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Abstract Background With the development of novel anti-HER2 targeted drugs, such as ADCs, it has become increasingly important to accurately interpret HER2 expression in breast cancer. Previous studies have demonstrated high intra-observer and inter-observer variabilities in evaluating HER2 staining by human eyes. There exists a strong requirement to develop artificial intelligence (AI) systems to achieve high-precision HER2 expression scoring for better clinical therapy. Methods In the present study, we collected breast cancer tissue samples and stained consecutive sections with anti-Calponin and anti-HER2 antibodies. High-quality digital images were selected from immunohistochemical slides and interpreted as HER2 3+, 2+, 1+, and 0. AI models were trained and assessed using annotated training and testing sets. The AI model was trained to automatically identify ductal carcinoma in situ (DCIS) by Calponin staining and myoepithelial annotation and filter out DCIS components in HER2-stained slides using image-overlapping techniques. Furthermore, we organized two-phase validation studies. In phase one, pathologists interpreted 112 HER2 whole-slide images (WSIs) without AI assistance, whereas in phase two, pathologists read the same slides using the AI system after a washing period of 2 weeks. Results Our AI model greatly improved the accuracy of reading (0.902 vs. 0.710). The number of HER2 1 + patients misdiagnosed as HER2 0 was significantly reduced (32/279 vs. 65/279), and they benefitted from ADC drugs. In addition, the AI algorithm improved the intra-group consistency of HER2 readings by pathologists with different years of experience (intra-class correlation coefficient [ICC]: 0.872–0.926 vs. 0.818–0.908), with the improvement most pronounced among junior pathologists (0.885 vs. 0.818). Conclusions We proposed a high-precision AI system to identify and filter out DCIS components and automatically evaluate HER2 expression in invasive breast cancer.

Abstract Purpose The survival rate of patients with medullary thyroid carcinoma (MTC) who fail to achieve a biochemical cure after surgery is reduced. This study aimed to investigate the prognostic factors affecting the survival of MTC patients who do not achieve a biochemical cure after surgery. Methods Cox univariate and multivariate proportional hazard models were used to determine the influence of different variables on overall survival (OS). Pearson’s chi-square test was used for categorical variables, and paired t-test was used for continuous variables. Results In our study of 277 MTC patients treated between 2012 and 2022, there were 96 with raised postoperative 1-month calcitonin (Ct) levels (0–9.52 pg/ml). The overall survival (OS) rates of patients with high postoperative 1-month Ct values at 1, 3, and 5 years were 97.9%, 94.6%, and 86.8%, respectively. The univariate analysis revealed that patients with a postoperative 1-month Ct > 441.9 pg/ml had a greater risk of mortality than patients with postoperative 1-month Ct values ranging from 9.52 to 73.4 pg/ml (p = 0.043). Subsequent analyses revealed that receiving targeted therapy did not improve the OS of patients with distant metastasis among those with high postoperative 1-month Ct values (p = 0.527). Conclusion This study confirmed that MTC patients who did not achieve biochemical remission after surgery had an increased risk of death when the Ct level was > 441.9 pg/ml 1 month after surgery. Additionally, for MTC patients who have not achieved biochemical remission and have experienced disease progression or distant metastasis after surgery, the use of targeted therapy does not prolong survival.

Abstract Background Lianhuaqingwen (LHQW) has been used in the treatment of chronic bronchitis, but the precise mechanism through which LHQW exhibits its anti-inflammatory effects in this context is not yet fully understood. The aim of this study was to investigate the active ingredients and signaling pathways responsible for LHQW's effectiveness in managing chronic bronchitis. Methods The research leveraged the TCMSP database to determine the active compounds and drug targets of LHQW. In parallel, the GeneCards, DrugBank, and PharmGkb databases were used to uncover targets pertinent to chronic bronchitis. To discern the potential mechanisms by which LHQW's active ingredients might treat chronic bronchitis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Network pharmacology facilitated the construction of a drug-active ingredient-disease target network, aiding in forecasting the core targets for chronic bronchitis treatment by LHQW. Subsequently, molecular docking techniques alongside in vitro experiments were applied to confirm the interactions between the active ingredients and the primary targets. Results A total of 157 active ingredients, 225 potential drug targets, and 594 bronchitis-related targets were derived from various databases. Following this, 76 potential gene targets were pinpointed by integrating drug and related targets. GO and KEGG enrichment analyses were employed to identify key pathways involved in LHQW's mechanism for treating chronic bronchitis. By constructing a protein–protein interaction (PPI) network for the 76 potential gene targets, four core targets (TNF, IL6, IFNG, and STAT3) were identified as primarily involved in responses to lipopolysaccharide, the TNF pathway, and the JAK-STAT pathway. Molecular docking results revealed a favorable affinity between multiple active ingredients of LHQW and the four core targets, suggesting that the therapeutic effects are mediated through the inhibition of inflammatory responses and signaling pathways. Interestingly, quercetin, an active ingredient of LHQW, was observed to bind to all four core targets simultaneously. Furthermore, cell experiment and western blot analysis indicated that both LHQW and quercetin exhibit anti-inflammatory effects by targeting the four core proteins and the JAK-STAT pathways. Conclusion This research emphasizes the diverse active ingredients, targets, channels, and pathways of LHQW in the treatment of chronic bronchitis, providing important perspectives for the creation of novel therapeutic drugs and clinical uses. Graphical Abstract

Summary: Background: Over 500,000 new cases are diagnosed with papillary thyroid cancer (PTC) globally per year, of whom the vast majority are in the low-risk stratification. Although thyroid-stimulating hormone (TSH) suppression is traditionally recommended for all postoperative PTCs in current guidelines, its necessity remains highly controversial in low-risk patients. Since relevant recommendations in current guidelines are still empirical, we aim to provide a direct, large-scale, real-world evidence. Methods: This large-scale real-world retrospective study included 11,140 low-risk PTC patients from two Chinese large-volume centers (Fudan University Shanghai Cancer Center [FUSCC] and Cancer Hospital of Chinese Academy of Medical Sciences [CH-CAMS]) treated from January 1, 2000 to June 30, 2022. The mean TSH level was calculated based on postoperative serum TSH values during follow-up. The primary outcome was the association between postoperative TSH level and structural recurrence assessed by Kaplan–Meier, log-rank, multivariate Cox regression analyses and equivalence testing by Two One-Sided Tests (TOST) procedure. Propensity score matching (PSM) was used to adjust for confounders among groups. Findings: A total of 11,140 patients with low-risk PTC were included with a median follow-up of 70 months. Based on the mean TSH level, we classified these patients into ≤0.5 (n = 1,504, 13.5%), (0.5–1] (n = 4,336, 38.9%), (1–2] (n = 4,285, 38.5%), (2–3] (n = 704, 6.3%) and >3 (n = 311, 2.8%) mU/L groups. After PSM adjusting for age, sex, T and N stage, 8991 patients were included in further analysis, for whom the log-rank analyses showed no significant differences between any two groups (all P > 0.05) in recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS), and suppressed TSH was not associated with tumor recurrence in the multivariate Cox analysis (TSH > 2 group vs TSH ≤ 2 group: HR = 1.30, 95% CI = 0.85–2.01, P = 0.23). Furthermore, the TOST equivalence tests showed that tumor recurrence status of any two TSH groups were statistically comparable (all Bonferroni-corrected P values

Abstract Background The presence of high-volume lymph node metastasis (LNM) and extranodal extension (ENE) greatly increases the risk of recurrence in patients with low-risk papillary thyroid microcarcinoma (PTMC). The goal of this research was to analyze the factors that contribute to high-risk lymph node metastasis in patients with low-risk PTMC. Methods We analyzed the records of 7344 patients who were diagnosed with low-risk PTMC and treated at our center from January 2013 to June 2018.LNM with a high volume or ENE was classified as high-risk lymph node metastasis (hr-LNM). A logistic regression analysis was conducted to identify the risk factors associated with hr-LNM. A nomogram was created and verified using risk factors obtained from LASSO regression analysis, to predict the likelihood of hr-LNM. Results The rate of hr-LNM was 6.5%. LASSO regression revealed six variables that independently contribute to hr-LNM: sex, age, tumor size, tumor location, Hashimoto’s thyroiditis (HT), and microscopic capsular invasion. A predictive nomogram was developed by integrating these risk factors, demonstrating its excellent performance. Upon analyzing the receiver operating characteristic (ROC) curve for predicting hr-LNM, it was observed that the area under the curve (AUC) had a value of 0.745 and 0.730 in the training and testing groups showed strong agreement, affirming great reliability. Conclusion Sex, age, tumor size, tumor location, HT, and microscopic capsular invasion were determined to be key factors associated with hr-LNM in low-risk PTMC. Utilizing these factors, a nomogram was developed to evaluate the risk of hr-LNM in patients with low-risk PTMC.

