Optimizing Paclitaxel Oral Absorption and Bioavailability: TPGS Co-Coating via Supercritical Anti-Solvent Fluidized Bed Technology.

Supercritical anti-solvent fluidized bed (SAS-FB) coating technology has the advantages of reducing particle size, preventing high surface energy particle aggregation, improving the dissolution performance and bioavailability of insoluble drugs. The poor solubility of Biopharmaceutics Classification System (BCS) class IV drugs poses challenges in achieving optimal bioavailability. Numerous anti-cancer drugs including paclitaxel (PTX) belong to the BCS class IV, hindering their therapeutic efficacy. To address this concern, our study explored SAS-FB technology to coat PTX with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) onto lactose. Under our optimized conditions, we achieved a PTX coating efficiency of 96.8%. Further characterization confirmed the crystalline state of PTX in the lactose surface coating by scanning electron microscopy and X-ray powder diffraction. Dissolution studies indicated that SAS-FB processed samples release over 95% of the drug within 1 min. Moreover, cell transmembrane transport assays demonstrated that SAS-FB processed PTX samples co-coated with TPGS had an enhanced PTX internalization into cells and a higher permeability coefficient compared to those without TPGS. Finally, compared to unprocessed PTX, SAS-FB (TPGS) and SAS-FB processed samples showed a 2.66- and 1.49-fold increase in oral bioavailability in vivo, respectively. Our study highlights the efficacy of SAS-FB co-coating for PTX and TPGS as a promising strategy to overcome bioavailability challenges inherent in BCS class IV drugs. Our approach holds broader implications for enhancing the performance of similarly classified medications.

Risk Factors of Chylothorax After Congenital Heart Surgery in Infants: A Single-Centre Retrospective Study.

Background: Studies of chylothorax after congenital heart disease in infants are rare. Chylothorax has a higher incidence in infancy, but its risk factors are not well understood. Objective: The purpose of this study is to investigate the risk factors of chylothorax after congenital heart surgery in infants. Methods: This retrospective study included 176 infants who underwent congenital heart disease surgery at the Guangdong Cardiovascular Institute, China, between 2016 and 2020. According to the occurrence of chylothorax, the patients were divided into a control group (n = 88) and a case group (n = 88). Univariate and multivariate logistic regression were performed to analyse the incidence and influencing factors of chylothorax after congenital heart surgery in infants. Results: Between 2016 and 2020, the annual incidence rate fluctuated between 1.55% and 3.17%, and the total incidence of chylothorax was 2.02%. Multivariate logistic regression analysis showed that postoperative albumin (p = 0.041; odds ratio [OR] = 0.095), preoperative mechanical ventilation (p = 0.001; OR = 1.053) and preterm birth (p = 0.002; OR = 5.783) were risk factors for postoperative chylothorax in infants with congenital heart disease. Conclusion: The total incidence of chylothorax was 2.02% and the annual incidence rate fluctuated between 1.55% and 3.17% between 2016 and 2020. Premature infants, longer preoperative mechanical ventilation and lower albumin after congenital heart surgery may be risk factors for chylothorax. In addition, infants with chylothorax are inclined to be infected, need more respiratory support, use a chest drainage tube for longer and remain longer in hospital.

Prognostic value of hyperthermic intraperitoneal chemotherapy in gastric cancer with synchronous peritoneal metastases: a real-world retrospective study.

PURPOSE: Peritoneal metastasis in gastric cancer (GC) is a late-stage condition with a poor prognosis. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a popular treatment for peritoneal metastases. Here, we aim to investigate the real-world application and efficacy of HIPEC alone for GC patients with synchronous peritoneal metastases. METHODS: We conducted a retrospective analysis on GC patients with synchronous peritoneal metastasis at the Sixth Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2022. Survival analyses and Cox regression models were performed based on overall survival (OS) and cancer-specific survival (CSS), and subgroup analysis was used to determine the prognostic value of HIPEC across different treatment. RESULTS: We enrolled 250 patients, of whom 120 (48%) received HIPEC while 130 (52%) did not. HIPEC showed no survival benefit for GC patients (P = 0.220 for OS and P = 0.370 for CSS). However, subgroup analysis found that HIPEC can only improve OS and CSS when combined with primary tumor resection (P = 0.034 for OS and P = 0.036 for CSS). Moreover, survival analyses also demonstrated that HIPEC independently improved OS (HR for OS = 0.58, 95% CI 0.37-0.92, P = 0.020) and CSS (HR for CSS = 0.58, 95% CI 0.37-0.93, P = 0.024) for patients who underwent primary site resection, but not for those who did not. CONCLUSION: HIPEC can improve survival in GC patients with synchronous peritoneal metastases who have primary tumor resection, but not in those without primary tumor resection.

