Clinical Stage Research Articles

Hsa_circ_0001776 targeting miR-1265 regulates the development of lung squamous cell carcinoma and clinical significance

Objective: To further explore the role and mechanism of hsa_circ_0001776 and mir-1265 in lung squamous carcinoma by verifying the expression level of hsa_circ_0001776 in plasma, tissues, and cells of lung squamous carcinoma. Methods: Plasma was collected from patients with lung squamous carcinoma treated at Tangshan People's Hospital and healthy individuals from 2020 to 2022. Lung squamous carcinoma tissue microarrays purchased from Shanghai Xinchao Biotechnology Company in 2022. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of hsa_circ_0001776 in lung squamous carcinoma plasma, tissues, and cells, and fluorescence in situ hybridization was used to verify the expression of hsa_circ_0001776 in lung squamous carcinoma. The localization of hsa_circ_0001776 in NCI-H1703 was verified by fluorescence in situ hybridization. The lung squamous carcinoma cells NCI-H1703 and NCI-H226 were cultured in vitro and divided into the circ-negative control (NC) group, hsa_circ_0001776 overexpression group, miR-NC group, miR-1265 mimic group, hsa_circ_0001776+miR-NC group, and hsa_circ_0001776+miR-1265 mimic group.The cell proliferation, motility and apoptosis were detected by the cell counting kit-8 (CCK-8) method, clone formation, Transwell invasion and migration, and scratch assay, and flow cytometry, respectively. The downstream of hsa_circ_0001776 was predicted by circular RNA interactome website, and the interaction between hsa_circ_0001776, miR-1265 was further determined by dual luciferase reporter gene assay, and nude mice subcutaneous tumorigenesis assay detected the growth of transplanted tumors. Results: Fluorescence in situ hybridization results showed that the fluorescence intensity of hsa_circ_0001776 in lung squamous carcinoma tissues was lower than that in paracancerous tissues, and the fluorescence intensity of miR-1265 in lung squamous carcinoma tissues was higher than that in paracancerous tissues (both P＜0.05). The expression level of hsa_circ_0001776 in the plasma of lung squamous carcinoma patients was lower than that in the plasma of healthy people, and the expression level of miR-1265 was higher than that in the plasma of healthy people (both P＜0.05). The expression levels of hsa_circ_0001776 in lung squamous carcinoma cells NCI-H1703, NCI-H226 and SK-MES-1 were lower than that in bronchial epithelial cells BEAS-2B (all P＜0.05), and the relative expression levels of miR-1265 in NCI-H1703 and NCI-H226 were higher than that in human bronchial epithelial cells BEAS -2B (all P＜0.05). The expression of hsa_circ_0001776 was correlated with age, lymph node metastasis, clinical stage, and tumor stage in patients with lung squamous carcinoma (all P＜0.05). Fluorescence in situ hybridization results showed that hsa_circ_0001776 was mainly expressed in the cytoplasm. The results of dual-luciferase reporter assay showed complementary binding of miR-1265 to hsa_circ_0001776. The absorbance values of the hsa_circ_0001776 overexpression group in NCI-H1703 and NCI-H226 cells were lower than that of the circ-NC group (P＜0.05). The number of cell clones in the hsa_circ_0001776 overexpressed group was (52±3) and (53±4), the number of migrating cells was (476±17) and (113±7), the number of invading cells was (100±2) and (184±2), and the cell migration rate was (25.00±4.36)% and (36.02±5.55)%, which were lower than those of the circ-NC group [(104±4) and (106±2), (783±29) and (517±16), (657±45) and (473±9), (48.95±8.69)% and (48.70±1.57)%, all P＜0.05]. The apoptosis rates in the overexpression hsa_circ_0001776 group were (24.77±2.303)% and (19.67±1.16)%, respectively, both higher than those in the circ-NC group [(11.83±1.15)% and (9.50±0.66)%, respectively, both P＜0.05]. MiR-1265 mimic group had a higher apoptotic rate in the NCI-H1703 and NCI-H226 than those of the miR-NC groups (P＜0.05). miR-1265 mimic group had (56±13) and (51±8) cell clones, (556±13) and (405±6) migrating cells, (486±6) and (359±7) invading cells, cell migration rates of (68.56±5.51)%, (81.74±8.04)%, were higher than those of miR-NC group [(31±4) and (21±8), (154±19) and (186±5), (227±6) and (176±7), (25.83±4.26)% and (53.12±4.14) %, all P＜0.05]. The apoptotic rates in the miR-1265 mimic group were (11.83±2.55)% and (17.50±1.05)%, respectively, which were lower than those in the miR-NC group [(32.67±4.44)% and (39.90±2.88)%, respectively, both P<0.05]. The absorbance values of NCI-H1703 and NCI-H226 in the overexpression of hsa_circ_0001776+miR-1265 mimic group were higher than those of the overexpression of hsa_circ_0001776+miR-NC group (P<0.05). The overexpression of hsa_circ_0001776+miR-1265 mimic group had (128±15) and (133±8) cell clones, (623±10) and (310±7) migrating cells, (643±16) and (420±7) invading cells, (66.39±4.46)% cell migration rate and (68.60±3.53)%, were higher than those of the hsa_circ_0001776+miR-NC group [(86±7) and (80±16), (380±11) and (115±5), (152±7) and (94±4), respectively, (31.41±5.91)% and (30.94±0.67)%, all P＜0.05]. The apoptotic rates in the overexpression of hsa_circ_0001776+miR-1265 mimic group were (19.27±0.15)% and (11.53±0.75)%, respectively, both lower than those in the overexpression of hsa_circ_0001776+miR-NC group [(27.77±1.29)% and (18.43±0.71)%, both P＜0.05]. The results of the subcutaneous tumorigenesis assay in nude mice showed that the volume of tumors in the overexpression of hsa_circ_0001776 group was lower than that in the circ-NC group (P＜0.05). Conclusion: hsa_circ_0001776 is downregulated in lung squamous cell carcinoma, and hsa_circ_0001776 can inhibit the development of lung squamous cell carcinoma by targeting miR-1265.

