Associations of change in body fat percentage with baseline body composition and diabetes remission after bariatric surgery.

OBJECTIVE: The objective of this study was to determine the role of body fat percentage (BFP) changes in diabetes remission (DR) and the association between baseline body composition and its changes after bariatric surgery. METHODS: We analyzed 203 patients with type 2 diabetes who underwent Roux-en-Y gastric bypass. Body composition was measured using a gold-standard-derived predictive equation and magnetic resonance imaging. Body composition changes were calculated as 100 × (baseline value - follow-up value)/baseline value. We verified the results in a laparoscopic sleeve gastrectomy cohort with 311 patients. RESULTS: Compared with non-remission patients in the Roux-en-Y gastric bypass cohort, those who achieved DR showed a higher baseline fat-free mass index (FFMI) and experienced the most significant changes in BFP (p < 0.001). In comparative analyses, BFP changes were significantly better than BMI changes in identifying short- and long-term DR. Linear regression analysis identified FFMI as the most significant baseline variable correlated with BFP changes (p < 0.001). Baseline BMI was positively correlated with changes in BFP but negatively correlated with changes in FFMI. These findings were replicated in the laparoscopic sleeve gastrectomy cohort. CONCLUSIONS: BFP changes determine DR after bariatric surgery, and baseline FFMI is crucial for BFP changes. A low initial BMI is associated with a smaller BFP reduction and greater FFMI loss after bariatric surgery.

A phase I study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer.

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics, tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients. Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles. Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks. Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea (85.7%), vomiting (28.6%), nausea (25.0%) and decreased appetite (17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response (CR), and three achieved partial response (PR). The objective response rate (ORR) and disease control rate (DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival (PFS) was 3.98 months. Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase III trial (No. NCT05122494).

Establishment of an immunogenic cell death-related model for prognostic prediction and identification of therapeutic targets in endometrial carcinoma.

OBJECTIVE: Studies have firmly established the pivotal role of the immunogenic cell death (ICD) in the development of tumors. This study seeks to develop a risk model related to ICD to predict the prognosis of patients with endometrial carcinoma (EC). MATERIALS AND METHODS: RNA-seq data of EC retrieved from TCGA database were analyzed using R software. We determined clusters based on ICD-related genes (ICDRGs) expression levels. Cox and LASSO analyses were further used to build the prediction model, and its accuracy was evaluated in the train and validation sets. Finally, in vitro and in vivo experiments were conducted to confirm the impact of the high-risk gene IFNA2 on EC. RESULTS: Patients were sorted into two ICD clusters, with survival analysis revealing divergent prognoses between the clusters. The Cox regression analysis identified prognostic risk genes, and the LASSO analysis constructed a model based on 9 of these genes. Notably, this model displayed excellent predictive accuracy when validated. Finally, increased IFNA2 levels led to decreased vitality, proliferation, and invasiveness in vitro. IFNA2 also has significant tumor inhibiting effect in vivo. CONCLUSIONS: The ICD-related model can accurately predict the prognosis of patients with EC, and IFNA2 may be a potential treatment target.

Itaconate inhibits corticosterone-induced necroptosis and neuroinflammation via up-regulating menin in HT22 cells.

Corticosterone (CORT) damages hippocampal neurons as well as induces neuroinflammation. The tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis is a form of programmed cell death, also known as inflammatory cell death. Menin is a multifunctional scaffold protein, which deficiency aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation as well as necroptosis and further investigated the mediatory role of Menin in this protective effect of itaconate by using an exposure of CORT to HT22 cells (a hippocampal neuronal cell line). The viability of HT22 cells was examined by the cell counting kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) were evaluated by western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1ß, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL-4, IL-10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis in HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.

Nomogram for Predicting Remission of Metabolic Syndrome 1 Year after Sleeve Gastrectomy Surgery in Chinese Patients with Obesity.