Abstract Background Kruppel-like factor 13 (KLF13) is a transcription factor and plays an important role in carcinogenesis. However, the significance of KLF13 in thyroid carcinoma (THCA) is underdetermined. In this study, we aimed to explore the clinical relevance and function of KLF13 in the progress of THCA. Methods The expression of KLF13 in thyroid carcinoma and normal tissue was investigated by qPCR and IHC assay. The expression of KLF13 and IFIT1 in cell samples was investigated with Western blot assay. Cell proliferation ability was detected with CCK8 and colony formation assay. Cell growth in vivo with or without KLF13 overexpression was evaluated on a xenograft model. Cell migration ability was measured with Transwell assay. Cell cycle was detected with flow cytometer. The downstream genes of KLF13 were screened using RNA-seq assay. Luciferase activity was employed to assess the transcriptional regulation of KLF13 on IFIT1 promoter. Results KLF13 expression was downregulated in THCA samples. KLF13 knockdown and overexpression promoted and inhibited the proliferation and migration of THCA cells, respectively. The RNA-seq, RT-qPCR and immunoblotting data showed that KLF13 knockdown significantly potentiated IFIT1 expression at both mRNA and protein levels. Luciferase assays showed that KLF13 suppressed the transcription activity of IFIT1 promoter. Besides, IFIT1 upregulation was critical for the proliferation and migration of THCA cell lines. Lastly, silencing of IFIT1 greatly reversed the proliferation and migration induced by KLF13 knockdown. Conclusions In conclusion, KLF13 may function as an anti-tumor protein in THCA by regulating the expression of IFIT1 and offer a theoretical foundation for treating thyroid carcinoma.

Abstract Background Guidelines recommend total thyroidectomy (TT) to facilitate radioactive ablation and serological follow-up for intermediate- to high-risk papillary thyroid carcinoma (PTC). However, the association between surgical extent and tumor recurrence in these patients has not been well validated. We aimed to examine the association between the extent of surgery and recurrence in patients with completely resected unilateral intermediate- to high-risk PTC. Methods Patients with completely resected unilateral PTC from 2000 to 2017 in a single institute were reviewed. Those who had extrathyroidal extension (ETE) or lymph node metastasis (LNM, cN1 or pN1 > 5 lymph nodes involved) were included for analysis. Cox proportional hazards models were applied to measure the association between surgical extent and recurrence-free survival (RFS) while adjusting for patient demographic, clinicopathological and treatment variables. Results A total of 4550 patients (mean[SD] age, 43.0[11.7] years; 3379 women[74.3%]) were included. Of these patients, 2262(49.7%), 656(14.4%), 1032(22.7%), and 600 (13.2%) underwent lobectomy, TT, lobectomy + neck dissection (ND) and TT + ND, respectively. With a median follow-up period of 68 months, after multivariate adjustment, lobectomy was associated with a compromised RFS compared with other surgical extents (HR[95%CI], TT 0.537[0.333–0.866], P = 0.011, lobectomy + ND 0.531[0.392–0.720] P

Abstract Background Identifying risk factors for occult lateral lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) can provide valuable insights into the necessity of lateral neck dissection (LND). The objective of this study was to develop a nomogram for predicting the probability of LLNM in patients with cN0 unifocal PTMC. Methods We conducted a retrospective analyzed a total of 4872 patients with cN0 unifocal PTMC who were treated at our center from January 2013 to June 2018. Logistic regression analysis was used to determine the risk factors for LLNM, and a nomogram was constructed based on these risk factors. Results The rate of LLNM was 3.2%. Tumors located in the upper lobe(odds ratio [OR] = 2.56, 95% confidence interval [CI] 1.80–3.62; p

Objective: This study assessed positive lymph node ratio (LNR) as a prognostic marker for patients with pyriform sinus cancer. Methods: The present study retrospectively analyzed 101 patients with pyriform sinus cancer to determine the association of LNR with recurrence-free survival (RFS) and disease-specific survival (DSS). Results: The patients were followed up for a median duration of 28 months (range: 6–196 months). The number of median dissected lymph nodes (LNs) was 41, and the number of median positive LNs was three. The receiver operating characteristic curve revealed an LNR cut-off value of 8.6%. Lymphovascular invasion (LVI) or perineural invasion (PNI) (P = 0.001), thyroid gland invasion (TGI, P = 0.000), positive LNs >4 (P = 0.036), and LNR >8.6% (P = 0.008) were significantly associated with poor RFS, and LVI or PNI (P = 0.005), tumor pT3/T4 stage (P = 0.028), positive LNs >4 (P = 0.033), TGI (P = 0.001), and LNR >8.6% (P = 0.003) were significantly associated with poor DSS. The multivariate analysis revealed that LVI or PNI (P = 0.010), TGI (P = 0.000), and LNR >8.6% (P = 0.022) were independent predictors for poor RFS, while tumor pT3/T4 stage (P = 0.049), TGI (P = 0.015), and LNR >8.6% (P = 0.001) were independent predictors for poor DDS. Conclusion: LNR and other clinicopathological data can be used to predict the RFS and DSS of pyriform sinus cancer patients.

Abstract Background and objectives The precise grading and characterization of cervical intraepithelial neoplasia (CIN) has been the focus of pathologists for a long time. This study aimed to explore known strategies for the grading of CINs. Methods After routine H&E review, 85 lesions graded CIN 1, 2, or 3 were investigated primarily by HPV RNAscope to detect HR-HPV and LR-HPV, in combination with an HPV-DNA test and P16/Ki67 immunohistochemistry (IHC). Then, the 85 cases were divided into a control group (49 cases) and a test group (36 cases). The former consisted of cases with consistency between morphology, HPV DNA detection and P16/Ki67 IHC. We used them to evaluate HPV RNA distribution patterns in CINs of different grades. The latter were ambiguous cases in which pathologists could not confirm the diagnosis because of inconsistencies between morphology, HPV DNA detection and P16/Ki67 IHC. We reassessed them by comparison to the pattern in the control group. Results The expression patterns of HPV mRNA signals were different in different CIN lesions. LSIL/CIN1 lesions were mostly expressed in superficial epithelium with diffuse clustered nuclear or cytoplasmic staining; HSIL/CIN2 were characterised by nuclear/cytoplasmic punctate or diffuse cluster nuclear staining in the mid-surface layer, and scattered nuclear/cytoplasmic punctate staining in basal and parabasal cells; whereas HSIL/CIN3 showed full-thickness nucleus/cytoplasmic scattered staining with a punctate pattern. According to the staining pattern, we corrected the diagnosis of 22 cases (22/36, 61.1%). Conclusion Because of its distinct location pattern, HPV RNAscope has obvious advantages over the HPV-DNA test, and combined with P16/Ki67 IHC, it can help pathologists correctly grade CIN. In addition, it can effectively discriminate true CIN from normal or CIN mimic lesions, such as immature squamous metaplasia, atrophy, and inflammatory/reactive changes. Therefore, HPV RNAscope is a valuable auxiliary diagnostic test to avoid the overtreatment and undertreatment of CIN lesions.

