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A crucial cellular mechanism that has a complex impact on the biology of cancer, particularly in solid tumors, is autophagy. This review explores how metabolic processes trigger autophagy, which helps metastatic tumor cells go dormant and recur. During metastasis, tumor cells frequently encounter severe stressors, such as low oxygen levels and nutritional deprivation, which causes them to activate autophagy as a survival tactic. This process allows cancer stem cells (CSCs) to withstand severe conditions while also preserving their features. After years of dormancy, dormant disseminated tumor cells (DTCs) may reappear as aggressive metastatic cancers. The capacity of autophagy to promote resistance to treatments and avoid immune detection is intimately related to this phenomenon. According to recent research, autophagy promotes processes, such as the epithelial-to-mesenchymal transition (EMT) and helps build a pre-metastatic niche, which makes treatment strategies more challenging. Autophagy may be a promising therapeutic target because of its dual function as a tumor suppressor in early-stage cancer and a survival promoter in advanced stages. To effectively treat metastatic diseases, it is crucial to comprehend how metabolic processes interact with autophagy and affect tumor behavior. In order to find novel therapeutic approaches that can interfere with these processes and improve patient outcomes, this study highlights the critical need for additional investigation into the mechanisms by which autophagy controls tumor dormancy and recurrence., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Biochemical recurrence (BCR) of prostate cancer (PCa) negatively impacts patients' post-surgery quality of life, and the traditional predictive models have shown limited accuracy. This study develops an AI-based prognostic model using deep learning that incorporates androgen receptor (AR) regional features from whole-slide images (WSIs). Data from 545 patients across two centres are used for training and validation. The model showed strong performances, with high accuracy in identifying regions with high AR expression and BCR prediction. This AI model may help identify high-risk patients, aiding in better treatment strategies, particularly in underdeveloped areas., Competing Interests: Declarations. Competing interests: A patent related to this work is currently under review. The patent application was filed by Southeast University, with the following inventors: Xu Bin, Wang Xiangxue, Zhang Jiawei, Ding Feng, Yang Yifan, and Chen Ming. The application, filed under the number CN202311480504.3, is titled “A Method and System for Predicting AR Staining Image Classification Using H & E Image Features” and is currently in the application process. Ethics approval and consent to participate: This retrospective study was approved by the institutional review board of Zhongda Hospital, Southeast University, and Huai’an First People’s Hospital(No. 2021ZDSYLL353-P01), and the requirement for informed consent was waived. The study was enrolled in a clinical trial(No. ChiCTR2200065689)., (© 2025. The Author(s).)

Background: Estrogen receptor (ER) status in breast cancer (BC) is routinely determined by immunohistochemistry (IHC); however, this technique is not without limitations, including false results. Imaging of Cerianna TM (fluoroestradiol F18) injection provides high diagnostic accuracy of ER expression, supplementing information from biopsy. A Clinical Decision Support (CDS) tool was developed to better assess its clinical usefulness in metastatic and recurrent breast cancer management. This study evaluated a conceptual tool that reflects clinical practice variables., Methods: Individual patient characteristics - candidacy for therapeutic treatment and rate of recurrence - determined initial eligibility. The CDS tool uses rules (IF-THEN statements) to produce an output on the diagnostic accuracy of ER status based on tumor burden, anatomical location(s) of metastasis, heterogeneity, and confidence in sample collection & pathology accuracy (CSC & PA). An Excel-based probability decision tree calculates the accuracy of ER expression., Results: 360 oncologists in the United States participated in the survey study. 223 respondents identified as medical oncologists (62%), 77 as clinical oncologists (21%), and 60 as hematologic oncologists (17%). 93% of respondents found the CDS tool intuitive and easy to follow with medical and clinical oncologists favoring the tool more than hematologic oncologists. Individual CDS attributes - clinical criteria, diagnostic comparator, true positive and true negative, patient inclusion and exclusion, and clinical patient level inputs - were tested with overall positive feedback., Conclusions: Based on respondent feedback, further development of CDS tools are warranted for potential use in patients' diagnostic workup., Competing Interests: Disclosure This study was funded by GE HealthCare. The funder provided support in the form of salaries for authors and funded the data collection executed by Eversana but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Backgrounds: SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity., Methods: Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival., Results: SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis., Conclusions: In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Oncotype DX is the only multigene assay supported by the National Comprehensive Cancer Network (USA) with Level 1 evidence for use on node-negative and postmenopausal node-positive patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)-breast cancer to predict the prognosis and to estimate chemotherapy add-on effects. However, the test's high cost prevents its use in most cases. Therefore, we aimed to obtain an alternative recurrence score (RS) prediction formula using the optimal clinicopathological factors. We retrospectively reviewed data of 81 patients with ER+/HER2- primary breast cancer in our hospital where Oncotype DX RS was measured. Stepwise multivariate linear regression analysis was conducted with several selected clinicopathological factors of 60 consecutive cases in the training group. The obtained RS-predicted values were validated against Oncotype DX RS using 21 additional consecutive cases. The RS prediction formula derived from the combination of ER, tumor-infiltrating lymphocytes (TILs), progesterone receptor (PgR), and Ki-67-labeling index produced a favorable model with a correlation coefficient (r) of 0.731103 for the Oncotype DX RS (p = 0.0002) and an adjusted R 2 coefficient of 0.510013. The RS-predicted values and the actual Oncotype DX RS were classified into four 2 × 2 groups, by using an RS of 26 as a threshold for adding chemotherapy with a concordance rate of 95.2 % (20/21) and a kappa coefficient of 0.829. RS-predicted values of combined ER, TILs, PgR, and Ki-67 may be an appropriate substitute for Oncotype DX RS in certain situations., Competing Interests: Declaration of competing interest I have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