PURPOSE: Sleeve gastrectomy (SG) is a widely used and effective treatment for patients with obesity and comorbid metabolic abnormalities. No specialized tool is available to predict metabolic syndrome (MS) remission after SG. We presented a nomogram that evaluated the probability of MS remission in obese patients 1 year after SG. MATERIALS AND METHODS: Patients with preoperative MS who underwent SG were enrolled in this retrospective study. They were divided into a training set and a validation set. Multivariate logistic regression analysis was performed to identify independent predictors of MS remission, and these predictors were included in the nomogram. Receiver operating characteristic curve was used to evaluate discrimination. Calibration was performed with the Hosmer-Lemeshow goodness-of-fit test. The net benefits of the nomogram were evaluated using decision curve analysis (DCA). RESULTS: Three hundred and eighteen patients with a median age of 34.0 years were analyzed. A training set and a validation set with 159 individuals each were established. A combination of age, preoperative high-density lipoprotein cholesterol, elevated triglycerides and glycated hemoglobin level independently and accurately predicted MS remission. The nomogram included these factors. The discriminative ability was moderate in training and validation sets (Area under curve 0.800 and 0.727, respectively). The Hosmer-Lemeshow X2 value of the nomogram was 8.477 (P = 0.388) for the training set and 5.361 (P = 0.718) for the validation set, indicating good calibration. DCA showed the nomogram had clinical benefits in both datasets. CONCLUSION: Our nomogram could accurately predict MS remission in Chinese patients with obesity 1 year after SG.

Clinicopathological and survival analysis of primary spindle cell carcinoma of the breast in Chinese patients.

Due to the low prevalence of Spindle cell carcinoma (SpCC) of the breast, the perception of the disease was limited. The aim of our study was to analyze the clinicopathological features, survival outcomes and prognostic factors of SpCC of the breast among Chinese. Patients diagnosed with SpCC of the breast in Cancer Hospital of Chinese Academy of Medical Sciences between 2004 to 2021 were retrospectively analyzed. Additionally, we searched Chinese databases and Pubmed websites for literature on breast SpCC in Chinese patients. The clinicalpathological characteristics, survival outcomes and prognostic factors were evaluated. A total of 160 eligible cases were enrolled, including 23 patients in our center and 137 cases from the literature search. The median age was 52 years old (range, 22-88). 84.8% (101/119) cases were in the early stage (stage I and II). 15.0% (20/133) had axillary lymph node involvement. The majority of patients were HR-HER2- (85.4%, 98/137). 77.5% (79/102) patients received adjuvant chemotherapy. 36.9% (31/84) of patients received adjuvant radiation. Of 126 patients available for a median follow-up with 38 (range, 1-211) months, 58 cases (46.0%, 58/126) recurred, including 31.0% (18/58) who had local recurrence and 69.0% (40/58) who had distant metastasis. The most common distant metastatic site was the lung (41.4%, 24/58). Most patients (91.5%) had recurrence within 3 years. The Kaplan-Meier curves showed that the 3-year and 5-year disease-free survival (DFS) were 55.9% and 46.8%, and the 3-year and 5-year overall survival (OS) were 67.0% and 54.9%, respectively. T stage was an independent prognostic factor for OS (T1-2 vs T3-4, HR=0.362, 95% CI: 0.139-0.945, P=0.038). Although SpCC of the breast was often diagnosed in the early stage with low lymph node involvement, the prognosis was poor. T stage was an indicator of prognosis for OS. Better treatments need to be explored to prevent recurrence and improve survival.

The current status and challenges of perioperative management of patients with a BMI of greater than or equal to 50 kg/m 2 undergoing bariatric surgery in China: a multicenter cross-sectional study.

BACKGROUND: Performing bariatric surgery on patients with a BMI of over 50 kg/m 2 is challenging. This study aimed to explore the status and challenges related to the perioperative management of such patients in China. MATERIALS AND METHODS: A prospective survey was designed to investigate the perioperative management of patients with a BMI of greater than or equal to 50 kg/m 2 undergoing bariatric surgery in China. The questionnaire of our survey included general information, preoperative management measures, surgical procedures performed, technical details regarding anaesthesia, and postoperative management measures. A response from only one attending physician per bariatric centre was accepted. RESULTS: Physicians from a total of 101 hospitals responded to the questionnaire, and the questionnaire data from 98 hospitals were complete. These centres had completed a total of 44 702 bariatric surgeries since the launch of such surgery to December 2021. A total of 3280 patients had a BMI exceeding 50 kg/m 2 . The preferred surgical procedures for patients with super obesity were sleeve gastrectomy by 62 centres, Roux-en-Y gastric bypass by 11 centres, sleeve gastrectomy plus jejunojejunal bypass by 19 centres, one anastomosis gastric bypass by 1 centre, and duodenal switch by 1 centre. The most worrying issues were cardiopulmonary failure and difficulty in extubation. 91 centres believed that preoperative weight loss was beneficial. A low-calorie diet was the specific measure mainly implemented, only three centres considered using intragastric balloon placement. Postoperative management measures varied greatly. CONCLUSION: Bariatric surgery has seen rapid development. Chinese physicians show significant differences regarding the perioperative management for patients with a BMI of over 50 kg/m 2 . The perioperative risks of these patients remain relatively high, making further development of clinical pathways is necessary.

