New techniques to identify the tissue of origin for cancer of unknown primary in the era of precision medicine: progress and challenges.

Despite a standardized diagnostic examination, cancer of unknown primary (CUP) is a rare metastatic malignancy with an unidentified tissue of origin (TOO). Patients diagnosed with CUP are typically treated with empiric chemotherapy, although their prognosis is worse than those with metastatic cancer of a known origin. TOO identification of CUP has been employed in precision medicine, and subsequent site-specific therapy is clinically helpful. For example, molecular profiling, including genomic profiling, gene expression profiling, epigenetics and proteins, has facilitated TOO identification. Moreover, machine learning has improved identification accuracy, and non-invasive methods, such as liquid biopsy and image omics, are gaining momentum. However, the heterogeneity in prediction accuracy, sample requirements and technical fundamentals among the various techniques is noteworthy. Accordingly, we systematically reviewed the development and limitations of novel TOO identification methods, compared their pros and cons and assessed their potential clinical usefulness. Our study may help patients shift from empirical to customized care and improve their prognoses.

Targeting non-muscle myosin II inhibits proliferative vitreoretinopathy through regulating epithelial-mesenchymal transition.

Proliferative vitreoretinopathy (PVR) is a common complication of rhegmatogenous retinal detachment, eventually leading to vision loss. To date, there are no effective drugs for the treatment of this disease. In this study, we investigated the effect of blebbistatin, a non-muscle myosin II inhibitor, on the ARPE-19 cell line and in a rabbit model of proliferative vitreoretinopathy. In vitro, we found that blebbistatin inhibited the epithelial-mesenchymal transition of retinal pigment epithelial (RPE) cells and inhibited the ability of RPE cells to migrate, proliferate, generate extracellular matrix, and affect contractility. In vivo the PVR model showed that blebbistatin significantly delayed PVR progression. It also partially prevents the loss of retinal function caused by PVR. Our results suggest that blebbistatin is a potential drug with clinical applications for the treatment of PVR.

Heterogeneity and Adjuvant Therapeutic Approaches in MSI-H/dMMR Resectable Gastric Cancer: Emerging Trends in Immunotherapy.

Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite instability (MSI) has become a major molecular typing approach for gastric cancer. MSI is well recognized for its important role during the immunotherapy of advanced GC. However, its value remains unclear in resectable gastric cancer. The reported incidence of microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) in resectable gastric cancer varies widely, with no consensus reached on the value of postoperative adjuvant therapy in patients with MSI-H/dMMR resectable GC. It has been established that MSI-H/dMMR tumor cells can elicit an endogenous immune antitumor response and ubiquitously express immune checkpoint ligands such as PD-1 or PD-L1. On the basis of these considerations, MSI-H/dMMR resectable GCs are responsive to adjuvant immunotherapy, although limited research has hitherto been conducted. In this review, we comprehensively describe the differences in geographic distribution and pathological stages in patients with MSI-H/dMMR with resectable gastric cancer and explore the value of adjuvant chemotherapy and immunotherapy on MSI-H/dMMR to provide a foothold for the individualized treatment of this patient population.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Sintilimab in Patients with Previously Treated Metastatic Neuroendocrine Neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) are a group of diseases that show high heterogeneity but have limited treatment options. This phase I study evaluated the safety and efficacy of sintilimab, anti-PD-1 monoclonal antibody, in treating advanced NENs. METHODS: We prospectively enrolled patients pathologically diagnosed with NENs after standard treatment failure. Neuroendocrine neoplasms were classified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine cancers (NECs). Every patient received sintilimab, and response was assessed every 9 weeks. RESULTS: Twenty-four patients with a median age of 57.0 years were enrolled from November 2016 to 2017. The median Ki-67 index was 60%. Five patients had NET, 1 had NET G3, 17 had NEC, and 1 had mixed adenocarcinoma-neuroendocrine carcinoma. The most common primary tumor sites were the pancreas and gastrointestinal tract in 7 and 10 patients, respectively. In phase Ia trial, 2 patients received sintilimab 1 mg/kg every 2 weeks, one received 3 mg/kg every 2 weeks, and 21 patients enrolled in the phase Ib trial received 200 mg every 3 weeks. The objective response rate was 20.8% in all enrolled patients and 27.8% in NEC patients. The median progression-free survival was 2.2 and 2.1 months in patients with NET and NEC, respectively. The median OS was not applicable (NA) and 10.8 months (95% CI, 4.3, NA) with NET and NEC, respectively. The duration of response (DOR) was not reached, with a median follow-up time of 20.7 months. Treatment-related adverse events (TRAE) occurred in 17 (70.8%) patients. The most frequent TRAE was thyroid dysfunction (41.7%), and a grade 3 pulmonary infection occurred in 1 patient. The programmed cell death 1-ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) rate was 18.8% (3 out of 16) and the expression of PD-L1 did not correlate with response. CONCLUSION: Sintilimab was well-tolerated and showed encouraging response in NECs. CLINICALTRIALS.GOV IDENTIFIER: NCT02937116.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.