DEAD-box helicase 21 (DDX21) is a conserved Asp-Glu-Ala-Asp (DEAD) box RNA helicase with multiple functions that is involved in various cellular processes and diseases. However, the role of DDX21 in the recurrence and prognosis of hepatocellular carcinoma (HCC) patients remains unknown. In the current study, we examined the protein expression of DDX21 in HCC tissues through immunohistochemical staining and analyzed the correlation between DDX21 protein expression and clinical outcome via Kaplan-Meier survival analysis. The Cox proportional hazards regression model was used to assess the interrelationships between the outcome and variable over time. Our results showed that increased expression of DDX21 protein was observed in HCC tissues compared with paracancerous tissues and was associated with advanced BCLC stage. Recurrent HCC patients had higher levels of DDX21 protein than nonrecurrent cases. Notably, DDX21 was an independent risk factor for predicting worse overall survival and recurrence-free survival in HCC patients. Furthermore, lack of DDX21 abated the growth and mobility of Hep3B cells. Taken together, our data highlight the clinical significance of DDX21 in the recurrence and prognosis of HCC patients and indicate that targeting DDX21 may represent an effective therapeutic strategy for the treatment of HCC., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Chengjie Ji et al. Analytical Cellular Pathology published by John Wiley & Sons Ltd.)

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA + Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA + Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4 + /CD8 + T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA + B cells are adjacent in the TME. Notably, tumor infiltrating CD8 + T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1 + CD8 + T cells and VISTA + Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the local Ethical Committes (“Area Vasta Emilia Nord”, protocol number 0018007/21; “Comitato Etico della Romagna”, protocol number 7043/2021). All participants involved in this study provided written informed consent for both sample collection and data analyses. Detailed clinical information and the analysis methods employed for each sample are reported in Supplementary Table 1. Competing interests: All authors declare no competing interests., (© 2025. The Author(s).)

Purpose: In-vivo proton magnetic resonance spectroscopy (MRS) is a non-invasive method of analyzing choline metabolism that has been used to predict breast cancer prognosis. A strong choline peak may be a surrogate for aggressive tumor biology but its clinical relevance is unclear. The present study assessed whether total choline (tCho), as measured by proton MRS, can predict late recurrence in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer., Methods: The study cohort included 261 HR+/HER2- breast cancer patients who underwent diagnostic single-voxel proton MRS (3.0T scanner) prior to first-line surgery from March 2011 to July 2014. The relationships between tCho compound peak integral (tChoi) values and others prognostic factor were analyzed, as were the effects of tChoi on 10-year disease-free survival (DFS) and overall survival (OS). The clinical significance of tChoi was also analyzed using Harrell's C-index., Results: Mean tChoi in HR+/HER2- study group was 15.47 and we set the cut-off for tChoi at 15 for survival analysis. 10-year DFS differed significantly between tChoi <15 and ≥15 (p = 0.017), with differences differing significantly for late (5-10 years; p = 0.02) but not early (0-5 years; p = 0.323) recurrence. Cox regression analysis showed that tChoi was significantly predictive of 10-year DFS (p = 0.046, OR 2.69) and tended to be predictive of late recurrence (HR 4.36, p = 0.066). Harrell's C-index showed that the Ki-67 index (AUC = 0.597) and lymphovascular invasion (AUC = 0.545) were also predictive of survival, with the addition of normalized tChoi improving the AUC to 0.622 (p = 0.014), indicating better predictive power., Conclusion: tChoi determined by in vivo MRS was predictive of prognosis in patients with HR+/HER2- early breast cancer. This parameter may serve as a valuable, non-invasive tool to predict prognosis when combined with other known prognostic factors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to investigate the influence of p16 immunohistochemical expression on the biochemical recurrence rate of pT2-pT3 prostate cancer., Materials and Methods: A total of 488 pT2-pT3 stage prostate adenocarcinomas undergoing radical prostatectomy were included in this study. Following a review of Gleason classification and retrieval of sociodemographic and clinicopathological data, as well as the date of last consultation and biochemical recurrence, immunohistochemistry for p16 was performed. Data were associated using the chi-square test, Fisher's exact test, and multinomial logistic regression model., Results: A total of 432(94.5%) cases showed positivity for p16 with an average of 37.38±27.32% positive cells and a mean histoscore of 2.70±2.24. A total of 117 (18.4%) patients experienced biochemical recurrence within three years, which was directly associated with high preoperative PSA (p=0.007), positive surgical margins (p<0.001), pT3 staging (p<0.001), nodal involvement (p<0.001), Gleason score > 3+4 (p<0.001), <50% positivity for p16 (p=0.035), and histoscore p16 =<3 (p=0.004). In multivariate analysis, Gleason score > 3+4 (HR = 3.08 (95% CI = 1.69-5.62), positive surgical margins (HR = 2.93 (95% CI = 1.70-5.04), and histoscore p16 =<3 (HR = 2.49 (95% CI = 1.17-5.32) were predictors of biochemical recurrence within three years., Conclusion: p16 immunostaining, along with classical features such as Gleason Score and surgical margin involvement, are significant predictors of biochemical recurrence in pT2-pT3 prostate tumors.

