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To determine potential correlates of immune recovery from AIDS-related cytomegalovirus retinitis (CMVR), multiparameter flow cytometry was used to characterize CMV-specific T cells from subjects with CMVR. Individuals with active retinitis were compared with those who had been clinically immunorestored by antiretroviral therapy and had >/=2 years of ophthalmologic follow-up without anti-CMV therapy or retinitis reactivation or progression. In comparison with patients with active retinitis, immunorestored patients had higher circulating CD4(+) and CD8(+) T cells expressing interleukin-2 and interferon- gamma in response to combined CMV pp65 and IE1 peptide pool stimulation. CD4(+) T cell responses were predominantly to pp65, whereas CD8(+) T cell responses were predominantly to IE. Immunorestored patients, compared with patients with active retinitis, had increased levels of circulating CMV-specific CD8(+) T cells with 'early' (CD27(+)CD28(+)CD45RA(+), CD27(+)CD28(+)CD45RA(-)) and 'intermediate' (CD27(-)CD28(+)CD45RA(-)) phenotypes. Recovery from AIDS-related CMVR after the initiation of antiretroviral therapy may be mediated by CMV-specific CD4(+) and CD8(+) T cells capable of promoting antigen-specific CD8(+) T cell proliferation. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Background & Aims: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC., Methods: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM., Results: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis., Conclusion: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Lipoprotein(a) [Lp(a)] is an established independent causal risk factor for cardiovascular disease and atherosclerosis. However, its association with young-onset ischemic stroke is not well-established. A systematic review and meta-analysis was performed to investigate the association of elevated Lp(a) with young ischemic stroke., Methods: Four electronic databases: PubMed (MEDLINE), EMBASE, Scopus and Cochrane Library were systematically searched, profiling studies from inception till 6 Mar 2024. We included studies investigating the relationship between stratified Lp(a) levels and young ischemic stroke. We compared the odds of young stroke patients (age <65 years) having elevated Lp(a) compared to age-matched controls without stroke or transient ischemic attack., Results: Five case-control studies comprising a total of 1345 patients were included; 57.7 % (776/1345) were females, with a mean age of 41.5 years. Among them, 22.5 % (264/1171) were smokers. Additionally, 16.8 % (197/1171) had hypertension, 5.9 % (69/1171) had diabetes, and 29.2 % (284/971) had hyperlipidemia. Young stroke patients were more likely to have high Lp(a) level than age-matched controls (OR 1.61, 95 %CI 1.24-2.10). Four studies defined a high Lp(a) level as ≥30mg/dL, whilst one study used a Lp(a) level of >23.2mg/dL as the cut-off. A sensitivity analysis excluding this study showed that young stroke patients were still more likely to have Lp(a) ≥30mg/dL than controls (OR 1.43, 95 %CI 1.08-1.88)., Conclusion: Young stroke patients are more likely to have elevated Lp(a) compared to age-matched controls, suggesting an association between elevated Lp(a) and young stroke. Further research is warranted to evaluate the causal relationships between Lp(a) and young-onset ischemic stroke, as well as to conduct a cost-benefit analysis of Lp(a) screening in young adults as part of a primary prevention strategy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 1. Dr Benjamin Tan has received research funding from Abbott and the National Medical Research Council, Singapore, and both fundings are unrelated to this study. 2. Dr Wann Jia Loh has received honoraria from Medtronic, Abbott, DKSH, Novartis,Roche and Amgen for giving talks., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the changes of the distribution and drug resistance profile of bacteria from ICU children with lower respiratory tract infection (LRTI) in Suzhou City, Jiangsu Province from 2017 to 2022. Methods: From January 2017 to December 2022, a cross-sectional observational study on the bacterial spectrum analysis among intensive care unit (ICU) children with LRTI was conducted in Children's Hospital of Soochow University. The bacteria was cultivated by culture methods from sputum samples, and identified by MALDI-TOF mass spectrometry. Drug sensitivity tests were performed by the VITEK2 Compact fully automated analysis system and the paper slide method. The χ 2 test or Fisher's exact probability was used to analyze the changes of the distribution of sputum culture-positive bacteria and drug resistance in ICU children. Results: The overall detection rate of sputum culture was 42.06% (1 182/2 810). Staphylococcus aureus (25.63%,303/1 182), Acinetobacter baumannii (13.62%,161/1 182) and Haemaphilus influenzae (13.28%,157/1 182) were the top three. Proportions of Acinetobacter baumannii (17.90% vs. 11.02%, χ ²=11.17, P =0.001), especially carbapenem-resistant Acinetobacter baumannii (43.70% vs. 23.50%, χ² =15.21, P <0.001) increased significantly from 2020 to 2022. However, the proportions of Haemophilus influenzae (8.50% vs. 16.19%, χ ²=14.27, P <0.001), Streptococcus pneumoniae (8.50% vs. 15.92%, χ ²=13.42, P <0.001) and extended-spectrum-lactamase producing Escherichia coli (8.89% vs. 18.00%, χ ²=5.45, P =0.025) decreased. Drug resistant results showed that Acinetobacter baumannii was obviously more resistant to imipenem ( χ² =4.43, P =0.035) and levofloxacin ( χ ²=12.53, P <0.001), while more sensitive to minocycline ( χ ²=8.34, P =0.004). Escherichia coli showed a significant increase in resistance to piperacillin tazobactam ( χ ²=8.29, P =0.008) and cefoperazone sulbactam ( χ ²=5.07, P =0.024) from 2020 to 2022; Klebsiella pneumoniae consistently maintained a resistance rate of more than 60% to first and second-generation cephalosporins, and remain susceptible to quinolones and carbapenems. Staphylococcus aureus remained highly susceptible to levofloxacin (drug resistance rate: 2.31%,7/303) and sulfamethoxazole/trimethoprim (drug resistance rate: 4.95%,15/303) from 2020 to 2022. Conclusion: Higher detection and resistance rates of Acinetobacter baumannii from sputum culture in ICU children from 2020 to 2022 were explored. Resistance of Escherichia coli to β-lactamase inhibitor combinations was more serious. Regular monitoring the changes of the etiology of respiratory tract infections in ICU Children is particularly important for the prevention and treatment of multidrug-resistant bacterial infections.