Comparison of short-term surgical outcomes and post-operative recovery between single-incision and multi-port laparoscopic distal gastrectomy for gastric cancer.

Background: To summarise data from previous reports and perform a meta-analysis to compare the short-term surgical outcomes and post-operative recovery between single-incision and multi-port laparoscopic distal gastrectomy (MLDG) for gastric cancer. Methods: A systematic literature search was performed using PubMed and Embase databases and relevant data were extracted. Short-term surgical outcomes and post-operative recovery of single-incision laparoscopic distal gastrectomy (SLDG) and MLDG for gastric cancer were compared using a fixed or random-effect model. Results: In total, we identified five relevant studies involving 983 participants for this systematic review and meta-analysis, and 45.8% (450/983) of patients underwent SLDG. The results demonstrated that mean operation time (weighted mean difference [WMD]:-3.22, 95% confidence interval [CI]: 14.64,8.19, P = 0.580; I2 = 75.6%), intra-operative blood loss (WMD:-19.77, 95% CI: 40.20,0.65, P = 0.058; I2 = 85.0%) and lymph node yield (WMD:-0.71, 95% CI: 1.47, 0.05, P = 0.068; I2 = 0%) of SLDG were comparable to those of MLDG for gastric cancer. In addition, SLDG had a similar incidence of post-operative complications compared with MLDG (odds ratio: 0.82, 95% CI: 0.55-1.22, P = 0.326; I2 = 0%). There was no significant difference between the two surgical procedures for the conversion to open surgery (OR: 0.32, 95%CI: 0.03-3.15, P = 0.331; I2 = 0%), the length of hospital stay (WMD:-0.05, 95% CI: 0.65, 0.55, P = 0.876; I2 = 44.1%), the time to first flatus (WMD:-0.24, 95% CI: 0.58, 0.10, P = 0.169; I2 = 85.3%) and the time to oral intake (WMD:-0.05, 95% CI: 0.20, 0.10, P = 0.500; I2 = 0%). Conclusion: Single-incision laparoscopic gastrectomy may be technically feasible and safe for gastric cancer. However, it did not show a more obvious advantage over MLDG.

Efficacy and safety of sintilimab in combination with chemotherapy in previously untreated advanced or metastatic nonsquamous or squamous NSCLC: two cohorts of an open-label, phase 1b study.

Combining chemotherapy with immunotherapy improves the therapeutic outcome for first-line (1L) patients with advance nonsmall-cell lung cancer (NSCLC). Two cohorts of a phase 1b study (NCT02937116) aimed to evaluate the safety and efficacy of sintilimab, a PD-1 inhibitor, plus chemotherapy in 1L patients with nonsquamous and squamous NSCLC (nsqNSCLC/sqNSCLC); and to identify potential biomarkers for treatment response. Treatment-naïve patients with nsqNSCLC were enrolled and intravenously given sintilimab (200 mg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2), every 3 weeks (Q3W) for 4 cycles in cohort D. Treatment-naïve patients with sqNSCLC were enrolled and intravenously given sintilimab (200 mg), gemcitabine (1250 mg/m2), and cisplatin (75 mg/m2), Q3W, for 6 cycles in cohort E. The primary objective was to evaluate the safety and efficacy of the treatment. The additional objective was to explore biomarkers for the treatment efficacy. Twenty-one patients with nsqNSCLC, and 20 patients with sqNSCLC were enrolled in cohort D and cohort E, respectively. By the data cutoff (April 17, 2019), 8 (38.1%) patients in cohort D and 17 (85.0%) patients in cohort E experienced grade 3-4 adverse events. The median follow-up duration was 16.4 months (14.8-23.0) in cohort D and 15.9 months (11.7-17.7) in cohort E. The objective response rate was 68.4% (95% CI 43.4%, 87.4%) in cohort D and 64.7% (95% CI 38.3%, 85.8%) in cohort E. Neither PD-L1 expression nor tumor mutation burden value was significantly associated with an improved treatment response. Sintilimab plus chemotherapy exhibited manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC.

Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer.

BACKGROUND: The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. METHODS: Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. RESULTS: Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. CONCLUSION: TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC.

TRIM23 overexpression is a poor prognostic factor and contributes to carcinogenesis in colorectal cancer.

The tripartite motif (TRIM) family proteins play a great role in carcinogenesis. However, the expression pattern, prognostic value and biological functions of tripartite motif containing 23 (TRIM23) in colorectal cancer (CRC) are poorly understood. Here, we found that TRIM23 is up-regulated and associated with tumour size, lymph node metastasis, American Joint Committee on Cancer (AJCC) stage and poor prognosis in CRC. Multivariate Cox regression analyses revealed that TRIM23 overexpression could be identified as an independent prognostic factor for CRC. TRIM23 could promote the proliferation of CRC cell in vitro and in vivo; additionally, TRIM23 depletion induced G1-phase arrest. Gene set enrichment analysis (GSEA) revealed that P53 and cell cycle signalling pathway-related genes were enriched in patients with high TRIM23 expression levels. We show in this study that TRIM23 physically binds to P53 and enhances the ubiquitination of P53, thereby promoting tumour proliferation. Thus, our data indicated that TRIM23 acts as an oncogene in colorectal carcinogenesis and may provide a novel therapeutic target for CRC management.

Safety and efficacy of sintilimab combined with oxaliplatin/capecitabine as first-line treatment in patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma in a phase Ib clinical trial.

BACKGROUND: Sintilimab blocks the interaction between programmed death-1 (PD-1) and its ligands. The safety and efficacy of sintilimab combined with oxaliplatin/capecitabine (CapeOx) as first-line treatment were evaluated in patients with gastric (G)/gastroesophageal junction (GEJ) adenocarcinoma in a phase Ib clinical trial. METHODS: Patients with locally advanced or metastatic G/GEJ adenocarcinoma without previous systemic treatment were enrolled as one cohort of a multi-cohort study. Sintilimab was administered at a dose of 200 mg intravenously (IV) in combination with CapeOx (1000 mg/m2 capecitabine orally, bid, D1-14 and 130 mg/m2 oxaliplatin IV, D1) every 21 days for up to 6 cycles. After combination treatment, patients continued to receive sintilimab (200 mg) at 3 weekly intervals as maintenance therapy until progressive disease (PD), unacceptable toxicity, withdrawal of informed consent, or for up to 24 months. Adverse events (AEs) were monitored to assess safety in terms of their frequency, intensity and causality. The efficacy endpoints included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Tumor mutation burden (TMB) was evaluated for its association with clinical response. RESULTS: A total of 20 patients were enrolled and received sintilimab plus CapeOx. All patients reported treatment-related AEs (TRAEs). Grade 3-4 TRAEs were found in 11 (55.0%) patients. Seventeen patients obtained partial response and the ORR was 85.0% (95% CI: 62.1-96.8%). Three (15.0%) had stable disease and DCR was 100.0% (95% CI: 83.2-100.0%). As data cutoff of May 1, 2019, the median follow-up was 7.8 months. The median PFS was 7.5 months (95% CI: 6.2-9.4) and median OS had not been reached. The OS rates at 6 months and 12 months were 100.0 and 68.0%. No association was observed between TMB and efficacy. CONCLUSIONS: Sintilimab combined with CapeOx as first-line treatment demonstrated acceptable safety and promising efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02937116 . Registered 8 October 2016.

Hyaluronidase Enzyme-responsive Targeted Nanoparticles for Effective Delivery of 5-Fluorouracil in Colon Cancer.

