Foxc1 and Foxc2 regulate growth plate chondrocyte maturation towards hypertrophy in the embryonic mouse limb skeleton.

The Forkhead box transcription factors Foxc1 and Foxc2 are expressed in condensing mesenchyme cells at the onset of endochondral ossification. We used the Prx1-cre mouse to ablate Foxc1 and Foxc2 in limb skeletal progenitor cells. Prx1-cre;Foxc1Δ/ Δ;Foxc2Δ/Δ limbs were shorter than controls, with worsening phenotypes in distal structures. Cartilage formation and mineralization was severely disrupted in the paws. The radius and tibia were malformed, while the fibula and ulna remained unmineralized. Chondrocyte maturation was delayed with fewer Indian Hedgehog-expressing, prehypertrophic chondrocytes forming and a smaller hypertrophic chondrocyte zone. Later, progression out of chondrocyte hypertrophy was slowed, leading to an accumulation of COLX-expressing hypertrophic chondrocyte zone and formation of a smaller primary ossification center with fewer osteoblast progenitor cells populating this region. Targeting Foxc1 and Foxc2 in hypertrophic chondrocytes with Col10a1-cre also resulted in an expanded hypertrophic chondrocyte zone and smaller primary ossification center. Our findings suggest that Foxc1 and Foxc2 direct chondrocyte maturation towards hypertrophic chondrocyte formation. At later stages, Foxc1 and Foxc2 regulate function in hypertrophic chondrocyte remodelling to allow primary ossification center formation and osteoblast recruitment.

Risk factors and clinical significance of lower perigastric lymph node metastases in Siewert type II and III esophagogastric junction adenocarcinoma: a retrospective cohort study.

BACKGROUND: No consensus has been concluded with regarding to the scope of lymph node (LN) dissection for Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). This study aimed to explore risk factors for lower perigastric LN (LPLN) metastases (including no. 4d, 5, 6, and 12a LN stations) and analyze the indications for LPLN dissection. METHODS: In total, 302 consecutive patients with Siewert type II and III AEG who underwent total gastrectomy (TG) were enrolled. The logistic regression model was used to perform uni- and multivariate analyses of risk factors for LPLN metastases. Kaplan-Meier curves were used for survival analysis, and log-rank tests were used for group comparisons. Basing on the guidelines of Japanese Gastric Cancer Association, the LN metastases (LNM) as well as the efficiency index (EI) of each LN station was further evaluated. RESULTS: The independent risk factors for LPLN metastases in patients with Siewert type II and III AEG were distance from the esophagogastric junction (EGJ) to the distal end of the tumor (> 4.0 cm), preoperative carcinoembryonic antigen (CEA) ( +), pT4 stage, and HER-2 ( +). LPLN metastases was an independent risk factor for overall survival following TG. The LNM and EI of LPLN were 8.6% and 2.31%, respectively. The LNM of LPLN > 10% under the stratification of the distance from the EGJ to the distal end of the tumor (> 4.0 cm), pT4, preoperative CEA ( +), and HER-2 ( +) exhibited EI values of 3.55%, 2.09%, 2.51%, and 3.64%, respectively. CONCLUSIONS: LPLN metastases was a malignant factor for the prognosis of patients with Siewert type II and III AEG. For patients with preoperative CEA ( +), pT4 stage, HER-2 ( +), and the distance from the EGJ to the distal end of the tumor (> 4.0 cm), TG with LPLN dissection is prioritized for clinical recommendation.

The safety and short-term effect of mixed approach in laparoscopic right hemicolectomy for right colon cancer compared with middle approach: a retrospective study.

