Total neoadjuvant therapy for locally advanced rectal cancer: a three-group propensity score matched study.

PURPOSE: Total neoadjuvant therapy (TNT) has emerged as a therapeutic approach for locally advanced rectal cancer (LARC). However, the optimal chemotherapy cycles within TNT remain uncertain. This study aimed to evaluate and compare the prognostic efficacy of varying cycles of chemotherapy during TNT for LARC. METHODS: Patients diagnosed with LARC (T3-4N0M0/T1-4N1-2M0), who underwent TNT or chemoradiotherapy followed by total mesorectal excision (TME) between 2015 and 2020, were retrospective included. Patients were categorized into three groups based on their neoadjuvant strategy: CRT (long-course chemoradiotherapy), STNT (long-course CRT with one to three cycles of chemotherapy), and LTNT (long-course CRT with four or more cycles of chemotherapy). Propensity score matching (PSM) based on gender, age, body mass index, tumor distance from the anal verge, clinical T stage, clinical N stage, and mesorectal fascia status was employed to reduce confounding bias. Primary endpoints were disease-free survival (DFS) and metastasis-free survival (MFS). RESULTS: The study comprised 372 patients, with 73 patients in each group after PSM. Compared with CRT, both STNT and LTNT demonstrated improved DFS (5-year rate: 59.7% vs. 77.8% vs. 76.5%, p = 0.027) and MFS (5-year rate: 65.1% vs. 81.3% vs. 81.4%, p = 0.030). There was no difference in DFS or MFS between STNT and LTNT. These favorable outcomes were consistent among subgroups defined by tumor distance from the anal verge ≥ 5 cm, clinical T3 stage, clinical N positive status, or involved mesorectal fascia. CONCLUSION: Compared to CRT, both STNT and LTNT demonstrated improved DFS and MFS outcomes. Notably, survival outcomes were similar between STNT and LTNT, suggesting that chemotherapy cycles in TNT may not significantly impact survival.

Survival outcomes of stage I colorectal cancer: development and validation of the ACEPLY model using two prospective cohorts.

BACKGROUND: Approximately 10% of stage I colorectal cancer (CRC) patients experience unfavorable clinical outcomes after surgery. However, little is known about the subset of stage I patients who are predisposed to high risk of recurrence or death. Previous evidence was limited by small sample sizes and lack of validation. METHODS: We aimed to identify early indicators and develop a risk stratification model to inform prognosis of stage I patients by employing two large prospective cohorts. Prognostic factors for stage II tumors, including T stage, number of nodes examined, preoperative carcinoma embryonic antigen (CEA), lymphovascular invasion, perineural invasion (PNI), and tumor grade were investigated in the discovery cohort, and significant findings were further validated in the other cohort. We adopted disease-free survival (DFS) as the primary outcome for maximum statistical power and recurrence rate and overall survival (OS) as secondary outcomes. Hazard ratios (HRs) were estimated from Cox proportional hazard models, which were subsequently utilized to develop a multivariable model to predict DFS. Predictive performance was assessed in relation to discrimination, calibration and net benefit. RESULTS: A total of 728 and 413 patients were included for discovery and validation. Overall, 6.7% and 4.1% of the patients developed recurrences during follow-up. We identified consistent significant effects of PNI and higher preoperative CEA on inferior DFS in both the discovery (PNI: HR = 4.26, 95% CI: 1.70-10.67, p = 0.002; CEA: HR = 1.46, 95% CI: 1.13-1.87, p = 0.003) and the validation analysis (PNI: HR = 3.31, 95% CI: 1.01-10.89, p = 0.049; CEA: HR = 1.58, 95% CI: 1.10-2.28, p = 0.014). They were also significantly associated with recurrence rate. Age at diagnosis was a prominent determinant of OS. A prediction model on DFS using Age at diagnosis, CEA, PNI, and number of LYmph nodes examined (ACEPLY) showed significant discriminative performance (C-index: 0.69, 95% CI:0.60-0.77) in the external validation cohort. Decision curve analysis demonstrated added clinical benefit of applying the model for risk stratification. CONCLUSIONS: PNI and preoperative CEA are useful indicators for inferior survival outcomes of stage I CRC. Identification of stage I patients at high risk of recurrence is feasible using the ACEPLY model, although the predictive performance is yet to be improved.

Total neoadjuvant therapy versus chemoradiotherapy for locally advanced rectal cancer: Bayesian network meta-analysis.

