Comprehensive Analyses of PANoptosome with Potential Implications in Cancer Prognosis and Immunotherapy.

Cell death resistance significantly contributes to poor therapeutic outcomes in various cancers. PANoptosis, a unique inflammatory programmed cell death (PCD) pathway activated by specific triggers and regulated by the PANoptosome, possesses key features of apoptosis, pyroptosis, and necroptosis, but these cannot be accounted for by any of the three PCD pathways alone. While existing studies on PANoptosis have predominantly centered on infectious and inflammatory diseases, its role in cancer malignancy has been understudied. In this comprehensive investigation, we conducted pan-cancer analyses of PANoptosome component genes across 33 cancer types. We characterized the genetic, epigenetic, and transcriptomic landscapes, and introduced a PANoptosome-related potential index (PANo-RPI) for evaluating the intrinsic PANoptosome assembly potential in cancers. Our findings unveil PANo-RPI as a prognostic factor in numerous cancers, including KIRC, LGG, and PAAD. Crucially, we established a significant correlation between PANo-RPI and tumor immune responses, as well as the infiltration of diverse lymphoid and myeloid cell subsets across nearly all cancer types. Moreover, a high PANo-RPI was consistently associated with improved immunotherapy response and efficacy, as evidenced by re-analysis of multiple immunotherapy cohorts. In conclusion, our study suggests that targeting PANoptosome components and modulating PANoptosis may hold tremendous therapeutic potential in the context of cancer.

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild-Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial.

PURPOSE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two-group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver-limited metastases (CLM) and BRAF/RAS wild-type. PATIENTS AND METHODS: Patients were enrolled to receive cetuximab (500 mg/m2 ) plus mFOLFOXIRI (oxaliplatin 85 mg/m2 , irinotecan 165 mg/m2 , folinic acid 400 mg/m2 , 5-fluorouracil 2,800 mg/m2 46-hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety. RESULTS: Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%-48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%-36.4%; p = .010) compared with those in control group. Progression-free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups. CONCLUSION: Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM. IMPLICATIONS FOR PRACTICE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver-limited metastases and BRAF/RAS wild-type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression-free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver-limited metastasis.

Comparison of pathological outcomes after transanal versus laparoscopic total mesorectal excision: a prospective study using data from randomized control trial.

INTRODUCTION: Total mesorectal excision (TME) is the standard procedure for middle lower rectal cancer, and transanal total mesorectal excision (taTME) was founded as a valid alternative to the open and laparoscopic TME. The quality of the procedure performed is important for prognosis of patients. This study was designed to compare the pathological results of taTME with those of laparoscopic TME (laTME), based on the data from a randomized control trial (RCT: NCT02966483). METHODS: Between April 2016 and November 2018, all rectal cancer patients who underwent taTME or laTME in the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) and enrolled in the RCT were included in this study. The data from all participants were prospectively input in a standardized database. RESULTS: In total 128 patients were included in the taTME group and 133 patients were included in the laTME group. The demographics and tumor characteristics were not significantly different between the two group. T3 or N0 lesions were most common in both groups. The mesorectum specimen was complete or nearly complete in all patients. The positive distal resection margin (DRM) was detected in 2 (1.5%) cases in the laTME group versus no cases in the taTME group (P = 0.498), and the distance between the tumor and DRM in the taTME group (1.4 ± 1.1) may have the longer tendency than that in the laTME group (1.3 ± 0.9) (P = 0.745). The positive circumferential resection margin was detected in 2 cases in each group (P = 0.674). The median number of resected lymph nodes was 15.0 in taTME group versus 16.0 in the laTME group (P = 0.069). CONCLUSION: The pathological outcomes between transanal and laparoscopic total mesorectal excision are similar. The rate of positive resection margin could not be significant decreased, nonetheless the decrease trend could be shown.

Evaluation of postoperative pain after tonsil-sparing styloidectomy.