Radiological Assessment of Different Retroperitoneal Lymph Node Measurements in Stage 1 Testicular Cancer Patients: Impact on Clinical Stage and Treatment

Background: In staging for testicular germ cell tumor (GCT), current guidelines lack consensus regarding the measurement of retroperitoneal lymph node metastasis, concerning the recommended plane and dimension. This exploratory study aimed to assess its impact on clinical stage (cS) and therapy. Methods: We retrospectively examined 154 cSI (retroperitoneal lymph nodes &lt; 10 mm in axial short-axis diameter (SAD)) GCT patients, without adjuvant therapy and a follow-up ≥ 24 months. Retroperitoneal lymph nodes were measured in staging images in different dimensions (SAD and long-axis diameter (LAD)) and planes (axial, sagittal and coronal). Results: Overall survival was 100%, with 82% free of recurrence after a median follow-up of 83 months. All patients were classified as cSI, based on axial SAD (RECIST 1.1). However, significantly more patients would have been classified as cSIIA (0% vs. 38% vs. 52%) or even cSIIB (0% vs. 1% vs. 25%) according to axial LAD (SWENOTECA, German S3 guideline) or maximum LAD in any plane (EAU, ESMO, AJCC and onkopedia) (p &lt; 0.001). Overtreatment was predicted in 0%, 31% and 61% of patients based on axial SAD, axial LAD and maximum LAD, while undertreatment was estimated at 18%, 10% and 2%, respectively, (p &lt; 0.001). Conclusions: These findings indicate considerable variability in cS based on current lymph node staging recommendations, suggesting that axial SAD (RECIST 1.1) could be the most appropriate parameter for standardized guideline recommendations.

Association between smoking status and the prognosis of brain metastasis in patients with non-small cell lung cancer

ObjectiveThis study aimed to explore the relationship between smoking status and the interval to brain metastasis in patients with non-small cell lung cancer (NSCLC) and its impact on survival time after brain metastasis.MethodsData were collected from patients with NSCLC with brain metastases who were treated at our centre between January 2005 and December 2017. Clinical indices such as clinicopathological features and smoking status were recorded, and patients were followed up until 1 September 2022. Based on our inclusion and exclusion criteria, 461 patients were analysed and matched using 1:1 propensity score matching. Three balanced groups were formed: non-smoking (n = 113), smoking cessation (n = 113), and smoking (n = 113). The interval to brain metastasis and overall survival were compared between the groups.ResultsThere was a statistically significant difference in the interval to brain metastasis between the non-smoking and smoking cessation groups (p = 0.001), as well as between the non-smoking and smoking groups (p &amp;lt; 0.001). However, the difference between the smoking cessation and smoking groups was not statistically significant (p = 0.106). Multivariate and univariate analyses identified smoking status, clinical stage, lung cancer surgery, chemotherapy, and chest radiotherapy as independent predictors of the interval to brain metastasis. Additionally, the multivariate analysis showed that smoking status, driver gene mutations, and chest radiotherapy independently influenced survival after brain metastasis.ConclusionSmoking status in patients with NSCLC affects the interval to brain metastasis and survival after brain metastasis.