BACKGROUND: Total neoadjuvant therapy is a promising treatment for locally advanced rectal cancer, utilizing either short-course radiotherapy or long-course chemoradiotherapy, but their relative efficacy remains unclear. The aim of this Bayesian network meta-analysis was to investigate clinical outcomes amongst patients receiving total neoadjuvant therapy with short-course radiotherapy or long-course chemoradiotherapy, and those receiving long-course chemoradiotherapy alone. METHODS: A systematic literature search was performed. All studies that compared at least two of these three treatments for locally advanced rectal cancer were included. The primary endpoint was the pathological complete response rate, and survival outcomes were adopted as secondary outcomes. RESULTS: Thirty cohorts were included. Compared with long-course chemoradiotherapy, both total neoadjuvant therapy with long-course chemoradiotherapy (OR 1.78, 95 per cent c.i. 1.43 to 2.26) and total neoadjuvant therapy with short-course radiotherapy (OR 1.75, 95 per cent c.i. 1.23 to 2.50) improved the pathological complete response rate. Similar benefits were observed in the sensitivity and subgroup analyses, except for short-course radiotherapy with one to two cycles of chemotherapy. No significant differences in survival outcomes were found amongst the three treatments. Long-course chemoradiotherapy with consolidation chemotherapy (HR 0.44, 95 per cent c.i. 0.20 to 0.99) exhibited higher disease-free survival than long-course chemoradiotherapy alone. CONCLUSION: Compared with long-course chemoradiotherapy, both short-course radiotherapy with greater than or equal to three cycles of chemotherapy and total neoadjuvant therapy with long-course chemoradiotherapy can improve the pathological complete response rate, and long-course chemoradiotherapy with consolidation chemotherapy may lead to a marginal benefit in disease-free survival. The pathological complete response rate and survival outcomes are similar for total neoadjuvant therapy with short-course radiotherapy or long-course chemoradiotherapy.

Interaction analysis of high-risk pathological features on adjuvant chemotherapy survival benefit in stage II colon cancer patients: a multi-center, retrospective study.

BACKGROUND: We aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy. METHODS: This study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect. RESULTS: A total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54-72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P < 0.001) and patients with the following high-risk features, such as T4 tumors (30.8% vs 7.8%; P < 0.001), grade 3 lesions (36.0% vs 22.7%; P < 0.001), lymphovascular invasion (22.1% vs 6.8%; P < 0.001) and perineural invasion (19.4% vs 13.6%; P = 0.031) were more likely to receive ACT. Patients with perineural invasion showed a worse OS and marginally worse DFS (hazardous ratio [HR] 2.166, 95% confidence interval [CI] 1.282-3.660, P = 0.004; HR 1.583, 95% CI 0.985-2.545, P = 0.058, respectively). Computing the interaction on a multiplicative and additive scale revealed that there was a significant interaction between PNI and ACT in terms of DFS (HR for multiplicative interaction 0.196, p = 0.038; RERI, -1.996; 95%CI, -3.600 to -0.392) and OS (HR for multiplicative interaction 0.112, p = 0.042; RERI, -2.842; 95%CI, -4.959 to -0.725). CONCLUSIONS: Perineural invasion had prognostic value, and it could also influence the effect of ACT after curative surgery. However, other high-risk features showed no implication of efficacy for ACT in our study. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov, NCT03794193 (04/01/2019).

Predictors of Symptomatic Intracranial Hemorrhage after Endovascular Thrombectomy in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

INTRODUCTION: This meta-analysis assessed the predictors of symptomatic intracranial hemorrhage (sICH) after endovascular thrombectomy (EVT) for patients with acute ischemic stroke. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for studies published from inception to February 16, 2021. We included studies that evaluated the predictors of sICH after EVT. The random-effect model or fixed-effect model was used to pool the estimates according to the heterogeneity. RESULTS: A total of 25 cohort studies, involving 15,324 patients, were included in this meta-analysis. The total incidence of sICH was 6.72 percent. Age (MD = 2.57, 95% CI: 1.53-3.61; p < 0.00001), higher initial NIHSS score (MD = 1.71, 95% CI: 1.35-2.08, p < 0.00001), higher initial systolic blood pressure (MD = 7.40, 95% CI: 5.11-9.69, p < 0.00001), diabetes mellitus (OR = 1.36, 95% CI: 1.10-1.69, p = 0.005), poor collaterals (OR = 3.26, 95% CI: 2.35-4.51; p < 0.0001), internal carotid artery occlusion (OR = 1.55, 95% CI: 1.26-1.90; p < 0.0001), longer procedure time (MD = 18.92, 95% CI: 11.49-26.35; p < 0.0001), and passes of retriever >3 (OR = 3.39, 95% CI: 2.45-4.71; p < 0.0001) were predictors of sICH, while modified thrombolysis in cerebral infarction score ≥2b (OR = 0.61, 95% CI: 0.46-0.79; p = 0.0002) was associated with a decreased risk of sICH. There were no significant differences in the female gender, initial serum glucose, initial ASPECT score, atrial fibrillation, oral anticoagulants, antiplatelet therapy, intravenous thrombolysis, general anesthesia, neutrophil-to-lymphocyte ratio, and emergent stenting. CONCLUSIONS: This study identified many predictors of sICH. Some of the results lack robust evidence given the limitations of the study. Therefore, larger cohort studies are needed to confirm these predictors.