Supercritical antisolvent-fluidized bed for the preparation of dry powder inhaler for pulmonary delivery of nanomedicine.

The supercritical antisolvent-fluidized bed coating process (SAS-FB) shows great potential as a technique to manufacture dry powder inhaler (DPI) that incorporate nanodrugs onto micronized matrix particles, capitalizing on the merits of both nanoparticle and pulmonary delivery. In this study, naringin (NAR), a pharmacologically active flavonoid with low solubility and in vivo degradation issues, was utilized as a model active pharmaceutical ingredient to construct nanomedicine-based DPI through SAS-FB. It is showed that processed NAR exhibited a near-spherical shape and an amorphous structure with an average size of around 130 nm. Notably, SAS-FB products prepared with different fluidized matrices resulted in varying deposition patterns, particularly when mixed with a coarse lactose to enhance the fine particle fraction (FPF) of the formulations. The FPF was positively associated with specific surface area of the SAS-FB products, while the specific surface area was directly related to surface roughness and particle size. In vitro dissolution studies using simulated lung fluid revealed that the NAR nanoparticles coated on the products were released immediately upon contact with solution, with a cumulative dissolution exceeding 90% within the first minute. Importantly, compared to oral raw NAR, the optimized DPI formulation demonstrated superior in vivo plasmatic and pulmonary AUC0→∞ by 51.33-fold and 104.07-fold respectively in a Sprague-Dawley rat model. Overall, SAS- FB technology provides a practical approach to produce nanomedicine DPI product that combine the benefits of nanoparticles with the aerodynamics properties of inhaled microparticles.

IGSF6 is a novel biomarker to evaluate immune infiltration in mismatch repair-proficient colorectal cancer.

Immunotherapy has dramatically changed the landscape of treatment for colorectal cancer (CRC), but currently lack of effective predictive biomarker, especially for tumors with mismatch repair (MMR) proficiency. The response of immunotherapy is associated with the cell-cell interactions in tumor microenvironment, encompassing processes such as cell-cell recognition, binding, and adhesion. However, the function of immunoglobulin superfamily (IGSF) genes in tumor immune microenvironment remains uncharacterized. This study quantified the immune landscape by leveraging a gene expression matrix from publicly accessible databases. The associations between IGSF6 gene expression and immune cell infiltration were assessed. The expression levels of IGSF6, CD8+ T cells, CD4+ T cells and CD68+ macrophage cells in cancer tissues from CRC patients and CRC cell lines were evaluated. IGSF6 was more highly expressed in CRC tumor tissues than adjacent normal tissues. And IGSF6 was significantly correlated with immune cell infiltration in MMR-proficient patients. Remarkably, MMR-proficient patients with high IGSF6 expression showed more sensitive to immunotherapy and chemotherapy than those with low IGSF6 expression. In summary, IGSF6 could be a novel biomarker to evaluate immune infiltration and predict therapeutic effect for MMR-proficient CRC.

Implication of perineural invasion in patients with stage II gastric cancer.