Objective: We sought to determine the safety and efficacy of the oral progesterone antagonist onapristone in combination with anastrozole in patients with recurrent progesterone receptor-positive adult-type granulosa cell tumor of the ovary., Methods: This was a single-institution phase II study of patients with progesterone receptor-positive adult-type granulosa cell tumor who received at least 1 prior line of chemotherapy. Patients were enrolled from November 2021 to August 2022 and tissue was evaluated for progesterone receptor status via immunohistochemistry. Eligible patients had progesterone receptor expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone extended-release twice daily and 1 mg of anastrozole by mouth daily until progression of disease or discontinuation of treatment. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary end point was the overall response rate by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were response duration, clinical benefit rate, progression-free survival, and safety., Results: Fourteen patients with adult-type granulosa cell tumor enrolled and completed stage 1 accrual. There were no objective responses seen during the study period. The study was closed when further development of onapristone extended-release was discontinued. All 14 patients were evaluable, with median progression-free survival of 3.6 months (range; 1.7-7.1), a 6-month progression-free survival rate of 28.6% (range; 8.8%-52.4%), a 12-month progression-free survival rate of 10.7% (range; 0.8%-35.4%), and a clinical benefit rate of 42.9% (range; 17.7%-71.7%)., Conclusion: The study did not meet its primary end point. Although the combination of onapristone extended-release and anastrozole was well-tolerated, there were no objective responses in patients with progesterone receptor-positive adult-type granulosa cell tumor., Competing Interests: Declaration of Competing Interests B.W. reports a research grant from REPARE Therapeutics paid to the institution and has an immediate family member who is employed by AstraZeneca, outside the submitted work. D.S.C. reports personal fees from AstraZeneca, Biom’Up, and Verthemia; he also has stock in BioN Tech and Doximity. V.M. reports institutional grants or contracts from AstraZeneca, Bristol Myers Squibb, Cullinan Oncology, DualityBio, Eisai, Faeth Therapeutics, Karyopharm Therapeutics, Merck, Takeda, and Zymeworks; personal meeting/travel support from AstraZeneca and Karyopharm; and consultant relations (unpaid) from Clovis Oncology, Cullinan Oncology, DualityBio, Eisai, Faeth Therapeutics, GlaxoSmithKline, Immunocore, iTeos Therapeutics, Karyopharm Therapeutics, Lilly, Merck, Mereo BioPharma, MorphoSys, MSD, Novartis, Regeneron, Sutro Biopharma, and Zymeworks. R.G. reports honoraria from GlaxoSmithKline, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. C.A. reports clinical trial funding paid to institution from AbbVie - MSKPI - GOG 3005; AstraZeneca - MSK PI, SOLO1/GOG 3004; National Coordinating Investigator and MSK PI, DO81RC00001; ENGOT-ov46; AGO-OVAR 23; GOG-3025; Clovis - MSK PI, ARIEL 2 &3; Genentech/Roche - MSK PI, GOG3015 (IMagyn050). She also participates on an Advisory Board for Blueprint Medicine - Advisory Board 6/30/21 (no consulting fee); Merck - Global Cervical and Ovarian Cancer Virtual Advisory Board 7/10/23 (no consulting fee) and AstraZeneca - AZ Evolve dmc 4/26/23-ongoing. She also serves on the GOG Foundation, Board of Directors (unpaid, occasional travel cost reimbursement to attend meetings), and NRG Oncology Board of Directors (unpaid). R.O. reports funding paid to the institution from Bayer/Celgene/Juno, Arsenalbio, Tesaro/GSK, Merck, Ludwig Cancer Institute, AbbVie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Genentech, Alkermes/Mural Oncology, Kite Pharma, Acrivon, OnCusp Therapeutics, and Gynecologic Oncology Foundation, Lyell Immunopharma; payments for lectures from GSK, Curio/Onclive/PER/MJH/Aptitude Health, SITC, Gynecologic Oncology Canada; support for meetings/travel from Hitech Health, Gathering Around Cancer (Ireland), GOG Foundation, SGO; steering committee participation (unpaid) from AstraZeneca (DU0-0) GSK (Moonstone, Prima) Acrivon Mural Oncology, OnCusp Therapeutics; advisory role (unpaid) from Carina Biotech, Link therapeutics; advisory board participation from Seattle Genetics/SeaGen/Pfizer Immunogen, Bayer, R-Pharm, Miltenyi, 2seventybio, Bayer, Loxo, OnCusp Therapeutics, GSK; and leadership positions at CPC, SGO (Vice Chair) and NRG Oncology (Chair, DT Committee). C.F. reports ongoing institutional research support from Merck, Bristol Myers Squibb, AstraZeneca, Mersana, Hotspot Therapeutics, Immunocore, Marengo, and Volastra; consulting fees from Bristol Myers Squibb, Seagen, Aadi Biosciences, and Eli Lily; honoraria for lectures from OncLive; meeting/travel support by Puma Biotechnology; and participation on data safety monitoring board or advisory board of Merck, Genentech, and Marengo (all uncompensated). C.K. received honoraria from OncLive, and Total Health, consults/has consulted for Scenic Immunology BV, and has received research funding from Bristol Myers Squibb, Merus, Gritstone bio, and Acrivon. The other authors report no disclosures., (Copyright © 2024 European Society of Gynaecological Oncology and the International Gynecologic Cancer Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to investigate the potential for using the phosphatase and tensin homolog (PTEN) gene as a prognostic marker in post-prostatectomy patients with castration-sensitive prostate cancer (PCa)., Methods: A total of 180 patients with castration-sensitive PCa who underwent radical prostatectomy at our institution were included in this study. PTEN expression was evaluated using immunohistochemistry, and patients were classified into two groups based on the staining intensity: PTEN-Normal and PTEN-Loss. The association between PTEN expression and biochemical recurrence was analyzed using the Cox proportional hazards