PURPOSE: To investigate whether the mixed approach is a safe and advantageous way to operate laparoscopic right hemicolectomy. METHODS: A retrospective study was performed on 316 patients who underwent laparoscopic right hemicolectomy in our center. They were assigned to the middle approach group (n = 158) and the mixed approach group (n = 158) according to the surgical approaches. The baseline data like gender、age and body mass index as well as the intraoperative and postoperative conditions including operation time, blood loss, postoperative hospital stay and complications were analyzed. RESULTS: There were no significant differences in age, sex, BMI, ASA grade and tumor characteristics between the two groups. Compared with the middle approach group, the mixed approach group was significantly lower in terms of operation time (217.61 min vs 154.31 min, p < 0.001), intraoperative blood loss (73.8 ml vs 37.97 ml, p < 0.001) and postoperative drainage volume. There was no significant difference in the postoperative complications like postoperative anastomotic leakage, postoperative infection and postoperative intestinal obstruction. CONCLUSIONS: Compared with the middle approach, the mixed approach is a safe and advantageous way that can significantly shorten the operation time, reduce intraoperative bleeding and postoperative drainage volume, and does not prolong the length of hospital stay or increase the morbidity postoperative complications.

Long-term health-related quality of life in patients with gastric cancer after total or distal gastrectomy: a propensity score-matched cohort study.

BACKGROUND: Surgical resection remains the cornerstone of treatment for locally advanced gastric cancer (LAGC) and is accompanied by potential deterioration in patients' health-related quality of life (HRQOL). As an important indicator of the psychosocial burden, HRQOL has become an essential endpoint to evaluate the efficacy and impact of cancer treatment. We examined longitudinal changes in HRQOL among patients with LAGC receiving total gastrectomy (TG) or distal gastrectomy (DG) over time. MATERIALS AND METHODS: The patients in this study were from a prospective observational study (NCT04408859) conducted during 2018-2022. We used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and the stomach module questionnaire to evaluate HRQOL at baseline and at postoperative months 1, 3, 6, and 12. We used linear mixed models to analyze longitudinal changes in HRQOL between groups and correlations with follow-up time. RESULTS: A total of 219 patients were included. After propensity score matching, 186 patients were ultimately analyzed. Compared with the DG group, patients in the TG group reported significantly poorer global health status, physical functioning, and role functioning and more severe fatigue, insomnia, appetite loss, pain, and financial problems. Gastric-specific symptoms, dysphagia, chest and abdominal pain, reflux, restricted eating, and anxiety were more common and severe in the TG group. Most scales showed deterioration at months 1 and 3 after surgery, with gradual recovery thereafter, except the scales for global health status, pain, chest and abdominal pain, and reflux, which improved continually compared with baseline. TG was associated with worsening in at least six HRQOL domains for each measure after baseline, compared with DG. CONCLUSIONS: In contrast with DG, TG had an adverse impact on postoperative HRQOL scales in patients with LAGC. Different HRQOL scales had various recovery trajectories after surgery. Effects of the gastrectomy scope on patients' HRQOL should be considered together with sound oncology principles.

Enhanced powder dispersion of dual-excipient spray-dried powder formulations of a monoclonal antibody and its fragment for local treatment of severe asthma.

The advent of biologics has brought renewed hope for patients with severe asthma, a condition notorious for being hampered by poor response to conventional therapies and adverse drug reactions owing to corticosteroid dependence. However, biologics are administered as injections, thereby precluding the benefits inhalation therapy could offer such as increased bioavailability at the site of action, minimal systemic side effects, non-invasiveness, and self-administration. Here, 2-hydroxypropyl-beta-cyclodextrin and ʟ-leucine were co-spray-dried, as protein stabiliser and dispersion enhancer, respectively, at various weight ratios to produce a series of formulation platforms. Powder aerosolisation characteristics and particle morphology were assessed for suitability for pulmonary delivery. The selected platform with the best aerosol performance, a 1:1 ratio of the excipients, was then incorporated with a monoclonal antibody directed against IL-4 receptor alpha or its antigen-binding fragment. The dual-excipient antibody formulations exhibited emitted fraction of at least 80% and fine particle fraction exceeding 60% in cascade impactor study, while the residual moisture content was within a desirable range between 1% and 3%. The in vitro antigen-binding ability and inhibitory potency of the spray-dried antibody were satisfactorily preserved. The results from this study corroborate the viability of inhaled solid-state biomacromolecules as a promising treatment approach for asthma.