BACKGROUND: Perineural invasion (PNI) is regarded as a prognostic factor for patients with GC. However, the significance of PNI in patients with stage II GC remains unclear. This study aimed to investigate the clinical implication of PNI in patients with stage II GC undergoing curative resection. METHODS: Patients with stage II GC who underwent curative resection were retrospectively evaluated from January 2010 to July 2019. According to PNI status, all patients were divided into two groups: with or without PNI. The prognostic value of PNI was analyzed by univariate and multivariate Cox proportional hazards regression models. RESULTS: A total of 233 patients were included in this study. There were 100 patients with PNI (42.92%) and 133 patients without PNI (57.08%). The overall survival (OS) and disease-free survival (DFS) rates for patients with PNI were significantly lower than that for patients without PNI (p = 0.019 and p = 0.032, respectively). Multivariate analysis indicated that the presence of PNI was an independent risk factor for OS (hazard ratio (HR): 1.76, 95% confidence interval (CI) 1.02-3.06, p = 0.044) and DFS (HR: 1.70, 95% CI 1.04-2.80, p = 0.035), while adjuvant chemotherapy (AC) was an independent protective factor for OS (HR: 0.51, 95% CI 0.30-0.88, p = 0.016) and DFS (HR: 0.52, 95% CI 0.31-0.86, p = 0.011). Furthermore, among patients with PNI, those who received AC had better OS (p = 0.022) and DFS (p = 0.027) than their counterparts. When patients with PNI received AC, the OS (p = 0.603) and DFS (p = 0.745) appeared to be similar to those without PNI and no AC. CONCLUSION: In patients with stage II GC undergoing curative resection, the presence of PNI was associated with worse survival, which appeared to improve with the treatment of AC, indicating a potential need for more intensive AC.

Elderly patients with stage II gastric cancer do not benefit from adjuvant chemotherapy.

BACKGROUND: With the aging of the population, the burden of elderly gastric cancer (EGC) increases worldwide. However, there is no consensus on the definition of EGC and the efficacy of adjuvant chemotherapy in patients with stage II EGC. Here, we investigated the effectiveness of adjuvant chemotherapy in defined EGC patients. METHODS: We enrolled 5762 gastric cancer patients of three independent cohorts from the Sixth Affiliated Hospital of Sun Yat-sen University (local), the Surveillance, Epidemiology, and End Results (SEER), and the Asian Cancer Research Group (ACRG). The optimal age cutoff for EGC was determined using the K-adaptive partitioning algorithm. The defined EGC group and the efficacy of adjuvant chemotherapy for them were confirmed by Cox regression and Kaplan-Meier survival analyses. Furthermore, gene set variation analyses (GSVA) were performed to reveal pathway enrichment between groups. RESULTS: The optimal age partition value for EGC patients was 75. In the local, SEER, and ACRG cohorts, the EGC group exhibited significantly worse overall survival and cancer-specific survival than the non-EGC group (P < 0.05) and was an independent risk factor. Stratified analyses based on chemotherapy showed that EGC patients derived little benefit from adjuvant chemotherapy. Furthermore, GSVA analysis revealed the activation of DNA repair-related pathways and downregulation of the p53 pathway, which may partially contribute to the observed findings. CONCLUSION: In this retrospective, international multi-center study, 75 years old was identified as the optimal age cutoff for EGC definition, and adjuvant chemotherapy proved to be unbeneficial for stage II EGC patients.

Lymphovascular or perineural invasion is associated with lymph node metastasis and survival outcomes in patients with gastric cancer.

BACKGROUND: Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with poorer prognosis in several human malignancies, but their significance in gastric cancer (GC) remains to be clearly defined. Our study aimed to investigate the prognostic value of LVI/PNI in patients with curative resected GC. METHODS: Records of 1488 patients with stage I--III GC and 3327 patients with stage I-III colorectal cancer (CRC) were reviewed retrospectively, and difference in the incidence of LVI/PNI between GC and CRC was compared. Univariate and multivariate analyses were used to evaluate whether LVI/PNI was an independent risk factor for lymph node metastasis (LNM) and overall survival (OS) in GC. RESULTS: Patients with stage I-III GC had a significantly higher incidence of LVI/PNI than patients with stage I-III CRC (50.54% vs. 21.91%, p < 0.001). LVI/PNI was significantly associated with higher CEA, higher CA199, deeper tumor invasion, more lymph node metastasis, and advanced TNM stage in GC ( p < 0.05). Multivariate logistic regression analysis identified LVI/PNI (OR = 2.64, 95%CI: 2.05-3.40, p < 0.001) as an independent risk factor for LNM in GC. The OS rate was significantly lower in the LVI/PNI-positive GC group than that in the LVI/PNI-negative GC group ( p < 0.001). On multivariate Cox regression analysis, LVI/PNI (HR = 1.34, 95%CI: 1.04-1.71, p  = 0.023) was an independent prognostic factor for OS in GC. CONCLUSION: GC has a high incidence of LVI/PNI, which was closely associated with disease progression. LVI/PNI could serve as an independent risk factor for LNM and the prognosis of patients with curative resected GC. These findings will be helpful in predicting survival outcomes more accurately and establishing individualized treatment plans.