Objective: Breast cancer has become the most prevalent malignant tumor in women, and the occurrence of distant metastasis signifies a poor prognosis. Utilizing predictive models to forecast distant metastasis in breast cancer presents a novel approach. This study aims to utilize readily available clinical data and advanced machine learning algorithms to establish an accurate clinical prediction model. The overall objective is to provide effective decision support for clinicians., Methods: Data from 239 patients from two centers were analyzed, focusing on clinical blood biomarkers (tumor markers, liver and kidney function, lipid profile, cardiovascular markers). Spearman correlation and the least absolute shrinkage and selection operator regression were employed for feature dimension reduction. A predictive model was built using LightGBM and validated in training, testing, and external validation cohorts. Feature importance correlation analysis was conducted on the clinical model and the comprehensive model, followed by univariate and multivariate regression analysis of these features., Results: Through internal and external validation, we constructed a LightGBM model to predict de novo bone metastasis in newly diagnosed breast cancer patients. The area under the receiver operating characteristic curve values of this model in the training, internal validation test, and external validation test1 cohorts were 0.945, 0.892, and 0.908, respectively. Our validation results indicate that the model exhibits high sensitivity, specificity, and accuracy, making it the most accurate model for predicting bone metastasis in breast cancer patients. Carcinoembryonic Antigen, creatine kinase, albumin-globulin ratio, Apolipoprotein B, and Cancer Antigen 153 (CA153) play crucial roles in the model's predictions. Lipoprotein a, CA153, gamma-glutamyl transferase, α-Hydroxybutyrate dehydrogenase, alkaline phosphatase, and creatine kinase are positively correlated with breast cancer bone metastasis, while white blood cell ratio and total cholesterol are negatively correlated., Conclusion: This study successfully utilized clinical blood biomarkers to construct an artificial intelligence model for predicting distant metastasis in breast cancer, demonstrating high accuracy. This suggests potential clinical utility in predicting and identifying distant metastasis in breast cancer. These findings underscore the potential prospect of developing economically efficient and readily accessible predictive tools in clinical oncology., (© 2024. The Author(s).)

Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent., (© 2024. The Author(s).)

Breast cancer metastasis significantly impacts women's health globally. This study aimed to construct predictive models using clinical blood markers and ultrasound data to predict distant metastasis in breast cancer patients, ensuring clinical applicability, cost-effectiveness, relative non-invasiveness, and accessibility of these models. Analysis was conducted on data from 416 patients across two centers, focusing on clinical blood markers (tumor markers, liver and kidney function indicators, blood lipid markers, cardiovascular biomarkers) and maximum lesion diameter from ultrasound. Feature reduction was performed using Spearman correlation and LASSO regression. Two models were built using LightGBM: a clinical model (using clinical blood markers) and a combined model (incorporating clinical blood markers and ultrasound features), validated in training, internal test, and external validation (test1) cohorts. Feature importance analysis was conducted for both models, followed by univariate and multivariate regression analyses of these features. The AUC values of the clinical model in the training, internal test, and external validation (test1) cohorts were 0.950, 0.795, and 0.883, respectively. The combined model showed AUC values of 0.955, 0.835, and 0.918 in the training, internal test, and external validation (test1) cohorts, respectively. Clinical utility curve analysis indicated the combined model's superior net benefit in identifying breast cancer with distant metastasis across all cohorts. This suggests the combined model's superior discriminatory ability and strong generalization performance. Creatine kinase isoenzyme (CK-MB), CEA, CA153, albumin, creatine kinase, and maximum lesion diameter from ultrasound played significant roles in model prediction. CA153, CK-MB, lipoprotein (a), and maximum lesion diameter from ultrasound positively correlated with breast cancer distant metastasis, while indirect bilirubin and magnesium ions showed negative correlations. This study successfully utilized clinical blood markers and ultrasound data to develop AI models for predicting distant metastasis in breast cancer. The combined model, incorporating clinical blood markers and ultrasound features, exhibited higher accuracy, suggesting its potential clinical utility in predicting and identifying breast cancer distant metastasis. These findings highlight the potential prospects of developing cost-effective and accessible predictive tools in clinical oncology., (© 2024. The Author(s).)

Objective: This study aims to develop an artificial intelligence model utilizing clinical blood markers, ultrasound data, and breast biopsy pathological information to predict the distant metastasis in breast cancer patients., Methods: Data from two medical centers were utilized, Clinical blood markers, ultrasound data, and breast biopsy pathological information were separately extracted and selected. Feature dimensionality reduction was performed using Spearman correlation and LASSO regression. Predictive models were constructed using LR and LightGBM machine learning algorithms and validated on internal and external validation sets. Feature correlation analysis was conducted for both models., Results: The LR model achieved AUC values of 0.892, 0.816, and 0.817 for the training, internal validation, and external validation cohorts, respectively. The LightGBM model achieved AUC values of 0.971, 0.861, and 0.890 for the same cohorts, respectively. Clinical decision curve analysis showed a superior net benefit of the LightGBM model over the LR model in predicting distant metastasis in breast cancer. Key features identified included creatine kinase isoenzyme (CK-MB) and alpha-hydroxybutyrate dehydrogenase., Conclusion: This study developed an artificial intelligence model using clinical blood markers, ultrasound data, and pathological information to identify distant metastasis in breast cancer patients. The LightGBM model demonstrated superior predictive accuracy and clinical applicability, suggesting it as a promising tool for early diagnosis of distant metastasis in breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Tan, Huang, Tan, Zhang, Chen and Wei.)

Introduction: Field cancerization is suggested to arise from imbalanced differentiation in individual basal progenitor cells leading to clonal expansion of mutant cells that eventually replace the epithelium, although without evidence., Methods: We performed deep sequencing analyses to characterize the genomic and transcriptomic landscapes of field change in two patients with synchronous aerodigestive tract tumors., Results: Our data support the emergence of numerous genetic alterations in cancer-associated genes but refutes the hypothesis that founder mutation(s) underpin this phenomenon. Mutational signature analysis identified defective homologous recombination as a common underlying mutational process unique to synchronous tumors., Discussion: Our analyses suggest a common etiologic factor defined by mutational signatures and/or transcriptomic convergence, which could provide a therapeutic opportunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tan, Shannon, Lim, Teo, Yap, Lek, Tan, Tan, Hendrikson, Liu, Ng, Chong, Guo, Koh, Ng, Rajasegaran, Wong, Seo, Ong, Lim, Teh, Kon, Chia, Soo, Iyer and Ong.)