Foxc1 and Foxc2 function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center.

The forkhead box transcription factor genes Foxc1 and Foxc2 are expressed in the condensing mesenchyme of the developing skeleton prior to the onset of chondrocyte differentiation. To determine the roles of these transcription factors in limb development we deleted both Foxc1 and Foxc2 in lateral plate mesoderm using the Prx1-cre mouse line. Resulting compound homozygous mice died shortly after birth with exencephaly, and malformations to this sternum and limb skeleton. Notably distal limb structures were preferentially affected, with the autopods displaying reduced or absent mineralization. The radius and tibia bowed and the ulna and fibula were reduced to an unmineralized rudimentary structure. Molecular analysis revealed reduced expression of Ihh leading to reduced proliferation and delayed chondrocyte hypertrophy at E14.5. At later ages, Prx1-cre;Foxc1Δ/ Δ;Foxc2 Δ / Δ embryos exhibited restored Ihh expression and an expanded COLX-positive hypertrophic chondrocyte region, indicating a delayed exit and impaired remodeling of the hypertrophic chondrocytes. Osteoblast differentiation and mineralization were disrupted at the osteochondral junction and in the primary ossification center (POC). Levels of OSTEOPONTIN were elevated in the POC of compound homozygous mutants, while expression of Phex was reduced, indicating that impaired OPN processing by PHEX may underlie the mineralization defect we observe. Together our findings suggest that Foxc1 and Foxc2 act at different stages of endochondral ossification. Initially these genes act during the onset of chondrogenesis leading to the formation of hypertrophic chondrocytes. At later stages Foxc1 and Foxc2 are required for remodeling of HC and for Phex expression required for mineralization of the POC.

Clinicopathological characteristics and treatment outcome of resectable gastric cancer patients with small para-aortic lymph node.

Background: Resectable gastric cancer (GC) patients with small para-aortic lymph node (smaller than 10mm in diameter, sPAN) were seldom reported, and existing guidelines did not provide definite treatment recommendation for them. Methods: A total of 667 consecutive resectable GC patients were enrolled. 98 patients were in the sPAN group, and 569 patients without enlarged para-aortic lymph node were in the nPAN group. Standard D2 lymphadenectomy was performed. Neoadjuvant and adjuvant chemotherapy were administrated according to the cTNM and pTNM stage, respectively. Clinicopathological features and prognosis were compared between these two groups. Results: The median size of sPAN was 6 (range, 2-9) mm and the distribution was prevalent in No. 16b1. cN stage (p=0.001) was significantly related to the presence of sPAN. sPAN was both independent risk factor for OS (p=0.031) and RFS (p=0.046) of all patients. The prognosis of patients with sPAN was significantly worse than that of patients with nPAN (OS: p=0.008; RFS: p=0.007). Preoperative CEA and CA19-9 were independent risk factors for prognosis of patients with sPAN. Furthermore, patients in the sPAN group with normal CEA and CA19-9 exhibited acceptable prognosis (5-year OS: 67%; RFS: 64%), while those with elevated CEA or CA19-9 suffered significantly poorer prognosis (5-year OS: 17%; RFS: 17%) than patients in the nPAN group (5-year OS: 64%; RFS 62%) (both p < 0.05). Conclusions: Standard D2 lymphadenectomy should be considered a valid approach for GC patients with sPAN associate to normal preoperative CEA and CA19-9 levels. Patients with sPAN associated to elevated CEA or CA19-9 levels could benefit from a multimodal approach: neoadjuvant chemotherapy; radical surgery with D2 plus lymph nodal dissection extended to No. 16 station.

Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study.

BACKGROUND: Approximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese. METHODS: We retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations in BRCA1, BRCA2, ATM, PALB2, BRIP1, CHEK1, CHEK2, FANCA and FANCL were selected for analysis. RESULTS: 89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly in ATM (30.33%), followed by BRIP1 (17.98%), BRCA2 (14.61%), BRCA1 (12.36%), FANCA (10.11%), PALB2 (10.11%), FANCL (6.74%), CHEK1 (3.37%) and CHEK2 (3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235). CONCLUSION: Our data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.