Advanced lung cancer inflammation index predicts the outcomes of patients with non-metastatic gastric cancer after radical surgical resection.

Background: The prognostic value of the advanced lung cancer inflammation index (ALI) has been demonstrated in various tumors. However, the prognostic significance of ALI in non-metastatic gastric cancer (GC) remains unclear. This study aimed to identify the prognostic values of ALI in patients with non-metastatic GC who underwent radical surgical resection. Methods: Patients who underwent radical surgery for non-metastatic GC from January 2008 to September 2020 were enrolled in this study. The preoperative ALI was calculated as follows: body mass index × serum albumin/neutrophil to lymphocyte ratio. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression analyses were performed to assess the association between ALI and survival. The potential of ALI was supported by sensitivity testing based on the propensity score matching (PSM) analysis. Results: Low preoperative ALI was significantly correlated with male gender (P=0.037), older age (P=0.004), T3/4 stage (P=0.001), lymph node metastasis (P=0.030), Tumor Node Metastasis (TNM) stage classification progression (P=0.004), and vessel invasion (P=0.001). Patients with low ALI showed worse OS (P<0.001) and CSS (P=0.001) compared to those with high ALI. Multivariable analysis showed that ALI was an independent prognostic factor for both OS [hazard ratio (HR) =1.55; 95% confidence interval (CI), 1.11-2.16]; P=0.010] and CSS (HR =1.46; 95% CI, 1.01-2.10; P=0.043) in non-metastatic GC patients who underwent radical surgical resection. Further PSM analysis confirmed the prognostic value of ALI in the PSM cohort. Conclusions: The preoperative ALI is associated with survival outcomes in patients who have undergone radical surgical resection for non-metastatic GC. Low ALI appears to predict a worse prognosis.

Characteristics of sublingual microcirculatory changes during the early postoperative period following cardiopulmonary bypass-assisted cardiac surgery-a prospective cohort study.

Background: Persistent microcirculatory dysfunction associated with increased morbidity and mortality. Interventions in the early resuscitation can be tailored to the changes of microcirculation and patient's need. However, there is usually an uncoupling of macrocirculatory and microcirculatory hemodynamics during resuscitation. Current research on the patterns of microcirculatory changes and recovery after cardiopulmonary bypass (CPB)-assisted cardiac surgery is limited. This study aimed to analyze changes in the microcirculatory parameters after CPB and their correlation with macrocirculation and to explore the characteristics of microcirculatory changes following CPB-assisted cardiac surgery. Methods: Between December 2018 and January 2019, 24 adult patients with indwelling pulmonary artery catheters after elective cardiac surgery using CPB were enrolled in this study. Both microcirculatory and macrocirculatory parameters were collected at 0, 6, 16, and 24 hours after admission to the intensive care unit (ICU). Video images of sublingual microcirculation were analyzed to obtain the microcirculatory parameters, including total vascular density (TVD), perfused small vessel density (PSVD), the proportion of perfused small vessels (PPV), microvascular flow index (MFI), and flow heterogeneity index (HI). The characteristics of microcirculatory parameter change following cardiac surgery and the correlation between microcirculatory parameters and macroscopic hemodynamic indicators, oxygen metabolic indicators, and carbon dioxide partial pressure difference (PCO2gap) were analyzed. Results: There were significant differences in the changes of TVD (P=0.012) and PSVD (P=0.005) during the first 24 hours postoperatively in patients who underwent CPB-assisted cardiac surgery. The microcirculatory density parameters (TVD: r=-0.5059, P=0.0456; PVD: r=-0.5499, P=0.0273) were correlated with oxygen delivery index (DO2I) at 24 hours after surgery. The microcirculatory flow parameters (PPV: r=0.4370, P=0.0327; MFI: r=0.6496, P=0.0006; and HI: r=-0.5350, P=0.0071) had a strong correlation with PCO2gap at 0 hour after surgery. Conclusions: TVD and PSVD might be two most sensitive indicators affected by CPB-assisted cardiac surgery. There was no consistency between microcirculation and macrocirculation until 24 hours following cardiac surgery, meaning the improvement of systemic hemodynamic indicators does not guarantee correspondently improvement in microcirculation. Early controlled oxygen supply after CPB-assisted cardiac surgery may be conducive to the resuscitation of patients to a certain extent.