IKKα has been shown to be responsible of multiple pro-tumorigenic functions and therapy resistance independent of canonical NF-κB, but its role in acquired chemotherapy resistance in breast cancer remains unclarified. In this study, we obtained pre-treatment biopsy and post-treatment mastectomy specimens from a retrospective cohort of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy(NAC) (n = 43). Immunohistochemical methods were used to detect the expression of IKKα before and after NAC, and the relationship between IKKα and the pathologic response to NAC was examined. In addition, we developed a new ADR-resistant MDA-MB-231 cell line(MDA-MB-231/ADR) and analyzed these cells for changes in IKKα expression, the role and mechanisms of the increased IKKα in promoting drug resistance were determined in vitro and in vivo. We demonstrated that the expression of IKKα in residual TNBC tissues after chemotherapy was significantly higher than that before chemotherapy, and was positively correlated with lower pathological reaction. IKKα expression was significantly higher in ADR-resistant TNBC cells than in ADR-sensitive cells, IKKα knockdown results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, IKKα knockdown promotes chemotherapeutic drug-induced tumor cell death in an transplanted tumor mouse model. Functionally, we demonstrated that IKKα knockdown significantly upregulated the expression of cleaved caspase 3 and Bax and inhibited the expression of Bcl-2 upon ADR treatment. Our findings highlighted that IKKα exerts an important and previously unknown role in promoting chemoresistance in TNBC, combining IKKα inhibition with chemotherapy may be an effective strategy to improve treatment outcome in chemoresistant TNBC patients., (© 2023. The Author(s).)

Objective: This systematic review assessed the quality of clinical practice guidelines (CPGs) on the treatment of insomnia disorder and their reporting of recommendations, while summarizing the evidence and providing guidance on an algorithmic approach to appropriate pharmacological treatment., Methods: The PubMed and EMBASE databases, guideline repositories, and specialist association websites were searched. The quality of the CPGs was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument, complemented by the AGREE-REX (Appraisal of Guidelines REsearch and Evaluation-Recommendations EXcellence). A multidisciplinary team identified the key clinical questions that a clinician would consider when taking an algorithmic approach to the use of medication for patients with insomnia disorder. By using a meta-synthesis approach, recommendations from the CPGs were characterized and summarized via a recommendation matrix., Results: A total of 10 records that met the inclusion criteria were included and appraised. Four CPGs were rated as high and 3 CPGs were rated as moderate in overall quality. Most of the CPGs recommended pharmacotherapy only if cognitive behavioral therapy for insomnia or other nonpharmacological interventions were unavailable, unsuccessful, or declined by patients. Recommendations on types of medicines and dose and duration of treatment varied and were nonspecific. Few of the CPGs provided recommendations on pharmacotherapy in special populations., Conclusions: Indications for starting medications are the only common thread in all of the reviewed CPGs. The CPGs diverged in the choice of first-line pharmacotherapy, and most of the CPGs did not provide recommendations on all subsequent clinical considerations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Clinically relevant animal models are crucial for effective development of therapeutics for peritoneal carcinomatosis (PC). This protocol describes the generation of patient-derived ascites-dependent xenograft (PDADX) models from the cellular component of ascites. The use of routine intraperitoneal injection of the fluid component of ascites is analogous to the biological events occurring intra-abdominally in patients with PC. By serving as a proxy, PDADX models represent a valuable tool for preclinical testing of new therapeutics for PC. For complete details on the use and execution of this protocol, please refer to Hendrikson et al. (2022)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has recently emerged as a palliative alternative for patients with unresectable peritoneal metastasis (PM). Quality of life (QoL) has increasingly been used as an endpoint to evaluate treatment outcomes. This review aims to identify evidence on how PIPAC would impact the QoL of PM patients., Content: A systematic review was performed on articles identified from Medline, EMBASE, PsycInfo, and Web of Sciences. A meta-analysis was conducted on further selected studies. ACROBAT-NRSI was attempted to assess the risk of bias (RoB)., Summary: Nine studies using the EORTC QLQ-C30 questionnaire to assess QoL after repeated PIPAC cycles were identified. Majority was found to be moderately biased and a great extent of heterogeneity was observed. Four studies on PM from either gastric cancer (GC) or epithelial ovarian cancer (EOC) were included for meta-analysis. In 31 GC patients and 104 EOC patients, QoL remained stable in 13/14 and 11/14 EORTC QLQ-C30 scales. PIPAC was inferior to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in global QoL and functioning but superior in symptom reduction., Outlook: PIPAC is a well-tolerated option for most GC and EOC patients with irresectable PM. Future trials are warranted to confirm the findings., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2022 Zhenyue Li et al., published by De Gruyter, Berlin/Boston.)

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) play an important role in the treatment of various peritoneal surface malignancies, but its efficacy in peritoneal sarcomatosis (PS) remains unknown. Hence, we performed a systematic review and meta-analysis to investigate outcomes of CRS-HIPEC in PS, in accordance with PRISMA guidelines. 16 studies with a total of 320 patients were included in the meta-analysis. Pooled mean length of hospital stay after CRS-HIPEC was 16.0 days (95% CI: 12.2-19.8) and rate of serious complications was 17.4% (95% CI: 9.8-26.3). The median DFS was 12.0 months (95% CI: 8.0-16.0) and the 5-year DFS was 21.8% (95% CI: 13.2-31.7). Overall pooled median OS was 29.3 months (95% CI: 23.8-34.8), with a 5-year OS of 35.3% (95% CI: 26.3-44.8). Subgroup analysis showed that patients with CC-0 cytoreduction had a higher median OS of 34.6 months (95% CI: 23.2-45.9). Median OS for patients with a primary tumour histology of leiomyosarcoma and liposarcoma was 33.5 months (95% CI: 15.9-51.1) and 39.1 months (95% CI: 20.8-57.5) respectively. The site of recurrence was locoregional in 57.3% (95% CI: 38.9-74.8), distant in 17.3% (95% CI: 3.9-35.6), and both in 17.4% (95% CI: 5.8-32.2). In conclusion, our results suggest that CRS-HIPEC may improve outcomes in a select group of PS patients., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space., Competing Interests: C.-A.J.O., J.H., Y.L., W.H.N., J.W.S.T., Q.X.T., G.H.C.T., C.S.C., and M.C.C.T. report a Patent Cooperation Treaty (PCT) filed by Singapore Health Services for PAI-1 as a biomarker with therapeutic implications for peritoneal carcinomatosis (PCT/SG2020/050177). All of the other authors declare no competing interests., (© 2022 The Author(s).)