Closure of pelvic peritoneum with bladder peritoneum flap reconstruction after laparoscopic extralevator abdominoperineal excision: A prospective stage II study.

BACKGROUND: Extralevator abdominoperineal resection (ELAPE) has increased perineal wound complications due to the extended resection area. Closure of the pelvic peritoneum (CPP) may exclude the abdominal content from descending into the pelvic cavity and reduce the incidence of perineal complications after ELAPE. We have previously introduced bladder peritoneum flap reconstruction (BLAPER) as a novel method for patients in whom traditional CPP is not possible. The aim of the present study was to report the development and preliminary outcomes of BLAPER. METHODS: This is a prospective single-arm study at the development and exploration phase and fulfills the IDEAL framework stage II. Ultralow rectal cancer patients with rigid pelvis who underwent ELAPE with BLAPER were enrolled. Primary outcomes were intraoperative complications and postoperative complications within 1 month after surgery. RESULTS: Among 27 patients included, the overall success rate of BLAPER was 96.3% (26/27). Indocyanine green fluorescence imaging and antiadhesive barrier placement were introduced to improve the BLAPER technique. The incidence of major pelvic wound complications was 7.7%. No patient who underwent BLAPER has suffered small bowel obstruction (SBO), presence of small bowel in the retrourogenital space, or perineal hernia (PH). CONCLUSIONS: BLAPER is safe and may prevent the small bowel from descending into the retrourogenital space and subsequently developing PH and SBO without increasing the intraoperative and postoperative complications. BLAPER may serve as an option when the primary suture of the pelvic peritoneum is not feasible.

Production improvement of FK506 in Streptomyces tsukubaensis by metabolic engineering strategy.

AIMS: Study of the effect of isoleucine on the biosynthesis of FK506 and modification of its producing strain to improve the production of FK506. METHODS AND RESULTS: Metabolomics analysis was conducted to explore key changes in the metabolic processes of Streptomyces tsukubaensis Δ68 in medium with and without isoleucine. In-depth analysis revealed that the shikimate pathway, methylmalonyl-CoA, and pyruvate might be the rate-limiting factors in FK506 biosynthesis. Overexpression of involved gene PCCB1 in S. tsukubaensis Δ68, a high-yielding strain Δ68-PCCB1 was generated. Additionally, the amino acids supplement was further optimized to improve FK506 biosynthesis. Finally, FK506 production was increased to 929.6 mg L-1, which was 56.6% higher than that in the starter strain, when supplemented isoleucine and valine at 9 and 4 g L-1, respectively. CONCLUSIONS: Methylmalonyl-CoA might be the key rate-limiting factors in FK506 biosynthesis and overexpression of the gene PCCB1 and further addition of isoleucine and valine could increase the yield of FK506 by 56.6%.

tsRBase: a comprehensive database for expression and function of tsRNAs in multiple species.

tRNA-derived small RNAs (tsRNAs) are a class of novel small RNAs, ubiquitously present in prokaryotes and eukaryotes. It has been reported that tsRNAs exhibit spatiotemporal expression patterns and can function as regulatory molecules in many biological processes. Current tsRNA databases only cover limited organisms and ignore tsRNA functional characteristics. Thus, integrating more relevant tsRNA information is helpful for further exploration. Here, we present a tsRNA database, named tsRBase, which integrates the expression pattern and functional information of tsRNAs in multiple species. In tsRBase, we identified 121 942 tsRNAs by analyzing more than 14 000 publicly available small RNA-seq data covering 20 species. This database collects samples from different tissues/cell-lines, or under different treatments and genetic backgrounds, thus helps depict specific expression patterns of tsRNAs under different conditions. Importantly, to enrich our understanding of biological significance, we collected tsRNAs experimentally validated from published literatures, obtained protein-binding tsRNAs from CLIP/RIP-seq data, and identified targets of tsRNAs from CLASH and CLEAR-CLIP data. Taken together, tsRBase is the most comprehensive and systematic tsRNA repository, exhibiting all-inclusive information of tsRNAs from diverse data sources of multiple species. tsRBase is freely available at http://www.tsrbase.org.