Postoperative Alanine Aminotransferase Levels Are Associated with Outcomes in Pediatric Patients Undergoing Total Cavopulmonary Connection.

BACKGROUND: This single-center, retrospective study aims to determine the association between alanine aminotransferase (ALT) and outcomes in pediatric patients undergoing total cavopulmonary connection (TCPC). METHODS: In total, 256 pediatric patients undergoing TCPC were included and divided into a normal-ALT group and a high-ALT group. Clinical data were collected for comparisons between groups, and risk factors of high postoperative ALT were identified by univariate and multivariate analysis. A ROC analysis of the predictive value of postoperative ALT was conducted. RESULTS: Compared to the normal-ALT group, the members of the high-ALT group were 1.6 years older and had significantly higher preoperative creatinine and direct bilirubin levels. The high-ALT group had increased fluid overload, higher vasoactive inotropic drug scores, and inferior central venous pressure. The short-term outcomes in the high-ALT group were markedly worse: they suffered a longer duration of mechanical ventilation (MV), had a higher ICU and hospital length of stay (LOS), and higher rates of mortality, infection, and reintubation. Prolonged ICU and hospital LOS, longer MV, and reintubation were identified as independent risk factors for high postoperative ALT. Postoperative ALT was of high value in predicting reintubation, MV, ICU LOS, and mortality. CONCLUSIONS: Elevated postoperative ALT levels are associated with poor short-term outcomes in pediatric patients undergoing TCPC.

Long-term effects of total vs. partial pancreatectomy among patients with pancreatic cancer: a population-based study.

Background: Total pancreatectomy (TP) for pancreatic cancer (PC) has been limited historically for fear of elevated perioperative morbidity and mortality. With advances in perioperative care, TP may be an alternative option to partial pancreatectomy (PP). Limited evidence clarified the indication for these two procedures in PC patients, especially in patients with different tumor staging and location. Thus, this study aims to compare the outcomes after TP and PP for PCs of different T stages and locations. Methods: The study identified 14,456 PC patients with potentially curable primary tumor (T1-3) who received TP or PP from the Surveillance, Epidemiology, and End Results (SEER) database during 2000 to 2016. Detailed clinical and tumor covariates were all collected. Overall survival (OS) and cancer-specific survival (CSS) were the primary endpoints of interest in this study. OS and CSS were compared between patients after TP and PP using log-rank analysis. Results: For all patients, except for tumor location, TP group was comparable to the PP group. OS and CSS of the TP group were worse than of the PP group (median OS: 19 vs. 20 months, P=0.0058; median CSS: 24 vs. 26 months, P=0.00098, respectively). In stratifying analyses, TP was significantly related to worse OS and CSS than PP in pancreatic head and neck cancer patients with T2-stage tumors (median OS: 18 vs. 19 months, P=0.0016; median CSS: 22 vs. 24 months, P=0.00055, respectively), whereas for patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer, OS and CSS of the two groups were similar (all P>0.05). Conclusions: Compared with PP, TP offered worse prognosis in pancreatic head and neck cancer patients with T2-stage tumors, furthermore, TP and PP achieved comparable prognosis in patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer.

Variations of urinary N-acetyl-ß-D-glucosaminidase levels and its performance in detecting acute kidney injury under different thyroid hormones levels: a prospectively recruited, observational study.

