to RPLS with CSE.

Transanal endoluminal repair for anastomotic leakage after low anterior resection.

BACKGROUND: There is still no consensus on the management of colorectal anastomotic leakage after low anterior resection. The goal was to evaluate the outcomes of patients who underwent transanal endoluminal repair + laparoscopic drainage ± stoma vs. drainage only ± stoma. METHODS: Retrospective chart review of patients sustaining anastomotic leakage after laparoscopic low anterior resection between January 2013 and September 2020 who required laparoscopic reoperation. RESULTS: Forty-nine patients were included, 22 patients underwent combined laparoscopy and transanal endoluminal repair and 27 patients had drainage with a stoma (n = 16) or drainage alone (n = 11), without direct anastomotic repair. The overall morbidity rate was 30.6% and the mortality rate was 2%. Combined laparoscopic lavage/drainage and transanal endoluminal repair of anastomotic leakage was associated with a lower complication rate (13.6% vs. 44.4%, p = 0.03) and fewer intraabdominal infections (4.5% vs. 29.6%, p = 0.03) compared with no repair. CONCLUSIONS: Combined laparoscopic lavage/drainage and transanal endoluminal repair is effective in the management of colorectal anastomosis leakage and was associated with lower morbidity-in particular intraabdominal infection-compared with no repair. However, our results need to be confirmed in larger, and ideally randomized, studies.

Laparoscopic redo anastomosis for management of intraperitoneal anastomotic leakage after colonic surgery.

BACKGROUND: There is still no consensus on the management of intraperitoneal anastomotic leakage after colonic surgery. Among of various treatment strategies, laparoscopic redo anastomosis for intraperitoneal leakage has rarely been reported in the literature and is condemned by some. The aim of this study is to demonstrate the feasibility and safety of laparoscopic redo anastomosis for intraperitoneal anastomotic leakage. METHODS: Retrospective chart review of laparoscopic redo anastomosis for intraperitoneal anastomotic leakage after colonic surgery from January 2013 to May 2020. An accompanying video demonstrates the technique. RESULTS: Fifteen consecutive patients underwent laparoscopic redo anastomosis for management of leakage after colonic surgery; two patients required conversion to open repair. A protective stoma was created in three patients during the second operation. There was no re-leakage nor mortality in this series. CONCLUSIONS: Laparoscopic redo anastomosis was feasible and safe for the management of intraperitoneal anastomotic leakage after colonic surgery. Considering the advantages of re-do laparoscopy, this procedure should be part of every surgeon's armamentarium to deal with anastomotic leakage and represents a logical alternative to the "Diversion and Drainage" technique.

ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.

Polymorphism of formyl peptide receptor 1 (FPR1) reduces the therapeutic efficiency and antitumor immunity after neoadjuvant chemoradiotherapy (CCRT) treatment in locally advanced rectal cancer.

Immunosurveillance and immunoscavenging prompted by preoperative chemoradiotherapy (CCRT) may contribute to improve local control and increase survival outcomes for patients with locally advanced rectal cancer (LARC). In this study, we investigated several genotypes of pattern recognition receptors (PRRs) and their impact on therapeutic efficacy in LARC patients treated with CCRT. We found that homozygosis of formyl peptide receptor 1 (FPR1) (E346A/rs867228) was associated with reduced 5-year overall survival (OS) by Kaplan-Meier analysis (62% vs. 81%, p = 0.014) and multivariate analysis [hazard ratio (HR) = 3.383, 95% CI = 1.374-10.239, p = 0.007]. Moreover, in an animal model, we discovered that the FPR1 antagonist, Boc-MLF (Boc-1), reduced CCRT therapeutic efficacy and decreased cytotoxic T cells and T effector memory cells after chemoradiotherapy treatment. Pharmacologic inhibition of FPR1 by Boc-1 decreased T lymphocyte migration to irradiated tumor cells. Therefore, these results revealed that the FPR1 genotype participates in CCRT-elicited anticancer immunity by reducing T lymphocytes migration and infiltration, and that the FPR1-E346A CC genotype can be considered an independent biomarker for chemo- and radiotherapy outcomes.

Laparoscopic retrojejunal trans-mesenteric anastomosis for extended left-sided colorectal resections - a new solution to an old problem.