PURPOSE: Styloidectomy is the mainstream treatment for Eagle's syndrome when conservative treatment fails. However, the clinical efficacy of tonsil-sparing styloidectomy remains controversial. This study aimed to evaluate postoperative pain after tonsil-sparing styloidectomy in patients with Eagle's syndrome. METHODS: This retrospective study enrolled 14 patients who underwent tonsil-sparing styloidectomy (TSS group) and 22 patients who underwent traditional tonsillect-styloidectomy (TTS group). Pain was evaluated using the 11-point numeric rating scale (NRS-11) at the following time points: on admission, 1 day after the operation, 3 days, postoperatively, 1 week postoperatively, 2 weeks, postoperatively, and 3 months, postoperatively. RESULTS: The postoperative course was uneventful in both groups. Pain with movement was significantly reduced 3 months, postoperatively (1.28 ± 1.1), compared with the preoperative baseline level (4.78 ± 0.9) (P < 0.001). There was no significant difference in the rate at which pain decreased between the TSS group (n = 9/14; 64.3%) and the TTS group (n = 17/22; 77.3%) (P = 0.396). One week postoperatively, resting pain in the TSS group (4.36 ± 0.7) was significantly lower than that in the TTS group (5.41 ± 0.8) (P = 0.001); pain with movement in the TSS group (5.00 ± 0.8) was significantly lower than that in the TTS group (5.86 ± 0.7) (P = 0.002). Two weeks postoperatively, resting pain in the TSS group (1.14 ± 0.4) was also significantly lower than that in the TTS group (1.73 ± 0.6) (P = 0.003). CONCLUSIONS: Tonsil-sparing styloidectomy is a safe and effective modality for treating Eagle's syndrome. Although there was no significant difference in surgical risk or long-term outcomes between tonsil-sparing styloidectomy and traditional tonsillect-styloidectomy, tonsil-sparing styloidectomy can alleviate perioperative pain.

Epigenetic silencing of TPM2 contributes to colorectal cancer progression upon RhoA activation.

Beta-tropomyosin (ß-tropomyosin, TPM2) has been found to be downregulated in colorectal cancer (CRC) in previous studies. In this study, we aimed to investigate the mechanisms and potential biological consequences of the downregulation of TPM2 in colorectal cancer. TPM2 expression in colorectal cancer was assessed by qRT-PCR and immunostaining. The biological functions of TPM2 were assessed in cell lines either overexpressing or underexpressingTPM2. Aberrant DNA methylation in the promoter region is associated with suppression of TPM2 expression in primary colorectal cancer tissue samples. Treatment with the demethylation agent 5-AZA can induceTPM2 expression in colorectal cancer cell lines. Reconstitution of TPM2 suppresses cell proliferation and migration in colorectal cancer cell lines, whereas the loss of TPM2 expression is associated with increased tumor proliferation and migration in vitro, which was accompanied by RhoA activation. In summary, our findings indicate that TPM2 appears to be commonly silenced by aberrant DNA methylation in colon cancer. TPM2 loss is associated with RhoA activation and tumor proliferation.

Application and comparison of different implanted ports in malignant tumor patients.

BACKGROUND: The current study aims to compare the application and convenience of the upper arm port with the other two methods of implanted ports in the jugular vein and the subclavian vein in patients with gastrointestinal cancers. METHODS: Currently, the standard of practice is placement of central venous access via an internal jugular vein approach. Perioperative time, postoperative complications, and postoperative comfort level in patients receiving an implanted venous port in the upper arm were retrospectively compared to those in the jugular vein and the subclavian vein from April 2013 to November 2014. RESULTS: Three hundred thirty-four patients are recruited for this analysis, consisting of 107 in the upper arm vein group, 70 in the jugular vein group, and 167 in the subclavian vein group. The occurrence of catheter misplacement in the upper arm vein is higher than that in the other two groups (13.1 vs. 2.9 vs. 5.4 %, respectively, P = 0.02), while the other complications in the perioperative period were not significantly different. The occurrence of transfusion obstacle of the upper arm vein group is significantly lower than that of the jugular and subclavian groups (0.9 vs. 7.1 vs. 7.2 %, P = 0.01). The occurrence of thrombus is also lower than that of other two groups (0.9 vs. 4.3 vs. 3.6 %, P = 0.03). Regarding the postoperative comfort, the influences of appearance (0 vs. 7.1 vs. 2.9 %, P = 0.006) and sleep (0.9 vs. 4.2 vs. 10.7 %, P = 0.003) are significantly better than those of the jugular and subclavian vein groups. CONCLUSIONS: Compared to the jugular and the subclavian vein groups, the implanted venous port in the upper arm vein has fewer complications and more convenience and comfort, and might be a superior novel choice for patients requiring long-term chemotherapy or parenteral nutrition.