PURPOSE: In this study, we have successfully prepared the hyaluronic acid (HA)-conjugated mesoporous silica nanoparticles loaded with 5-fluorouracil (5-FU) to increase the anticancer efficacy in colon cancers. METHODS: The particles were nanosized and perfectly spherical. In vitro release kinetics clearly showed the enzyme-sensitive release of 5-FU from HA-conjugated 5-FU loaded mesoporous silica nanoparticles (HA/FMSN). RESULTS: The presence of HA on the surface of nanoparticles targeted the CD44 receptors overexpressed in the colon cancer cells In vitro cell viability and apoptosis assay clearly showed the superior anticancer effect of HA/FMSN in HT29 colon cancer cells. HA/FMSN exhibited a remarkably higher 43% of cells in early apoptosis phase and 55% of cells in late apoptosis phase indicating the superior anticancer effect of HA/FMSN. HA/FMSN exhibited a significant reduction in the tumor burden compared to that of any group. HA/FMSN was 3-fold more effective than free drug and 2-fold more effective than -FU loaded mesoporous silica nanoparticles (FMSN). CONCLUSIONS: Overall, results suggest that the novel delivery strategy could hold enormous potential in colon cancer targeting.

microRNA-577 suppresses tumor growth and enhances chemosensitivity in colorectal cancer.

In this work, we aimed to determine the expression and biological functions of microRNA (miR)-577 in colorectal cancer (CRC). The results showed that miR-577 was downregulated in CRC specimens and cell lines. Restoration of miR-577 significantly suppressed the proliferation and colony formation and induced a G0/G1 cell cycle arrest in CRC cells. 5-Fluorouracil (5-FU)-resistant SW480 cells (SW480/5-FU) were found to have elevated levels of miR-577. Ectopic expression of miR-577 enhanced 5-FU sensitivity in SW480/5-FU cells. Heat shock protein 27 (HSP27) was identified as a target gene of miR-577. Enforced expression of HSP27 reversed the effects of miR-577 on CRC cell growth and 5-FU sensitivity. Xenograft tumors derived from miR-577-overexpressing SW480 cells exhibited significantly slower growth than control tumors. In conclusion, our results support that miR-577 acts as a tumor suppressor in CRC likely through targeting HSP27. Therefore, miR-577 may have therapeutic potential in the treatment of CRC.

Cilostazol induces mitochondrial fatty acid ß-oxidation in C2C12 myotubes.

Cilostazol is a drug licensed for the treatment of intermittent claudication. Its main action is to elevate intracellular levels of cyclic monophosphate (cAMP) by inhibiting the activity of type III phosphodiesterase, a cAMP-degrading enzyme. The effects of cilostazol on fatty acid oxidation (FAO) are as yet unknown. In this study, we report that cilostazol can elevate complete FAO and decrease both triacylglycerol (TAG) accumulation and TAG secretion. This use of cilostazol treatment increases expression of PGC-1α and, subsequently, its target genes, such as ERRα, NOR1, CD36, CPT1, MCAD, and ACO. Expression of these factors is linked to fatty acid ß-oxidation but this effect is inhibited by H-89, a specific inhibitor of the PKA/CREB pathway. Importantly, knockdown of PGC-1α using siRNA abolished the effects of cilostazol in fatty acid oxidation (FAO) and TAG metabolism. These findings suggested that the PKA/CREB/PGC-1α pathway plays a critical role in cilostazol-induced fatty acid oxidation and TAG metabolism.

A retrospective study of adjuvant albumin-bound paclitaxel plus S-1 after D2 gastrectomy versus oxaliplatin plus S-1 in gastric cancer.

Adjuvant oxaliplatin plus S-1 (SOX) chemotherapy for gastric cancer (GC) after D2 gastrectomy has been proven effective. There has yet to be a study that evaluates adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1. In this single-center, retrospective study, GC patients after D2 gastrectomy received either nab-paclitaxel plus S-1 (AS group) or SOX group were recruited between January 2018 and December 2020 in The First Affiliated Hospital of Zhejiang University. Intravenous nab-paclitaxel 120 mg/m2 or 260 mg/m2 and oxaliplatin 130 mg/m2 were administered as eight 3 week cycle, especially in the AS and SOX group. Patients received S-1 twice daily with a dose of 40 mg/m2 in the two groups on days 1-14 of each cycle. The end points were disease-free survival (DFS) rate at 3 years and adverse events (AEs). There were 56 eligible patients, 28 in the AS group and 35 in the SOX group. The 3 year DFS rate was 78.0% in AS group versus 70.7% in SOX group (p = 0.46). Subgroup analysis showed that the patients with signet-ring positive in the AS group had a prolonged DFS compared with the SOX group (40.0 vs. 13.8 m, p = 0.02). The diffuse-type GC or low differentiation in the AS group was associated with numerically prolonged DFS compared with the SOX group, but the association was not statistically significant (p = 0.27 and p = 0.15 especially). Leukopenia (14.3%) were the most prevalent AEs in the AS group, while thrombocytopenia (28.5%) in the SOX group. Neutropenia (7.1% in AS group) and thrombocytopenia (22.8% in SOX group) were the most common grade 3 or 4 AEs. In this study analyzing past data, a tendency towards a greater 3 year DFS was observed when using AS regimen in signet-ring positive patients. AS group had fewer thrombocytopenia compared to SOX group. More studies should be conducted with larger sample sizes.