Gliomedin drives gastric cancer cell proliferation and migration, correlating with a poor prognosis

Gastric cancer (GC) is a prevalent global malignancy, often diagnosed at advanced stage due to a lack of early symptoms and reliable markers. Previous research has identified gliomedin (GLDN) as a potential predictive marker for poor prognosis in cancer patients. However, the specific relationship between GLDN expression and GC prognosis has been unclear. Using the Tumor-Immune System Interaction Database (TISIDB), we examined GLDN expression in GC tissues and found a positive correlation with advanced clinical stages. Kaplan-Meier Plotter analysis further demonstrated that elevated GLDN levels were closely associated with poor prognosis in GC patients. To explore the functional significance of GLDN in GC, we conducted experiments involving GLDN overexpression and knockdown in GC cell lines, as well as subcutaneous tumor formation in nude mice. Our findings provided compelling evidence that GLDN promotes GC cell proliferation, viability, and migration, significantly enhancing tumor growth in vivo. Mechanistically, RNA-sequencing (RNA-seq) combined with bioinformatics analysis revealed that GLDN influences genes enriched in the p53 signaling pathway. Our data suggest that GLDN likely regulates cell proliferation through the p53-p21-CyclinD/CDK4 signaling axis. In conclusion, our study underscores GLDN's critical role in regulating GC cell proliferation and migration, and proposes its potential as a prognostic marker for GC patients.

Long-term prognostic characteristics of patients with clinical stage IA part-solid lung adenocarcinoma: a conditional survival analysis

Abstract OBJECTIVES Despite excellent 5-year survival, there is limited data on the long-term prognostic characteristics of clinical stage IA (cIA) part-solid lung adenocarcinoma (LUAD). The objective was to elucidate the dynamics of prognostic characteristics through conditional survival analysis. METHODS Consecutive patients who underwent complete resection for cIA part-solid LUAD between 2011 and 2015 were retrospectively reviewed. Conditional survival is defined as the probability of surviving further y years, conditional on the patient has already survived x years. The conditional recurrence-free survival (CRFS) and conditional overall survival (COS) were analysed to evaluate prognosis over time, with conditional Cox regression analysis performed to identify time-dependent prognostic factors. RESULTS A total of 1539 patients were included with a median follow-up duration of 98.4 months, and 80 (5.2%) patients experienced recurrence. Among them, 20 (1.3%) recurrence cases occurred after 5 years of follow-up with 100% intrathoracic recurrence. The 5-year CRFS increased from 95.8% to 97.4%, while the 5-year COS maintained stable. Multivariable Cox analysis revealed that histologic subtype was always an independent prognostic factor for CRFS even after 5 years of follow-up, while the independent prognostic value of consolidation-to-tumour ratio, visceral pleural invasion, and lymph node metastasis was observed only within 5 years. Besides, age, pathologic size and lymph node metastasis maintained independent predictive value for COS during long-term follow-up, while consolidation-to-tumour ratio was predictive for COS only within 5 years of follow-up. CONCLUSIONS The independent prognostic factors for cIA part-solid LUAD changed over time, along with gradually increasing 5-year CRFS and stable 5-year COS.

Analysis of clinicopathological characteristics and prognostic factors in 54 metaplastic breast carcinoma patients from northwest China