Pancreatic Cancer: An Exocrine Tumor with Endocrine Characteristics.

OBJECTIVE: To examine the characteristics of pancreatic cancer patients with long-term survival. BACKGROUND: Although pancreatic cancer is a highly lethal malignancy, a minority of patients experience long-term survival. The characteristics of these patients remain largely unidentified. METHODS: An indolent subgroup was established using carbohydrate antigen 19-9 (CA19-9), which is the best-validated biomarker for pancreatic cancer. Of 1558 patients, 13.9% were included in the CA19-9-normal (≤ 37 U/mL) subgroup. RESULTS: A normal A19-9 level was an independent variable for overall survival (median survival, 18.1 vs. 9.7 months, hazard ratio = 0.53, P < 0.001). The 5-year survival of patients with stage IV CA19-9-normal cancer was higher than that of patients with stage I-IV CA19-9-high cancer (22.4% vs. 6.8%, P = 0.034). The CA19-9-normal subgroup exhibited reduced levels of circulating glucose (P < 0.001) and increased expression of insulin (P < 0.001) compared with the CA19-9-high subgroup. Glucose was a substrate for CA19-9 biosynthesis through the hexosamine biosynthesis pathway. In addition, in pancreatic cancer animal models of diabetes, glucose control decreased CA19-9 levels and improved overall survival. In a clinical trial (NCT05306028) of patients before undergoing major anticancer treatments, glucose control decreased CA19-9 levels in 90.9% of the patients. CONCLUSIONS: CA19-9-normal pancreatic cancer is a strikingly indolent subgroup with low glucose and high insulin. Glucose control is a promising therapeutic strategy for pancreatic cancer.

Efficacy of everolimus-based therapy in advanced triple-positive breast cancer: Experience from three cancer centers in China.

BACKGROUND: Triple-positive breast cancer (TPBC) is highly invasive and lacks well-established treatment strategies, especially in patients with advanced stage disease. This study aimed to explore the efficacy of everolimus in patients with metastatic TPBC (mTPBC) in a multicenter real-world setting. METHODS: A total of 2518 cancer patients who received everolimus-based therapy were enrolled from three cancer institutes in China from 2014 to 2022. Their clinicopathological characteristics were collected from medical records. The indicators for the efficacy of everolimus were progression-free survival (PFS), objective response rate (ORR) and clinical benefit rate (CBR). RESULTS: We collected 79 HER2-enriched patients that were treated with everolimus-based therapy, 43 of whom were mTPBC. The most commonly used therapeutic combinations was everolimus plus endocrine therapy (18/43, 41.9%). Among all combinations, everolimus plus chemotherapy plus trastuzumab developed the longest PFS of 10.9 months (95% CI: 1.5-20.3). Seventeen patients (32.6%) with mTPBC received everolimus as frontline treatment (1 L/2 L/3 L, FL), and 26 patients (67.4%) as backline treatment (>3 L, BL). Among all the population, the median PFS for everolimus was 4.5 months (range: 3.0-6.0), ORR was 30.2%, and CBR was 48.8%. PFSFL of 10.9 months was significantly longer than 4.0 months for PFSBL (p = 0.003, HR = 0.31, 95% CI: 0.14-0.67). ORRFL was 41.2%, showing no significance compared to ORRBL of 23.1% (one-sided p = 0.11). CBRFL was observed better of 76.5% versus CBRBL of 46.2% (one-sided p = 0.026). CONCLUSION: Everolimus as frontline treatment achieves clinical benefits for Chinese patients with mTPBC, which may provide some references for the management of Chinese mTPBC patients.

Safety and efficacy study of oral metronomic capecitabine combined with pyrotinib in HER2-positive metastatic breast cancer: A phase II trial.

PURPOSE: To analyze the safety and efficacy of orally administered metronomic capecitabine plus pyrotinib in HER2 positive metastatic breast cancer (MBC) patients, we conducted a prospective phase II study with a single-arm design. METHODS: HER2 positive patients received oral metronomic capecitabine 500 mg three times a day and pyrotinib 400 mg per day. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR) and safety. RESULTS: The study included 50 patients with MBC that was HER2-positive, while 1 patient was excluded due to nonstandard medication. The median PFS and OS was 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse events included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15(30.6%) patients, including hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). 1 grade 4 adverse event of diarrhea (2.0%) was observed. CONCLUSION: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2 positive metastatic breast cancer patients.