Application of a modified lateral thoracic artery perforator flap in partial breast defects.

Background: Breast cancer has become the most frequently diagnosed cancer in the world. Detection at an early stage, frequently allows women to benefit from breast conserving surgery. However, some patients are not satisfied with the breast shape after breast-conserving surgery, and autologous tissue flaps are needed to fill the defect in the resection area. The modified lateral thoracic artery perforator (LTAP) flap isn't one of the commonly used flaps in breast surgery and has the advantages of a reliable blood supply, simple operation and few postoperative complications. In this study, we aimed to evaluate the feasibility and effectiveness of a modified LTAP flap for repairing partial breast defects after breast-conserving surgery. Methods: In this study, we retrospectively analyzed the clinical data of 126 patients treated with LTAP flaps to repair local breast defects at Affiliated Hospital of Guangdong Medical University between January 2020 and June 2021. Data were collected on the demographic characteristics of these patients, tumor size and location, type of axillary lymph node surgery, availability of adjuvant chemotherapy and radiotherapy, and postoperative complications. Results: The median weight of the tumor specimen was 185 g (range, 170-320 g), and this glandular tissue accounted for 30% to 40% of the total breast volume. The average flap size was 10.5 cm ×2.5 cm (length range, 8-15 cm, width range: 2-4 cm). The minimum follow-up time was 6 months, with an average of 10 months (range, 6-22 months). The mean operative time was 130 minutes (range: 90-180 minutes), and the mean hospital stay was 3 days (range, 2-5 days). All modified LTAP flaps survived completely without donor site complications. None of the patients required revision surgery on the postoperative breast. Conclusions: The modified LTAP flap is a reliable method for repairing partial breast defects after breast-conserving surgery. It has the advantages of a simple operation, a reliable blood supply, fewer postoperative complications, and a high flap survival rate. It is especially suitable for Asian women with small breast volumes and can achieve good breast contouring effects.

Functional mouse hepatocytes derived from interspecies chimeric livers effectively mitigate chronic liver fibrosis.

Liver disease is a major global health challenge. There is a shortage of liver donors worldwide, and hepatocyte transplantation (HT) may be an effective treatment to overcome this problem. However, the present approaches for generation of hepatocytes are associated with challenges, and interspecies chimera-derived hepatocytes produced by interspecies blastocyst complementation (IBC) may be promising donor hepatocytes because of their more comprehensive hepatic functions. In this study, we isolated mouse hepatocytes from mouse-rat chimeric livers using IBC and found that interspecies chimera-derived hepatocytes exhibited mature hepatic functions in terms of lipid accumulation, glycogen storage, and urea synthesis. Meanwhile, they were more similar to endogenous hepatocytes than hepatocytes derived in vitro. Interspecies chimera-derived hepatocytes could relieve chronic liver fibrosis and reside in the injured liver after transplantation. Our results suggest that interspecies chimera-derived hepatocytes are a potentially reliable source of hepatocytes and can be applied as a therapeutic approach for HT.

Neutrophil Extracellular Traps-Inhibiting and Fouling-Resistant Polysulfoxides Potently Prevent Postoperative Adhesion, Tumor Recurrence, and Metastasis.

Peritoneal metastasis (PM) is considered one of the most dreaded forms of cancer metastases for both patients and physicians. Aggressive cytoreductive surgery (CRS) is the primary treatment for peritoneal metastasis. Unfortunately, this intensive treatment frequently causes clinical complications, such as postoperative recurrence, metastasis, and adhesion formation. Emerging evidence suggests that neutrophil extracellular traps (NETs) released by inflammatory neutrophils contribute to these complications. Effective NET-targeting strategies thus show considerable potential in counteracting these complications but remain challenging. Here, one type of sulfoxide-containing homopolymer, PMeSEA, with potent fouling-resistant and NET-inhibiting capabilities, is synthesized and screened. Hydrating sulfoxide groups endow PMeSEA with superior nonfouling ability, significantly inhibiting protein/cell adhesion. Besides, the polysulfoxides can be selectively oxidized by ClO- which is required to stabilize the NETs rather than H2O2, and ClO- scavenging effectively inhibits NETs formation without disturbing redox homeostasis in tumor cells and quiescent neutrophils. As a result, PMeSEA potently prevents postoperative adhesions, significantly suppresses peritoneal metastasis, and shows synergetic antitumor activity with chemotherapeutic 5-Fluorouracil. Moreover, coupling CRS with PMeSEA potently inhibits CRS-induced tumor metastatic relapse and postoperative adhesions. Notably, PMeSEA exhibits low in vivo acute and subacute toxicities, implying significant potential for clinical postoperative adjuvant treatment.