Effect of Tumor Location on Outcome After Laparoscopic Low Rectal Cancer Surgery: A Propensity Score Matching Analysis.

BACKGROUND: Dissection of the distal anterolateral aspect of the mesorectum remains a surgical challenge for low rectal cancer, posing a higher risk of residual mesorectum, which might lead to the increased incidence of local recurrence for patients with anterior wall involvement. OBJECTIVE: This study aimed to assess the effect of tumor location on outcome after laparoscopic low rectal cancer surgery. DESIGN: This is a single-center, retrospective study. SETTINGS: The study was conducted at West China Hospital in China. PATIENTS: Patients with low rectal cancer who underwent laparoscopic total mesorectal excision from 2011 to 2016 were enrolled. Patients were divided into anterior and nonanterior groups according to tumor location. Propensity score matching analysis was used to reduce the selection bias. MAIN OUTCOME MEASURES: The primary end point was local recurrence. The secondary end points included overall survival, disease-free survival, and the positive rate of circumferential resection margin. RESULTS: A total of 404 patients were included, and 176 pairs were generated by propensity score matching analysis. Multivariate analysis showed that anterior location was an independent risk factor of local recurrence (HR, 12.6; p = 0.006), overall survival (HR, 3.0; p < 0.001), and disease-free survival (HR, 2.3; p = 0.001). For patients with clinical stage II/III or T3/4, anterior location remained a prognostic factor for higher local recurrence and poorer survival. Local recurrence was rare in patients with clinical stage II/III (1.4%) or T3/4 (1.5%) tumors that were not located anteriorly. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: Anterior location is an independent risk factor of local recurrence, overall survival, and disease-free survival for low rectal cancer. More strict and selective use of neoadjuvant therapy should be considered for patients who have clinical stage II/III or T3/4 tumors that are not located anteriorly. A larger cohort study is warranted to validate the prognostic role of anterior location for low rectal cancer. See Video Abstract at http://links.lww.com/DCR/B622. IMPACTO DE LA LOCALIZACIN DEL TUMOR EN EL RESULTADO POSTERIOR A CIRUGA LAPAROSCPICA DE CNCER DE RECTO INFERIOR UN PUNTAJE DE PROPENSIN POR ANLISIS DE CONCORDANCIA: ANTECEDENTES:La disección de la cara anterolateral distal del mesorrecto sigue siendo un desafío quirúrgico en el cáncer de recto inferior, constituyendo un alto riesgo de mesorrecto residual, que podría ocasionar una mayor incidencia de recurrencia local en pacientes con compromiso de la pared anterior.OBJETIVO:El objetivo del estudio fue evaluar el efecto de la localización del tumor en el resultado posterior a la cirugía laparoscópica de cáncer de recto inferior.DISEÑO:Estudio restrospectivo de un único centro.ÁMBITO:El estudio se realizó en el West China Hospital en China.PACIENTES:Pacientes con cáncer de recto inferior que se sometieron a excisión mesorrectal total laparoscópica entre 2011 y 2016. Los pacientes se dividieron en grupos, anterior y no anterior, según la localización del tumor. Se utilizó un puntaje de propensión por análisis de concordancia para reducir el sesgo de selección.PRINCIPALES VARIABLES EVALUADAS:El objetivo principal fue la recurrencia local. Los objetivos secundarios incluyeron la sobrevida global, la sobrevida libre de enfermedad y la tasa de positividad del margen de resección circunferencial.RESULTADOS:Se incluyeron un total de 404 pacientes y se generaron 176 pares mediante un puntaje de propensión por análisis de concordancia. El análisis multivariado mostró que la localización anterior era un factor de riesgo independiente de recidiva local (HR = 12,6, p = 0,006), sobrevida global (HR = 3,0, p <0,001) y sobrevida libre de enfermedad (HR = 2,3, p = 0,001). En pacientes con estadio clínico II /III o T3/4, la ubicación anterior continuó como un factor pronóstico para una mayor recurrencia local y una menor sobrevida. La recidiva local fue excepcional en pacientes con tumores en estadio clínico II / III (1,4%) o T3 / 4 (1,5%) que no estaban localizados hacia anterior.LIMITACIONES:Este estudio estuvo limitado por su carácter retrospectivo.CONCLUSIONES:La localización anterior es un factor de riesgo independiente de recidiva local, sobrevida global y sobrevida libre de enfermedad para el cáncer de recto inferior. Se debe considerar un uso más estricto y selectivo de la terapia neoadyuvante para pacientes en estadio clínico II / III o T3 /4 de tumores que no se localizan hacia anterior. Se justifica un estudio de cohorte más grande para validar el impacto pronóstico de una ubicación anterior del cáncer de recto inferior. Consulte Video Resumen en http://links.lww.com/DCR/B622. (Traducción-Dr. Lisbeth Alarcon-Bernes).