Background: Peritoneal metastasis (PM) is a late-stage manifestation of intra-abdominal malignancies. The current standard of care indicates that cure can only be achieved with cytoreductive surgery (CRS) which is often indicated with concurrent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). However, the utility of HIPEC within subsets of PM is not fully understood. We seek to compare the effectiveness of HIPEC in improving peritoneal recurrence rates in PM of different origins., Methods: We conducted a systematic review of trials on the PubMed, EMBASE, and Cochrane databases, last searched in August 2021. Biases were assessed using the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials as well as the Methodological Index for Non-Randomized Studies (MINORS) framework., Results: 7 gastric PM studies, 3 ovarian PM studies, and 3 colorectal PM studies were included. Recurrence-free survival was improved in the HIPEC + CRS cohort in 5 gastric trials but only 1 ovarian trial and none of colorectal origin., Discussion: Our findings indicate decent effectiveness of HIPEC in gastric PM, but limited utility in ovarian and colorectal PM. Limitations in the current literature are attributed to the paucity of data available, a lack of homogeneity and consideration of novel and personalised treatment regimens. We implore for further studies to be conducted with a focus on patient selection and stratification, and suggest a reframing of approach towards modern molecular and targeted therapeutic options in future studies of HIPEC., Systematic Review Registration: https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/60c1ffff0c1b78001e8efbe3/, identifier reviewregistry1166., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yap, Wong, Tan, Tan, Chia and Ong.)

Background: The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs., Methods: Data were collected from a prospectively maintained database of PC patients treated at the authors' institution from April 2001 to March 2019. The platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR), and the lymphocyte-monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan-Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters., Results: The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4-7), high postoperative NLR (days 8-21), and high postoperative PLR (days 22-56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57-90) and low postoperative LMR (days 8-21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC., Conclusions: The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods., (© 2021. The Author(s).)

Ovarian cancer is associated with poor prognosis. Platinum resistance contributes significantly to the high rate of tumour recurrence. We aimed to identify a set of molecular markers for predicting platinum sensitivity. A signature predicting cisplatin sensitivity was generated using the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas databases. Four potential biomarkers (CYTH3, GALNT3, S100A14, and ERI1) were identified and optimized for immunohistochemistry (IHC). Validation was performed on a cohort of patients (n = 50) treated with surgical resection followed by adjuvant carboplatin. Predictive models were established to predict chemosensitivity. The four biomarkers were also assessed for their ability to prognosticate overall survival in three ovarian cancer microarray expression datasets from The Gene Expression Omnibus. The extreme gradient boosting (XGBoost) algorithm was selected for the final model to validate the accuracy in an independent validation dataset (n = 10). CYTH3 and S100A14, followed by nodal stage, were the features with the greatest importance. The four gene signature had comparable prognostication as clinical information for two-year survival. Assessment of tumour biology by means of gene expression can serve as an adjunct for prediction of chemosensitivity and prognostication. Potentially, the assessment of molecular markers alongside clinical information offers a chance to further optimise therapeutic decision making., (© 2021. The Author(s).)

Peritoneal carcinomatosis (PC) is often associated with malnutrition and an inability to tolerate enteral feeding. Although total parenteral nutrition (TPN) can be lifesaving for patients with no other means of nutritional support, its use in the management of PC patients remains controversial. Therefore, a systematic review and meta-analysis was performed to evaluate the benefit of TPN on the overall survival of PC patients, in accordance with PRISMA guidelines. A total of 187 articles were screened; 10 were included in this review and eight were included in the meta-analysis. The pooled median overall survival of patients who received TPN was significantly higher than patients who did not receive TPN ( p = 0.040). When only high-quality studies were included, a significant survival advantage was observed in PC patients receiving TPN ( p < 0.001). Subgroup analysis of patients receiving chemotherapy demonstrated a significant survival benefit ( p = 0.008) associated with the use of TPN. In conclusion, TPN may improve survival outcomes in PC patients. However, further studies are needed to conclude more definitively on the effect of TPN.

Up to 10% of well-differentiated liposarcoma (WDLS) progress to dedifferentiated liposarcoma (DDLS). We aimed to identify gene expression changes associated with dedifferentiation and whether these were informative of tumour biology of DDLS. We analysed datasets from the Gene Expression Omnibus (GEO, ID = GSE30929) database to identify differentially expressed genes between WDLS ( n = 52) and DDLS ( n = 39). We validated the signature on whole and laser-capture microdissected samples from patients with tumours consisting of mixed WDLS and DDLS components. A subset of this signature was applied to an independent dataset from The Cancer Genome Atlas (TCGA, n = 58 DDLS) database to segregate samples based on gene expression and compared for recurrence and overall survival (OS). A 15-gene signature consisting of genes with increased expression in DDLS compared to WDLS was generated. This signature segregated WDLS and DDLS samples from patients with mixed component tumours and across multiple recurrences. A further subset of this signature, consisting of five genes (AQP7, ACACB, FZD4, GPD1, LEP), segregated DDLS in a TCGA cohort with a significant difference in OS ( p = 0.019) and recurrence-free survival (RFS) ( p = 0.061). The five-gene model stratified DDLS into prognostic groups and outperformed clinical factors in existing models in retroperitoneal DDLS.