OBJECTIVE: Changes in thyroid function will be accompanied by changes in urinary N-acetyl-ß-D-glucosaminidase (uNAG) levels. Therefore, whether thyroid hormones interfere the ability of uNAG in detecting acute kidney injury (AKI) has raised concern in patients with critical illness. DESIGN: A prospectively recruited, observational study was performed. SETTING: Adults admitted to the intensive care unit of a grade A tertiary hospital in China. PARTICIPANTS: A total of 1919 critically ill patients were enrolled in the study. MAIN OUTCOME MEASURES: To investigate the variations of the ability of uNAG to detect AKI in patients with critical illness under different thyroid hormones levels (differences in area under the curve (AUC) for uNAG diagnosis and prediction of AKI with different thyroid hormones levels). RESULTS: The bivariate correlation analysis revealed that FT3 and TT3 levels were independently associated with uNAG levels (p<0.001). FT3 and uNAG also showed correlation in multivariable linear regression analysis (p<0.001). After stratification according to the levels of FT3 or TT3, significant variation was observed in the uNAG levels with different quartiles (p<0.05). However, in patients with varying FT3 and TT3 levels, no significant difference was found in the AUCs of uNAG to detect AKI (p>0.05). CONCLUSIONS: Even if uNAG levels varied with FT3 and TT3 levels, these hormones did not interfere with uNAG's ability to detect AKI in patients with critical illness.

Mutation of MUC16 Is Associated With Tumor Mutational Burden and Lymph Node Metastasis in Patients With Gastric Cancer.

BACKGROUND: Lymph node metastasis (LNM) is a critical factor in determining the prognosis of gastric cancer (GC), but its underlying mechanism remains unclear. The tumor mutational burden (TMB) has recently been recognized as a biomarker for predicting prognosis and response to immune checkpoint inhibitors, while mucin 16, cell surface associated (MUC16) is frequently mutated in GC. This study explored whether MUC16 mutation status is associated with TMB, LNM, and prognosis in patients with GC. METHODS: Somatic mutation data were downloaded from three GC cohorts. TMB values were calculated and associations between the TMB and clinical characteristics were analyzed. The mutational landscapes of these three GC cohorts were individually explored and visualized using waterfall diagrams. Univariate logistic regression and Kaplan-Meier survival analysis were performed to screen for mutated genes associated with LNM and overall survival (OS). Associations between MUC16 mutations and TMB, microsatellite instability (MSI), LNM, and tumor microenvironment signatures were explored. RESULTS: TMB was associated with LNM and OS in patients with GC. Analyzing the three GC cohorts (The Cancer Genome Atlas-Stomach Adenocarcinoma, International Cancer Genome Consortium [ICGC]-China, and ICGC-Japan) revealed that MUC16 was one of the most frequently mutated genes in patients with GC. MUC16 mutations were associated with better prognosis, including lower LNM rates and improved OS rates. In addition, MUC16 mutation status was associated with TMB and MSI statuses. Fifteen upregulated and 222 downregulated genes were identified in patients with MUC16 mutations, compared to in those in patients with wild-type MUC16. An altered tumor microenvironment signature was also identified in GC samples with MUC16 mutations; it was characterized by significantly decreased infiltration regarding stromal cells, CD4+ T cells, and macrophages. CONCLUSION: MUC16 mutation status was associated with TMB, microsatellite status, LNM, and survival in patients with GC. These findings may provide new insights into the mechanism of LNM and could act as a signpost for prognostic predictions and immunotherapy guidance for patients with GC.

Characterization of excipients to improve pharmaceutical properties of sirolimus in the supercritical anti-solvent fluidized process.