Distinctive features of small vessels on the mesorectal and parietal pelvic fascia as important landmarks in guiding precise inter-fascial dissection for low rectal cancer.

BACKGROUND: The confinement of the pelvis and the complexity of pelvic fascial anatomy still pose difficulties in achieving good quality surgery for rectal cancer. We aimed to introduce small vessels on the mesorectal fascia and the parietal pelvic fascia as novel landmarks to aid in the identification of the inter-fascial dissection plane. Besides, the perioperative, survival, and functional outcomes of this surgical technique were reported. METHODS: We first described that small vessels running on the mesorectal fascia and the parietal pelvic fascia showed distinctive features, which included (1) small vessels on the parietal fascia took the same orientation as the ureter or the sympathetic and parasympathetic nerve; (2) small vessels on the mesorectal fascia were coursing cranially and medially on the anterolateral aspect, and medially and caudally on the posterolateral aspect; (3) small vessels on the mesorectal fascia became invisible at the interface between the pelvic wall and the mesorectal fascia. These features could be applied in fascial identification and separation. Then, we reported the outcomes of low rectal cancer surgery with small vessels-guided technique. RESULTS: From 2013 to 2016, a consecutive series of 310 patients with low rectal cancer underwent laparoscopic total mesorectal excision with small vessels-guided technique. The positive rate of circumferential resection margin was 3.2%, and complete mesorectal excision was achieved in 97.8% (303/310) patients. The 3-year overall survival, disease-free survival, and local recurrence rates were 89.4%, 79.7%, and 2.6%, respectively. The urinary function was considered normal in 96.8% of patients, with a moderate dysfunction in 3.2% of patients. Besides, 29.5% of male patients occurred sexual function injury. CONCLUSION: Distinctive features of small vessels on the parietal pelvic fascia and the mesorectal fascia can serve as novel and additive landmarks in guiding precise inter-fascial dissection for low rectal cancer.

Frailty index is useful for predicting postoperative morbidity in older patients undergoing gastrointestinal surgery: a prospective cohort study.

BACKGROUND: Many assessment tools have been used to identify frail surgical patients. This study was designed to explore the prediction value of the frailty index (FI) for postoperative morbidity in older patients undergoing elective gastrointestinal surgery. METHODS: Between January 2019 and September 2020, we conducted a prospective study in our hospital, and patients aged over 65 years were enrolled. The FI assessment was conducted by two specialist nurses based on the 38-item scale, and patients were considered frail if the FI score was ≥ 0.25. The primary outcome was 30-day postoperative morbidity. Univariable and multivariable analyses were used to find the risk factors related to postoperative morbidity. RESULTS: A total of 246 consecutive patients were enrolled, for whom the median age was 72.0 [interquartile range (IQR): 67.0-77.0] years old, and 175 (71.1%) were male. Of these, 47 (19.1%) were frail. Patients with frailty were associated with older age (p < 0.001), higher American Society of Anesthesiologists (ASA) grade (p = 0.006), lower body mass index (p = 0.001), lower albumin (p = 0.003) and haemoglobin (p < 0.001) levels, increased blood loss (p = 0.034), increased risk of postoperative morbidity (p < 0.001), increased median length of stay (p = 0.017), and increased median postoperative hospital stay (p = 0.003). Multivariable analysis revealed that ASA grade [odds ratio (OR): 2.59, 95% confidence interval (CI) 1.19-5.64, p = 0.016], FI score (OR 7.68, 95% CI 3.19-18.48, p < 0.001) and surgical complexity (OR 22.83, 95% CI 5.46-95.51, p < 0.001) were independent predictors of 30-day postoperative morbidity. However, for patients with major surgery, FI score was the only independent predictor (OR 8.67, 95% CI 3.23-23.25, p < 0.001). CONCLUSION: Frailty was associated with adverse perioperative outcomes, and the 38-item FI scale was a useful frailty screening tool for older patients undergoing elective gastrointestinal surgery. For patients with major surgery, frailty was a more reliable predictor of postoperative 30-day morbidity than age and ASA grade.

Early response to upfront neoadjuvant chemotherapy (CAPOX) alone in low- and intermediate-risk rectal cancer: a single-arm phase II trial.