The clinical significance of the family with sequence similarity 189 member B (FAM189B) gene remains largely unknown in gastric cancer (GC). A comprehensive investigation combining multiple detection methods was carried out in the current study to unveil the clinical implications and prospective molecular characterization of FAM189B protein and mRNA in GC. The protein level of FAM189B was clearly upregulated in the tumor tissues of GC as compared to noncancerous gastric tissues with 179 GC cases and 147 noncancerous gastric controls assessed by immunohistochemistry. The upregulation of the FAM189B protein was also found in the more deteriorating period of the tumor, as there were increasing trends in the groups of larger tumors, with lymph node metastasis, a further advanced clinical stage, and a higher histological grade. Next, we focused on the mRNA level of FAM189B in GC tissues using various high-throughput data. After the screening of GEO, ArrayExpress, and SRA, we finally achieved 18 datasets, including an RNA sequencing dataset of TCGA. Altogether, 1095 cases of GC tissue samples were collected, with 305 unique examples of noncancerous controls. Concerning the mRNA level of FAM189B in GC, the final standard mean difference (SMD) was 0.46 and the area under the curve (AUC) was 0.79 for the upregulation of FAM189B mRNA, which confirmed that the FAM189B mRNA level was also markedly upregulated in GC tissues and comparable to its protein level. The survival analysis showed that the higher expression of FAM189B was a risk factor for the overall survival, first progression, and postprogression survival of GC. For the Affymetrix ID 1555515&#95;a&#95;at of FAM189B, the higher expression level of FAM189B predicted a lower overall survival, first progression survival, and postprogression survival with the hazard ratio (HR) being 1.56 (1.24, 1.95), 1.69 (1.32, 2.17), and 1.97 (1.5, 2.6), respectively. For the Affymetrix ID 203550&#95;s&#95;at of FAM189B, a similar result could be found with corresponding HR being 1.49 (1.24, 1.8), 1.49 (1.21, 1.83), and 1.66 (1.32, 2.08), respectively. The interaction of MEM, COXPRESdb coexpressed genes, and DEGs of GC finally generated 368 genes, and the pathway of the cell cycle was the top pathway enriched by KEGG. In conclusion, the overexpression of the FAM189B protein and mRNA might enhance the incidence of GC., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Chang-Liang Wu et al.)

Objectives: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC., Materials and Methods: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting., Results: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels., Conclusion: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the transfusion effectiveness of suspended leucocyte depleted red blood cells (sld RBC) and fresh and irradiated apheresis platelets (fia Plt) in patients with myelodysplastic syndromes (MDS), and to explore the causes and mechanisms of ineffective platelet transfusion in patients with MDS., Methods: Clinical data of 37 patients with confirmed MDS (WHO standard) such as the sex, age, Hb levels, Plt count, hemorrhage and coagulation functions, TEG and so on, were retrospectively analyzed., Results: Among the 37 patients, 15 patients (40.5%) received only sld RBC transfusion, 9 patients (24.3%) received only fia Plt transfusion, and 13 patients (35.1%) received both transfusion. Among the 15 patients with only red blood cell transfusion, 3 patients were ineffective and the ineffectual transfusion rate was 20.0%. Among the 9 patients with only received platelet transfusion, 5 patients were ineffective and the ineffectual transfusion rate was 55.6%, there were significant statistical differences between the two groups (P﹤0.01). The red blood cell transfusion ineffective were 3 patients (23.1%) , the platelet transfusion ineffective were 8 patients (61.5%) and the both transfusion ineffective were 2 patients (15.4%) among the patients both transfusion . The positive rate of platelet antibody in MDS patients with ineffective platelet transfusion was 23.1%. Compared with the normal control group, Human P selectin (P-SelectinCD62P) (P＜0.001) and human anti-thrombin 3 antibody (AT-III Ab) (P＜0.001) significantly increased and human tissue factor pathway inhibitor (TFPI) significantly decreased (P＜0.05) in MDS patients with ineffective platelet transfusion., Conclusion: In the process of component transfusion for MDS patients, compared with the transfusion of red blood cells, the inefficiencies of platelet transfusion significantly increased, mainly due to the disorder of blood coagulation and the generation of platelet antibodies in MDS patients with ineffective platelet transfusion. Compared with the normal control group, human P selectin and human anti-thrombin 3 antibody significantly increase and human tissue factor pathway inhibitor significantly decreases in MDS patients with ineffective platelet transfusion. Human P selectin, human anti-thrombin 3 antibody and human tissue factor pathway inhibitor in molecular markers and fibrinolytic markers can be used as indicators of platelet transfusion time and efficiency in patients with MDS.

Generation of large amounts of genomic data is now feasible and cost-effective with improvements in next generation sequencing (NGS) technology. Ribonucleic acid sequencing (RNA-Seq) is becoming the preferred method for comprehensively characterising global transcriptome activity. Unique to cytoreductive surgery (CRS), multiple spatially discrete tumour specimens could be systematically harvested for genomic analysis. To facilitate such downstream analyses, laser capture microdissection (LCM) could be utilized to obtain pure cell populations. The aim of this protocol study was to develop a methodology to obtain high-quality expression data from matched primary tumours and metastases by utilizing LCM to isolate pure cellular populations. We demonstrate an optimized LCM protocol which reproducibly delivered intact RNA used for RNA sequencing and quantitative polymerase chain reaction (qPCR). After pathologic annotation of normal epithelial, tumour and stromal components, LCM coupled with cDNA library generation provided for successful RNA sequencing. To illustrate our framework's potential to identify targets that would otherwise be missed with conventional bulk tumour sequencing, we performed qPCR and immunohistochemical technical validation to show that the genes identified were truly expressed only in certain sub-components. This study suggests that the combination of matched tissue specimens with tissue microdissection and NGS provides a viable platform to unmask hidden biomarkers and provides insight into tumour biology at a higher resolution.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant perioperative morbidity and mortality. We aim to generate and validate a biomarker set predicting sensitivity to Mitomycin-C to refine selection of patients with colorectal peritoneal metastasis (CPM) for this treatment. A signature predicting Mitomycin-C sensitivity was generated using data from Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas. Validation was performed on CPM patients who underwent CRS-HIPEC (n = 62) using immunohistochemistry (IHC). We determined predictive significance of our set using overall survival as a surrogate endpoint via a logistic regression model. Three potential biomarkers were identified and optimized for IHC. Patients exhibiting lower expression of PAXIP1 and SSBP2 had poorer survival than those with higher expression (p = 0.045 and 0.140, respectively). No difference was observed in patients with differing DTYMK expression (p = 0.715). Combining PAXIP1 and SSBP2 in a set, patients with two dysregulated protein markers had significantly poorer survival than one or no dysregulated marker (p = 0.016). This set independently predicted survival in a Cox regression model (HR 5.097; 95% CI 1.731-15.007; p = 0.003). We generated and validated an IHC prognostic set which could potentially identify patients who are likely to benefit from HIPEC using Mitomycin-C.