Enhanced drug release and bioavailability of poorly soluble active pharmaceutical ingredient (API) can be achieved via a fluidized bed coating integrated with supercritical anti-solvent (SAS-FB) - a process of precipitating drug particles onto carrier granules. However, in the absence of excipients, SAS-FB often results in crystalline of the API on the surface of carriers, limiting the improvement of pharmaceutical properties. Co-processing with excipients is considered an effective approach to improve drug release in the SAS-FB process. Our study used sirolimus, an immune suppressive agent, as the model API to characterize excipients for their effect on pharmaceutical properties in the SAS-FB process. We show that co-precipitation of excipients and sirolumus impacts on carrier specific surface area and drug yield. Among the tested excipients, formulation containing polyvinylpyrrolidone K30 achieved the highest drug yield. Importantly, compared with Rapamune® tablet, our optimized formulation displayed a superior in vivo oral bioavailability by 3.05-fold in Sprague-Dawley rats and 3.99-fold in beagle dogs. A series of characterization of the processed API was performed to understand the mechanism by which excipients contributed to drug dissolution properties. Our study provides a useful guidance for the use of excipients in the SAS-FB technology to improve pharmaceutical properties of sirolimus and other poorly soluble drugs.

Triplet versus doublet neoadjuvant chemotherapy regimens for locally advanced gastric cancer: a propensity score matching analysis.

BACKGROUND: To investigate the differences between doublet and triplet neoadjuvant chemotherapy (NAC) regimens in efficacy and safety profile. METHODS: A total of 227 locally advanced gastric cancer (LAGC) patients who received NAC and sequential radical gastrectomy were reviewed. After propensity score matching (PSM), 140 patients with similar baseline characteristics were selected. Among them, 70 received doublet NAC regimens consisted of platinum and fluorouracil; the other 70 received triplet NAC regimens consisted of docetaxel, platinum, and fluorouracil. RESULTS: The efficacy of doublet and triplet regimens was comparable after propensity score matching in terms of tumor regression (pathological complete response, Doublet 11.4% vs. Triplet 15.7%, p = 0.642), achieving of R0 resection (Doublet 88.6% vs. Triplet 88.6%, p = 1), 1-year disease-free survival (DFS) (Doublet 77.1% vs. Triplet 68.6%, p = 0.178), 3-years overall survival (OS) (Doublet 54.3% vs. Triplet 60.9%, p = 0.941). Post-surgery complications were more common in the triplet cohort (Doublet 5.7% vs. Triplet 27.1%, p = 0.001), especially abdominal infection (Doublet 0% vs. Triplet 11.1%, p = 0.001). CONCLUSIONS: A more intense preoperative triplet NAC regimen does not bring extra downstage effect and survival benefit compared to a doublet regimen. It may even result in a higher risk of post-surgery complications.

Using Acetone/Water Binary Solvent to Enhance the Stability and Bioavailability of Spray Dried Enzalutamide/HPMC-AS Solid Dispersions.

We demonstrated a facile approach, by adjusting the solvent ratio of water/acetone binary mixture, to alter the intermolecular interactions between Enzalutamide (ENZ) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) for spray drying process, which can be readily implemented to produce spray-dried dispersions (SDD) with enhanced stability and bioavailability. The prepared SDD of ENZ/HPMC-AS were examined systematically in terms of particle size, morphology, dissolution, solubility, stability, and bioavailability. Our results show that the introduction of water (up to 30% volume fraction) can effectively reduce the hydrodynamic diameter of HPMC-AS from approximately 220 nm to 160 nm (a reduction of c.a. 20%), which increases the miscibility of the drug and polymer, delaying or inhibiting the crystallization of ENZ during the spray drying process, resulting in a homogeneous amorphous phase. The benefits of using acetone/water binary mixture were subsequently evidenced by an increased specific surface area, improved dissolution profile and relative bioavailability, enhanced stability, and elevated drug release rate. This fundamental finding underpins the great potential of using binary mixture for spray drying process to process active pharmaceutical ingredients (APIs) that are otherwise challenging to handle.

Correlation between blood transfusion and postoperative acute kidney injury after heart transplantation / 中国胸心血管外科临床杂志