Dysregulation of phosphoenolpyruvate carboxykinase in cancers: A comprehensive analysis.

BACKGROUND: Phosphoenolpyruvate carboxykinase (PEPCK) plays a crucial role in gluconeogenesis, glycolysis, and the tricarboxylic acid cycle by converting oxaloacetate into phosphoenolpyruvate. Two distinct isoforms of PEPCK, specifically cytosolic PCK1 and mitochondrial PCK2, have been identified. Nevertheless, the comprehensive understanding of their dysregulation in pan-cancer and their potential mechanism contributing to signaling transduction pathways remains elusive. METHODS: We conducted comprehensive analyses of PEPCK gene expression across 33 diverse cancer types using data from The Cancer Genome Atlas (TCGA). Multiple public databases such as HPA, TIMER 2.0, GEPIA2, cBioPortal, UALCAN, CancerSEA, and String were used to investigate protein levels, prognostic significance, clinical associations, genetic mutations, immune cell infiltration, single-cell sequencing, and functional enrichment analysis in patients with pan-cancer. PEPCK expression was analyzed about different clinical and genetic factors of patients using data from TCGA, GEO, and CGGA databases. Furthermore, the role of PCK2 in Glioma was examined using both in vitro and in vivo experiments. RESULTS: The analysis we conducted revealed that the expression of PEPCK is involved in both clinical outcomes and immune cell infiltration. Initially, we verified the high expression of PCK2 in GBM cells and its role in metabolic reprogramming and proliferation in GBM. CONCLUSION: Our study showed a correlation between PEPCK (PCK1 and PCK2) expression with clinical prognosis, gene mutation, and immune infiltrates. These findings identified two possible predictive biomarkers across different cancer types, as well as a comprehensive analysis of PCK2 expression in various tumors, with a focus on GBM.

The Relationship Between Jugular Foramen Schwannoma and Surrounding Membrane Structures and Its Surgical Application.

BACKGROUND AND OBJECTIVES: Surgical resection of jugular foramen (JF) schwannomas with minimal neurological complications is challenging because of their difficult-to-access location and complex relationships with surrounding neurovascular structures, even for experienced neurosurgeons. In this article, we elucidate the membranous anatomy of JF schwannomas, with the aim of reducing iatrogenic injury to the lower cranial nerves (LCNs) during surgery. METHODS: The clinical data of 31 consecutive patients with JF schwannomas were reviewed. The relationship between the tumor and the surrounding membranous structures was observed during dissection. Samples were analyzed using Masson's trichrome and immunofluorescence staining to study the membranous characteristics. Histological-radiographic correlations were also summarized. RESULTS: In this series, we found that all 3 type B, 2 type C, and 8 type D tumors (according to the Kaye-Pellet grading system) were entirely extradural in location, whereas the 18 type A tumors could be subdural (9 cases) or extradural (9 cases), which frequently could not be predicted preoperatively based on whether the tumor had intraforaminal extension. The dural capsule, when present, could be used as an insulating layer to protect LCNs. With this subcapsular dissection technique, postoperative LCN dysfunction occurred in 10 patients (32.3%), which was usually temporary and mild. CONCLUSION: The different relationships between the tumor and membranous structures of the JF is related to the distinct point of tumor origin and the complex anatomy of the meningeal dura within the JF. Subcapsular dissection technique is recommended for better preservation of LCNs when the dural capsule is identified.