Objective: To investigate the expression of factor that binds to inducer of short transcripts-1 of HIV (FBI-1)in breast cancer pre- and pro-neoadjuvant chemotherapy and explore the relationship between FBI-1 expression and treatment efficacy. Methods: We collected 50 patients with breast cancer who received neoadjuvant chemotherapy before operation in the Affiliated Tumor Hospital of Guangxi Medical University from January, 2010 to December, 2014. The expression of FBI-1 in breast cancer tissues pre- and pro-neoadjuvant chemotherapy was detected by immunohistochemical staining. We compared the level of FBI-1 expression pre- and pro-neoadjuvant chemotherapy, and tried to explore its relationship with patient and tumor characteristics and treatment efficacy. Results: (1) The rate of upregulated expression of FBI-1 in breast cancer tissues was 70% (35/50). The upregulated expression of FBI-1 was related to the higher clinical stage and trend of lymph node metastasis ( P <0.05), whereas not related to the age and expression of ER, PR, Ki-67, and Her-2( P >0.05); (2) the setting of FBI-1 lower expression pre-neoadjuvant chemotherapy had superior treatment outcome than the high expression setting based on either clinical assessment (86.7% vs 51.4%, P =0.027) or pathological assessment(80.0% vs 28.6%, P =0.001); (3) the rate of upregulated FBI-1 expression was significantly decreased post-neoadjuvant chemotherapy(70.0% vs 38.0%, P =0.004), with FBI-1 expression of 22 patients downregulated (62.9%); (4) the expression of FBI-1 in responded setting was significantly decreased than that in the non-responded setting based on either clinical (77.4% vs 26.3%, P =0.001) or pathological (72.7% vs 39.3%, P =0.024) assessment. The downregulation of FBI-1 was correlated to either clinical efficacy ( r =0.440, P <0.01) or pathological efficacy ( r =0.491, P <0.05) of neoadjuvant chemotherapy. Conclusion: In breast cancer patients receiving neoadjuvant chemotherapy, the upregulated expression of FBI-1 in breast cancer lesion is associated with clinical stage and lymph node metastasis. The neoadjuvant chemotherapy can significantly reduce the expression of FBI-1. The upregulated expression of FBI-1 may be predictive of resistance to chemotherapeutic drugs, and has predictive value for the efficacy of neoadjuvant chemotherapy in breast cancer patients.

This work aimed to observe the effects of short hairpin RNA (shRNA)-silenced FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231. qRT-PCR and Western blot analysis were applied to detect the mRNA and/or protein expression of FBI-1, Bcl-2, Bax, cleaved-Caspase 3 and Survivin. RNA interference method was used to silence FBI-1 expression in MDA-MB-231 cells. CCK-8 and colony formation assay were employed to detect the cell proliferation. Flow cytometry was employed for examining cell apoptosis. In vivo tumorigenicity of MDA-MB-231 cells was detected by tumor transplantation in nude mice. The results showed that the mRNA and protein expressions of FBI-1 were higher in MDA-MB-231 cells compared with those in normal human mammary epithelial cells MCF-10A. FBI-1 gene silencing inhibited proliferation and induced apoptosis of MDA-MB-231 cells in vitro, together with decreased Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Moreover, FBI-1 gene silencing inhibited the tumorigenesis of MDA-MB-231 cells in vivo. These results suggest that silencing of FBI-1 gene inhibits proliferation, induces apoptosis and suppresses the tumorigenesis of MDA-MB-231 cells.

Objective: To assess the efficacy and side effects of (125)I seed implantation for locoregional recurrent and metastatic breast cancer, and to discuss its role in the comprehensive therapy of breast cancer., Methods: Forty-three patients with locoregional recurrent or metastatic breast cancer were included in this study. They received (125)I seed implantation and were followed up to evaluate the efficacy and adverse reactions of the treatment., Results: Among 54 lesions in the 43 cases, there were complete response (CR) in 39, partial response (PR) in 13, stable disease (SD) in 2 patients, with a response rate of 96.3%. All 17 cases with local pain achieved pain relief. With a median follow up of 36 months (range 14 to 60 months), the 1-, 3-, and 5-year local control rate was 85.2%, 53.7% and 1.9%, and the 1-, 3-, and 5-year survival rate was 95.3%, 67.4% and 37.2%, respectively. No serious radiotherapy side effect was observed., Conclusion: In patients with unresectable locoregional recurrent or metastatic breast cancer, (125)I seed implantation shows proved efficacy and few complications, and can be an important treatment option.

Background: A new diagnostic and prognostic biomarker may be of value in cancer diseases. Our study aimed to evaluate the CDKN1A/p21 and TGFBR2 level measurable in a cohort of patients with breast cancer after mastectomy, and to confirm their suitability to serve as prognostic biomarkers of the cancer., Methods: The expression levels of CDKN1A/p21 and TGFBR2 were detected by reverse transcription-PCR (RT-PCR), western blot assay and immunohistochemical staining for 65 primary tumor samples and paired adjacent noncancerous breast tissues. Their relations to clinicopathologic parameters and to the prognosis of patients with breast cancer were analyzed., Results: We found the mRNA and protein expression levels of CDKN1A/p21 were significantly upregulated in breast cancer tissues compared with adjacent nontumorous breast tissues. Increased CDKN1A/p21 expression showed a significant correlation with larger tumor size (P=0.014), higher tumor dedifferentiation grade (P=0.021), lymph node metastasis (P=0.019) and a shorter disease-free survival (P=0.044). Contrarily, the expression levels of TGFBR2 mRNA and protein were significantly decreased in breast cancer tissues compared with adjacent nontumorous breast tissues. Underexpression of TGFBR2 in breast cancer was correlated with larger tumor size (P=0.034), lymph node metastasis (P=0.039) and a shorter disease-free survival (P=0.035). Statistical analysis suggested that there was no significant association between CDKN1A/p21 and TGFBR2 expression., Conclusions: in summary, our results suggested that high CDKN1A/p21 and low TGFBR2 expression was closely correlated with adverse pathological parameters and poor prognosis in breast cancer. Both CDKN1A/p21 and TGFBR2 are presented as possible candidates for breast cancer biomarkers.