@#Objective    To explore the correlation between perioperative blood transfusion and acute kidney injury (AKI) after heart transplantation. Methods    A retrospective study was performed on 67 patients who underwent heart transplantation in the Department of Cardiac Surgery, Guangdong Provincial People's Hospital from January 2016 to December 2018, and finally 63 patients were included according to the exclusion criteria. There were 53 males and 10 females with an average age of 44.3±12.9 years. Twenty patients who adopted continuous renal replacement therapy (CRRT) after heart transplantation were divided into a RT group and the other 43 patients who did not use CRRT were divided into a non-RT group. Baseline characteristics, perioperative blood transfusion data and clinical prognosis were compared between the two groups. Results    The preoperative baseline characteristics of the two groups were basically the same. There were significant differences in perioperative infusion of red blood cells and plasma, postoperative 24 h bleeding and re-exploration (P<0.05) between the two groups. The area under the receiver operating characteristic (ROC) curve was 0.923 (95%CI 0.852 to 0.995, P<0.001). The ROC curve showed that perioperative infusion of red blood cells more than 18 mL/kg would increase the incidence of AKI after heart transplantation. Conclusion    Perioperative blood transfusion is closely related to AKI after heart transplantation. The more blood transfusion is in clinics, the higher incidence of renal injury is and the worse prognosis is. It is suggested that various blood-saving measures can be carried out.

Prognosis of acute kidney injury after total cavopulmonary connection: A retrospective cohort study / 中国胸心血管外科临床杂志

@#Objective    To investigate the prevalence, severity and consequences of acute kidney injury (AKI) in the patients who underwent total cavopulmonary connection (TCPC). Methods    The clinical data of TCPC patients in our center from January 1, 2010 to December 31, 2014 were collected and retrospectively analyzed. The patients with renal replacement therapy, missing serum creatinine data before operation or combined with valve procedures were excluded. We identified whether AKI was associated with hospital length of stay, ICU duration, mechanical ventilation duration, hospital acquired infection, and early mortality by univariable and multivariable analyses. Results    A total of 163 patients were included. AKI occurred in 57% of patients (n=93), mild AKI in 26.4% (n=43), moderate AKI in 12.3% (n=20) and severe AKI in 18.4% (n=30). Compared with the no AKI group, the AKI group had higher hospital acquired infection rate (15.1% vs. 0.0%, P<0.001). AKI was independently associated with hospital length of stay (median, 10 d, 95%CI  3.9-16.0,  P=0.001), ICU duration (median, 103.9, 95%CI 48.6-159.2, P<0.001) , but not associated with mechanical ventilation duration (median, 8 h vs. 7 h, P=0.529). Conclusion    Postoperative AKI in the patients undergoing TCPC is common. AKI is associated with higher hospital acquired infection rate, longer hospital length of stay and ICU duration, but not associated with mechanical ventilation duration.

Arterial switch operation: A double cohort study of 20 years’ outcomes of 571 patients in a single center / 中国胸心血管外科临床杂志

@#Objective    To define the patient characteristics and perioperative management, and to define the mortality and its risk factors after arterial switch operation (ASO). Methods    We conducted a bidirectional cohort study with 571 consecutive patients undergoing ASO from 1997 to 2016 in our hospital. We enrolled patients who underwent ASO before 2012 retrospectively and after 2012 prospectively and followed up all the patients prospectively. Demographic characteristics, clinical information and mortality of these patients were summarized. Joinpoint regression analysis was used to identify the time trend of the overall mortality. Kaplan-Meier survival analysis was used to evaluate the mid- and long-term survival rate after ASO. Cox proportional hazards regression models were used to explore the potential factors associated with mortality. The cumulative incidence of complications after ASO was predicted using competing risk models. Results    Several aspects of patients’ characteristics and perioperative management in our center differed from those in the developed countries. The overall mortality and in-hospital mortality after ASO was 16.3% and 15.1%, respectively. The overall cumulative survival rate at 5, 10 and 15 years after ASO was 83.3%, 82.8% and 82.8%, respectively. A significant decrease of overall mortality from 1997 to 2016 was observed. Independent risk factors of mortality included earlier ASO (1997-2006), single or intramural coronary anatomy and longer cardiopulmonary bypass time. Ten years after ASO, re-intervention, arrhythmia, pulmonary and anastomotic stenosis were the most common complications with a cumulative incidence over 10%. Conclusion    Significant improvements in the results of the ASO were observed and the postoperative mortality rate is close to reports from developed countries. Nonetheless, we have identified the need for further improvement in the early and late postoperative periods after ASO. Pulmonary stenosis, anastomotic stenosis and arrhythmia should be paid attention to during the long-term follow-up after ASO.