Serum and peritoneal biomarkers for the early prediction of symptomatic anastomotic leakage in patients following laparoscopic low anterior resection: A single-center prospective cohort study.

BACKGROUND: Anastomotic leakage (AL) is one of the common complications after rectal cancer surgery. This study aimed to evaluate the combination of biomarkers for the early prediction of symptomatic AL after surgery. METHODS: A prospective cohort study evaluated the serum and peritoneal biomarkers of patients who underwent laparoscopic low anterior resection (Lap LAR) from November 1, 2021, to May 1, 2022. Multivariate-penalized logistic regression was performed to explore the independent biomarker with a P-value <.1, and receiver operating characteristic (ROC) curve was used to analyze the area under the curve (AUC), sensitivity, and specificity of the independent biomarkers. A predictive model for symptomatic AL was built based on the independent biomarkers and was visualized with a nomogram. The calibration curve with the concordance index (c-index) was further applied to evaluate the efficacy of the predictive model. RESULTS: A total of 157 patients were included in this study, and 7 (4.5%) were diagnosed with symptomatic AL. C-reactive protein/album ratio (CAR) on postoperative day 1 and systemic immune-inflammation index (SII) and peritoneal interleukin-6 (IL-6) on postoperative day 3 were proven to be independent predictors for the early prediction of symptomatic AL. The optimal cutoff values of CAR, SII, and peritoneal IL-6 were 1.04, 916.99, and 26430.09 pg/ml, respectively. Finally, the nomogram, including these predictors, was established, and the c-index of this nomogram was 0.812, indicating that the nomogram could be used for potential clinical reference. CONCLUSION: The combination of CAR, SII, and peritoneal IL-6 might contribute to the early prediction of symptomatic AL in patients following Lap LAR. Given the limitations of this study and the emergence of other novel biomarkers, multicenter prospective studies are worthy of further exploration.

Driver and targetable alterations in Chinese patients with small bowel carcinoma.

PURPOSE: Small bowel carcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis. Recent genomic profiling studies revealed that the landscape of molecular alterations in SBA was distinct from colorectal cancer (CRC) and gastric cancer (GC). To explore driver and targetable alterations in SBA, we performed next-generation sequencing in 107 Chinese SBA patients. METHODS: DNA from paraffin-embedded SBA samples and the corresponding peripheral blood control samples were analyzed through a next-generation sequencing panel. Somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants were characterized. RESULTS: More than half of SBA cases carried KRAS mutations, including canonical (G12, G12, Q61) and atypical mutations (A146, L19, and K117). To our best knowledge, this was the first report of rare driver alterations including KRAS A146V/L19F, PIK3CA N345K/G364R/Q546E, and ZKSCAN1-MET fusion in SBA. Compared to KRAS-mutant patients, alternative activating alterations were enriched in KRAS wild-type patients, and some of them are targetable. Among BRAF-mutated SBA patients, class 1/2 BRAF mutants were mutually exclusive with RAS mutations, but class 3 BRAF mutants were not. Activating ERBB2 alternations, including amplification and activating mutations, represent the most common targetable alternation in this SBA cohort. Of note, the spectrums of BRAF and PIK3CA mutations in this Chinese SBA cohort were distinct from those of a European SBA cohort. Patients with three druggable mutations (PIK3CA, MAP2K1, KRAS G12C) had a high prevalence of concurring drivers, which may interfere with the clinical efficacy of single-target therapy. CONCLUSION: Taken together, our work provided a comprehensive analysis of driver and targetable alterations in SBA, which can facilitate the practice of precision oncology in this challenging disease.

Lymph node yield less than 12 is not a poor predictor of survival in locally advanced rectal cancer after laparoscopic TME following neoadjuvant chemoradiotherapy.