model., Results: Patients in the PTEN-Loss group had a higher risk of biochemical recurrence (hazard ratio, 4.642; 95% confidence interval, 2.137-10.083; p < 0.001) and a lower recurrence-free rate compared to the PTEN-Normal group (35% vs. 75%). In addition to clinicopathological factors, such as the serum prostate-specific antigen level, Gleason score, and T stage, evaluation of PTEN expression improved the prediction of biochemical recurrence after prostatectomy (area under the curve, 0.577 vs. 0.688)., Conclusions: Low PTEN expression is a significant predictor of biochemical recurrence in patients with castration-sensitive PCa who have already undergone prostatectomy., (© 2024 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Purpose: To analyze the predictive capacity for local disease control of the transcriptional expression of neogenin-1 (NEO1) gene in patients with head and neck squamous cell carcinoma (HNSCC)., Methods/patients: A retrospective study was performed on tumor biopsies from 107 patients with HNSCC treated surgically. The transcriptional expression of NEO1 was determined by RT-PCR. NEO1 transcriptional expression value was categorized according to local disease control by recursive partitioning analysis., Results: Lower NEO1 transcriptional expression was associated with worse local control after surgical treatment. Patients with lower NEO1 expression (n = 25, 23.4%) had a 5-year local recurrence-free survival of 61.8% (95% CI: 42.1-81.5%), while patients with higher NEO1 expression (n = 82, 76.6%) had a 5-year local recurrence-free survival of 85.6% (95% CI: 77.6-93.6%), (P = 0.003). According to the result of multivariable analysis, patients with lower NEO1 expression had a 2.7-fold increased risk of local tumor recurrence (95% CI: 1.0-7.0, P = 0.043) compared to patients with higher NEO1 expression., Conclusions: HNSCC patients with a lower transcriptional expression of NEO1 have a significantly higher risk of local recurrence after surgical treatment., Competing Interests: Declarations. Conflict of interest: The authors declare that they do not have any conflict of interest. Ethical approval: The study has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. The study was approved by the Hospital de Sant Pau Institutional Review Board of the center (IIBSP-CCC-2022-108). Informed consent: All patients provided informed consent for tissue analysis., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer, with 5-10% of cases progressing into invasive disease. Herein, we investigated the association between HER2-low and clinico-pathological characteristics in DCIS and subsequent ipsilateral loco-regional relapse (LRR)., Materials and Methods: We accessed our prospectively maintained institutional database. HER2 status was determined by immunohistochemistry and classified as null (score 0), over-expressed (3+), and low (1+ or 2+); in situ hybridization was not considered since it is not used for routine DCIS diagnostics., Results: Among 375 patients with DCIS, median age was 54 (27-88) years, with a primary tumor size < 2.5 cm in 63%, grade III in 33%, and positive hormone receptor status (HR) in 81% of cases; 71% underwent breast-conserving surgery, 34% received adjuvant endocrine and 39% radiotherapy. A total of 197 (52%) had tumors with low HER2 expression, which resulted significantly associated with grade I/II (P < .001), Ki67< 20% (P < .001), and HR-positive status (P < .001). HER2-low distribution varied from 19.61% and 50% in ER negative and ER-low (<10%) to 60% and 69% in ER high (50%-95%) and very high tumors (> 95%) (P < .001). After a median 39-month follow-up (IQR 16-65), cumulative incidences of LRR was 0.054. Among 17 patients with paired primary tumor and LRR, 5 had discordant HER2 status, with an even distribution of increased and decreased HER2 expression., Conclusions: Low HER2 expression in DCIS is associated with features of reduced aggressiveness. Importantly, changes in HER2 expression may occur prompting retesting in recurrent cases, in line with observations in invasive breast cancer., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lung cancer remains a leading cause of global cancer‑related deaths, therefore the identification of prognostic factors for lung cancer is critical. Casein kinase 2 alpha (CK2α) is one of the driver kinases in various cancers, and it was previously demonstrated that CK2α localization was associated with a poor prognosis in invasive breast cancer. In the present study, the importance of CK2α in the nucleolus was explored as a potential prognostic marker for surgically resected early‑stage lung adenocarcinoma. The present study included 118 patients who underwent pulmonary lobectomy between 2014 and 2018 in Fukushima Medical University Hospital (Fukushima, Japan), and in whom CK2α localization in tumor samples was assessed by immunohistochemistry. Patient and tumor characteristics, including pathological stage, histological type and histological grade, were analyzed. Recurrence‑free survival (RFS) and overall survival were evaluated in relation to nucleolar CK2α staining. CK2α staining in the nucleoli was observed in 50.8% of lung adenocarcinoma tumors. Positive nucleolar CK2α staining was independent of pathological stage, histological type and histological grade. Patients with positive nucleolar CK2α staining exhibited significantly worse RFS compared with patients with negative staining. Multivariate analysis identified nucleolar CK2α staining and lymph node metastasis as independent poor prognostic factors. The results of the present study suggested that nucleolar CK2α staining is a novel and independent prognostic factor in surgically resected early‑stage lung adenocarcinoma. These findings indicated the potential of nucleolar CK2α as a predictive biomarker for future recurrence, and a guide to treatment decisions. Further research is required, particularly in understanding the molecular mechanisms linking nucleolar CK2α to recurrence.