AIM: Following extended left-sided colorectal resection, creation of the anastomosis can be challenging due to insufficient length of the remaining proximal and distal bowel. Retroileal pull-through and the Deloyers procedure are feasible but require ligation of the middle colic vessels and additional right colonic mobilization. The aim of this study was to describe our initial experience with an alternative technique for performing tension-free anastomosis following minimally invasive left-sided resection. METHOD: This was a retrospective case series of all patients who underwent a retrojejunal trans-mesenteric pull-through following elective laparoscopic left-sided colorectal surgery between September 2019 and September 2020. Placing the retrojejunal window 15-20 cm distal to the duodenojejunal junction allows the transverse colon to pass via the most direct route through the base of the proximal jejunal mesentery to the distal colon or rectal stump instead of passing over the small bowel, yielding additional length for the anastomosis. An accompanying video demonstrates this technique for three different case scenarios. RESULTS: Seven consecutive patients underwent this approach following colorectal resection; three had inherently shorter left colons, two had synchronous left-sided tumours and two had inadvertent intraoperative marginal artery injury. There were no anastomotic complications or early postoperative morbidity related to the mesenteric window. The additional time taken for the procedure ranged from 5 to 35 min. The risk of complications related to extended left-sided resections may possibly be reduced, although further studies are required to evaluate this. CONCLUSION: Retrojejunal trans-mesenteric pull-through is a novel, but straightforward, safe and useful option for reducing tension in laparoscopic left-sided colorectal anastomoses.

Long-term Oncologic Outcomes of Laparoscopic Anterior Resections for Cancer with Natural Orifice Versus Conventional Specimen Extraction: A Case-Control Study.