Purpose: Previous studies have confirmed that neoadjuvant chemoradiotherapy (nCRT) may reduce the number of lymph nodes retrieved in rectal cancer. However, it is still controversial whether it is necessary to harvest at least 12 lymph nodes for locally advanced rectal cancer (LARC) patients who underwent nCRT regardless of open or laparoscopic surgery. This study was designed to evaluate the relationship between lymph node yield (LNY) and survival in LARC patients who underwent laparoscopic TME following nCRT. Methods: Patients with LARC who underwent nCRT followed by laparoscopic TME were retrospectively analyzed. The relationship between LNY and survival of patients was evaluated, and the related factors affecting LNY were explored. To further eliminate the influence of imbalance of clinicopathological features on prognosis between groups, propensity score matching was conducted. Results: A total of 257 consecutive patients were included in our study. The median number of LNY was 10 (7 to 13) in the total cohort. There were 98 (38.1%) patients with 12 or more lymph nodes harvested (LNY ≥12 group), and 159 (61.9%) patients with fewer than 12 lymph nodes retrieved (LNY <12 group). There was nearly no significant difference between the two groups in clinicopathologic characteristics and surgical outcomes except that the age of LNY <12 group was older (P<0.001), and LNY <12 group tended to have more TRG 0 cases (P<0.060). However, after matching, when 87 pairs of patients obtained, the clinicopathological features were almost balanced between the two groups. After a median follow-up of 65 (54 to 75) months, the 5-year OS was 83.9% for the LNY ≥12 group and 83.6% for the LNY <12 group (P=0.893), the 5-year DFS was 78.8% and 73.4%, respectively (P=0.621). Multivariate analysis showed that only patient age, TRG score and ypN stage were independent factors affecting the number of LNY (all P<0.05). However, no association was found between LNY and laparoscopic surgery-related factors. Conclusions: For LARC patients who underwent nCRT followed by laparoscopic TME, the number of LNY less than 12 has not been proved to be an adverse predictor for long-term survival. There was no correlation between LNY and laparoscopic surgery-related factors.

Creb5 coordinates synovial joint formation with the genesis of articular cartilage.

While prior work has established that articular cartilage arises from Prg4-expressing perichondrial cells, it is not clear how this process is specifically restricted to the perichondrium of synovial joints. We document that the transcription factor Creb5 is necessary to initiate the expression of signaling molecules that both direct the formation of synovial joints and guide perichondrial tissue to form articular cartilage instead of bone. Creb5 promotes the generation of articular chondrocytes from perichondrial precursors in part by inducing expression of signaling molecules that block a Wnt5a autoregulatory loop in the perichondrium. Postnatal deletion of Creb5 in the articular cartilage leads to loss of both flat superficial zone articular chondrocytes coupled with a loss of both Prg4 and Wif1 expression in the articular cartilage; and a non-cell autonomous up-regulation of Ctgf. Our findings indicate that Creb5 promotes joint formation and the subsequent development of articular chondrocytes by driving the expression of signaling molecules that both specify the joint interzone and simultaneously inhibit a Wnt5a positive-feedback loop in the perichondrium.

The validity of neoadjuvant chemotherapy with paclitaxel plus S-1 is not inferior to that of SOX regimen for locally advanced gastric cancer: an observational study.

BACKGROUND: Paclitaxel plus S-1(PTXS) has shown definite efficacy for advanced gastric cancer. However, the efficacy and safety of this regimen in neoadjuvant setting for locally advanced gastric cancer (LAGC) are unclear. This study aimed to compare the efficacy of neoadjuvant chemotherapy (NAC) PTXS and oxaliplatin plus S-1 (SOX) regime for patients with LAGC. METHODS: A total of 103 patients with LAGC (cT3/4NanyM0/x) who were treated with three cycles of neoadjuvant SOX regimen (n = 77) or PTXS regimen (n = 26) between 2011 and 2017 were enrolled in this study. NAC-related clinical response, pathological response, postoperative complication, and overall survival were analyzed between the groups. RESULTS: The baseline data did not differ significantly between both groups. After NAC, the disease control rate of the SOX group (94.8%) was comparable with that of the PTXS group (92.3%) (p = 0.641). Twenty-three cases (29.9%) in the SOX group and 10 cases (38.5%) in the PTX group got the descending stage with no statistical difference (p = 0.417). No significant differences were observed in the overall pathological response rate and the overall postoperative complication rate between the two groups (p > 0.05). There were also no differences between groups in terms of 5-year overall and disease-free survival (p > 0.05). CONCLUSIONS: The validity of NAC PTXS was not inferior to that of SOX regimen for locally advanced gastric cancer in terms of treatment response and overall survival. PTXS regimen could be expected to be ideal neoadjuvant chemotherapy for patients with LAGC and should be adopted for the test arm of a large randomized controlled trial.