Purpose: The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dose. However, the clinical significance of endoxifen for the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication., Materials and Methods: The study included 478 breast cancer patients. Tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry. An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff., Results: An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and the high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% confidence interval [CI], 77.0 to 89.9) and 88.3% (95% CI, 83.3 to 93.5) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor associated with prognosis., Conclusion: Endoxifen could serve as a marker for appropriate tamoxifen treatment with a cutoff of 21.00 ng/mL. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying suboptimal endoxifen concentrations.

Background: To evaluate how prostate-specific antigen (PSA) levels decrease after removal of isolated prostate cancer (PCa) nodal metastases in relation to their diameter/volume ("PSA-density of PCa-metastases") and maximum standardized uptake value (SUV max )., Methods: A total of 83 consecutive patients with solitary nodal recurrence after radical prostatectomy who underwent prostate-specific membrane antigen-radioguided salvage surgery were retrospectively analyzed. Using multivariable linear regression models, the PSA-decrease after removal of each PCa-metastases (=PSA-contribution of each PCa-metastases) was correlated with the long axis diameter/estimated volume and the SUV max of each removed metastasis. Sizes were measured by imaging and histopathologic examination., Results: A total of 83 patients were included with a median (interquartile range [IQR]) PSA-decrease of 0.56 [0.22, 1.31] ng/mL after salvage surgery. The median [IQR] long axis diameters in imaging and histopathological examination were 8.0 [6.0, 11.0] mm and 8.4 [5.5, 11.1] mm, respectively. The median [IQR] estimated volumes were 0.13 [0.05, 0.32] cc (imaging) and 0.05 [0.02, 0.17] cc (pathology). In multivariable linear regression analyses, the estimated PSA-contribution ([95% confidence interval [CI]) of each millimeter of long axis diameter was 0.09 [0.03, 0.14] ng/mL (imaging) or 0.08 [0.03, 0.12] ng/mL (histology). The minimum diameter for biochemical recurrence (PSA ≥ 0.2 ng/mL) was >2.2 mm (imaging) or >2.5 mm (histology). The estimated PSA-contribution [95% CI] of each cc cancer volume was 1.23 [0.51, 1.94] ng/mL (imaging) or 1.46 [0.40, 2.52] ng/mL (histology). SUV max as surrogate parameter for tissue composition was associated with increased PSA-contribution of PCa-metastases (+0.03-0.05 ng/mL per unit increase)., Conclusions: The diameter/volume and SUV max of metastatic tissue correlate with its contribution to PSA levels. Therefore, very small metastases may produce too little PSA for biochemical recurrence., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

SPiReL is a phase II clinical trial evaluating combination immunotherapy, pembrolizumab and cyclophosphamide, with maveropepimut-S, in survivin-expressing relapsed/refractory (R/R) Diffuse Large B Cell Lymphoma (DLBCL). We describe baseline tumor survivin expression and associations with clinico-pathological variables in 25 participants. The median number of survivin-expressing cells was 99%, and the intensity of survivin expression within tumors was heterogeneous by semi-quantitative immunohistochemistry assessment. Tumors with higher numbers of cells expressing 2+/3+ survivin were associated with characteristics of poor outcome, (Lactate dehydrogenase and cell-of-origin). Greater total baseline tumor area was associated with lower proportions of 1+ cells and greater proportions of 2+/3+ cells. High intensity survivin expression is associated with aggressive clinical features supporting a pathobiological role in R/R DLBCL. Future prognostic models incorporating survivin as a clinical biomarker require assessment of intensity, overall expression and should include potential threshold effects of survivin in DLBCL pathobiology.