Effects of tumour budding on adjuvant chemotherapy in colorectal cancer.

BACKGROUND: High tumour budding has been indicated as a risk factor of poor survival in colorectal cancer. This study aimed to investigate the impact of tumour budding grades and the use of adjuvant chemotherapy on prognosis in patients with colorectal cancer. METHODS: This study included consecutive colorectal cancer patients who underwent radical surgery for primary colorectal adenocarcinoma at The Sixth Hospital of Sun Yat-sen University between 2009 and 2019. Tumour budding was assessed based on the recommendations of the International Tumor Budding Consensus Conference using haematoxylin and eosin (H&E)-stained slides with tumour samples. The primary outcome of interest was to correlate tumour budding with disease-free survival and overall survival; the secondary outcome was investigation of the impact of adjuvant therapy on different tumour budding grades. In addition, a subgroup analysis was performed for the effects of lymphocytic infiltration on adjuvant chemotherapy in patients with Bd3. RESULTS: Of 709 eligible patients, 412 with colorectal cancer were included. According to the International Tumor Budding Consensus Conference, 210 (50.9 per cent), 127 (30.8 per cent) and 75 (18.2 per cent) were classified as low budding (Bd1), intermediate budding (Bd2) and high budding (Bd3) respectively. Patients with Bd1, Bd2 and Bd3 had 5-year disease-free survival rates of 82.9 per cent, 70.1 per cent and 49.3 per cent respectively, and 5-year overall survival rates of 90 per cent, 79.5 per cent and 62.7 per cent respectively (P <0.001). Adjuvant chemotherapy yielded a significant survival benefit in patients with Bd3 (5-year disease-free survival, 65 per cent versus 31.4 per cent, P <0.001; 5-year overall survival, 84.4 per cent versus 63.1 per cent, P <0.001), but not in those with Bd1 or Bd2. In patients with Bd3, the benefit of adjuvant chemotherapy was maintained in those with low, but not high lymphocytic infiltration. CONCLUSION: High grade of tumour budding was strongly correlated with poorer survival outcomes in colorectal cancer. Patients with Bd3 benefited from adjuvant chemotherapy, with the exclusion of patients with high lymphocytic infiltration.

Evaluation of transrectal ultrasound-guided tru-cut biopsy as a complementary method for predicting pathological complete response in rectal cancer after neoadjuvant treatment: a phase II prospective and diagnostic trial.

IMPORTANCE: Patients with pathological complete response (pCR) of rectal cancer following neoadjuvant treatment had better oncological outcomes. However, reliable methods for accurately predicting pCR remain limited. OBJECTIVE: To evaluate whether transrectal ultrasound-guided tru-cut biopsy (TRUS-TCB) adds diagnostic value to conventional modalities for predicting pathological complete response in patients with rectal cancer after neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated data of patients with rectal cancer who were treated with neoadjuvant treatment and reassessed using TRUS-TCB and conventional modalities before surgery. This study is registered with ClinicalTrials.gov. MAIN OUTCOMES AND MEASURES: The primary outcome was accuracy, along with secondary outcomes including sensitivity, specificity, negative predictive value, and positive predictive value in predicting tumour residues. Final surgical pathology was used as reference standard. RESULTS: Between June 2021 and June 2022, a total of 74 patients were enroled, with 63 patients ultimately evaluated. Among them, 17 patients (28%) exhibited a complete pathological response. TRUS-TCB demonstrated an accuracy of 0.71 (95% CI, 0.58-0.82) in predicting tumour residues. The combined use of TRUS-TCB and conventional modalities significantly improved diagnostic accuracy compared to conventional modalities alone (0.75 vs. 0.59, P =0.02). Furthermore, TRUS-TCB correctly reclassified 52% of patients erroneously classified as having a complete clinical response by conventional methods. The occurrence of only one mild adverse event was observed. CONCLUSIONS AND RELEVANCE: TRUS-TCB proves to be a safe and accessible tool for reevaluation with minimal complications. The incorporation of TRUS-TCB alongside conventional methods leads to enhanced diagnostic performance.