Patterns and predictors of recurrence after laparoscopic resection of rectal cancer.

Purpose: This study was designed to evaluate the patterns and predictors of recurrence in patients who underwent laparoscopic resection of rectal cancer. Methods: Patients with rectal cancer receiving laparoscopic resection between April 2009 and March 2016 were retrospectively analyzed. The association of recurrence with clinicopathological characteristics was evaluated using multivariate analyses. Results: A total of 405 consecutive patients were included in our study. Within a median follow-up time of 62 months, 77 patients (19.0%) experienced disease recurrence: 10 (2.5%) had locoregional recurrence (LR), 61 (15.1%) had distant metastasis (DM), and 6 (1.5%) developed LR and DM synchronously. The lung was the most common site of metastasis. Multivariate analyses indicated that involved circumferential resection margin (CRM) was the only independent predictor for LR (OR=13.708, 95% CI 3.478-54.026, P<0.001), whereas elevated baseline level of CA19-9 (OR=3.299, 95% CI 1.461-7.449, P=0.032), advanced pN stage (OR=2.292, 95% CI 1.177-4.462, P=0.015) and harvested lymph nodes less than 12 (OR=2.418, 95% CI 1.245-4.695, P=0.009) were independently associated with DM. Patients receiving salvage surgery showed superior 3-year survival compared with palliative treatment after relapse (90.9% vs. 20.5%; P=0.017). The estimated 5-year DFS and CSS for the entire cohort was 80.2% and 83.1%, respectively. Conclusions: DM was more common than LR after laparoscopic resection of rectal cancer, and there were several clinicopathological factors related to LR and DM. Involved CRM and suboptimal lymph node yield were adverse surgery-related factors of tumor recurrence, which should be paid more attention to during the operation.

Effect of lateral lymph nodes without malignant characteristics on the prognosis of patients with rectal cancer.

Background: Lateral lymph node (LLN) metastasis is a poor prognostic factor for rectal cancer patients. However, the effect of LLNs without malignant characteristics on the prognosis of rectal cancer patients has been uncertain. Methods: Consecutive patients who underwent laparoscopic-assisted low anterior resection were included. Patients with MRI-detected LLNs, but without malignant characteristics, were compared with patients with no MRI-detected LLNs. Results: The local recurrence rate was higher in the LLN-present group than in the LLN-absent group (9.8% vs 2.5%; p = 0.056). The overall survival of patients with no MRI-detected LLNs was significantly better than that of patients with MRI-detected LLNs (p = 0.021). Conclusion: The presence of LLNs, even without malignant features, may lead to worse local control and overall survival.

Lymph node metastasis in the pelvic sidewall of patients with rectal cancer is a serious disease that affects the patient's life expectancy. At present, the assessment of lateral lymph node (LLN) metastasis relies mainly on MRI. Currently, there is no consensus on whether small lymph nodes without malignant features detected by MRI affect patient prognosis. Therefore, the authors designed this study to compare the survival of patients with small LLNs detected by MRI with that of patients without LLNs. The authors found that the presence of LLNs, even without malignant features, may lead to worse local control and overall survival. Therefore, for patients with MRI-detected LLNs, LLN dissection should be conducted by experienced surgeons to improve patient prognosis.

Modified π-shaped esophagojejunostomy in totally laparoscopic total gastrectomy: a report of 40 consecutive cases from a single center.