Objective: Explored the correlation between CD1a expression in recurrence and prognosis of ovarian cancer (OV)., Methods: The CD1a expression profile in OV, recurrent OV, and normal tissues, as well as corresponding clinical data, were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Gene Expression Omnibus (GEO), and Genotype Tissue Expression (GTEx) databases. Meanwhile, immunohistochemical detection of CD1a expression in normal and OV tissues. Kaplan-Meier curves were plotted to estimate the hazard ratio (HR) of survival in OV. In addition, the correlation between CD1a and immune cells in OV, as well as the CD1a expression profile and corresponding survival time in pan-cancer were obtained from TCGA database., Results: CD1a was overexpressed in OV and was significantly under-expressed in recurrent OV (TCGA-OV, p < 0.0001 and ICGC-OV, p < 0.0001). CD1a immunohistochemistry is significantly overexpressed in OV compared to normal tissue (p < 0.05). Recurrent OV (ICGC, p < 0.001; GSE17260, p < 0.001; GSE32062, p < 0.05). The prognosis in OV was significantly better when CD1a is overexpressed compared to under-expressed (HR [low], 1.426: 95% confidence interval [CI], 0.912-2.128; p = 0.050). Meanwhile, the overexpression of CD1a has a better prognosis than low expression in OV and recurrent OV (p = 0.004, HR [low] = 2.462, 95%CI [1.346-4.504] and p = 0.011, HR [low] = 2.199, 95%CI [1.202-4.024]). In addition, CD1a expression was closely correlated with immune cells, the CD8+ T cells, macrophages, and NK cells, while uncharacterized cells were significantly different (p = 2.65e-6, p = 7.52e-13, p = 8.28e-12, and p = 5.89e-8, respectively). Moreover, CD1a expression affected the prognosis in various other cancers., Conclusions: CD1a expression affected the recurrence and prognosis of OV and is closely related to various immune cell levels., (© 2024 Japan Society of Obstetrics and Gynecology.)

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common subtype, representing over two-thirds of new diagnoses. Adjuvant therapy, which encompasses various medications and treatment durations, is the standard approach for managing early stage HR+ HER2- breast cancer. Optimizing treatment is essential to minimize unnecessary side effects while addressing the biological variability inherent in HR+/HER2- breast cancers. Incorporating biological biomarkers into treatment decisions, alongside traditional clinical factors, is vital. Gene expression assays can identify patients unlikely to benefit from adjuvant chemotherapy, thereby refining treatment strategies and improving risk assessment. This paper reviews evidence for several genomic tests, including Oncotype DX, MammaPrint, Breast Cancer Index, RucurIndex, and EndoPredict, which assist in tailoring adjuvant therapy. Additionally, we explore the role of liquid biopsies in personalizing treatment, emphasizing the importance of considering late relapse risks and potential benefits of extended systemic therapy for HR+/HER2- breast cancer patients.

Sushi domain-containing protein 2 (SUSD2), a transmembrane protein containing a sushi motif, has been reported to have tumor-promoting functions in various types of cancer, including breast cancer. However, the regulatory mechanism of SUSD2 and its function in HER2-positive (HER2+) breast cancer have not been fully identified as yet. In this study, we explored the potential of targeting SUSD2 to overcome trastuzumab (TRZ) resistance in HER2+ breast cancer. SUSD2 expression was found to be significantly increased in HER2-overexpressing cells. Endogenous SUSD2 expression was observed in HER2+ breast cancer cells but not in estrogen receptor-positive or triple-negative breast cancer cells. We also found that SUSD2 expression was positively correlated with HER2 expression in a publicly available human primary breast cancer dataset. Although SUSD2 expression was associated with HER2, its expression levels were not affected by TRZ. Through kinase array experiments, we found that SUSD2 expression was modulated downstream of STAT3-dependent signaling in breast cancer cells overexpressing HER2. STAT3 activity was increased in EGFR+ HER2+ breast cancer cells compared to EGFR+ cells. Furthermore, we observed that SUSD2 expression was decreased by C188-9, a STAT3-specific inhibitor. Finally, we analyzed the association between patient survival and SUSD2 expression in breast cancer. Our results showed that SUSD2 expression had a negative correlation with the relapse-free survival of patients with EGFR+ HER2+ breast cancer when compared to EGFR+ breast cancer patients. Collectively, our results demonstrate that SUSD2 expression is mediated by STAT3 and imply the potential of using SUSD2 as a biomarker to stratify HER2+ breast cancer.

Purpose: The objective of the current research was to assess the clinicopathological characteristics and long-term prognosis of triple-negative breast cancer (TNBC) patients with human epidermal growth factor receptor 2 (HER2)-low status following breast surgery., Methods: A total of 202 TNBC patients treated at Qingdao Central Hospital from January 2010 to December 2019 were included, comprising 71 HER2-low and 131 HER2-zero patients. Propensity score matching (PSM) was applied to minimize differences between the cohorts., Results: HER2-low TNBC patients had lower histological grade, lower Ki-67 expression levels, and a higher prevalence of hypertension compared to HER2-zero TNBC patients. Before and after PSM, the HER2-low group consistently exhibited a lower recurrence rate and longer RFS compared to HER2-zero TNBC patients. HER2-low status was validated as an independent low-risk factor for RFS both pre-PSM (HR 0.354, 95% CI 0.178-0.706, p = 0.003) and post-PSM (HR 0.405, 95% CI 0.185-0.886, p = 0.024). No statistically significant differences in mortality rate and OS were observed, both before and after PSM., Conclusions: HER2-low and HER2-zero TNBC patients show significant clinicopathological differences. Compared to HER2-zero, HER2-low status is linked to better long-term prognosis and serves as an independent low-risk factor for RFS in TNBC patients., Competing Interests: Declarations. Ethical approval: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Qingdao Central Hospital. Written informed consent requirement was waived by the Ethics Committee. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The resistance of colorectal cancer liver metastases (CRLMs) to 5-fluorouracil (5-FU) chemotherapy remains a significant global health challenge. We investigated the phosphoproteomic dynamics of serial tissue sections obtained from initial metastases and recurrent tumors collected from 24 patients to address this unmet need for innovative therapeutic strategies for patients with CRLM with a poor prognosis. Our analysis revealed the activation of PAK kinase in patients with CRLM with a poor prognosis. Using an unbiased computational approach, we conducted a correlation analysis between PAK1 kinase activity and 545 drug sensitivity profiles across 35 colorectal cancer cell lines and identified PI3K inhibitors as potential therapeutic candidates. The efficacy of the FDA-approved PI3K inhibitor copanlisib was validated in 5-FU-resistant cell lines with high PAK1 kinase activity both in vitro and in vivo. This study presents an effective strategy for drug target discovery based on kinase activity, and the concept of this approach is widely applicable., Competing Interests: Declaration of interests T.T. and J.A. are co-founders of Proteobiologics Co., Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We aim to explore the impact of excessive glutathione (GSH) intake on chemotherapy sensitivity in breast cancer., Methods: Clinicopathological data were collected from 460 breast cancer patients who underwent adjuvant chemotherapy from January 2016 to December 2019 from Zhengzhou University People's Hospital. The clinicopathological characteristics following GSH treatment were collected and compared with those in Non-GSH group after 1:2 propensity score matching (PSM). Intracellular GSH levels and the expression of antioxidant enzymes (NRF2, GPX4 and SOD1) were evaluated in tumor tissues in 51 patients receiving neoadjuvant chemotherapy., Results: The recurrence rate after adjuvant chemotherapy was significantly higher in the GSH group (n = 28, 31.8%) than that in the Non-GSH group (n = 39, 22.2%; P = 0.010). Additionally, patients in the HGSH group (high GSH intake, ≥ 16 days) exhibited an elevated recurrence rate compared to that in the LGSH group (low GSH intake, < 16 days) (n = 15 (46.8%) vs. n = 52 (22.4%); P = 0.003). Cox regression revealed that High GSH intake, Ki67 ≥ 30%, Triple negative and Lymphovascular invasion were independent risk factors of progression after adjuvant chemotherapy. Among patients receiving neoadjuvant chemotherapy, intracellular GSH levels and the expression levels of antioxidant enzymes (NRF2, GPX4 and SOD1) in the resistant patients were substantially higher (P < 0.001)., Conclusions: Excessive GSH intake may contribute to chemotherapy resistance in breast cancer, and the levels of intracellular GSH and antioxidant enzymes are elevated in resistant patients after neoadjuvant chemotherapy, indicating that the standardization of GSH intake may assist in reducing chemotherapy resistance., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of Zhengzhou University People’s Hospital. All patients or their families provided written informed consent. Consent for publication: We confirm that the manuscript has been read and approved by all named authors, and that there are no other persons who satisfied the criteria for authorship but are not listed. We also confirm that the order of the authors listed in the manuscript has been approved by all of us. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Small cell lung cancer (SCLC) is a lethal and recalcitrant malignancy with early metastases. However, the molecular and cellular mechanisms underlying its aggressive characteristics remain relatively elusive., Methods: In this study, we conducted a comprehensive proteomic analysis of 90 primary tumors, 15 patient-matched lymph node metastatic tumors, and 15 brain metastatic tumors derived from a cohort of 105 SCLC patients. The potential mechanism for SCLC metastasis was investigated based on the variety of protein expression profiles., Results: Primary tumors were divided into two categories according to the their different protein expression profiles, using metastatic tumors as reference. Proteomic comparisons across different groups revealed that lipid metabolism, especially phospholipid metabolism, and immune response had a critical role in SCLC metastasis. Additionally, it was shown that high- and low-density lipoprotein cholesterol were both independent prognostic factors for disease free survival of SCLC patients. To identify critical regulators of metastasis in SCLC, support vector machine was adopted to generate a biomarker combination of ten proteins, all of which significantly correlated with the infiltration of immune cells. Furthermore, it was demonstrated that high expression of phospholipase A2 group IIA in stroma was associated with delayed disease recurrence in limited stage SCLC., Conclusions: This study highlighted the critical significance of lipid metabolism, especially phospholipid metabolism in the disease recurrence and metastasis of SCLC., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Commitee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (23/032-3771). Written informed consent was exempted by the Institutional Review Board. Consent for publication: Not applicable. Competing interests: All authors declare no competing interests., (© 2024. The Author(s).)