Objective: Metaplastic breast carcinoma (MBC) is a special type of morphologically heterogeneous and aggressively invasive breast cancer. MBC is characterized by the transformation of tumor epithelium into squamous epithelium and/or mesenchymal components, including differentiation into spindle cells, chondrocytes, and osteocytes. Due to its rarity and invasiveness, there is a paucity of research on MBC prognosis. Furthermore, there are currently no treatment guidelines for MBC. This study analyzed the clinicopathological characteristics, immunophenotype, and prognostic features of MBC. Our aim was to better characterize MBC, thereby identifying potential prognostic factors and new treatment methods. Moreover, we also describe an MBC case treated experimentally with anti-vascular targeted therapy. Material and Methods: We retrospectively analyzed clinical pathological data on 54 female patients with MBC from Shaanxi Provincial People’s Hospital and the XiJing Hospital of Air Force Medical University. These cases were diagnosed with MBC between January 1st, 2013, and October 1st, 2018. All patients were from the northwest region of China. The gross morphological, histological, and immunohistochemical features of MBC were analyzed. Kaplan–Meier analysis was used to calculate the survival rate, and univariate analysis was performed to identify significant prognostic factors. In addition, the treatment of an MBC patient with anti-angiogenic therapy was described, and a relevant literature review was conducted. Results: MBC was diagnosed in 32 left breasts and 22 right breasts from 54 women aged 21–76 years (median age of 57 years). The maximum tumor diameter ranged from 0.6 to 14 cm (average of 4.1 cm). Of the 54 patients, 47 underwent surgical treatment, with lymph node metastasis found in 17.0% (8/47). According to the World Health Organization classification criteria for breast tumors, the study cohort consisted of 15 cases of squamous cell carcinoma, ten cases of spindle cell carcinoma, nine cases of carcinoma with associated stromal differentiation, 18 cases of mixed carcinoma, and two cases of adenocarcinoma with squamous differentiation. Based on the American Joint Committee on Cancer clinical staging criteria, the patients were classified as Stage I (10 cases, 18.5%), Stage II (26 cases, 48.1%), Stage III (11 cases, 20.4%), and Stage IV (7 cases, 13.0%). Immunohistochemical analysis revealed that 94.4% of patients had triple-negative breast cancer (TNBC), 47 cases showed mutant tumor protein 53 (TP53) expression, 29 cases showed positive epidermal growth factor receptor (EGFR) expression, 43 cases showed positive E-cadherin expression, and 37 cases showed positive Cluster of Differentiation 24 expression. The Ki-67 index ranged from 20% to 90%. Univariate analysis showed that the Ki-67 index was not significantly associated with either progression-free survival (PFS) or overall survival (OS) in MBC patients. Patients with negative axillary lymph nodes had significantly better PFS and OS than those with positive nodes (P &lt; 0.05), and patients with clinical stage I-II disease had better PFS and OS than those with stage III-IV disease (P &lt; 0.05). Patients treated with anthracycline-containing chemotherapy had significantly better PFS than those who did not receive chemotherapy. Univariate analysis revealed that the high expression of EGFR correlated with worse PFS (P &lt; 0.05). The type of surgical approach employed did not affect the prognosis of MBC patients. Following the application of anti-angiogenic therapy, a rapid partial response was observed in an MBC patient with carcinoma and associated stromal differentiation. This patient subsequently underwent surgery and radiation therapy and has now achieved over 6 years of PFS. Conclusion: MBC is a heterogeneous group of tumors with high malignancy and poor prognosis. The large majority is TNBC and exhibits unique immune phenotypes. The poor PFS of MBC patients may be related to EGFR expression, which could become a potential therapeutic target in these patients. Surgery remains the primary treatment method for MBC. The present study found that sentinel lymph node biopsy was feasible in appropriate patients, and that chemotherapy regimens incorporating anthracycline-class drugs did not appear to improve OS. Anti-angiogenic therapy holds promise as a potentially effective treatment approach for MBC, and the optimization of systemic treatment strategies should be a priority in the management of these patients.

SNAI1: a key modulator of survival in lung squamous cell carcinoma and its association with metastasis

BackgroundSnail family zinc finger 1 (SNAI1) has been implicated in cancer progression and prognosis across various malignancies. This study aims to elucidate the prognostic significance of SNAI1 expression in Lung Squamous Cell Carcinoma (LUSC) using data from The Cancer Genome Atlas (TCGA) database.MethodsSNAI1 expression levels in LUSC patients were stratified using X-tile software to establish optimal cut-off values. Kaplan-Meier survival analysis was performed to assess the impact of SNAI1 expression on overall survival (OS). Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic value of SNAI1, considering clinical parameters such as age, clinical stage, and TNM classification. Additionally, we explored the interaction between SNAI1 expression and metastatic status, and performed Gene Set Enrichment Analysis (GSEA) to investigate associated cellular pathways. Correlations between SNAI1 and immune checkpoint molecules were also examined.ResultsKaplan-Meier analysis revealed significant differences in OS among high, medium, and low SNAI1 expression groups (p < 0.001), with median survival times of 1.6, 3.0, and 5.8 years, respectively. Dichotomizing patients into high and low SNAI1 expression groups confirmed that high SNAI1 expression was associated with significantly poorer OS (p < 0.001). SNAI1 remained an independent prognostic factor in multivariate analysis. High SNAI1 expression correlated with poorer survival outcomes regardless of metastatic status, and the combination of high SNAI1 expression and metastasis resulted in the poorest survival. GSEA identified significant associations between SNAI1 and inflammatory, immune response pathways. Positive correlations were observed between SNAI1 and key immune checkpoint molecules, suggesting an interplay with immune checkpoint mechanisms.ConclusionsHigh SNAI1 expression is a robust prognostic indicator of poor survival in LUSC, independent of other clinical factors. Its association with immune checkpoint molecules highlights its potential as a therapeutic target. These findings underscore the prognostic and therapeutic relevance of SNAI1 in LUSC and possibly other cancers. Further research is warranted to explore targeted therapies against SNAI1.