OBJECTIVE: Intracorporeal esophagojejunostomy remains a challenging technique in totally laparoscopic total gastrectomy (TLTG) because of the lack of an established standard anastomosis method. However, π-shaped esophagojejunostomy in TLTG is reportedly safe and feasible. Therefore, we evaluated the short-term surgical outcomes of our modified π-shaped esophagojejunostomy in TLTG. METHODS: This study involved patients without neoadjuvant therapy diagnosed with gastric cancer who underwent TLTG by the same surgeon with modified π-shaped esophagojejunostomy from April 2018 to October 2019. Clinicopathologic data were collected and retrospectively analyzed. RESULTS: Forty patients diagnosed with gastric cancer were included. The mean operative time and estimated blood loss were 264.6 ± 56.9 minutes and 68.5 ± 53.3 mL, respectively. Postoperative flatus occurred at 4.6 ± 1.7 days. The mean time to resumption of diet was 7.4 ± 1.7 days postoperatively. One patient was diagnosed with anastomotic leakage and managed with conservative therapy. Pleural effusion was the most common complication, occurring in four (10%) patients. One patient developed intra-abdominal bleeding that required reoperation. Other complications were atrial fibrillation and wound infection. No mortality occurred during the 6-month follow-up. CONCLUSIONS: Modified π-shaped esophagojejunostomy is safe and feasible for intracorporeal anastomosis in TLTG and showed favorable surgical outcomes in this study.

Spray-Dried and Spray-Freeze-Dried Powder Formulations of an Anti-Interleukin-4Rα Antibody for Pulmonary Delivery.

OBJECTIVE: The therapeutic options for severe asthma are limited, and the biological therapies are all parenterally administered. The purpose of this study was to formulate a monoclonal antibody that targets the receptor for IL-4, an interleukin implicated in the pathogenesis of severe asthma, into a dry powder intended for delivery via inhalation. METHODS: Dehydration was achieved using either spray drying or spray freeze drying, which exposes the thermolabile biomacromolecules to stresses such as shear and adverse temperatures. 2-hydroxypropyl-beta-cyclodextrin was incorporated into the formulation as protein stabiliser and aerosol performance enhancer. The powder formulations were characterised in terms of physical and aerodynamic properties, while the antibody was assessed with regard to its structural stability, antigen-binding ability, and in vitro biological activity after drying. RESULTS: The spray-freeze-dried formulations exhibited satisfactory aerosol performance, with emitted fraction exceeding 80% and fine particle fraction of around 50%. The aerosolisation of the spray-dried powders was hindered possibly by high residual moisture. Nevertheless, the antigen-binding ability and inhibitory potency were unaffected for the antibody in the selected spray-dried and spray-freeze-dried formulations, and the antibody was physically stable even after one-year storage at ambient conditions. CONCLUSIONS: The findings of this study establish the feasibility of developing an inhaled dry powder formulation of an anti-IL-4R antibody using spray drying and spray freeze drying techniques with potential for the treatment of severe asthma.

Effect of the transanal drainage tube on preventing anastomotic leakage after laparoscopic surgery for rectal cancer: a systematic review and meta-analysis.

PURPOSE: Anastomotic leakage (AL) is a common postoperative complication of rectal cancer, and transanal drainage tube (TDT) efficacy is still contentious. This study aimed to evaluate the TDT effect on AL prevention. METHODS: All relevant papers were searched by using a predefined search strategy (two randomized controlled trials (RCTs), one prospective study, and four retrospective studies). Meta-analysis was conducted to estimate AL and re-operation pooled rates. RESULTS: A total of 7 studies (1556 patients) were included: No significant statistic difference was found between two groups on AL rate (odds ratio (OR) 0.61, P = 0.11) and re-operation rate (OR 0.52, P = 0.10). For subgroup analysis, significant statistic difference was found between two groups on AL rate (OR 0.29, P = 0.002) and re-operation rate (OR 0.15, P = 0.04) in patients without neoadjuvant therapy. As for patients without diverting stoma, the AL rate (OR 0.35, P = 0.002) was significantly lower than that in patients without TDT. CONCLUSIONS: TDT may reduce AL morbidity and re-operation rate for patients without high risk of AL, but may be useless for those in high-risk situations.