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients.

OBJECTIVE: Inhibition of fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling demonstrates potent anticancer activity. EVER4010001 is a highly selective FGFR4 inhibitor and pembrolizumab is approved for the treatment of several solid tumors. This study determined the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors. METHODS: This Phase 1, multicenter, open-label study enrolled 19 Asian-Chinese patients (57.9% male: median age 58 years) with advanced solid tumors. For "3+3" dose escalation, 3-6 patients received treatment at each dose level (EVER4010001 40, 60, 80, or 100 mg twice daily [BID] plus pembrolizumab 200 mg every 3 weeks). RESULTS: At the data cutoff (August 12, 2021), no dose-limiting toxicities (DLTs) were reported at 40 mg-80 mg. At 100 mg, 2 (40.0%) patients had 3 DLTs within the 28-day DLT observation period after first administration. Median time to peak EVER4010001 concentration (Tmax ) was 0.55-1.03 hours. Mean terminal EVER4010001 half-life (T1/2 ) was 4.00-4.92 hours. The area under the concentration-time curve (AUC0-t ) and maximum observed concentration (Cmax ) ranged from 2370.87-5475.77 hour*ng/ml and 606.07-1348.86 ng/ml, respectively. The most common EVER4010001-related treatment-emergent adverse events were diarrhea (94.7%), increased aspartate aminotransferase (57.9%), and increased alanine aminotransferase (47.4%). CONCLUSION: Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.

In vitro study of piwi interaction RNA-31106 promoting breast carcinogenesis by regulating METTL3-mediated m6A RNA methylation.

Background: Breast cancer is the most common gynecological malignancy and the leading cause of cancer-related deaths in women. P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are novel non-coding RNAs whose abnormal expressions have been closely associated with multiple cancers. This study explored the roles and possible mechanisms of piRNA-31106 in breast cancer. Methods: The expression of piRNA-31106 in breast cancer tissues and cells was detected by reverse transcription polymerase chain reaction (RT-PCR). The pcDNA vector containing piRNA-31106 (pcDNA-piRNA-31106) and a short hairpin (sh)RNA containing piRNA-31106 (shRNA-piRNA-31106) were used to interfere with piRNA-31106 expression in breast cancer cells. The effects on cell proliferation, apoptosis/cell cycle, invasion, and metastasis were detected via Cell Counting Kit-8 (CCK-8), flow cytometry, transwell assays, and scratch tests, respectively. The protein expressions of murine double minute 2 (MDM2), cyclin-dependent kinase 4 (CDK4), and cyclinD1 were detected by Western blot analysis. The N6-methyladenosine (m6A) RNA methylation level and the binding relationship between piRNA-31106 and METTL3 were analyzed. The role of METTL3 in the regulation of breast cancer by piRNA-31106 was further analyzed by using small interfering (si)RNA targeting METTL3. Results: PiRNA-31106 was highly expressed in breast cancer tissues and cell lines MDA-MB-231 and MCF-7. Overexpression of piRNA-31106 promoted the viability, invasion, and migration of breast cancer, inhibited apoptosis, and promoted the expressions of MDM2, CDK4, and cyclinD1. Inhibition of piRNA-31106 showed the opposite effect. In addition, piRNA-31106 promoted the m6A methylation levels and facilitated methyltransferase-like 3 (METTL3) expression in MDA-MB-231 and MCF-7 cells. RNA immunoprecipitation (RIP) assays confirmed the binding relationship between piRNA-31106 and METTL3. Further experiments demonstrated that si-METTL3 could inhibit the regulatory effects of piRNA-31106 on breast cancer. Conclusions: PiRNA-31106 was significantly highly expressed in breast cancer and could promote breast cancer progression by regulating METTL3-mediated m6A RNA methylation.