BACKGROUND: With local recurrence of rectal cancer continuing to decrease, distant recurrence is becoming a major concern, especially for patients with low- and intermediate-risk stage II/III rectal cancer. Therefore, a new treatment strategy is warranted for these patients. This single-arm phase II trial aimed to assess the effect of neoadjuvant chemotherapy (NCT) in low- and intermediate-risk stage II/III rectal cancer and explore candidate radiological and clinical parameters for early prediction of tumour response after two cycles of CAPOX. METHODS: Patients with mid-low stage II/III rectal cancer with low and intermediate risk were examined. The primary outcome was defined as a clinicopathological response by integrating tumour longitudinal length reduction (TLLR) on MRI into pathological tumour regression grade (TRG). After completing NCT, patients with TRG0-2 and TRG3 with a TLLR rate greater than 30 per cent were considered to be responders. Secondary outcomes included pathological complete response (pCR), adverse events and local and distant recurrence. RESULTS: This study enrolled 61 eligible patients. No patient was converted to neoadjuvant chemoradiotherapy owing to tumour progression. The clinicopathological response and pCR rates were 78.7 and 21.3 per cent respectively. After two cycles of CAPOX, TLLR, TRG on MRI, and mucosal lesion regression grade on endoscopy had potential discriminative ability (area under the curve greater than 0.7) for predicting both clinicopathological and pathological response. CONCLUSION: NCT alone achieves good tumour response rates in patients with low- and intermediate-risk stage II/III rectal cancer, and predicting tumour response to NCT is feasible at an early treatment phase. REGISTRATION NUMBER: NCT03666442 (http://www.clinicaltrials.gov).

A Modified Technique of Laparoscopic Lateral Lymph Node Dissection Combining Fascia-Oriented Dissection and Routine Upfront Distal Visceral Vessels Ligation for Mid- to Low-Lying Rectal Cancer.

INTRODUCTION: Lateral pelvic recurrence can be a cause of local failure after surgery for low rectal cancer. Lateral lymph node dissection is often performed in East Asia for patients with enlarged lateral lymph nodes or because of the presence of risk factors. However, the outcomes of the conventional lateral lymph node dissection are unsatisfactory, with a considerably high local recurrence rate for patients with positive lateral nodes. Here, we introduce a modified technique to improve lateral nodes clearance. TECHNIQUE: This modified technique has 4 key steps: 1) separation of the ureterohypogastric nerve fascia medially, 2) identification of the visceral pelvic fascia and dissection along the inferior vesical or vaginal veins down to the pelvic floor, 3) division of the distal ends of visceral vessels according to the orientation of ureterohypogastric nerve fascia and visceral pelvic fascia for better nerve preservation, and 4) en bloc dissection through a lateral approach over the surfaces of the sacral plexus and piriformis muscle to reveal the course of distal internal iliac vessels before the division of visceral veins. RESULTS: Twenty-nine patients underwent laparoscopic lateral lymph node dissection successively with no conversion. The median blood loss for each lateral procedure was 37.5 mL (range, 0-300.0 mL). Eleven lateral nodes (median; range, 1-22 lateral nodes) were harvested for each lateral side. There was no perioperative mortality, and 4 patients developed major complications (Clavien-Dindo III-IV). CONCLUSION: This modified technique characterized by the routine division of visceral vessels based on ureterohypogastric nerve fascia and visceral pelvic fascia is feasible and safe. It provides good lymph node harvest, autonomic nerve preservation, and improved bleeding control. Additional investigation is warranted to evaluate the safety, functional outcomes, and oncologic outcomes.

Improvement of FK506 production via metabolic engineering-guided combinational strategies in Streptomyces tsukubaensis.

BACKGROUND: FK506, a macrolide mainly with immunosuppressive activity, can be produced by various Streptomyces strains. However, one of the major challenges in the fermentation of FK506 is its insufficient production, resulting in high fermentation costs and environmental burdens. Herein, we tried to improve its production via metabolic engineering-guided combinational strategies in Streptomyces tsukubaensis. RESULTS: First, basing on the genome sequencing and analysis, putative competitive pathways were deleted. A better parental strain L19-2 with increased FK506 production from 140.3 to 170.3 mg/L and a cleaner metabolic background was constructed. Subsequently, the FK506 biosynthetic gene cluster was refactored by in-situ promoter-substitution strategy basing on the regulatory circuits. This strategy enhanced transcription levels of the entire FK506 biosynthetic gene cluster in a fine-tuning manner and dramatically increased the FK506 production to 410.3 mg/mL, 1.41-fold higher than the parental strain L19-2 (170.3 mg/L). Finally, the FK506 production was further increased from 410.3 to 603 mg/L in shake-flask culture by adding L-isoleucine at a final concentration of 6 g/L. Moreover, the potential of FK506 production capacity was also evaluated in a 15-L fermenter, resulting in the FK506 production of 830.3 mg/L. CONCLUSION: From the aspects of competitive pathways, refactoring of the FK506 biosynthetic gene cluster and nutrients-addition, a strategy for hyper-production and potentially industrial application of FK506 was developed and a hyper-production strain L19-9 was constructed. The strategy presented here can be generally applicable to other Streptomyces for improvement of FK506 production and streamline hyper-production of other valuable secondary metabolites.

Single-incision versus conventional multiport laparoscopic surgery for colorectal cancer: a meta-analysis of randomized controlled trials and propensity-score matched studies.

PURPOSE: To compare single-incision laparoscopic surgery (SILS) and multiport laparoscopic surgery (MLS) for colorectal cancer in terms of short- and long-term outcomes. METHODS: A systematic literature search was performed in PubMed, Web of Science, and Embase. Randomized controlled trials (RCTs) and propensity-score matched (PSM) studies comparing SILS and MLS for colorectal cancer were enrolled. Outcomes of interests included intraoperative, postoperative, pathological, and survival outcomes. RESULTS: Sixteen studies (6 RCTs and 10 PSM studies) published between 2012 and 2020 with a total of 2425 patients were enrolled. Compared with MLS, SILS was associated with less postoperative pain at postoperative day (POD) 1 (P = 0.02, MWD = -0.73, 95%CI: -1.37, -0.09) and POD2 (P < 0.001, MWD= -1.10, 95%CI: -1.45, -0.74) and shorter length of total incision length (P < 0.001, MWD = -3.31, 95%CI: -3.95, -2.67). No differences were observed in terms of operative time, blood loss, intraoperative and postoperative complications, incision hernia, and pathological or survival outcomes between SILS and MLS. Subgroup analysis for right-sided colon cancer, sigmoid colon cancer, and rectosigmoid colon cancer showed that the SILS group was only associated with less postoperative pain and shorter total incision length. The surgical and pathological outcomes were comparable between SILS and MLS. CONCLUSIONS: SILS is a beneficial alternative to MLS in select colorectal cancer patients, especially for right-sided colon cancer, sigmoid colon cancer, and rectosigmoid cancer, with better cosmetic effects and less postoperative pain. Simultaneously, SILS does not compromise intraoperative and postoperative complications, surgical quality, or long-term outcomes.

Activation and discovery of tsukubarubicin from Streptomyces tsukubaensis through overexpressing SARPs.

Genome sequencing has revealed that each Streptomyces contains a wide range of biosynthetic gene clusters (BGCs) and has the capability to produce more novel natural products than what is expected. However, most gene clusters for secondary metabolite biosynthesis are cryptic under normal growth conditions. In Streptomyces tsukubaensis, combining overexpression of the putative SARPs (Streptomyces antibiotic regulatory proteins) and bioactivity-guided screening, the silent gene cluster (tsu) was successfully activated and a novel bioactive anthracycline tsukubarubicin was further isolated and identified. Biological activity assays demonstrated that tsukubarubicin possessed much better antitumor bioactivities against various human cancer cell lines (especially the breast cancer cell lines) than clinically used doxorubicin. Moreover, the previously unreported gene cluster (tsu) for biosynthesis of tsukubarubicin was first characterized and detailed annotations of this gene cluster were also conducted. Our strategy presented in this work is broadly applicable in other Streptomyces and will assist in enriching the natural products for potential drug leads. KEY POINTS: • Generally scalable strategy to activate silent gene clusters by manipulating SARPs. • The novel anthracycline tsukubarubicin with potent antitumor bioactivities. • Identification and annotation of the previously uncharacterized tsu gene cluster.

Differential expression of lncRNAs in hypertension-induced pericytes.

Pericytes facilitate vessel maturation and endothelial barrier functions closely related with the pathogenesis of organ damage from cardiovascular and cerebrovascular diseases such as hypertension. We used a computational-based strategy to first screen for differentially expressed genes and lncRNAs and characterized associations between lncRNAs of microvascular pericytes and hypertension. In total, 22 lncRNAs were upregulated and 46 were downregulated in the rats afflicted with spontaneous hypertension. Expression profiles for lncRNAs were significantly altered in the hypertension afflicted tissue samples and the transcripts have good potential for use as molecular targets to inhibit the progression of hypertension.

Two novel compound heterozygous mutations in NGLY1as a cause of congenital disorder of deglycosylation: a case presentation.