Survival Outcomes and Efficacy of Platinum in Early Breast Cancer Patients with Germline BRCA1 or BRCA2 Mutation: A Multicenter Retrospective Cohort Study.

Purpose: The study aimed to compare the survival outcomes and efficacy of platinum in early breast cancer patients with BRCA1 and BRCA2 mutations. Methods: Patients diagnosed with stage I-III breast cancer and carrying germline pathogenic/likely pathogenic BRCA mutations in three medical institutions in China from April 2016 to January 2021 were retrospectively analyzed. Data on clinical and pathological characteristics, treatment information, pathogenic variants of BRCA, and survival outcomes were collected for all eligible patients. Outcomes: One hundred and sixty-nine patients with BRCA mutations were enrolled, including BRCA1 mutation (53.3%, n = 90) and BRCA2 mutation (46.7%, n = 79). The median age was 39 years, and most patients (68.1%, n = 115) were stage I-II. Patients with BRCA1 mutations were characterized by histological grade III (55.6%) and higher Ki-67 index (Ki-67 ≥ 30%, 78.9%) compared with patients with BRCA2 mutations (27.8%, 58.2%). BRCA1 mutation patients accounted for a significantly higher proportion of triple negative breast cancer than BRCA2 mutation patients (71.1% vs 19.0%, P < 0.0001). A total of 142 (84.0%) patients received neo/adjuvant chemotherapy, including anthracycline and/or taxane-based regimens (55.6%) or platinum-based regimens (27.2%). Median follow-up was 33.2 months. Three-year DFS (disease-free survival) and DRFS (distant recurrence-free survival) had no significant differences between patients with BRCA1 and BRCA2 mutations (82.0% vs 85.4%, P = 0.35; 94.3% vs 94.6%, P = 0.39). The 3-year DFS rate in BRCA1 mutation cohort of patients received platinum regimen was significantly higher than patients received non-platinum regimen (96.0% vs 75.2%, P = 0.01). No differences between DFS and DRFS were observed in patients with BRCA2 mutation received platinum regimen and non-platinum regimen. Conclusion: Similar survival outcomes were observed in early breast cancer patients with BRCA1 and BRCA2 mutation, though they had different biological characteristics. Patients with BRCA1 mutations are more benefit from platinum-regimen. The value of platinum-regimen for early breast cancer patients with BRCA1 and BRCA2 needs to be verified further.

Management and outcomes of gastric leak after sleeve gastrectomy: results from the 2010-2020 national registry.

BACKGROUND: Management of gastric leak after sleeve gastrectomy (SG) is challenging due to its unpredictable outcomes. We aimed to summarize the characteristics of SG leaks and analyze interventions and corresponding outcomes in a real-world setting. METHODS: To retrospectively review of 15,721 SG procedures from 2010 to 2020 based on a national registry. A cumulative sum analysis was used to identify a fitting curve of gastric leak rate. The Kaplan-Meier method and log-rank tests were performed to calculate and compare the probabilities of relevant outcomes. The logistic regression analysis was conducted to determine the predictors of acute leaks. RESULTS: A total of 78 cases of SG leaks were collected with an incidence of 0.5% (78/15,721) from this registry (6 patients who had the primary SG in non-participating centers). After accumulating 260 cases in a bariatric surgery center, the leak rate decreased to a stably low value of under 1.17%. The significant differences presented in sex, waist circumference, and the proportion of hypoproteinemia and type 2 diabetes at baseline between patients with SG leak and the whole registry population ( P = 0.005, = 0.026, <0.001, and = 0.001, respectively). Moreover, 83.1% (59/71) of the leakage was near the esophagogastric junction region. Leakage healed in 64 (88.9%, 64/72) patients. The median healing time of acute and non-acute leaks was 5.93 months and 8.12 months, respectively. Acute leak (38/72, 52.8%) was the predominant type with a cumulative reoperation rate >50%, whereas the cumulative healing probability in the patients who required surgical treatment was significantly lower than those requring non-surgical treatment ( P = 0.013). Precise dissection in the His angle area was independently associated with a lower acute leak rate, whereas preservation ≥2 cm distance from the His angle area was an independent risk factor. CONCLUSIONS: Male sex, elevated waist circumference, hypoproteinaemia, and type 2 diabetes are risk factors of gastric leaks after SG. Optimizing surgical techniques, including precise dissection of His angle area and preservation of smaller gastric fundus, should be suggested to prevent acute leaks.