EGFR-TKI combined with radiotherapy in 105 patients of lung adenocarcinoma with brain metastasis: a retrospective study of prognostic factors analysis.

This study aimed to retrospectively analyze the response and prognosis factors for patients of lung adenocarcinoma with brain metastasis and epidermal growth factor receptor (EGFR) mutation, who were treated by EGFR-tyrosine kinase inhibitor (TKI) combined with brain radiotherapy (RT). From Jan 2021 to Jan 2024, the clinicopathological data of lung adenocarcinoma patients were collected from the First Affiliated Hospital of Hebei North University. SPSS version 26.0 statistical software was used for statistical analysis. P &lt; 0.05 was determined to be statistically significant. 105 patients were included. The 1, 2, 3-year overall survival (OS) rate was 82.9%, 61.2%, and 33.7%, respectively. 1, 2 ,3-year progression-free survival 1 (PFS1) rate was 62.7%, 36.6%, 22.1%. 1,2,3-year PFS2 rate was 80.8%, 54.6%, and 31.4%. The median OS, PFS1 and PFS2 was 29.8, 18.0 and 28.1 months, respectively. The COX multivariate analysis showed that gene mutation status and brain radiation dose were independent prognostic factors for OS; Gene mutation status, brain radiation dose, and response evaluation to initial treatment (response evaluation) are independent prognostic factors for PFS1; Clinical stage, gene mutation status, brain radiation dose, and response evaluation are independent prognostic factors for PFS2. TKI combined with brain radiotherapy is effective on lung adenocarcinoma patients with EGFR mutation and brain metastasis. Patients with 19 Del or 21 L858R mutation and brain radiation doses ≥ 40 Gy have longer OS, PFS1, and PFS2, and complete remission (CR) + partial remission (PR) is associated with longer PFS1 and PFS2, Patients in stage IVA have longer PFS2.

Endometriosis as a risk factor for ovarian cancer: an update on screening, risk reduction, treatment and prognosis

Key content Endometriosis affects up to 10% of women. While many regard endometriosis as a benign (non‐cancerous) disease, there are well‐established links to epithelial ovarian cancer (EOC). Proposed mechanisms for malignant transformation include chronic inflammation, hyperestrogenism and oxidative stress. Mutations in the tumour suppressor gene ARID1A have also been implicated in the development of endometriosis‐associated ovarian cancer (EAOC). Endometriosis is reported to almost double a woman's background risk of ovarian cancer. Risk reduction strategies are effective in reducing the incidence of EAOC. These include tubal ligation, excision of endometriosis and combined hormonal contraception. Novel therapies targeting tumour suppressor gene mutations present in EAOC are undergoing phase I &amp; II clinical trials. Learning objectives To increase knowledge of the association between endometriosis and EOC. To understand the updated evidence for screening, risk and risk reduction strategies. To be informed of potential novel therapies currently in the clinical trial stage of development. Ethical issues Increased public awareness and improved clinician knowledge may lead to more and earlier‐stage disease detection. Women are more informed, necessitating clinicians to deliver evidence‐based counselling to meet their informational needs.

Mitophagy regulates kidney diseases

Background: Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions. Summary: Mitophagy plays a pivotal role in the development of kidney diseases. Upregulation and downregulation of mitophagy have been observed in various kidney diseases, such as renal ischemia-reperfusion injury, contrast-induced acute kidney injury, diabetic nephropathy, kidney fibrosis, and several inherited renal diseases. A growing body of research has suggested that PINK1 and Parkin， the main mitophagy regulatory proteins， represent promising potential therapeutic targets for kidney diseases. In this review, we summarize the latest insights into how the progression of renal diseases can be mitigated through the regulation of mitophagy, while highlighting their performance in clinical trials. Key Message: This review comprehensively outlines the mechanisms of mitophagy and its role in numerous kidney diseases. While early research holds promise, most mitophagy-centered therapeutic approaches have yet to reach the clinical application stage.