Background: Iodine 125 ((125)I) seed irradiation is an effective non-surgical treatment for unresectable hepatocellular carcinoma (HCC) patients. However, the safety and tolerability of (125)I seed sequential irradiation therapy remain unclear, there is no unified standard of brachytherapy radiation dose, and further study on the basic radiobiology of continuous rate irradiation is necessary., Methods: Forty Kunming-mice (KM-mice, China) were injected with suspensions of human hepatocellular carcinoma cells (H22) to create an animal model and mimic (125)I seed implantation. The survival rates of mice, curative effect, pathological impairments including apoptosis and necrosis were investigated. The mice were randomly divided into four groups, A, B, C and D. In group A, 0.78 mCi (125)I seeds were implanted into the tumor focus. In groups B and C, 0.58 mCi and 0.38 mCi (125)I seeds were inserted at the same location, respectively. Group D was a control group, without any treatment. After 28 days of therapy, the survival rates and the tumor size were measured, and pathological impairments was measured by light or electron microscopy., Results: The tumor volume inhibition rate was 68.21% ± 3.21%, 51.38% ± 4.96%, and 35.71% ± 2.79% after 0.78 mCi, 0.58 mCi, and 0.38 mCi (125)I seeds irradiation, respectively. However, radiation-related side effects were also observed in the high-dose group. Pathological results showed that radiation effect was closely associated with radiation dose, as the increase of radiation dose, an increase in apoptosis and necrosis was detected. Significant cellular impairments were noted by pathological analysis under electron microscopy., Conclusions: Our results demonstrate that the Kunming-mouse is an ideal animal to study (125)I brachytherapy, and the curative effect was closely associated with radiation dose. High-dose of brachytherapy may effectively increase apoptosis and necrosis in liver cells in KM-mice. A dose of 0.58 mCi (125)I radioactive particles may be a safe, effective and minimally invasive therapeutic option for liver cancer.

Background: Immunohistochemical (IHC) expression of Ki67 has been identified as a prognostic and predictive marker in hormone receptor (HR)-positive breast cancer, however, there is little evidence of the association of Ki67 with prognosis in HR-negative patients. We aimed to assess the benefit of Ki67 assessment in HR-negative breast cancers after neoadjuvant chemotherapy (NAC)., Methods: In the present study, a total of 183 HR-negative breast cancer patients with Stage II to III that treated with anthracycline and/or taxane-based neoadjuvant chemotherapy between 2004 and 2011 were retrospectively analyzed. Endocrine therapy and trastuzumab was not administered to any patients in this study. Clinical and pathological features of the patients with breast cancer were retrieved from the hospital records. Predictive factors for NAC response and survival were analyzed., Results: Of the 183 patients, 122 (66.6%) were HR- HER2+, and 61 (33.3%) were triple-negative. The clinical response rates were similar across breast cancer subtype. Patients whose tumors contained high Ki67 expression effectively responded to NAC. Ki67 labeling index was a predictive marker for pathologic complete response (pCR). Ki67 expression showed a positive correlation with HER2 status, tumor size, lymph node status, lymphovascular invasion and tumor grade. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free survival (DFS), but no correlation of Ki-67 expression with overall survival (OS) was observed., Conclusions: Our results suggest that Ki67 expression in HR-negative breast cancer may improve the assessment of pathological response after NAC, and Ki67 score in residual tumor was an independent prognosticator for DFS in the HR-negative breast cancer patients.

Background: To investigate the prognostic value of hormone receptor (HR) status conversion after neoadjuvant chemotherapy (NAC) in patients with primary breast cancer., Methods: 267 stage II-III breast cancer patients treated with NAC who had residual disease in the breast after NAC were retrospectively studied. The patients were divided into four groups based on the HR status: Group A, patients with HR-positive both before and after NAC; Group B, patients with HR status positive-to-negative change; Group C, patients with HR status negative-to-positive change; Group D, patients with HR-negative both before and after NAC. Patients with positive HR status (regardless of before or after NAC) were treated with adjuvant endocrine therapy, and a survival analysis was performed., Results: In total, 15.7% of patients had HR status change after NAC. progression-free survival (PFS) in Group A was similar to that in Group C (hazard ratio, 1.16; P = 0.652), but that in Group B was significantly lesser than that in Group A (hazard ratio, 6.88; P = 0.001), and that in Group C was significantly longer than that in Group D (hazard ratio, 6.88; P = 0.001). A similar pattern of results was obtained for overall survival (OS)., Conclusions: The switch of HR status after NAC is remarkable for breast cancer. An HR switch may identify patients who would benefit from adjuvant endocrine therapy and impact the long-term outcome.

A standard systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) is yet to be identified. Sorafenib has been developed for the treatment of solid tumors, including breast cancer, as an oral multikinase inhibitor with antiangiogenic and antiproliferative activity. The aim of the present study was to assess the efficacy and safety of sorafenib in patients with HER2-negative ABC by performing a meta-analysis. A literature search was applied to databases, including PubMed, EMBASE, the Cochrane Library Databases, American Society of Clinical Oncology and the European Society for Medical Oncology, with the search terms 'advanced breast cancer' and 'sorafenib' and relevant studies were selected for analysis. The data extracted from the selected studies included progression-free survival (PFS), time to progression (TTP), overall survival (OS) and overall response rate (ORR). Major adverse events (AEs) were also analyzed. A total of four randomized controlled trials containing 844 cases were identified. Combined results revealed that when compared with chemotherapy (or with anti-hormone receptor therapy) alone, sorafenib-based therapy significantly increased the PFS [hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.54-1.02] and TTP (HR, 0.74; 95% CI, 0.50-0.97), but not the OS (HR, 0.95; 95% CI, 0.75-1.15) and ORR (relative risk, 1.19; 95% CI, 1.01-1.39). In addition, the incidence of grade 3/4 AEs, including hand-foot skin syndrome, anemia, fatigue, rash and stomatitis, were significantly increased in patients that received sorafenib-based therapy. Therefore, the results from the current meta-analysis indicated that sorafenib-based therapy improved the PFS and TTP in patients with HER2-negative ABC, but not the OS and ORR. In addition, combination treatment was associated with increased toxicities and frequently required dose reductions.