Health-Related Quality of Life in Patients With Locally Advanced Gastric Cancer Undergoing Perioperative or Postoperative Adjuvant S-1 Plus Oxaliplatin With D2 Gastrectomy: A Propensity Score-Matched Cohort Study.

Background: Some high-quality clinical trials have proven the efficacy and safety of perioperative and postoperative S-1 with oxaliplatin (peri-SOX and post-SOX) for patients with locally advanced gastric cancer (LAGC) undergoing D2 gastrectomy. However, little is known about how health-related quality of life (HRQOL) changes over time in patients receiving peri-SOX or post-SOX chemotherapy. Methods: A prospective observational cohort (NCT04408859) identified 151 eligible patients with LAGC who underwent D2 gastrectomy with at least six cycles of peri-SOX or post-SOX chemotherapy from 2018 to 2020. HRQOL was assessed using the EROTC QLQ-C30 and its gastric module, QLQ-STO22, at indicated measurements, including the baseline, 1st, 3rd, 6th and 12th month after initiation of therapy. Baseline characteristics, therapeutic effects, and longitudinal HRQOL were compared between the peri-SOX and post-SOX groups after propensity score matching. HRQOL changes over time and the risk factors for scales with severe deterioration were further analyzed. Results: No statistically significant differences in longitudinal HRQOL were observed between patients in the peri-SOX and post-SOX groups, with comparable surgical outcomes and adverse chemotherapy events. Scales of social functioning, abnormal taste, and anxiety improved earlier in the peri-SOX group than in the post-SOX group. Score changes in both groups indicated that general deterioration and slower recovery usually occurred in the scales of physical, social, and role functioning, as well as symptoms of fatigue, reflux, diarrhea, and anxiety. Conclusion: Peri-SOX showed a longitudinal HRQOL comparable to post-SOX in patients with LAGC who underwent D2 gastrectomy. The peri-SOX group had better performance in social functioning, abnormal taste, and anxiety at some measurements.

Oncological results in rectal cancer patients with a subcentimetre distal margin after laparoscopic-assisted sphincter-preserving surgery.

BACKGROUND: Distal resection margin (DRM) is closely associated with sphincter-preserving surgery and oncological safety for patients with mid-low rectal cancers. However, the optimal DRM has not been determined. METHODS: Data of 378 rectal cancer patients who underwent laparoscopic-assisted sphincter-preserving surgery from 2009 to 2015 were retrospectively analysed. Patients were divided into two groups based on DRM: ≤1 cm (n = 74) and >1 cm (n = 304). To minimize the differences between the two groups, propensity-score matching on baseline features was performed. RESULTS: Before propensity-score matching, no significant differences in 5-year disease-free survival (DFS) (92.8% versus 81.3%, P = 0.128) and 5-year overall survival (OS) (83.7% versus 82.2%, P = 0.892) were observed in patients with DRMs of ≤1 cm (n = 74) and >1 cm (n = 304), respectively. After propensity-score matching (1:1), there were also no significant differences in DFS (88.1% versus 78.2%, P = 0.162) and OS (84.5% versus 84.9%, P = 0.420) between the DRM of ≤1 cm group (n = 65) and >1 cm group (n = 65), respectively. A total of 44 patients received preoperative chemoradiotherapy (CRT). In this cohort, the 5-year local recurrence (LR) rates (P = 0.118) and the 5-year DFS rates (P = 0.298) were not significantly different between the two groups. A total of 334 patients received surgery without neoadjuvant CRT. There were also no significant differences in the 5-year LR rates (P = 0.150) and 5-year DFS rates (P = 0.172) between the two groups. CONCLUSIONS: When aiming to achieve at least a 1-2 cm distal clinical resection margin, a histological resection margin of <1 cm on the DRM gave equivalent clinical outcomes to a DRM of >1 cm.