Development of a short version of the German subjective cognitive decline questionnaire (SCD-Q17): a principal component analysis approach to item reduction

AbstractSince it was shown that Alzheimer’s disease (AD) begins many years before the onset of symptoms with subjective cognitive decline (SCD), there has been increasing interest in the early clinical stages where disease-modifying drugs are expected to have the greatest benefit. However, at this early stage cognitive testing may yield unremarkable results, it is necessary to find a tool that can provide a simple and reliable indication of SCD as a part of a screening tool for AD in the general population. The German version of the 24-item Subjective Cognitive Decline Questionnaire (SCD-Q) with a dichotomous answer scale was tested, which then revealed some challenges. For this reason, an adaptation of the questionnaire was necessary. 360 participants completed the SCD-Q, all of whom were outpatients at a memory clinic. The most relevant subitems were identified by principal component analysis. This analysis focused on the self-perceived perspective of the decline. Results of the principal component analysis, consultations with experts and feedback from respondents were integrated into a short version of the SCD-Q with 17 items and a Likert scale – the SCD-Q17. The SCD-Q17 was sent to 100 participants of the original questionnaire for re-completion and, a new cut-off value was calculated by receiver operator characteristic (ROC) curves. The SCD-Q17 is a useful tool for the reliable detection of subjective symptoms, and thus may prompt more in-depth assessments of the underlying etiology. CogScreen has been retrospectively registered at clinical trials (NCT06191952).

Pilot implementation of the revised criteria for staging of Alzheimer's disease by the Alzheimer's Association Workgroup in a tertiary memory clinic.

We aimed to evaluate the feasibility of the 2024 Alzheimer's Association Workgroup's integrated clinical-biological staging scheme in outpatient settings within a tertiary memory clinic. The 2018 syndromal cognitive staging system, coupled with a binary biomarker classification, was implemented for 236 outpatients with cognitive concerns. The 2024 numeric clinical staging framework, incorporating biomarker staging, was specifically applied to 154 individuals within the Alzheimer's disease (AD) continuum. The 2024 staging scheme accurately classified 95.5% AD. Among these, 56.5% exhibited concordant clinical and biological stages (canonical), 34.7% demonstrated more advanced clinical stages than biologically expected (susceptible), and 8.8% displayed the inverse pattern (resilient). The susceptible group was characterized by a higher burden of neurodegeneration and inflammation than anticipated from tau, whereas the resilient group showed the opposite. The 2024 staging scheme is generally feasible. A discrepancy between clinical and biological stages is relatively frequent among symptomatic patients with AD. The 2024 AA staging scheme is generally feasible in a tertiary memory clinic. A discrepancy between clinical and biological stages is relatively frequent in AD. The mismatch may be influenced by a non-specific pathological process involved in AD. Individual profiles like aging and lifestyles may contribute to such a mismatch. Matched and mismatched cases converge toward similar clinical outcomes.

Comprehensive analysis of clinicopathological characteristics in oral squamous cell carcinoma arising from oral submucous fibrosis: a retrospective study

BackgroundOral squamous cell carcinoma arising from oral submucous fibrosis is recognized as a clinicopathologically distinct disease. This study aims to summarize and compare the population and clinicopathologic characteristics of OSCC-OSF with other OSCC in Hunan Province, China. The objective is to formulate treatment strategies more in line with regional characteristics.MethodsA retrospective review of OSCC cases recruited from the Second Xiangya Hospital from 2010 to 2020 was conducted. A total of 1,413 OSCC patients were selected, including 481 patients with OSCC-OSF and 932 were other OSCC. Population characteristics, risk factors and clinicopathological manifestations were explored in OSCC-OSF and other OSCC, as well as thinprep cytologic test and DNA quantification.ResultsWe found that OSCC-OSF patients were younger than those with other OSCC. Both types of disease were predominantly observed in males compared to females. Tumor biopsy analysis indicated that tumor cells within OSCC-OSF patients were more likely to be well differentiated and showed a higher frequency of lymph node metastases. Clinicopathological factors, such as the chewing betel nuts habit and smoking, were more prevalent in OSCC-OSF patients in contrast to other OSCC. DNA quantification revealed that the number of DNA aneuploid cells was higher in OSCC-OSF compared to other OSCCs.ConclusionIn this study, OSCC-OSF is considered a clinicopathologically distinct disease. Compared with other OSCC, OSCC-OSF patients have a higher incidence of nodal metastases, an early clinical TNM stage, and a lower three-year survival rate. Therefore, early diagnosis and treatment are crucial to improving the prognosis of OSCC-OSF.

Translational modelling to predict human pharmacokinetics and pharmacodynamics of a Bruton's tyrosine kinase-targeted protein degrader BGB-16673.