The water-level fluctuation zone of the Three Gorges Reservoir (TGR) exposes in spring and summer, then, green plants especially herbaceous plants grow vigorously. In the late of September, water-level fluctuation zone of TGR goes to inundation. Meanwhile, annually accumulated biomass of plant will be submerged for decaying, resulting in organism decomposition and release a large amount of dissolved organic carbon (DOC). This may lead to negative impacts on water environment of TGR. The typical herbaceous plants from water-level fluctuation zone were collected and inundated in the laboratory for dynamic measurements of DOC concentration of overlying water. According to the determination, the DOC release rates and fluxes have been calculated. Results showed that the release process of DOC variation fitted in a parabolic curve. The peak DOC concentrations emerge averagely in the 15th day of inundation, indicating that DOC released quickly with organism decay of herbaceous plant. The release process of DOC could be described by the logarithm equation. There are significant differences between the concentration of DOC (the maximum DOC concentration is 486.88 mg x L(-1) +/- 35.97 mg x L(-1) for Centaurea picris, the minimum is 4.18 mg x L(-1) +/- 1.07 mg x L(-1) for Echinochloacrus galli) and the release amount of DOC (the maximum is 50.54 mg x g(-1) for Centaurea picris, the minimum is 6.51 mg x g(-1) for Polygonum hydropiper) due to different characteristics of plants, especially, the values of C/N of herbaceous plants. The cumulative DOC release quantities during the whole inundation period were significantly correlated with plants' C/N values in linear equations.

Background: the immune reconstitution inflammatory syndromes (IRIS) are a spectrum of inflammatory conditions associated with opportunistic infections and occurring in approximately16% of human immunodeficiency type 1 (HIV-1)-infected patients given antiretroviral therapy. It has been proposed that these conditions are linked by a dysregulated immune system that is prone to exaggerated responses. However, immunologic studies have been limited by the availability of longitudinal samples from patients with IRIS and appropriate matched control subjects. Cytomegalovirus (CMV) immune recovery uveitis (IRU) is an IRIS occurring in up to 38% of patients with CMV retinitis. Although the pathologic immune responses occur in the eye, immune dysregulation that allows for development of pathologic responses is presumably caused by faulty systemic immune cell reconstitution., Methods: we examined CMV-specific T cell responses, regulatory T (T(reg)) cell function and polyclonal T cell responses, including IL-17 production, in 25 patients with CMV IRU and 49 immunorestored control subjects with CMV retinitis who did not develop IRU., Results: patients with CMV IRU had poor CMV-specific CD4(+) T cell responses, as compared with control subjects, whereas CD8(+) T cell responses were comparable. Patients with CMV IRU were characterized by smaller numbers of circulating Th17 cells. Deficiency in anti-CMV responses was not associated with differences in T(reg) cell function., Conclusions: the T(reg) cell compartment is intact in patients with CMV IRU, and these patients do not develop exaggerated systemic CMV-specific or polyclonal immune responses. Cases are instead characterized by more profound depletion of Th17 cells and poor antiviral immune responses. CMV IRU may be most likely to develop in persons experiencing the greatest degree of immune dysfunction before initiating highly active antiretroviral therapy.

Little is known about the manipulation of IL-17 producing CD4+ T cells (T(H)17) on a per-cell basis in humans in vivo. Previous studies on the effects of IL-2 on IL-17 secretion in non-HIV models have shown divergent results. We hypothesized that IL-2 would mediate changes in IL-17 levels among recently HIV-1-infected adults receiving anti-retroviral therapy. We measured cytokine T cell responses to CD3/CD28, HIV-1 Gag, and CMV pp65 stimulation, and changes in multiple CD4+ T cell subsets. Those who received IL-2 showed a robust expansion of naive and total CD4+ T cell counts and T-reg counts. However, after IL-2 treatment, the frequency of T(H)17 cells declined, while counts of T(H)17 cells did not change due to an expansion of the CD4+ naïve T cell population (CD27+CD45RA+). Counts of HIV-1 Gag-specific T cells declined modestly, but CMV pp65 and CD3/CD28 stimulated populations did not change. Hence, in contrast with recent studies, our results suggest IL-2 is not a potent in vivo regulator of T(H)17 cell populations in HIV-1 disease. However, IL-2-mediated T-reg expansions may selectively reduce responses to certain antigen-specific populations, such as HIV-1 Gag.

Background: We examined the potential clinical utility of using a cytomegalovirus (CMV)-specific T cell immunoassay to determine the risk of developing new-onset CMV retinitis (CMVR) in patients with acquired immunodeficiency syndrome (AIDS)., Methods: CMV-specific T cell assays were performed by multiparameter flow cytometry using stored peripheral blood mononuclear cells that had been obtained in an observational study 2-6 months before new-onset CMVR was diagnosed in case patients (at a study visit during which a dilated ophthalmologic examination revealed no evidence of CMVR) and at the same study visit in control subjects (matched by absolute CD4(+) T cell count at entry) who did not subsequently develop retinitis during 1-6 years of study follow-up., Results: There were no significant differences in CMV-specific CD4(+) or CD8(+) T cell interferon-gamma or interleukin-2 expression in peripheral blood mononuclear cells from case patients and control subjects. Although there were trends toward lower percentages and absolute numbers of CMV-specific, cytokine-expressing CD8(+) T cells with a "late memory" phenotype (CD27(-)CD28(-)) as well as with an "early memory" phenotype (CD27(+)CD28(+)CD45RA(+)) in case patients than in control subjects, these differences were not statistically significant., Conclusions: Many studies have reported that CMV-specific CD4(+) and CD8(+) T cell responses distinguish patients with active CMVR (i.e., who lack CMV-protective immunity) from those with inactive CMVR after immune restoration by antiretroviral treatment (i.e., who have CMV-protective immunity). However, the multiple CMV-specific immune responses we measured do not appear to have clinical utility for predicting the risk for patients with AIDS of developing new-onset CMVR with sufficient accuracy to be used in guiding therapeutic management.

Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV-negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression.