Appraising non-linear association between pre-diagnostic platelet counts and cancer survival outcomes: observational and genetic analysis.

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 109/L) and inferior OS (HR: 1.07; 95% CI: 1.04-1.10; p < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (p < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998-1.001; p = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

What is the context? Previous studies have reported inconsistent associations between platelet counts (PLTs) and cancer survival. However, it is unclear whether there is a linear causal effect, as most studies measured PLTs at the time of cancer diagnosis, which could be influenced by the cancer itself.This study aimed to investigate the association and potential causality between pre-diagnostic PLTs and cancer survival outcomes using a large prospective cohort and genetic analysis.What is new? The observational cohort study found a significant association between elevated pre-diagnostic PLTs and poorer overall and cancer-specific survival. We also identified a U-shaped relationship between PLTs and cancer survival, suggesting that both high and low PLTs may be detrimental.The Mendelian randomization analysis did not support a causal effect of PLTs on overall cancer survival, although it hinted at potential non-linear effects at lower PLT ranges.The study also identified several genes (TPM4, PDIA5, PSMD13, TMCC2, ZFPM2, BAZ2A, CDKN2A, GP1BA, TAOK1, CABLES1, and THPO) related to PLTs that were associated with cancer survival.What is the impact? The findings suggest that early detection of elevated PLTs may indicate occult cancer development and poorer subsequent survival outcomes. However, PLTs are less likely to be a promising therapeutic target for improving cancer survival, as the observed associations could be influenced by confounding factors.The study highlights the need for further research into the complex relationship between PLTs and cancer prognosis, as well as the exploration of other platelet-related traits as potential drug targets.

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.

Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial.

PURPOSE: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. METHODS AND MATERIALS: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). CONCLUSIONS: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Neoadjuvant chemotherapy (CAPOX) alone for low- and intermediate-risk stage II/III rectal cancer: Long-term follow-up of a prospective single-arm study.

BACKGROUND: Stratified treatment has been recommended for rectal cancer. Our previous multicenter randomized trial showed that low-/intermediate-risk rectal cancer patients did not benefit much from neoadjuvant chemoradiotherapy. In our phase II study, we found that stage II/III rectal cancer patients with low-/intermediate risks can be managed by neoadjuvant chemotherapy alone and achieve a good response. The current study aimed to report the long-term survival outcomes in the expanded phase II trial. METHOD: Consecutive patients diagnosed with mid-low stage II/III rectal cancer with low/intermediate risk factors were included. Four cycles of neoadjuvant chemotherapy (CAPOX) were given, and MRI was used for tumour response detection. The primary endpoint was disease-free survival. The secondary endpoints were tumour response to NCT, tumour-related death, and overall survival. RESULTS: This study enrolled 121 eligible patients. The good tumour response rate based on MRI was 82.6 %, with a pathological complete response (pCR) rate of 18.3 %. The disease-free survival rate was 82.6 %, and the overall survival rate was 96.7 % after a median follow-up time of 40 months. Two patients (1.7 %) suffered local recurrence, and 15 patients (12.4 %) suffered distant metastasis. The median disease-free survival and overall survival were 37 (9-60) and 40 (16-60) months, respectively. Tumour longitudinal length reduction and tumour regression grade on MRI were identified as predictors for poor tumour response to neoadjuvant chemotherapy. CONCLUSION: In stage II/III rectal cancer patients with low-/intermediate risks, neoadjuvant chemotherapy alone may result in an acceptable tumour response and disease-free survival. Tumour response might be predicted early.

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).

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%.

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.

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.

Day-case loop ileostomy reversal based on the community hospital joined enhanced recovery after surgery (CHJ-ERAS) program in China: Safe and feasible.

BACKGROUND: This study was performed to determine the feasibility of Day-case loop ileostomy reversal (DLIR) in China based on the community hospital joined enhanced recovery after surgery (CHJ-ERAS) program. METHOD: Patients who underwent loop ileostomy were enrolled in the CHJ-ERAS program for DLIR after rigorous evaluation. The primary outcome was the results of short-term follow-ups. RESULTS: From August 2017 to April 2022, 216 patients have been enrolled in the CHJ-ERAS program for DLIR. After DLIR, 14 patients (14/216, 6.5%) have recorded 17 episodes of postoperative complications within 1 month after surgery, including 10 readmission and 2 reoperation. Compared with in-patient loop ileostomy reversal, DLIR based on CHJ-ERAS did not increase the postoperative complications and reoperations. CONCLUSION: The CMJ-ERAS program for DLIR in our center is a safe and feasible alternative option for inpatient LIR and an acceptable transitional approach for the development of day-case DLIR in developing countries.