Bifunctional small molecule degraders, which link the target protein with E3 ubiquitin ligase, could lead to the efficient degradation of the target protein. BGB-16673 is a Bruton's tyrosine kinase (BTK) degrader. A translational PK/PD modelling approach was used to predict the human BTK degradation of BGB-16673 from preclinical in vitro and in vivo data. A simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo BTK degradation by BGB-16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD-8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model. BGB-16673 showed potent BTK degradation in mouse whole blood, human whole blood, and TMD-8 tumour cells in vitro. Furthermore, BGB-16673 showed BTK degradation in a murine TMD-8 xenograft model in vivo. The PK/PD model predicted human PD and the observed BTK degradation in clinical studies both showed robust BTK degradation in blood and tumour at clinical dose range. The presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.

Factors Affecting the Response of Triple-Negative Breast Cancer (TNBC) to Neoadjuvant Chemotherapy: A Meta-Analysis

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Neoadjuvant chemotherapy (NAC) is often used to downstage tumors before surgery, but response rates vary. This meta-analysis aims to identify factors that influence TNBC’s response to NAC. Methods: PubMed, Embase, and Cochrane Library databases were searched (2018-2024) for studies evaluating factors associated with TNBC response to NAC. Data on patient demographics, tumor characteristics, NAC regimens, and response rates were extracted. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models. Results: Twenty-three studies (n=4,512 patients) were included. Younger age (OR 1.82, 95% CI 1.35-2.46), smaller tumor size (OR 0.58, 95% CI 0.41-0.82), lower clinical stage (OR 0.39, 95% CI 0.27-0.56), and absence of lymph node involvement (OR 0.42, 95% CI 0.31-0.57) were associated with improved pathological complete response (pCR) rates. NAC regimens containing platinum agents (OR 2.15, 95% CI 1.54-2.99) and immune checkpoint inhibitors (OR 1.78, 95% CI 1.23-2.58) also showed higher pCR rates. Conclusion: This meta-analysis identified several factors associated with improved TNBC response to NAC, including younger age, smaller tumor size, lower clinical stage, absence of lymph node involvement, and use of platinum-based or immunotherapy-containing NAC regimens. These findings can inform patient selection and treatment optimization for NAC in TNBC.

Assessing renal function with the use of cystatin C in a rural cohort of people living with HIV on highly active antiretroviral therapy within the Limpopo Province, South Africa

The kidneys in people living with HIV (PLWH) are constantly exposed to highly antiretroviral therapy (HAART) which may cause renal dysfunction. Cystatin C (CystC), a biomarker of renal function, is well associated with renal impairment in various populations, however, it is underexplored in the South African population of PLWH, as compared to creatinine-based measurements. Creatinine-based measurements for assessing kidney function in people with HIV can be limited due to the influence of muscle wasting, altered creatinine metabolism, and the potential for certain antiretroviral medications to impact creatinine secretion. Therefore, the current study aimed to explore the effect of HAART on renal function among PLWH with the use of Cyst C-based measures. We conducted a cross-sectional study of 111 adults PLWH, 84 on HAART, and 27 on HAART-naïve. The cluster of differentiation 4 (CD4 +) count, plasma CystC, as well as the estimated glomerular filtration rate (eGFR) using the chronic kidney disease-epidemiology collaboration (CKD-EPI) formula, were determined. In the present study, no significant differences were observed between HAART-treated and HAART-naïve groups in terms of plasma CystC and eGFRCystC. Participants who were on HAART for > 5 years were significantly associated with eGFRCystC < 90 mL/min/1.73 m2, as indicated by substantial odds ratio of 4.39 (confidence interval: 1.60–12.02, p = 0.004) in the unadjusted analysis and even after adjustment for age, sex and smoking status, with odds ratio of 4.10 (confidence interval: 1.41–11.86, p = 0.009). Advanced World Health Organization (WHO) clinical stage significantly associated with eGFRCystC < 90 mL/min/1.73 m2 as indicated by odds ratio of 11.73 (confidence interval: 2.27–60.75, p = 0.003) in the unadjusted analysis. Even after adjusting for confounders which included age, sex, and smoking status, the association persisted, with an odds ratio of 16.71 (confidence interval: 2.57–108.75, p = 0.003). In conclusion, CystC and eGFRCystC levels were not different between PLWH on HAART and not on HAART but prolonged HAART use for over five years and advanced HIV disease were associated with reduced renal function in this population of PLWH on HAART, as assessed using CystC-based measures. These findings may suggest that HAART had initial beneficial effects and long-term adverse effects. The future risk of progressive eGFR decline may be increased in this HIV population on HAART due to the cumulative effect of prolonged tenofovir disoproxil fumarate (TDF) use. These findings remain important to guide future research with larger populations on the management of conditions related to renal function decline in PLWH.Highlights.