Epidemiology and clinicopathologic features of breast cancer in China and the United States.

Background: Breast cancer has kept increasing since the past decades and the incidence rate is the highest among all neoplasms nowadays. China, as well as other countries, faces severe burden from the increasing population with breast cancer. This study aimed to analyze the epidemiology and clinicopathologic features of breast cancer in China and the United States (US). Methods: Data of hospitalized patients diagnosed with primary breast cancer between 1 January 1999 and 31 December 2014 in the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) were reviewed. Clinical and demographic data were extracted from medical history systems, and the sixteen-year trends were analyzed. Meanwhile, retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database from 1999 to 2014 were used for comparisons. Results: A total of 18,768 breast cancer patients were included from CHCAMS, China, with 18,685 female cases (99.57%) and 81 male cases (0.43%). A total of 762,954 breast cancer patients were included from the SEER database, US, with 757,357 female cases (99.27%) and 5,597 male cases (0.73%). The peak age of breast cancer was 45-49 years old from 1999 to 2014 in China, while the peak age was 55-59 years from 1999 to 2006 and 60-64 years from 2007 to 2014 in the US. There were more young (<35 years, 6.56% vs. 1.97%, P<0.001), less elderly (≥65 years, 9.99% vs. 40.88%, P<0.001), less stage I (24.93% vs. 48.84%, P<0.001) and more stage III (21.00% vs. 12.35%, P<0.001) breast cancer patients in China than in the US. Patients aged 30-49 years old had a decreased trend (P<0.001), while 55-64 years old patients had an increased trend (P<0.001) from 1999 to 2014 in China, the same trend was also observed in the US. Mucinous carcinoma and histological grade I breast cancer patients increased with age both in China and the US (P<0.001). Conclusions: The unique epidemiology and clinicopathologic features of breast cancer (earlier peak age, more younger patients, more advanced stage, etc.), as well as the typical trend in China, should be seriously recognized, so as to guide future prevention and management strategies.

Safety, Tolerability, and Pharmacokinetics of Senaparib, a Novel PARP1/2 Inhibitor, in Chinese Patients With Advanced Solid Tumors: A Phase I Trial.

BACKGROUND: Senaparib, a novel poly(ADP-ribose) polymerase 1/2 inhibitor, demonstrated antitumor activity in preclinical studies. This phase I, first-in-human, dose-escalation/-expansion study explored the pharmacokinetics, safety and tolerability, and preliminary antitumor activity of senaparib in Chinese patients with advanced solid tumors. PATIENTS AND METHODS: Adults with advanced solid tumors who had failed ³1 line of prior systemic treatment were enrolled. Senaparib (once daily [QD]) dose was escalated from 2 mg until the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) using a modified 3 + 3 design. Dose expansion included: dose groups with ≥1 objective response and one dose higher, as well as those at the MTD/RP2D. Primary objectives were to evaluate the safety and tolerability, and determine the MTD and/or RP2D of senaparib. RESULTS: Fifty-seven patients were enrolled across 10 dose groups (2-120 mg QD, and 50 mg twice daily). No dose-limiting toxicities were observed. The most common senaparib-related adverse events were anemia (80.9%), white blood cell count decreased (43.9%), platelet count decreased (28.1%), and asthenia (26.3%). Senaparib exposure increased dose proportionately at 2-80 mg; absorption saturated at 80-120 mg. Senaparib accumulation was minimal after repeated QD administration (accumulation ratio=1.1-1.5). The objective response rate was 22.7% (n=10/44) overall (all partial responses) and 26.9% (n=7/26) for patients harboring BRCA1/BRCA2 mutations. Disease control rates were 63.6% and 73.1%, respectively. CONCLUSIONS: Senaparib was well tolerated and demonstrated promising antitumor activity in Chinese patients with advanced solid tumors. The RP2D for this clinical study in China was identified as 100 mg QD. CLINICALTRIALS.GOV IDENTIFIER: NCT03508011.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Combined chemo-endocrine therapy as a potential new option for HR+/HER2- advanced breast cancer: a prospective study of fulvestrant plus oral vinorelbine.

OBJECTIVE: Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro. This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) recurrent or metastatic breast cancer. METHODS: Patients were intramuscularly administered fulvestrant 500 mg (day 1 per cycle for 28 days) and oral vinorelbine (60 mg/m2 on days 1, 8, and 15 of each cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, objective response rate, disease control rate, duration of response, and safety. RESULTS: A total of 38 patients with HR+/HER2- advanced breast cancer included in the study were followed up for a median time of 25.1 months. The overall median PFS was 9.86 months [95% confidence interval (CI) 7.2-23.13], and the median PFS of the first-line and the second-line treatment population was 20.73 months (95% CI 9.82 to NR) and 4.27 months (95% CI 3.68 to NR), respectively. Most adverse events reported were of grade 1/2, and none were of grade 4/5. CONCLUSIONS: This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2- recurrent and metastatic breast cancer. The combination chemo-endocrine therapy was efficacious, safe, and promising for patients with HR+/HER2- advanced breast cancer.

Inhibition of Staphylococcus aureus biofilms by poly-L-aspartic acid nanoparticles loaded with Litsea cubeba essential oil.

Staphylococcus aureus (S. aureus) biofilms contamination on various food-contacting surfaces is considered a significant threat in the field of food. Poly-L-aspartic acid (PASP) was proven to damage biofilm by affecting bacterial adhesion, metabolic activity, and extracellular polymeric substances in this study. Especially for eDNA, its generation was reduced by 49.4 %. After treatment with 5 mg/mL of PASP, the number of S. aureus in the biofilm at different growth stages decreased by 1.20-1.68 log CFU/mL. The nanoparticles prepared by PASP and hydroxypropyl trimethyl ammonium chloride chitosan were used to embed LC-EO (EO@PASP/HACCNPs). The results indicated that the particle size of the optimized nanoparticles was 209.84 nm with an encapsulation rate of 70.28 %. Compared to LC-EO alone, EO@PASP/HACCNPs had more significant permeation and dispersion effects on biofilms and possessed long-lasting anti-biofilm activity. For the biofilm grown for 72 h, the population of S. aureus in the EO@PASP/HACCNPs-treated biofilm was additionally reduced by 0.63 log CFU/mL compared with the LC-EO-treated group. EO@PASP/HACCNPs were also applied to different food-contacting materials. The lowest inhibition rate of EO@PASP/HACCNPs on S. aureus biofilm still reached 97.35 %. The sensory properties of the chicken breast were not affected by EO@PASP/HACCNPs.

Targeted metabolomics reveals serum changes of amino acids in mild to moderate ischemic stroke and stroke mimics.

Background: The pathophysiological processes linked to an acute ischemic stroke (IS) can be reflected in the circulating metabolome. Amino acids (AAs) have been demonstrated to be one of the most significant metabolites that can undergo significant alteration after a stroke. Methods: We sought to identify the potential biomarkers for the early detection of IS using an extensive targeted technique for reliable quantification of 27 different AAs based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). A cohort with 216 participants was enrolled, including 70 mild to moderate ischemic stroke patients (National Institutes of Health Stroke Scale < 15, MB group), 76 stroke mimics (MM group) and 70 healthy controls (NC group). Results: It was found that upon comparing MB and MM to control patients, AAs shifts were detected via partial least squares discrimination analysis (PLS-DA) and pathway analysis. Interestingly, MB and MM exhibited similar AAs pattern. Moreover, ornithine, asparagine, valine, citrulline, and cysteine were identified for inclusion in a biomarker panel for early-stage stroke detection based upon an AUC of 0.968 (95% CI 0.924-0.998). Levels of ornithine were positively associated with infract volume, 3 months mRS score, and National Institutes of Health Stroke Scale (NIHSS) score in MB. In addition, a metabolites biomarker panel, including ornithine, taurine, phenylalanine, citrulline, cysteine, yielded an AUC of 0.99 (95% CI 0.966-1) which can be employed to effectively discriminate MM patients from control. Conclusion: Overall, alternations in serum AAs are characteristic metabolic features of MB and MM. AAs could serve as promising biomarkers for the early diagnosis of MB patients since mild to moderate IS patients were enrolled in the study. The metabolism of AAs can be considered as a key indicator for both the prevention and treatment of IS.

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

BACKGROUND: Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients. METHODS: We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers. RESULTS: A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7-93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4-12.9 months) and median OS was 31.0 months (95% CI: 16.5-45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013). CONCLUSIONS: The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC. TRIAL REGISTRATION: ClinicalTrials.gov. (NCT01937689, NCT02361112).