BACKGROUND: Although the short-term advantages of natural orifice specimen extraction are widely recognized, controversy exists concerning oncologic safety after laparoscopic surgery for colorectal cancer. OBJECTIVE: This study aimed to investigate the impact of natural orifice specimen extraction on local recurrence and long-term survival of patients undergoing colorectal cancer surgery. DESIGN: This is a propensity score-matched comparative study. SETTING: This study presents a single-center experience. PATIENTS: We retrospectively analyzed the records of patients who underwent curative laparoscopic anterior resection for American Joint Committee on Cancer stage I to III sigmoid or upper rectal cancer in 2011 to 2014, based on prospectively collected data. INTERVENTIONS: Oncologic outcomes were compared between patients undergoing natural orifice or conventional specimen extraction by minilaparotomy. Patients were matched 1:1 according to propensity scores calculated by logistic regression analysis with the following covariates: American Joint Committee on Cancer stage, tumor diameter, age, sex, BMI, and T stage. Cox proportional hazards regression analysis was performed to determine the impact on oncologic outcome. MAIN OUTCOME MEASURES: The primary outcomes measured were local recurrence and disease-free survival rates at 5 years. RESULTS: Of 392 eligible patients, 188 were matched (94 undergoing natural orifice specimen extraction and 94 undergoing conventional extraction by minilaparotomy). Median follow-up was 50.3 months. The cumulative local recurrence risk at 5 years was 2.3% and 3.5% (p = 0.632), whereas 5-year disease-free survival for all tumor stages combined was 87.3% and 82.0% (p = 0.383) in laparoscopic anterior resection with natural orifice specimen extraction and conventional extraction groups. T3 and T4 stages were the only variables independently associated with disease-free survival. LIMITATIONS: This study was limited because it focused on a single center, was a retrospective analysis, contained no long-term anorectal function testing, and had a small sample size. CONCLUSION: Long-term oncologic outcomes of patients undergoing laparoscopic anterior resection with natural orifice specimen extraction for sigmoid and upper rectal cancer do not differ from those undergoing conventional extraction. Thus, natural orifice specimen extraction could be a viable alternative to reduce abdominal wall insult in laparoscopic colorectal operations for malignancy in selected patients. See Video Abstract at http://links.lww.com/DCR/B241. RESULTADOS ONCOLÓGICOS A LARGO PLAZO DE RESECCIONES ANTERIORES LAPAROSCÓPICAS PARA CÁNCER A TRAVÉS DE ORIFICIO NATURAL FRENTE A EXTRACCIÓN CONVENCIONAL DEL ESPÉCIMEN: UN ESTUDIO DE CASOS Y CONTROLES: Si bien las ventajas a corto plazo de la extracción de especímenes por orificio natural son ampliamente reconocidas, existe controversia con respecto a la seguridad oncológica después de la cirugía laparoscópica para el cáncer colorrectal.Investigar el impacto de la extracción de especímenes por orificio natural en la recurrencia local y la supervivencia a largo plazo de pacientes sometidos a cirugía de cáncer colorrectal.Estudio comparativo con emparejamiento por puntuación de propensión.Experiencia en un centro único.Analizamos retrospectivamente los registros de pacientes que se sometieron a resección anterior laparoscópica curativa para cáncer sigmoideo o rectal superior AJCC en estadio I-III en 2011-2014, con base en datos recolectados prospectivamente.Los resultados oncológicos se compararon entre pacientes sometidos a extracción por orificio natural o convencional mediante minilaparotomía de especímenes. Los pacientes fueron emparejados 1:1 de acuerdo con los puntajes de propensión calculados por análisis de regresión logística con las siguientes covariables: estadio AJCC, diámetro del tumor, edad, sexo, índice de masa corporal y estadio T. Se realizó un análisis de regresión de riesgos proporcionales de Cox para determinar el impacto en el resultado oncológico.Recurrencia local y tasas de supervivencia libre de enfermedad a los 5 años.De 392 pacientes elegibles, 188 fueron emparejados (94 sometidos a extracción de espécimen por orificio natural y 94 a extracción convencional por minilaparotomía). La mediana de seguimiento fue de 50.3 meses. El riesgo cumulativo de recurrencia local a 5 años fue de 2.3% y 3.5% (p = 0.632), mientras que la supervivencia libre de enfermedad a 5 años para todas las etapas tumorales combinadas fue de 87.3% y 82.0% (p = 0.383) en los grupos de resección anterior laparoscópica con extracción de espécimen por orificio natural y extracción convencional, respectivamente. Las etapas T3 y T4 fueron las únicas variables asociadas independientemente con la supervivencia libre de enfermedad.Centro único, análisis retrospectivo, ausencia de pruebas de función anorrectal a largo plazo y tamaño de muestra pequeño.Los resultados oncológicos a largo plazo de los pacientes sometidos a resección anterior laparoscópica con extracción de espécimen por orificio natural para cáncer sigmoideo y rectal superior no difieren de los de aquellos sometidos a extracción convencional. Por lo tanto, la extracción de especímenes por orificio natural podría ser una alternativa viable para reducir el insulto a la pared abdominal en operaciones colorrectales laparoscópicas por malignidad en pacientes selectos. Consulte Video Resumen en http://links.lww.com/DCR/B241.

Antrodia camphorata inhibits epithelial-to-mesenchymal transition by targeting multiple pathways in triple-negative breast cancers.

Antrodia camphorata (AC) exhibits potential for engendering cell-cycle arrest as well as prompting apoptosis and metastasis inhibition in triple-negative breast cancer (TNBC) cells. We performed the current study to explore the anti-epithelial-to-mesenchymal transition (EMT) properties of fermented AC broth in TNBC cells. Our results illustrated that noncytotoxic concentrations of AC (20-60 µg/ml) reversed the morphological changes (fibroblastic-to-epithelial phenotype) as well as the EMT by upregulating the observed E-cadherin expression. Furthermore, we discovered treatment with AC substantially inhibit the Twist expression in human TNBC (MDA-MB-231) cells as well as in those that were transfected with Twist. In addition, we determined AC to decrease the observed Wnt/ß-catenin nuclear translocation through a pathway determined to be dependent on GSK3ß. Notably, AC treatment consistently inhibited the EMT by downregulating mesenchymal marker proteins like N-cadherin, vimentin, Snail, ZEB-1, and fibronectin; at that same time upregulating epithelial marker proteins like occludin and ZO-1. Bioluminescence imaging that was executed in vivo demonstrated AC substantially suppressed breast cancer metastasis to the lungs. Notably, we found that western blot analysis confirmed that AC decreased lung metastasis as demonstrated by upregulation of E-cadherin expression in biopsied lung tissue. Together with our results support the anti-EMT activity of AC, indicating AC as having the potential for acting as an anticancer agent for the treatment of human TNBC treatment.

Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers.

The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-γ upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-γ exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-γ were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.

A comparative study of subsequent liver cirrhosis risk in non-Helicobacter pylori-infected peptic ulcer patients with and without vagotomy: An Asian population cohort study.

OBJECTIVES: Hepatic parasympathetic nerves branch off the vagus nerve. The vagal and hepatic nervous systems are important in liver physiological processes and some diseases such as diabetes, obesity, and liver cirrhosis. We were interested in vagal nerve integrity and subsequent diseases in peptic ulcer patients. Herein, we used National Health Insurance database in Taiwan and retrospectively assessed the risk of developing liver cirrhosis in peptic ulcer patients with and without complications by surgical treatments. METHODS: A cohort of 357 423 peptic ulcer patients without Helicobacter pylori, hepatitis B/C virus infection, and alcoholism from 2001 to 2008 was established. A randomly selected cohort of 357 423 people without peptic ulcer that matched by age, gender, comorbidities, and index year was used for comparison. The risks of developing liver cirrhosis were assessed both in cohorts and in peptic ulcer patients with and without vagotomy at the end of 2011. RESULTS: Peptic ulcer patients were with higher incidence of liver cirrhosis than those without peptic ulcer (2.63 vs 0.96 per 1000 person-years) and with a 2.79-fold adjusted hazard ratio (HR) (95% confidence interval = 2.66-2.93) based on the multivariable Cox proportional hazards regression analysis. Comparing with different peptic ulcer management strategies, the HR value for subsequent liver cirrhosis risk was the lowest in vagotomy group (HR = 0.46, 95% confidence interval = 0.33-0.64). CONCLUSIONS: Peptic ulcer patients have an increased risk of developing liver cirrhosis. Moreover, there were association of vagotomy and decreased risk of subsequent liver cirrhosis in complicated peptic ulcer patients. However, further studies are warranted.

Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy.

Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto-HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy.

Combined repeat laparoscopy and transanal endolumenal repair (hybrid approach) in the early management of postoperative colorectal anastomotic leaks: technique and outcomes.

BACKGROUND: Few clear recommendations exist for the management of colorectal anastomotic leaks, often based on surgeon preferences or institutional protocols. The primary goal was to evaluate the feasibility and safety of the combined laparoscopic and transanal (hybrid) approach to treat postoperative colorectal anastomotic leaks. The secondary goals included comparison of outcomes following early (< 5 days after initial resection) versus late (≥ 5 days) detection of leaks. MATERIALS AND METHODS: Sixteen hemodynamically stable patients, with anastomotic dehiscence < 50% of the circumference after laparoscopic anterior resection underwent repeat laparoscopy (lavage/drainage) and transanal endolumenal repair (7 low (< 5 cm from the anal verge) with an ordinary anoscope and 9 high (≥ 5 cm from the anal verge) with a transanal endoscopic operations (TEO®) platform). RESULTS: The median delay to detection and management was 4.5 days. The procedure was feasible in 13/16 patients (3 patients required conversion to laparotomy). Primary healing of the anastomosis was obtained in 14 patients (13 with the combined procedure, one after conversion). Two patients (1 early, 1 late) sustained persistent purulent discharge via their drain, but the repair healed secondarily. All patients requiring conversion to laparotomy (n = 3) or sustaining intra-operative complications (n = 3) were in the delayed group. No patients required further intervention or died. Protective stomas, created either at index surgery (n = 7) or at re-operation (n = 9), were closed in 14/16 patients within 6 months and no anastomotic sinus, persistent or recurrent fistula, was noted at 1-year follow-up. LIMITATIONS: This is a single-center study consisting of small sample size. CONCLUSIONS: Combined repeat laparoscopy and transanal endolumenal repair is feasible and safe, potentially reducing postoperative morbidity associated with repeat laparotomy and anastomotic leaks. Early detection and re-intervention are fundamental to success. Currently missing from the International Study Group of Rectal Cancer recommendations, laparoscopy and endolumenal repair could be added as a therapeutic option in Grade B.