RCC-Supporter: supporting renal cell carcinoma treatment decision-making using machine learning

BackgroundThe population diagnosed with renal cell carcinoma, especially in Asia, represents 36.6% of global cases, with the incidence rate of renal cell carcinoma in Korea steadily increasing annually. However, treatment options for renal cell carcinoma are diverse, depending on clinical stage and histologic characteristics. Hence, this study aims to develop a machine learning based clinical decision-support system that recommends personalized treatment tailored to the individual health condition of each patient.ResultsWe reviewed the real-world medical data of 1,867 participants diagnosed with renal cell carcinoma between November 2008 and June 2021 at the Pusan National University Yangsan Hospital in South Korea. Data were manually divided into a follow-up group where the patients did not undergo surgery or chemotherapy (Surveillance), a group where the patients underwent surgery (Surgery), and a group where the patients received chemotherapy before or after surgery (Chemotherapy). Feature selection was conducted to identify the significant clinical factors influencing renal cell carcinoma treatment decisions from 2,058 features. These features included subsets of 20, 50, 75, 100, and 150, as well as the complete set and an additional 50 expert-selected features. We applied representative machine learning algorithms, namely Decision Tree, Random Forest, and Gradient Boosting Machine (GBM). We analyzed the performance of three applied machine learning algorithms, among which the GBM algorithm achieved an accuracy score of 95% (95% CI, 92–98%) for the 100 and 150 feature sets. The GBM algorithm using 100 and 150 features achieved better performance than the algorithm using features selected by clinical experts (93%, 95% CI 89–97%).ConclusionsWe developed a preliminary personalized treatment decision-support system (TDSS) called “RCC-Supporter” by applying machine learning (ML) algorithms to determine personalized treatment for the various clinical situations of RCC patients. Our results demonstrate the feasibility of using machine learning-based clinical decision support systems for treatment decisions in real clinical settings.

AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

Primary retroperitoneal lymph node dissection in testicular germ cell cancer in clinical stage IIA/B-renaissance of an established treatment?

The guideline-recommended treatment of choice for clinical stage IIA/B testicular germ cell tumors is chemotherapy with three cycles of PEB/four cycles of PE or, alternatively, radiation for seminomas. Despite their high curative efficacy, both options are associated with significant long-term toxicities. We evaluated the functional and oncological outcomes of primary retroperitoneal lymph node dissection (RPLND) as atherapeutic alternative. Between 2018 and 2022, 76patients (n = 34 seminomas, n = 42 nonseminomas) underwent primary RPLND for marker-negative clinical stage IIA/B testicular germ cell cancer. All patients underwent nerve-sparing RPLND with a unilateral or bilateral template dissection and had a follow-up ≥ 3months. None of the patients received adjuvant chemotherapy. In 24patients, the serum concentration of miR371a-3p was evaluated preoperatively. Follow-up was performed according to EAU guidelines. Median age and median follow-up were 30.1 (17-62)years and 29.3 (3-72)months, respectively. Mean operation time, blood loss, and duration of hospitalization were 131 (105-195) min, < 150 ml, and 4.5 (3-9) days, respectively. AClavien-Dindo IIIa complication was experienced by 8 (10.9%) patients. Antegrade ejaculation was preserved in 90.8%. Amean number of 19(7-68) lymph nodes were dissected. The mean number of positive lymph nodes was 1.1 (1-5), and the mean diameter of positive lymph nodes was 2.4 (0.8-4.6)cm. Eleven (14.5%) patients had stage pN0 (3/34 seminomas, 8/42 nonseminomas). In 24/27patients (88.9%) miR371 was positive, and it was negative in 4/4 with pN0 and 3/3 (100%) with teratoma. An outfield relapse was experienced by 7patients (9.2%), who then received salvage chemotherapy. Primary RPLND for marker-negative clinical stageIIA/B germ cell tumors results in high cure rates without adjuvant chemotherapy and is associated with alow rate of complications if performed in experienced hands. Therefore, primary RPLND should be included in the management of these patients.

Incidence of anaemia and its predictors among HIV-infected children receiving highly active antiretroviral treatment in North-West Ethiopia: a multicentre retrospective follow-up study

BackgroundAnaemia is one of the most common problems in HIV-infected patients associated with increased HIV progression, decreased functional capacity, survival and quality of life. For better interventions, up-to-date information concerning...