Abstract Background Lateral neck is not recommended for dissection in patients with pN1a papillary thyroid cancer (PTC), but its recurrence risk has not been well stratified. We aimed to develop a risk stratification system for lateral neck recurrence in patients with pN1a PTC. Methods Patients with pN1a PTC who underwent thyroidectomy and unilateral central compartment dissection from 2000–2016 were enrolled. The association between number of central lymph node metastases (CLNMs) and lateral neck recurrence was comprehensively assessed using a Cox proportional hazards model with restricted cubic spline. Stratification was then performed based on CLNMs and other significant risk factors selected by multivariate analysis. Lateral neck recurrent-free survival (LRFS) rate of each stratification was estimated with Kaplan–Meier curve and comparison was performed using log-rank test. Results Ninety-six (3.8%) lateral neck recurrences were identified during a median follow-up of 62 months among a total of 2500 admitted cases. An increasing number of CLNMs was associated with compromised LRFS for up to 6 CLNMs (P 3 indicated significantly worse 5-year LRFS than that of CLNM ≤ 3 (90.6% vs. 98.1%, P 3 and primary tumor size > 2 cm), intermediate- (CLNMs > 3 and primary tumor size 1–2 cm) and low-risk (primary tumor size ≤ 1 cm or CLNMs ≤ 3) groups were 78.5%, 90.0% and 97.9%, respectively (P

Abstract Purpose Concurrent chemoradiotherapy (CCRT) is a standard treatment choice for locally advanced hypopharyngeal carcinoma. The aim of this study was to investigate whether induction chemotherapy (IC) followed by CCRT is superior to CCRT alone to treat locally advanced hypopharyngeal carcinoma. Methods and materials Patients (n = 142) were randomized to receive two cycles of paclitaxel/cisplatin/5-fluorouracil (TPF) IC followed by CCRT or CCRT alone. The primary end point was overall survival (OS). The secondary end points included the larynx-preservation rate, progression-free survival (PFS), distant metastasis-free survival (DMFS), and toxicities. Results Ultimately, 113 of the 142 patients were analyzed. With a median follow-up of 45.6 months (interquartile range 26.8–57.8 months), the 3-year OS was 53.1% in the IC + CCRT group compared with 54.8% in the CCRT group (hazard ratio, 1.004; 95% confidence interval, 0.573–1.761; P = 0.988). There were no statistically significant differences in PFS, DMFS, and the larynx-preservation rate between the two groups. The incidence of grade 3–4 hematological toxicity was much higher in the IC+ CCRT group than in the CCRT group (54.7% vs. 10%, P

Background: To retrospectively analyze the outcomes of patients treated with isthmusectomy for a solitary papillary thyroid carcinoma (PTC) confined to the isthmus, and re-assess the role of isthmusectomy in these patients. Methods: The medical records of 65 patients who underwent isthmusectomy for a solitary PTC confined to the isthmus at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College between 1985 and 2015 were retrospectively reviewed. Demographic data, surgical procedures, pathological characteristics, stages, and outcomes were analyzed. Results: Patients’ median age was 39 years (range, 19–63), and the majority were female (86.2% female, 13.8% male). All patients had a solitary PTC confined to the isthmus and were treated with isthmusectomy. Pretracheal lymph node dissection was performed in 34 patients, in which unilateral central neck dissection was performed in 4 patients and bilateral central neck dissection in 2 patients. Microscopic extrathyroidal extension (ETE) was observed in 23 (35.4%) patients, and macroscopic ETE was observed in 3 (4.6%) patients. Thirty-eight (58.5%) patients were stage pT1a, 19 (29.2%) patients were stage pT1b, 5 (7.7%) patients were stage pT2, and 3 (4.6%) patients were stage p3b. Fifteen (23.1%) patients were stage pN1a. Median follow-up time was 78 months (range, 12–274). Two patients experienced a recurrence and both achieved remission after re-operation. The 10-year recurrence-free survival was 92.1%. The 10-year overall survival and disease specific survival were 98.3% and 100%, respectively. Conclusions: Isthmusectomy is effective and sufficient for select patients with a solitary PTC confined to the isthmus.

ObjectiveTo determine the predictive ability of multifocality for central lymph node metastasis in initially treated 18-55 years old female patients with unilateral papillary thyroid microcarcinoma.Study designRetrospective review.SettingTertiary medical center.MethodsWe retrospectively collected clinical data from initially treated papillary thyroid microcarcinoma (PTMC) patients at Cancer Hospital Chinese Academy of Medical and sciences between January 1st, 2018, and December 31st, 2018. Data from 975 initially treated 18-55 years old female patients with unilateral PTMC was collected. We also collected data from 340 initially treated 18-55 years old male patients with unilateral PTMC patients to compare the results between genders. Clinicopathological factors associated with central lymph node metastasis (CLNM) were investigated by univariate and multivariate analysis.Results(1) In the female group, there were 196 (20.1%) cases that had tumor multifocality, including 126 (12.9%) with 2 foci and 70 (7.2%) with >2 foci. The risk of CLNM in patients with 2 foci was not significantly higher than patients with 1 focus (37.3% vs 38.6%, P=0.775). However, diagnosed with >2 foci were independently and positively correlated with CLNM (OR=2.708, 95%CI=1.592-4.607, P0.55cm (OR=2.047, 95%CI=1.535-2.730, P

BackgroundThis study aimed to explore the efficacy and safety of pembrolizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable locally advanced head and neck squamous cell carcinomas (LA-HNSCCs).MethodsIn this prospective, single-arm, single-centre clinical trial, patients meeting the inclusion criteria were treated with preoperative neoadjuvant therapy with 200 mg pembrolizumab combined with 75 mg/m2 cisplatin and 175 mg/m2 paclitaxel. This was followed by surgery and postoperative adjuvant therapy. The primary endpoint was the postoperative pathological complete response (pCR) rate. All statistical analyses were performed using SPSS 26.ResultsA total of 22 patients were enrolled. The location of primary lesion showed: hypopharynx were 15 (68.2%), oropharynx were 6 (27.3%) and oral cavity was 1 (4.5%). The postoperative pCR rate, was 36.4% (8/22), and there was no delay to surgery due to adverse drug reactions. The rate of laryngeal function preservation was 90.9% (20/22). Delayed wound healing was the main surgical complication, with an incidence of 22.7% (5/22). The median follow-up time was 9.5 months, and only 1 patient (4.55%) suffered a regional recurrence.ConclusionPreoperative treatment with pembrolizumab and chemotherapy in resectable LA-HNSCC has a high pCR rate with no significant impact on surgical safety. This treatment was found to increase the rate of laryngeal function preservation. However, the effects of neoadjuvant immunotherapy on long-term prognosis in LA-HNSCCs require further study.

The static demolition of structures via soundless chemical demolition agent (SCDA) is attracting increasing attention because of its environmental friendliness and safety, especially in the dense urban areas. However, the research on the application of SCDA in demolishing the reinforced concrete is still scarce, seriously limiting the development of static demolition. In this work, with the combined efforts of experiments and theoretical analysis, we investigate the critical role of borehole layouts in the static demolition of reinforced concrete (RC) by determining the occurrence and expansion of cracks during static demolition, and the resulting residual mechanical properties of RC. The results show that the growth of cracks is significantly dependent on the reaction of SCDA. Additionally, the initiation time of cracking exhibits minimal sensitivity to variations in the layouts pattern of boreholes, while the progression of cracking is predominantly governed by the layouts of boreholes. We demonstrate that cracks formed in static demolition process can significantly reduce the strength of RC with about the remaining bearing capacity is only 10% to 33% of the original and change its failure mode. Further, it is point out that the key factor controlling the failure of RC under axial compression (i.e., the integrity of structures), and the RC with larger crack size and less structural integrity is more prone to fail. The results and findings in this work further clarify the role of borehole layouts and are of great significance in improving the efficiency of static demolition.

Anaplastic thyroid carcinoma, BRAF non-V600, NRAS, combination immunotherapy and targeted therapy, case report. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with a mortality rate near 100%. BRAF V600 and NRAS mutations are the most common drivers of ATC. While patients with BRAF V600-mutated ATC can be treated with BRAF-targeted therapy, there is no effective treatment for ATC driven by NRAS or non-V600 BRAF mutations. For patients with untargetable driver mutations, immunotherapy provides an alternative treatment option. Here, we present a metastatic ATC patient with PD-L1 positive (tumor proportion score of 60%) tumor and NRAS Q61R/BRAF D594N mutations, who progressed on PD-1 antibody sintilimab plus angiogenesis inhibitor anlotinib. The class 3 BRAF mutant D594N is sensitive to the inhibition of MEK inhibitor trametinib, and its oncogenic activity also depends on CRAF, which can be inhibited by BRAF inhibitor dabrafenib. For these reasons, the patient received a salvage treatment regime of dabrafenib, trametinib, and sintilimab, which resulted in a complete pathological response. To our best knowledge, this is the first report of successful treatment of ATC patients with concurrent NRAS/BRAF non-V600 mutations with the combination of immunotherapy and targeted therapy. Further investigation is required to decipher the mechanism by which the combination of dabrafenib/trametinib with PD-1 antibody overcomes initial immunotherapy resistance likely mediated by concurrent BRAF and NRAS mutations.

Abstract Background To investigate the clinical characteristics of metachronous second primary malignancies (Met‐SPMs) and its impact on prognosis in hypopharyngeal carcinoma (HPC). Methods We reviewed 593 newly diagnosed HPC patients without invasive synchronous SPMs (Syn‐SPMs) who were treated in our cancer center between 2009 and 2019. According to the status during follow‐up, patients were classified into three groups: (a) without SPMs (No‐SPMs, n = 440), (b) with tumors in situ in the esophagus or stomach (Tis, n = 80), or (c) with Met‐SPMs (n = 73). Results The median follow‐up time for entire cohort (n = 593) was 66.7 months. Met‐SPMs were present in 12.3% of the cohort (73/593). The predominant site of SPMs was esophagus, followed by lung, oral cavity, thyroid, stomach, and oropharynx. In Met‐SPMs group, both index tumor and SPMs were the main causes of death. Tis group exhibited comparable 5‐year overall survival (OS) and disease‐specific survival (DSS) with that of No‐SPMs group. The Met‐SPMs group had similar 5‐year OS rate and better 5‐year DSS rate of 47.3% versus 43.6% (odds ratio [OR], 0.931; 95% confidence interval [CI], 0.681–1.274, p = 0.657) and 66.3% vs. 46.2% (OR, 0.600; 95% CI, 0.402–0.896, p = 0.012), respectively, compared with the No‐SPMs group. Conclusion The overall incidence of Met‐SPMs in HPC was 12.3%. The occurrence of Met‐SPMs does not jeopardize the survival outcome of HPC. Routine surveillance of Met‐SPMs was requisite for patients with HPC.

Prevalent copy number alteration is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immune response in OV. Through interrogating the RAD21-regulated transcriptional program, we found that RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti–PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Our study identifies a RAD21–YAP/TEAD4–NuRD corepressor complex in immune modulation, and thus provides a potential target and biomarker for precision immunotherapy in OV.

BackgroundSurgical interventions for tumors in the cervical esophageal region are complicated and laryngeal function is frequently sacrificed. Therefore, we attempted the tracheal transection approach to resect the tumor while preserving laryngeal function.MethodsThree patients with papillary thyroid cancer (PTC), six with cervical esophageal cancer (CEC), and four with CEC mixed with thoracic esophageal cancer (TEC) were enrolled. The esophagus was exposed after the trachea was transected between the second and third tracheal rings. CEC/TEC: Resection of the esophagus or/and a portion of the hypopharynx with acceptable safety margins and repair with free jejunum or tubular stomach. PTC: Suture the small esophageal incision immediately after removing the tumor. The tracheal dissection was repaired with interrupted sutures throughout the entire layer after the esophageal lesion was resected. The status of the recurrent laryngeal nerve (RLN) determined whether a tracheotomy was necessary.ResultsAll 13 patients had effective esophageal lesion excision, with six of them requiring intraoperative tracheotomy. Postoperative complications included a tracheoesophageal fistula (one case, 7.7%), postoperative RLN paralysis (two cases, 15.4%), and aspiration (three cases, 23.1%). Except for two patients with distant metastases, there was no recurrence in the remaining patients after 5–92 months of follow-up.ConclusionThe tracheal transection approach, as a new surgical technique, can retain laryngeal function while ensuring appropriate exposure and satisfactory surgical resection. Before surgery, the feasibility of this approach must be carefully assessed. The RLN should be protected during the procedure. The operation is both safe and effective, with a wide range of applications.

Radiotherapy has already been developed as the standard of care for patients with nasopharyngeal carcinoma (NPC), and precision staging, target volume delineation, prognosis prediction, and post-treatment surveillance are essential in the management of NPC. Positron emission tomography/computed tomography (PET/CT) is increasingly recognized as an imaging modality to guide precision radiotherapy in these areas. The feasibility and efficacy of 18F-FDG PET/CT have been confirmed in tumor diagnosis, treatment planning, prognosis, surveillance, and assessment. Coupled with the capability of revealing tumor metabolic information, 18F-FDG PET/CT is more accurate in identifying primary lesions and metastases of NPC than other conventional imaging methods including CT and MRI and shows the independently diagnostic and prognostic value for radiotherapy. However, 18F-FDG has limitations due to its physiological distribution in brain tissue and increasing uptake in post-radiation inflammation. Novel PET radiotracers including FAPI, NaF, CHO, and FLT are explored as alternatives with potential superiority for radiotherapy in NPC. In this review, we summarized the evolving role of PET/CT in the management of radiotherapy in NPC patients, aiming to facilitate precision radiotherapy from a molecular imaging aspect.

Heart failure (HF) is the end stage of various cardiovascular diseases, with high morbidity and mortality, and is associated with a poor prognosis. One of the primary causes of HF is aortic valve disease, manifested by progressive aortic valve stenosis (AVS), resulting in increased left ventricular load, ventricular hypertrophy, ultimately ventricular dysfunction, and HF. Early assessment of the degree of cardiomyopathy and timely intervention is expected to improve patients’ cardiac function and delay or even avoid the occurrence of HF. The Wnt signaling pathway is mainly involved in regulating myocardial insufficiency after valve stenosis. Connexin 43 protein (Cx43) is an essential target of Wnt signaling pathway that forms gap junction (GJ) structures and is widely distributed in various organs and tissues, especially in the heart. The distribution and transformation of Cx43 among cardiac cells are crucial for the development of HF. To specifically label Cx43 in vivo, we established a new Cx43-BFP-GFP mouse model with two loxp sites on both sides of the tag BFP-polyA box, which can be removed by Cre recombination. This double-reporter line endowed us with a powerful genetic tool for determining the area, spatial distribution, and functional status of Cx43. It also indicated changes in electrical conduction between cells in a steady or diseased state.

BackgroundThyroid cancer (TC), was the fastest-rising tumor of all malignancies in the world and China, predominantly differentiated thyroid cancer (DTC). However, evidence on TC stage distribution and influencing factors of late-stage were limited in China.MethodsWe carried out a retrospective study and enrolled TC patients who were first diagnosed and hospitalized in 8 hospitals in China in 2017. Logistic regression was used to evaluate associations between influencing factors and DTC stage. We extracted eligible primary DTC records newly diagnosed in 2017 from the USA's Surveillance, Epidemiology, and End Results (SEER) database. We compared clinicopathological features and surgical treatment between our DTC records and those from the SEER database.ResultsA total of 1970 eligible patients were included, with 1861 DTC patients with known stage. Among patients ≥45 years old, males (OR = 1.76, 95%CI 1.17–2.65) and those with new rural cooperative medical scheme insurance (NCMS) (OR = 1.99, 95%CI 1.38–2.88) had higher risks of late-stage DTC (stage III-IV). Compared with SEER database, over-diagnosis is more common in China [more DTC patients with onset age< 45 years old (50.3 vs. 40.7%, P < 0.001), with early-stage (81.2 vs. 76.0%, P < 0.001), and with tumors

BackgroundThe endothelial glycocalyx (EG) is essential for maintaining microvascular homeostasis. However, the relationship between the EG and coronary microcirculation remains to be elucidated. One of the main components of EG is syndecan-1, and its shedding has been claimed to represent the state of the EG. In this study, we aimed to analyze the association between syndecan-1 and the coronary microcirculation.MethodsWe enrolled suspected coronary artery disease (CAD) patients who consecutively underwent coronary angiography (CAG) and angiography-based analysis of physiological indices in the left anterior descending artery (LAD). Serum syndecan-1 was measured by enzyme-linked immunosorbent assay (ELISA). The coronary microcirculation was evaluated by the presence of coronary microvascular dysfunction (CMD) and an impaired microvascular vasodilatory capacity (IMVC), which were quantified by an angiography-derived index of microcirculatory resistance (IMRangio) in the maximum hyperemic state (H-IMRangio) induced by adenosine triphosphate and the ratio (RRRangio) of IMRangio in the non-hyperemic phase to H-IMRangio, respectively.ResultsA total of 528 patients were enrolled in this study. There was no difference in epicardial coronary complexity between patients with high syndecan-1 (HSG) and low syndecan-1 (LSG) levels grouped by the median concentration of syndecan-1 (SYNTAX: 7[3, 10] vs. 9[4, 12], P = 0.15). However, H-IMRangio and RRRangio were different between the LSG and HSG groups (H-IMRangio: 23.64 ± 6.28 vs. 27.67 ± 5.59, P < 0.01; RRRangio: 1.74[1.46, 2.08] vs. 1.55[1.34, 1.72], P < 0.01). Patients with CMD (H-IMRangio > 25) and patients with IMVC (RRRangio below the median value) both had higher syndecan-1 levels (CMD: 86.44 ± 54.15 vs. 55.2 ± 43.72, P < 0.01; IMVC: 83.86 ± 55.41 vs. 59.68 ± 45.06, P < 0.01). After adjustment for confounding factors, HSG remained associated with the presence of CMD and IMVC (CMD: odds ratio [OR]: 2.769, P < 0.01; IMVC: OR: 1.908, P < 0.01).ConclusionHigh levels of syndecan-1 are independently associated with the presence of CMD and IMVC among patients with suspected CAD.

BackgroundMedullary thyroid cancer (MTC) can only be cured by surgery, but the management of lateral lymph nodes is controversial, especially for patients with cN0+cN1a. To address this challenge, we developed a multivariate logistic regression model to predict lateral lymph node metastases (LNM).MethodsWe retrospectively collected clinical data from 124 consecutive MTC patients who underwent initial surgery at our institution. The data of 82 patients (from 2010 to 2018) and 42 patients (from January 2019 to November 2019) were used as the training set for building the model and as the test set for validating the model, respectively.ResultsIn the training group, the multivariate analyses indicated that male and MTC patients with higher preoperative basal calcitonin levels were more likely to have lateral LNM (P = 0.007 and 0.005, respectively). Multifocal lesions and suspected lateral LNM in preoperative ultrasound (US) were independent risk factors (P = 0.032 and 0.002, respectively). The identified risk factors were incorporated into a multivariate logistic regression model to generate the nomogram, which showed good discrimination (C-index = 0.963, 95% confidence interval [CI]: 0.9286–0.9972). Our model was validated with an excellent result in the test set and even superior to the training set (C-index = 0.964, 95% CI: 0.9121–1.000).ConclusionHigher preoperative basal calcitonin level, male sex, multifocal lesions, and lateral lymph node involvement suspicion on US are risk factors for lateral LNM. Our model and nomogram will objectively and accurately predict lateral LNM in patients with MTC.

ObjectiveTo observe the outcomes of nonsuspicious contralateral nodules with active surveillance in patients with papillary thyroid carcinoma (PTC).Methods4pt?>Consecutive patients who underwent lobectomy for PTC were retrospectively reviewed. Patients with one or more nodules with nonsuspicious ultrasonography (US) features in the contralateral lobe were included.ResultsTwo hundred and eighty-three patients were included. All patients underwent thyroid lobectomy with ipsilateral prophylactic central neck dissection. A total of 123 patients (43.5%) were classified as ATA low-risk, and 160 patients (56.5%) were classified as intermediate-risk. The median size of the contralateral nodules was 3 mm (range, 2 to 16 mm). After a period of follow-up, the median size change of contralateral nodules was 0 mm (range, -7 to 8 mm). Eight patients (2.8%) had nodule growth >3 mm, 223 patients (78.8%) had stable or decreased nodules, and 52 patients (18.4%) had no detectable nodules. Nodules in 24 patients had suspicious US features, 16 of which were diagnosed with PTMC by either cytology after FNA (in 7 patients) or histopathology after completion thyroidectomy (in 9 patients). Another four patients received completion thyroidectomy for ipsilateral cervical lymph node metastasis. The 5-year residual lobe recurrence (RLR) rate and recurrence-free survival (RFS) rate were 7.4% and 89.8%, respectively. Multivariate analysis showed that multifocality and ATA intermediate-risk were independent predictors for RLR (HR4.083, 95%CI 1.480-11.261, P = 0.007; HR 6.045, 95%CI 1.370-26.662, P = 0.017, respectively) and RFS (HR 5.240, 95%CI 2.114-12.991, P

Rapid antidepressant effects of S-ketamine have repeatedly been confirmed in patients with depression, as well as in chronic unpredictable mild stress (CUMS) animal models. However, the pharmacological study of S-ketamine for anti-postpartum depression has not been considered. In this study, the classical method of reproductive hormone withdrawal was used to construct a rat model of postpartum depression (PPD). Subsequently, the study evaluated the effects of low-dose S-ketamine on behavior and synaptic plasticity, which is related to depression, in the hippocampus of PPD rats. Multiple behavioral tests were used to evaluate depression-like behaviors in PPD models. Synaptic plasticity of the hippocampus can be demonstrated by Western blot, Golgi staining, transmission electron microscopy, and electrophysiological recording. Our study provides insight into the role of low-dose S-ketamine in antidepressant as well as antianxiety and indicates that maintaining synaptic plasticity is a key target for S-ketamine therapy for postpartum depression induced by reproductive hormone withdrawal.

This study investigated the effects of a novel antibacterial film based on chitosan, carboxymethyl cellulose, sodium alginate, tea polyphenols, ascorbic acid, and tangelo peel extract on the postharvest quality and reactive oxygen species metabolism of tangelo fruit during storage. The composite film significantly reduced the fruit decay rate and weight loss, delayed the reduction in total soluble solids and titratable acidity, and retained fruit firmness and the appearance of tangelo fruit during storage. Furthermore, the composite film effectively reduced the fruit respiration rate, inhibited the increase in cell-membrane permeability, markedly reduced the generation of superoxide anion, hydrogen peroxide, and malondialdehyde, and enhanced the activity of the antioxidant enzymes superoxide dismutase, catalase, and ascorbate peroxidase. The composite film also reduced losses of the nonenzymatic antioxidants ascorbic acid and glutathione. Overall, the chitosan-based composite antibacterial film effectively maintained the quality of tangelo fruit during storage, enhanced ROS scavenging capacity and antioxidant properties, and then reduced the rot rate of postharvest tangelo.

A novel virus named SARS-CoV-2 has caused a worldwide pandemic, resulting in a disastrous impact to the public health since 2019. The disease is much more lethal among patients with malignant disease. Vaccination plays an important role in the prevention of infection and subsequent severe COVID-19. However, the efficacy and safety of vaccines for cancer patients needs further investigation. Encouragingly, there have been important findings deduced from research so far. In this review, an overview of the immunogenicity, effectiveness, and safeness of COVID-19 vaccines in patients with cancer to date is to be shown. We also highlight important questions to consider and directions that could be followed in future research.

Abstract Purpose The purpose of this study was to determine the associations between pathological complete remission (pCR) and clinical outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who received preoperative radiotherapy or chemoradiotherapy in a phase 3 clinical study. Methods A total of 222 newly diagnostic stage III/IVM0 HNSCC patients were randomly assigned to a preoperative concurrent chemoradiotherapy group (n = 104) or preoperative radiotherapy alone group (n = 118). Over a mean follow-up of 59 months, 72 patients were defined as non-responders to preoperative therapy and subsequently underwent resection of the primary lesion with or without neck dissection. The relationship between the pathological tumor response of the primary lesion and treatment prognosis was analyzed. Kaplan–Meier and Cox regression multivariate analyses were performed to evaluate the impact of pCR on local control (LC), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). Results Among the 72 non-responders, 25 patients, 10 in the chemotherapy group and 15 in the radiotherapy group, achieved pCR. The 5-year LC, OS, PFS, and DMFS of pCR patients and non-pCR patients were 93.2% vs. 67.7% (p = 0.007), 83.3% vs. 39.7% (p = 0.0006), 76.1% vs. 44.0% (p = 0.009), and 90.4% vs. 56.3% (p = 0.005), respectively. In multivariate analysis, pCR is also an independent prognostic factor in prognosis, with statistically significant differences. Conclusion pCR after preoperative radiotherapy or concurrent chemoradiotherapy is a good prognostic factor in locally advanced HNSCC. Trial registration Number:ChiCTR-TRC-114004322 Date:05 Mar, 2014

ObjectiveDistant metastasis in papillary thyroid microcarcinoma (PTMC) is rare but fatal, and its relationship with patient age remains unclear. The objective of this study was to examine the association between age at diagnosis and metachronous distant metastasis in PTMC.MethodsConsecutive patients who underwent thyroidectomy for PTC measuring 10 mm or less at a tertiary hospital from January 2000 to December 2016 were enrolled. Patients who had evidence of distant metastasis at diagnosis or underwent postoperative radioiodine (RAI) ablation were excluded. A Cox proportional hazards model with restricted cubic splines (RCS) was applied to examine the association between age at diagnosis and distant metastasis.ResultsA total of 4,749 patients were evaluated. The median age was 44 years (range, 8–78 years), and 3,700 (78%) were female. After a median follow-up of 65 months, 21 distant metastases (20 lung, 1 liver) were recognized. A univariate Cox proportional model using a 5-knot RCS revealed a significant overall (p = 0.01) and a potential nonlinear association (p = 0.08) between distant metastasis and age at diagnosis. In multivariate analysis, age at diagnosis, extrathyroidal extension (ETE), and lymph node metastasis (pN+) were independent risk factors for distant metastasis. Compared with the middle-aged group (30–45 years old), younger and older patients had a higher risk of distant metastasis [HR, 95% CI, p-value, age ≤ 30, 4.54 (0.91–22.60), 0.06, age > 45, 6.36 (1.83–22.13),

Background: Ciliated muconodular papillary tumors (CMPTs) is a descriptive diagnostic term which indicates the composition of tumor cells (ciliated and mucous cells) and the pattern of growth (papillary). It is shown that the proportion of the various cells is different and the papillary structure is not necessary for diagnosis of this tumor. As a result, several scholars proposed that CMPT is a proximal-type bronchiolar adenoma (BA), a possibility which expanded the spectrum of CMPT. These morphological variations therefore introduced major challenges when diagnosing CMPTs. Case presentation: Multiple small nodules in both lungs were found in a 79-year-old female patient. A frozen section of the nodules was performed. Grossly, the nodules were jelly-like with clear boundaries and had a maximum diameter of approximately 4 mm. Microscopic examination showed glandular ducts, papillary, and even micropapillary structures. The cavities were lined by columnar and mucous cells. A conspicuous mucin pool was observed in low-power fields, in addition to floating tumor cells in the mucin pool. Based on these findings, atypical adenomatous hyperplasia of the lung was reported as the intraoperative rapid diagnosis, and the surgeon performed a lobectomy in the patient. A typical hematoxylin-eosin (HE) stain showed that the tumor consisted of three kinds of cells in different proportions, including ciliated columnar, mucous, and basal cells which were confirmed by CK5/6 and P63 immunohistochemistry staining. BRAF V600E protein was expressed in the tumor and at the same time the tumor was shown to harbor the BRAF gene mutation. Conclusion: We report a classic CMPT with a BRAF mutation that expressed BRAF protein. Classic lesions are easy to identify, whereas in cases of morphological variants the key to diagnosis of the disease is the diversity of cell components and the presence of basal cells.

BackgroundMost hypopharyngeal cancers (HPCs) develop lymph node metastasis (LNM) at initial diagnosis. Understanding the pattern of LNM in HPC could help both surgeons and radiologists make decisions in the management of cervical lymph nodes.MethodsA total of 244 newly diagnosed HPC patients between January 2010 and December 2018 were recruited from three specialized cancer hospitals in mainland China. All patients received pre-treatment magnetic resonance imaging (MRI), and definitive radiotherapy with or without concurrent chemotherapy. We reassessed the features of the primary tumor (tumor size, primary location, and extent of invasion) and the involvement of lymph nodes at each level. According to the incidence of LNM, these levels were sequenced and sorted into drainage stations. Univariate and multivariate analyses were used to determine the risk factors for bilateral and regional lymph node metastasis.ResultsThe cohort consisted of 195 piriform sinus cancers (PSC), 47 posterior wall cancers (PWC), and 2 post-cricoid cancers (PCC). A total of 176 patients (72.1%) presented with MRI-detectable LNMs. The overall LNM rates for level II-VI and retropharyngeal lymph nodes (RPLNs) were 59.0%, 52.9%, 14.3%, 1.6%, 2.9%, and 16.4%, respectively. Based on the prevalence of LNM at each level, we hypothesize that the lymphatic drainage of PSC was carried out in sequence along three stations: Level II and III (61.0% and 55.4%), Level IV and RPLN (15.9% and 11.3%), and Level V and VI (1.5% and 3.1%). For PWCs, lymphatic drainage is carried out at two stations: Level II, III, and RPLN (48.9%, 40.4%, and 34.0%) and Level IV-VI (6.4%, 0%, and 2.1%). According to univariate and multivariate analyses, posterior wall invasion was significantly correlated with bilateral LNM (P = 0.030, HR = 2.853 95%CI, 1.110-7.338) and RPLN metastasis (P = 0.017, HR = 2.880 95%CI, 1.209-6.862). However, pyriform sinus invasion was less likely to present with bilateral LNM (P = 0.027, HR = 0.311, 95%CI, 0.111-0.875) and RPLN metastasis (P = 0.028, HR = 0.346, 95%CI, 0.134-0.891).Conclusions and RelevanceThe primary tumor site and extent of invasion are related to the pattern of lymph node metastasis. That is, the metastasis would drainage station by station along different directions.

BackgroundTo assess the prevalence, risk factors and prognostic significance of retropharyngeal lymph node (RPLN) metastasis diagnosed by magnetic resonance imaging (MRI) in patients with hypopharyngeal squamous cell carcinoma (HPSCC).Methods259 patients from three cancer institutions in China from Jan 2010 to Dec 2018 were analyzed, retrospectively. All the patients had been given pre-treatment magnetic resonance imaging (MRI) of head and neck and were then treated with definitive radiotherapy with or without chemotherapy. Pretreatment diagnostic MRIs were reviewed by a dedicated head and neck radiologist, for the presence or absence of radiographically positive RPLN, cervical LN and tumor invasion.Demographic variables were analysed by descriptive statistics using SPSS 20.0. Predictors of the presence of RPLN and its prognostic significance were examined.ResultsRPLN metastasis was discovered in 44 patients (17%). Logistic analysis showed that posterior pharyngeal wall (PPW) primary tumor; PPW invasion; N2-3; multiple cervical lymph node (LN) involvement (>2 LNs) were associated with RPLN metastasis, with metastasis rates 37%, 30%, 31% and 33% respectively. Patients with RPLN metastasis had a significantly reduced 5-year overall survival (OS) and disease-free survival (DFS) compared to the non-RPLN metastasis group (OS 28% vs. 48%, p=0.001; DFS 25% vs. 41%, p=0.040).ConclusionsRPLN metastasis was not uncommon in HPSCC patients. Risk factors were: PPW primary tumor, PPW invasion and cervical LN status. RPLN metastasis is a poor prognosticator for survival.

Abstract Background Primary hyperoxaluria (PH) is a rare inborn disorder of the metabolism of glyoxylate, which causes the hallmark production oxalate and forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Since the manifestation of PH varies from recurrent nephrolithiasis, nephrocalcinosis, and end-stage renal disease with age at onset of symptoms ranging from infancy to the sixth decade, the disease remains undiagnosed until after kidney transplantation in some cases. Case presentation Herein, we report 3 cases of PH diagnosed after kidney transplantation failure, providing the comprehensive clinical course, the ultrasonic image of renal graft and pathologic image of the biopsy, highlighting the relevance of biopsy findings and the results of molecular genetic testing. We also focus on the treatment and the unfavorable outcome of the patients. Meanwhile, we review the literature and show the additional 10 reported cases of PH diagnosed after kidney transplantation. Additionally, we discuss the progressive molecular understanding of the mechanisms involved in PH and molecular therapy. Conclusions Overall, the necessity of preoperative screening of PH in all patients even with a minor history of nephrolithiasis and the importance of proper treatment are the lessons we learn from the 3 cases, which prompt us to avoid tragedies.

Novel therapy strategies are crucial for thyroid carcinoma treatment. It is increasingly important to clarify the mechanism of thyroid carcinoma progression. Several studies demonstrate that α-Enolase (ENO1) participates in cancer development; nevertheless, the role of ENO1 in thyroid carcinoma progression remains unclear. In the present study, we found that the expression of ENO1 was upregulated in thyroid carcinoma samples. Proliferation and migration of thyroid carcinoma cells were suppressed by depletion of ENO1; conversely, ENO1 overexpression promoted thyroid carcinoma cell growth and invasion. To elucidate the mechanisms, we found that the hypoxia-related mTOR/HIF1 pathway regulated ENO1 expression. ENO1 regulated the expression of CST1; knockdown of CST1 reversed the tumorigenicity enhanced by ENO1 overexpression. Taken together, our findings provide a theoretical foundation for thyroid carcinoma treatment.

Objective Many methods for tissue microarray (TMA) construction were described in previous reports. Because TMA-based methods are expensive and complicated, their widespread application may be restricted. This study aimed to develop a simple method for TMA construction. Methods High-density TMAs were constructed using simple equipment, and hematoxylin and eosin and immunohistochemical staining were performed to analyze the effect on the TMA block. Results A recipient block with 162 holes of 0.9 mm in diameter was prepared using a mini-drill and plastic mold. Tissue cores of 1.0 mm in diameter were obtained from multiple donor blocks with stainless-steel capillary tubes driven by the mini-drill. Under the fixation and guidance of the plastic mold, tissue cores could be easily injected into the holes in the recipient block by inserting a stainless-steel wire into the stainless-steel tube with the tissue core and then pressing using the stainless-steel wire. Conclusion A high-density TMA block with 162 1.0-mm cores was created. This new modified technique could be a good alternative in many laboratories.

18F-choline (CHO) PET image remains noisy despite minimum physiological activity in the normal brain, and this study developed a deep learning-based denoising algorithm for brain tumor CHO PET. Thirty-nine presurgical CHO PET/CT data were retrospectively collected for patients with pathological confirmed primary diffuse glioma. Two conventional denoising methods, namely, block-matching and 3D filtering (BM3D) and non-local means (NLM), and two deep learning-based approaches, namely, Noise2Noise (N2N) and Noise2Void (N2V), were established for imaging denoising, and the methods were developed without paired data. All algorithms improved the image quality to a certain extent, with the N2N demonstrating the best contrast-to-noise ratio (CNR) (4.05 ± 3.45), CNR improvement ratio (13.60% ± 2.05%) and the lowest entropy (1.68 ± 0.17), compared with other approaches. Little changes were identified in traditional tumor PET features including maximum standard uptake value (SUVmax), SUVmean and total lesion activity (TLA), while the tumor-to-normal (T/N ratio) increased thanks to smaller noise. These results suggested that the N2N algorithm can acquire sufficient denoising performance while preserving the original features of tumors, and may be generalized for abundant brain tumor PET images.

ObjectiveTo investigate the prevalence and distribution of cervical lymph node metastasis (LNM) in locally advanced supraglottic squamous cell carcinoma (LASCC) and guide the delineation of clinical lymph node target volumes.Materials and MethodsWe reviewed patients defined as LASCC from January 2000 to December 2017 in our hospital. The primary tumor was operated on using partial or total laryngectomy, and all patients underwent bilateral neck dissection (levels II–IV at least). Univariate and multivariate logistic regressions were used to find risk factors associated with LNM.ResultsA total of 206 patients were enrolled. In the whole group, the rate of ipsilateral metastasis (IM) was 60.9% (67 patients), whereas contralateral metastasis was 25.5% (28 patients). Only positive ipsilateral lymph nodes contributed to contralateral metastasis (p = 0.001). Seventy-six cases were diagnosed with clinical positive lymph nodes (cN+). IM of primary lesions mainly located within the unilateral sites (n = 49 patients) was detected in levels II, III, and IV with lymph node metastasis ratios of 73.5% (36 patients), 63.3% (31 patients), and 20.4% (10 patients), respectively, and contralateral metastasis of 36.7% (18 patients), 16.3% (8 patients), and 6.1% (3 patients), respectively. Involvement of level II or III was associated with metastasis of level IV. No one developed contralateral level IV involvement without metastasis of contralateral levels II and III. A total of 130 cases had clinically negative neck lymph nodes (cN0). The prevalence of occult metastasis (OM) was 35.4%. Among 62 patients with unilateral lesions, the rates of OM to ipsilateral neck levels II, III, and IV were 21, 11.1, and 1.6%, respectively, whereas contralateral neck levels were 6.3, 4.8, and 0%, respectively. In terms of the risk factors, histopathological differentiation was related to OM (p = 0.003). Two of 25 people were with level VIb metastasis, and both of them were with subglottic involvement.ConclusionNeck levels II to IV are most frequently involved and should be included in clinical target volume (CTV) in cN+ patients. Contralateral IV may be omitted when contralateral levels II and III are negative. In cN0 patients, ipsilateral levels II and III are suggested to be included in the CTV, whereas whether contralateral levels II and III should be included needs further research.

Object: Skull base meningiomas with extracranial extensions are rarely described. This study describes the clinical features, surgical management and clinical outcomes of these rare tumors and investigates risk factors associated with progression-free survival (PFS).Methods: The clinical data of 34 consecutive patients who underwent surgery for skull base meningiomas with extracranial extensions from 2007 to 2018 were retrospectively collected and analyzed.Results: The mean patient age was 47.9 ± 13.9 years; 50.0% were male. The most common symptoms on admission were ophthalmic. All patients underwent a multidisciplinary consultation before surgery, and received individualized surgical management. The gross total resection (GTR) rate was 55.9% (19/34). Twelve patients received post-operative adjuvant radiotherapy (RT). Twelve patients experienced tumor recurrence during the follow-up period. The median PFS duration was 54 months. The mean overall survival (OS) duration was 111 months. By univariate analysis, a higher histological grade (WHO grade II and III), Ki-67 LI ≥ 5 and the extent of resection (EOR) were significantly associated with tumor recurrence. Multivariate analysis revealed Ki-67 LI ≥ 5, the EOR and adjuvant RT as prognostic factor of PFS.Conclusions: These relatively rare meningiomas are difficult to resect and have a poor prognosis; they are more common in males and have a higher histological grade than intracranial meningiomas. Multidisciplinary collaboration and individualized surgical strategies are crucial for surgically managing these complex tumors. Total removal of the tumor remains challenging. Subtotal resection (STR) or partial resection (PR) followed by RT is a reasonable strategy when radical resection is infeasible. Adjuvant RT should be recommended especially for tumors with histopathological risk factors (Ki-67 LI ≥ 5 or high histological grade).

Frailty has been implicated as a prognostic factor for ischemic cardiovascular diseases. However, the effects of frailty on platelet responses to aspirin and clopidogrel remain under investigation. In this study, we enrolled consecutive elderly patients with coronary artery disease (CAD) who were treated by percutaneous coronary intervention (PCI) to evaluate this association. A total of 264 patients (aged 70-95 years) were included. Patients were divided into 2 groups: a nonfrail (nFR) group and a frail (FR) group according to the Clinical Frailty Scale. Platelet reactivity was assessed with a light transmittance aggregometry method, and arachidonic acid and adenosine diphosphate induced maximum platelet aggregation (AA-MPA/ADP-MPA) were calculated to evaluate the platelet response to aspirin and clopidogrel. The results showed that the AA-MPA and ADP-MPA of the FR group were significantly higher than those in the nFR group (17.49 ± 6.65 vs 15.19 ± 6.33, P < .01; 56.13 ± 10.14 vs 45.45 ± 11.59, P < .01). High on-aspirin platelet response (HAPR) and high on-clopidogrel platelet response (HCPR) were significantly more common in the FR group than in the nFR group (24.67% vs 13.16%, P = .028, 37.33% vs 15.79%, P < .01). According to multivariable regression analyses, frailty was found to be independently associated with AA-MPA (β coefficient = 1.883, P = .042) and ADP-MPA (β coefficient = 9.287, P < .001), and it was an independent predictor of HAPR (odds ratio [OR]: 2.696, P < .01) and HCPR (OR: 2.543, P < .01). It was concluded that among elderly patients with CAD undergoing PCI, frailty is an independent predictor of HAPR and HCPR, and the state of frailty is independently associated with the platelet responses to clopidogrel and aspirin.

Proteolytic processing of Bacillus thuringiensis (Bt) Cry protoxins by insect midgut proteases is critical to their insecticidal activities against target insects. Although transgenic Bt cotton expressing Cry1Ac and Cry2Ab proteins have been widely used for control of the cotton bollworm (Helicoverpa armigera) in the field, the proteolytic cleavage sites in the two protoxins targeted by H. armigera midgut proteases are still not clear. In this study, the proteolysis of Cry1Ac and Cry2Ab protoxins by midgut juice prepared from midgut tissue of H. armigera larvae was investigated. Cleavage of Cry1Ac protoxin by midgut proteases formed a major protein fragment of ~65 kDa, and N-terminal sequencing revealed that cleavage occurred at Arg28 in the fore-end of helix α-1 in domain I of Cry1Ac. Cleavage of Cry2Ab protoxin by midgut juice proteases produced a major protein fragment of ~50 kDa, and the cleavage occurred at Arg139 between helices α-3 and α-4 in domain I of Cry2Ab. The amino acids Arg28 of Cry1Ac and Arg139 of Cry2Ab were predicted as putative trypsin cleavage sites. Bioassay data showed that the toxicities (LC50s) of Cry1Ac and Cry2Ab protoxins were equivalent to those of their respective midgut juice-activated toxins in the susceptible SCD strain of H. armigera. Identification of the exact sites of N-terminal activation of Cry1Ac and Cry2Ab protoxins will provide a basis for a better understanding of the mode of action and resistance mechanisms based on aberrant activation of these protoxins in H. armigera.

Abstract Background Although cases of cervical squamous cell carcinoma metastatic to the ovary have been previously documented, we report the first case of superficially invasive squamous cell carcinoma metastatic to the ovary. Case presentation A 45-year-old woman with a two-year history of ovarian endometriosis confirmed by ultrasound underwent oophorectomy. On microscopic examination, a focus of malignant stratified epithelium, initially interpreted as transitional cell carcinoma, was identified within the endometriotic cyst wall. Examination of the hysterectomy specimen revealed superficially invasive squamous carcinoma of the cervix. In addition, two triploid, CD45-negative cells were detected during the analysis of the peripheral blood for circulating tumor cells (CTC). High-risk HPV was detected on the sections of endometriosis containing cancerous area by using hybrid capture 2 assay, supporting the diagnosis of metastatic squamous cell carcinoma originating from the uterine cervix. Conclusion This is the first report of superficially invasive squamous cell carcinoma metastatic to the ovary. Such finding could be misdiagnosed as primary ovarian transitional cell carcinoma, squamous cell carcinoma originating from metaplastic epithelium within endometriosis, or squamous cell carcinoma arising in a teratoma.

Abstract Background The treatment modalities for recurrent locally advanced head and neck cancer failure after radiotherapy are limited with poor prognosis. Salvage supra-radical operation seems to be an option. It has not been established which patients will benefit from salvage total pharyngolaryngoesophagectomy. Methods We retrospectively reviewed 66 patients with previously irradiated recurrent T4 head and neck cancer who underwent salvage total pharyngolaryngoesophagectomy at our institution between January 2001 and June 2014. The clinical outcome and toxicities were analyzed. Results Flap loss occurred in 2 patients, and the incidence of fistulas and anastomosis strictures was 15.6% (10/66) and 13.6% (9/66), respectively. The median survival time of the entire cohort was 12 months. The interval between radiation and salvage surgery, and microscopic carotid artery invasion were identified as independent prognostic factors for overall survival. The 3-year overall survival rates of patients with (n = 33) and without (n = 33) risk factors were 9.1% and 47.2%, respectively (p = 0.007). A time interval between radiation and salvage surgery ≤6 months and previous concurrent chemotherapy or targeted therapy were risk factors for severe post-operative complications. Conclusions Salvage total pharyngolaryngoesophagectomy is beneficial to selected patients with recurrent locally advanced head and neck cancer after radiotherapy.

Vasodilatation is one of the key therapeutic strategies for the treatment of various cardiovascular diseases with high blood pressure. Therefore, development of drugs assisting blood vessel dilation is promising. It has been proven that many drugs display definite vasorelaxant effects. However, there are very few studies that systemically explore the effective vasodilators. In this work, we build a transcriptome-based functional gene module reference approach for systematic pursuit of agents with vasorelaxant effects. We firstly curate two functional gene modules that are specifically involved in positive and negative regulation of vascular diameter based on the known gene functional interaction knowledge. Secondly, a collection of gene expression profiles following herbal component treatment are collected from a public gene expression database. Then, the correlation of the gene modules is evaluated in each herbal component–induced gene expression profile by gene set enrichment analysis. The vasorelaxant effects of the candidate compounds can be predicted and ordered by the values of a defined index. Finally, the top 10 candidate compounds are experimentally tested for their vasorelaxant effects on vessel contraction induced by Phe in aortic rings. This strategy integrating different types of technologies is expected to help to create new opportunities for the development of novel vasodilators.

Objective: Abnormal proliferation or migration of vascular smooth muscle cells (VSMCs) can lead to vessel lesions, resulting in atherosclerosis and in stent-restenosis (IRS). The purpose of our study was to establish the role of miR-378a-5p and its targets in regulating VSMCs function and IRS.Methods: EdU assays and Cell Counting Kit-8 (CCK-8) assays were applied to evaluate VSMCs proliferation, wound healing assays and transwell assays were applied to assess cells migration. Furthermore, quantitative reverse transcription–polymerase chain reaction (qRT-PCR) was performed to investigate the expression level of miR-378a-5p IRS patients and healthy individuals. Target genes were predicted using Target Scan and miRanda software, and biological functions of candidate genes were explored through bioinformatics analysis. Moreover, RNA-binding protein immunoprecipitation (RIP) was carried out to analyze the miRNAs interactions with proteins. We also used Immunofluorescence (IF) and fluorescence microscopy to determine the binding properties, localization and expression of miR-378a-5p with downstream target CDK1.Results: The expression of miR-378a-5p was increased in the group with stent restenosis compared with healthy people, as well as in the group which VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB) compared with NCs. MiR-378a-5p over-expression had significantly promoted proliferative and migratory effects, while miR-378a-5p inhibitor suppressed VSMC proliferation and migration. CDK1 was proved to be the functional target of miR-378a-5p in VSMCs. Encouragingly, the expression of miR-378a-5p was increased in patients with stent restenosis compared with healthy people, as well as in PDGF-BB-stimulated VSMCs compared with control cells. Furthermore, co-transfection experiments demonstrated that miR-378a-5p over-expression promoted proliferation and migration of VSMCs specifically by reducing CDK1 gene expression levels.Conclusion: In this investigatory, we concluded that miR-378a-5p is a critical mediator in regulating VSMC proliferation and migration by targeting CDK1/p21 signaling pathway. Thereby, interventions aimed at miR-378a-5p may be of therapeutic application in the prevention and treatment of stent restenosis.

This work investigated the influence of three different lithium compounds, lithium carbonate (Li2CO3), lithium sulfate (Li2SO4) and lithium chloride (LiCl), on the hydration and mechanical properties of calcium sulfoaluminate (CSA) cement mixtures. Five concentrations of Li+, 0, 0.05, 0.11, 0.16 and 0.22 mmol/g of cement, were chosen, and then the proportions (by mass) of three lithium compounds were determined. Compressive strengths at 8 h, 24 h and 28 days were tested. Meanwhile, an early hydration heat test, thermogravimetric (TG) analysis, X-ray diffraction (XRD) and scanning electron microscope (SEM) techniques were performed to study the influences of different lithium compounds on properties of CSA cement mixtures. The experimental results show that three lithium compounds can all accelerate the early hydration process of CSA cement. There is not a remarkable difference on the properties of CSA cement pastes with a different content of Li+. The anion of lithium compounds can also affect the properties of CSA cement pastes, the accelerating effects of LiCl and Li2SO4 are more significant than that of Li2CO3, but there is not a distinct difference between LiCl and Li2SO4.