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.

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.

Can patients with good tumor regression grading after neoadjuvant chemoradiotherapy be exempted from lateral lymph node dissection?

OBJECTIVE: To investigate whether lateral lymph node (LLN) dissection (LLND) can be exempted in patients with good tumor regression grading (TRG) after neoadjuvant chemoradiotherapy (nCRT)? METHODS: A retrospective study was conducted on consecutive patients with advanced rectal cancer who underwent nCRT and total mesorectal resection plus selective LLND at our institution. The primary outcomes are the relationship between LLN metastasis (LLNM) and magnetic resonance imaging TRG (mrTRG) and the relationship between LLNM and pathological TRG (pTRG). RESULTS: A total of 91 patients were included, of which 24 patients (26.4%) had LLNM, 67 patients (73.6%) had no LLNM. There were significant differences of the maximum short-axis of LLN before and after nCRT, short-axis reduction rate of the LLN with maximum short-axis, length diameter reduction rate of primary tumor, mrTRG, and pTRG between the two groups. Multivariate logistic regression showed that mrTRG (P = 0.026) and pTRG (P = 0.013) were independent predictors for LLNM. The combination used by mrTRG and the maximum short-axis of LLNs ≥ 8 mm before nCRT and the maximum short-axis of LLN ≥ 5 mm after nCRT achieved specificity of 0.970, positive predictive value (PPV) of 0.867, and negative predictive value (NPV) of 0.855. The same combination used by pTRG achieved the specificity of 0.970, PPV of 0.857 and NPV of 0.844. CONCLUSION: The suspected positive LLNs tend to be sterilized by nCRT in patients who have a very good response to nCRT. It is rational to avoid LLND in patients whose primary tumor and LLNs both show good response to nCRT.

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).

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.

The clinic factors in evaluating long-term outcomes of patients with stage I colorectal cancer.

BACKGROUND: This study aimed to explore the survival and recurrences of stage I colorectal cancer (CRC) patients. Through the analysis of the results of preoperative serological values, we seek to find factors associated with the survival and recurrence of patients with stage I CRC. METHODS: We retrospectively enrolled patients from 2012 January to 2015 April. Survival rates were calculated with the Kaplan-Meier method and survival curves were compared using the log-rank test. The independent prognostic factors were assessed by the Cox proportional hazard regression analysis. RESULTS: A total of 476 patients with stage I disease were included to analysis. Median follow-up was 68 months (4-84 months) for OS. The OS rates were related to age,CEA, CHOL, LDL-C levels,HBDH, WBC, NLR, LMR, LWR, PNI, SII, NPS and CONUT at univariate analysis. At multivariate analysis, age, WBC and SII were confirmed to be independent prognostic factors for OS. The median DFS was 68 months (2-84 months). In this period, 38 (8.0%) experienced tumor relapse, and 17 (44.7%) died due to recurrence. The DFS rates were related to higher CEA, higher NLR values and lower LMR values at univariate analysis. At multivariate analysis, just elevated CEA levels was confirmed to be independent prognostic factors. CONCLUSIONS: Patients with stage I colorectal cancers still have a clinically significant risk of recurrence. We still need to expand the number of cases to validate our findings and better identify patients who are at high risk of relapse with less severe disease.

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.

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).

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.

Non-inferiority in cancer clinical trials was associated with more lenient margins and higher hypothesized outcome event rates.

OBJECTIVE: To identify potential bias in non-inferiority design of published cancer trials, and to provide suggestions for future practice. STUDY DESIGN AND SETTING: We systematically searched MEDLINE, Embase and CENTRAL databases (until April 17, 2020) to obtain non-inferiority phase III cancer trials and protocols. Distribution of essential characteristics and study design parameters was compared between trials with and without concluding non-inferiority using multivariable logistic regression. RESULTS: A total of 291 eligible trials were included. We observed that increased odds of concluding non-inferiority was significantly associated with more lenient non-inferiority margins (OR = 1•94, 95% CI 1•02-3•69) and higher hypothesized event rate (OR = 1•24, 95% CI 1•06-1•47). Trials that established non-inferiority adopted margins that were more dispersedly distributed (dispersion OR = 2•90, 95% CI 1•88-4.48). CONCLUSION: Although limited by the exploratory nature, our study demonstrated existence of possible distorted non-inferiority design which could incur excess non-inferiority in cancer clinical trials. Pre-registration and transparent reporting of detailed non-inferiority design is imperative for future research.