BACKGROUND: NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) is a multisystemic neurodevelopmental disorder in which affected individuals show developmental delay, epilepsy, intellectual disability, abnormal liver function, and poor growth. This study presents a 10-month-old female infant with elevated liver transaminases, developmental delay, epilepsy (subclinical seizures), and constipation who possesses two compound heterozygous mutations in NGLY1. CASE PRESENTATION: The proband was admitted to the Department of Gastroenterology, Children's Hospital of Soochow University, with elevated liver transaminases. She had a history of intrauterine growth retardation and exhibited elevated transaminases, global developmental delay, seizures and light constipation during early infancy. Whole-exome sequencing (WES) and Sanger sequencing revealed two compound heterozygous mutations in NGLY1 that had been inherited in an autosomal recessive manner from her parents. One was a termination mutation, c.1168C > T (p.R390*), and the other was a missense mutation, c.1156G > T (p.D386Y). NGLY1-CDDG is a rare disorder, with a few dozen cases. The two mutations of this proband has not been previously identified. CONCLUSIONS: This study investigated a Chinese proband with NGLY1-CDDG born from healthy parents who was studied using WES and Sanger sequencing to identify the causative mutations. We identified two novel compound heterozygous mutations in NGLY1, c.1168C > T (p.R390*)/c.1156G > T (p.D386Y), which are probably causative of disease.

Low-residual diet versus clear-liquid diet for bowel preparation before colonoscopy: meta-analysis and trial sequential analysis of randomized controlled trials.

BACKGROUND AND AIMS: The aim of this study was to compare a low-residual diet (LRD) with a clear-liquid diet (CLD) for bowel preparation before colonoscopy. METHODS: A systematic literature search was performed in PubMed, Ovid, and Cochrane databases for randomized clinical trials comparing LRD with CLD for bowel preparation before colonoscopy. The last search was performed on September 20, 2019. The primary outcome was adequate bowel preparation. The outcomes were compared using systematic review with meta-analysis and trial sequential analysis (TSA). RESULTS: Twenty randomized controlled trials published between 2005 and 2019 with 4323 participants were included. LRD was comparable with CLD for adequate bowel preparation (P = .79; odds ratio [OR], 0.96; 95% confidence interval [CI], 0.72-1.29). The detection rates for polyps (P = .68; OR, 1.04; 95% CI, 0.86-1.27) or adenomas (P = .78; OR, 1.03; 95% CI, 0.86-1.23) were similar between the groups. There were significantly fewer advents in individuals in the LRD group: nausea (P = .02; OR, 0.72; 95% CI, 0.56-0.94), vomiting (P = .04; OR, 0.61; 95% CI, 0.38-0.98), hunger (P < .001; OR, 0.36; 95% CI, 0.24-0.53), and headache (P = .02; OR ,0.64; 95% CI, 0.44-0.93). In addition, significantly more individuals in the LRD group found it easy to complete the diet (P = .01; OR, 1.86; 95% CI, 1.15-3.00) and showed willingness to repeat it (P = .005; OR, 2.23; 95% CI, 1.28-3.89). TSA demonstrated that the cumulative Z curve crossed both the traditional boundary and the trial sequential monitoring boundary for adequate bowel preparation. CONCLUSION: The present study demonstrated that LRD was comparable with CLD in the quality of bowel preparation before colonoscopy. More clinical trials are needed to confirm other outcomes.

Oxaliplatin versus mitomycin C in HIPEC for peritoneal metastasis from colorectal cancer: a systematic review and meta-analysis of comparative studies.

BACKGROUND: Hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) following cytoreductive surgery (CRS) has been applied for peritoneal metastasis (PM) from colorectal cancer (CRC). This study aimed to compare oxaliplatin (OX) with mitomycin C (MMC) in HIPEC for PM from CRC in surgical and survival outcomes. METHODS: A systematic literature search was performed in PubMed and Ovid databases for studies comparing OX with MMC in HIPEC for PM from CRC. The last search was performed on June 21, 2020. RESULTS: Eleven articles published between 2006 and 2020 with 2091 patients were included. When compared with MMC group, the OX group showed significantly higher rate of major complications (P = 0.006, OR = 1.57, 95% CI [1.14, 2.16], I2 = 0%). Besides, no significant difference was observed between the two groups for survival outcomes, regardless of 3-year overall survival (P = 0.98, OR = 1.00, 95% CI [0.83, 1.22], I2 = 0%), 3-year disease-free survival (P = 0.98, OR = 1.00, 95% CI [0.83, 1.22], I2 = 0%), or 5-year overall survival (P = 0.91, OR = 1.01, 95% CI [0.81, 1.26], I2 = 0%). CONCLUSION: OX and MMC could achieve comparable survival in HIPEC for PM from CRC. However, in consideration of the high incidence of major complication in OX group, MMC might be the safer one in clinical routines.