Lighting a Fire: Gasdermin-Mediated Pyroptosis Remodels the Glioma Microenvironment and Promotes Immune Checkpoint Blockade Response.

Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and "pRRophetic" package in R were used to estimate temozolomide (TMZ) sensitivity. The "Submap" package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma.

Background: Pyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas. Methods: The TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated. Results: Patients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas. Conclusion: The pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.

mFOLFOXIRI with or without bevacizumab for conversion therapy of RAS/BRAF/PIK3CA mutant unresectable colorectal liver metastases: the FORBES non-randomized phase II trial.

Background: The aim of this non-randomized single-center phase II trial was to prospectively assess the clinical efficacy of triplet chemotherapy with modified 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (mFOLFOXIRI) plus bevacizumab as conversion therapy for initially unresectable rat sarcoma viral oncogene homolog (RAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/phosphatidylinositol-3 kinase catalytic alpha (PIK3CA) mutant colorectal liver-limited metastases (CRLMs). Methods: Patients with RAS/BRAF/PIK3CA mutant initially unresectable CRLMs were recruited at a ratio of 2:1 to receive mFOLFOXIRI plus bevacizumab (experimental group) or mFOLFOXIRI alone (control group). The rate of patients attaining no evidence of disease (NED) was the primary endpoint. The secondary endpoints included objective response rate (ORR), depth of tumor response (DpR), secondary resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: The rate of NED achieved was 40.7% and 30.8%, respectively, in the experimental (n=54) and control groups (n=26); the adjusted odds ratio was 4.519 [95% confidence interval (CI): 1.247-16.375, P=0.022]. The ORR was 77.4% in the experimental group and 60.0% in the control group (P=0.112). The median DpR was significantly greater in the experimental group (45.6% vs. 34.9%, P=0.041). The median PFS was 12.6 months in the experimental group and 9.1 months in the control group [adjusted hazard ratio (HR): 0.584, 95% CI: 0.304-1.121, P=0.106]. Median OS was prolonged in the experimental group compared with the control group (42.6 vs. 35.3 months, adjusted HR: 0.443, 95% CI: 0.195-1.006, P=0.052). Thirty patients (55.6%) in the experimental group and 16 (61.5%) in the control group experienced grade 3/4 adverse events. Conclusions: We observed that the combination of mFOLFOXIRI and bevacizumab increased the rate of clinical NED and showed a trend toward improved survival compared with mFOLFOXIRI alone. This could represent a conversion therapy option for fit patients with initially unresectable RAS/BRAF/PIK3CA mutant CRLMs.

Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial.

BACKGROUND: PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. METHODS: The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS: Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8-17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. INTERPRETATION: Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. FUNDING: The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Tracheal window resection and reconstruction via sternocleidomastoid flap for invasive thyroid carcinoma.

OBJECTIVES: The aim of this study was to present surgical techniques and evaluate outcomes of a sternocleidomastoid muscle (SCM) myoperiosteal flap used for the reconstruction of tracheal or laryngotracheal defects after the radical resection of invasive thyroid carcinoma. METHODS: A retrospective study was performed for patients at Peking Union Medical College Hospital from January 2008 to December 2018 of papillary thyroid carcinoma with tracheal or laryngotracheal invasion. Patients were enrolled only when they received window resection and reconstruction via an SCM myoperiosteal flap. The primary outcome was a stable airway, and the secondary outcome was survival. RESULTS: A total of 15 invasive thyroid carcinoma patients were enrolled in this study. Laryngotracheal and tracheal reconstruction were performed in 11 and 4 patients respectively, with a median vertical defect of 3.5 cm (3.0, 4.5). A stable airway was achieved in 14 patients postoperatively. One patient experienced tracheal stenosis and received a second operation of tracheal sleeve resection and end-to-end anastomosis 105 days after the first operation. Tracheostomy was conducted in 5 out of 15 patients in whom the vertical defects were larger than 4 cm, and the tubes were extubated after a median time of 56 days (32, 84). The median observation time was 55 months (48, 86), and all 15 patients achieved a stable airway and showed no evidence of local recurrence at the end of follow-up. CONCLUSIONS: For thyroid carcinoma with tracheal or laryngotracheal invasions, window resection with the SCM myoperiosteal flap reconstruction presented positive results in terms of a stable airway as well as oncological outcomes. The SCM myoperiosteal flap can be an appropriate reconstruction strategy, especially when the defects reach the thyroid cartilage.

Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy.

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF- pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma.

Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4+ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4+ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.

Quantitative CT measurement of left colonic and pelvic mesenteric adipose volume in radiation proctitis.

BACKGROUND: The edema of left colonic and pelvic mesenteric adipose tissues has long been recognized in surgery as a characteristic feature of radiation proctitis (RP). However, the correlation between mesenteric adipose volume and RP has not been extensively clarified. The purpose of this study was thus to assess the variation of left colonic and pelvic mesenteric adipose volume in RP. METHODS: From March 2013 to June 2015, the data of 52 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy, including 23 patients with RP and 29 with non-RP (nRP), were retrieved. The mesenteric adipose volume was quantified via a computed tomography (CT) reconstruction method. Corresponding analyses were conducted to observe the correlation between the relative change of mesenteric adipose volume and the thickening degree of the rectal wall. RESULTS: The baseline data of the RP group and the nRP group were comparable. There was no significant difference in the relative change of the left colonic mesenteric adipose volume in each vertebral space from the third lumbar vertebra to the first sacral vertebra before and after radiotherapy. The relative change of pelvic mesenteric adipose volume (ΔVp%) was notably higher in the RP group compared to the nRP group. With a ΔVp% cutoff value of 3.67%, the sensitivity and specificity for the diagnosis of RP were 65.2% and 86.2%, respectively. According to the correlation analysis, ΔVp% in the RP group was significantly correlated with the thickening degree of the rectal wall after radiotherapy (r=0.47, P=0.024). CONCLUSIONS: The increment of the relative change of pelvic mesenteric adipose volume quantitatively measured by CT can be clinically useful in identifying RP.

EEF1D Promotes Glioma Proliferation, Migration, and Invasion through EMT and PI3K/Akt Pathway.

Eukaryotic translation elongation factor 1δ (EEF1D), a subunit of the elongation factor 1 complex of proteins, mediates the elongation process of protein synthesis. Besides this canonical role, EEF1D was found overexpressed in many tumors, like hepatocarcinomas and medulloblastomas. In the present study, we demonstrated for the first time that EEF1D may interact with other putative proteins to regulate cell proliferation, migration, and invasion through PI3K/Akt and EMT pathways in glioma. Furthermore, knockdown of EEF1D could reduce cell proliferation and impaired epithelial-mesenchymal transition (EMT) phenotypes, including cell invasion. Taken together, these results indicate that EEF1D and its partner proteins might play a critical role in glioma and serve as a potential therapeutic target of glioma.

Changes in the Population Genetic Structure of Captive Forest Musk Deer (Moschus Berezovskii) with the Increasing Number of Generation under Closed Breeding Conditions.

We investigated the genetic diversity of the population of captive forest musk deer (Moschus berezovskii) in Barkam Musk Deer Breeding Centre using twelve microsatellite markers, and then analyzed the change in genetic structure of successive generation groups from the population. The data provide a new understanding for the evaluation and usage of the breeding management system. Microsatellite marker analysis detected 141 alleles with an average of 11.75 alleles for each marker. The average expected heterozygosity (HE) was 0.731. Performing an F-statistical analysis on the data showed that the genetic diversity of population decreased, and the inbreeding coefficient significant increased with the increase of generation, and FIS of the 1st generation is significantly lower than that of the second to fifth generation (p < 0.01). The result suggested that the captive population was facing the pressure of inbreeding (FIS = 0.115) and the subsequent loss of genetic diversity. Therefore, it is necessary to improve the breeding management system of the captive population by preventing close relatives from mating or inducing new individuals from the exotic population.