Object: Aim to investigate the multi-omic characteristics of the bone marrow supernatant of relapsed acute myeloid leukemia (AML) and search for proteins and metabolites associated with relapse., Methods: A total of 40 bone marrow supernatant from 7 patients with relapsed AML and 33 patients with non-relapsed AML were collected for proteomics and metabonomics analysis. Unsupervised clustering was used to discover the characteristics of proteins and metabolites. The prognostic significances of proteins were assessed concerning the relapse status(including death) and relapse-free survival., Result: Totally 996 proteins and 4,831 metabolites were identified in bone marrow supernatant, and two of 7 clusters were revealed through unsupervised clustering and were associated with ASXL1, TP53, and RUNX1 mutations, which were listed as high-risk factors in the 2022 edition of the WHO classification of tumors of the hematopoietic and lymphoid tissues. Among the identified proteins and metabolites, 57 proteins and 190 metabolites were found to be closely related to relapse., Conclusion: This study has revealed a significant correlation between protein expression in the bone marrow microenvironment of AML and three high-risk mutations: ASXL1, TP53, and RUNX1. Based on this finding, we further identified 227 differential proteins closely associated with these three mutations, as well as 57 proteins directly related to disease recurrence. Additionally, lipid metabolism plays a crucial role in the occurrence and development of AML within its bone marrow microenvironment., Competing Interests: Declarations. Ethics approval and consent to participate: The application for exemption of informed consent for this study has been approved by the Ethics Committee of Chongqing General Hospital.(Ethics Review number: KY S2022-008-01). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor characterized by a high infiltration capability and recurrence rate. Early diagnosis is crucial to improve the prognosis and to personalize the therapeutic approach. This research explored, by LC-MS proteomic analysis after proteolytic digestion, the molecular profile of pre- and post-operative saliva pools from newly diagnosed (ND) GBM patients by comparing different times of collection and tumor recurrence (R). CYCS, PRDX2, RAB1C, PSMB1, KLK6, TMOD3, PAI2, PLBD1, CAST, and AHNAK, all involved in processes of tumor invasiveness and chemo- and radio-resistance, were found to depict the pre-surgery saliva of both ND and R GBM. PADI4 and CRYAB proteins, identified among the most abundant proteins exclusive of ND GBM pre-surgery saliva and classified as proteins elevated in glioma, could have a potential role as disease biomarkers. Selected panels of S100 proteins were found to potentially differentiate ND from R GBM patient saliva. TPD52 and IGKV3, exclusively identified in R GBM saliva, could be additionally distinctive of tumor relapse. Among the proteins identified in all pools, label-free relative quantitation showed statistically significant different levels of TXN, SERPINB5, FABP5, and S100A11 proteins between the pools. All of these proteins showed higher levels in both ND&#95; and R&#95;T0 pre-surgery saliva with respect to CTRL and different modulation after surgery or chemo-radiotherapy combined treatment, suggesting a role as a potential panel of GBM predictive and prognostic biomarkers. These results highlight and confirm that saliva, a biofluid featured for an easily accessible and low invasiveness collection, is a promising source of GBM biomarkers, showing new potential opportunities for the development of targeted therapies and diagnostic tools.

The intricate cellular process, known as the epithelial-mesenchymal transition (EMT), significantly influences solid tumors development. Changes in cell shape, metabolism, and gene expression linked to EMT facilitate tumor cell invasion, metastasis, drug resistance, and recurrence. So, a better understanding of the intricate processes underlying EMT and its role in tumor growth may lead to the development of novel therapeutic approaches for the treatment of solid tumors. This review article focuses on the signals that promote EMT and metabolism, the intracellular signaling pathways leading to EMT, and the network of interactions between EMT and cancer cell metabolism. Furthermore, the functions of EMT in treatment resistance, recurrence, and metastasis of solid cancers are covered. Lastly, treatment approaches that focus on intracellular signaling networks and metabolic alterations brought on by EMT will be discussed., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Mesenchymal tumors may display morphologic and immunohistochemical overlap with melanocytic tumors, presenting a pitfall for misdiagnosis. We report a 62-year-old woman who presented with a recurrent dermal and subcutaneous tumor over the Achilles tendon 15 years following complete excision. Both the primary and the recurrent tumors were characterized by nests and sheets of epithelioid and spindle cells with eosinophilic cytoplasm and uniform ovoid nuclei. The tumor was positive for S100, SOX10, HMB45, cathepsin K, and p63 (weak), while negative for Melan-A, MiTF, smooth muscle actin, and desmin. Gene fusion analysis of the recurrent tumor revealed a NONO::TFE3 fusion which has been recently reported in two similar cutaneous cases. Our case highlights the potential of a NONO::TFE3 cutaneous epithelioid and spindle cell tumor to recur after a prolonged disease-free interval without evidence of high-grade transformation or distant metastasis. Our findings support its classification as a cutaneous mesenchymal neoplasm of intermediate malignancy., (© 2024 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Salvage radiation therapy (SRT) is a mainstay of treatment for biochemical relapse following radical prostatectomy; however, few studies have examined genomic biomarkers in this context., Objective: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT., Design, Setting, and Participants: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays., Intervention: All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT., Results and Limitations: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design., Conclusions: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features., Patient Summary: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Given increased neoadjuvant therapy use in early-stage, hormone receptor (HR)-positive/HER2-negative breast cancer, we sought to quantify likelihood of breast-conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) or endocrine therapy (NET) as a function of ER%/PR%/Ki-67%, 21-gene recurrence scores (RS), or 70-gene risk groups., Methods: We analyzed the 2010-2020 National Cancer Database. Surgery was categorized as "mastectomy/BCS." Logistic regression was performed. Adjusted odds ratios (AOR) were per 10-unit increase in ER%/PR%/Ki-67%., Results: Overall, 42.3% underwent BCS after NACT, whereas 64.0% did after NET. Increasing ER% (AOR = 0.96, 95% confidence interval [CI] 0.94-0.97) or PR% (AOR=0.98, 95% CI 0.96-0.99) was associated with lower odds of BCS after NACT. Increasing Ki-67% was associated with greater odds of BCS (AOR = 1.07, 95% CI 1.04-1.10). Breast-conserving surgery rates increased by ~20 percentage points, with Ki-67% ≥15 or RS >20. Patients with a low (43.0%, AOR = 0.50, 95% CI 0.29-0.88) or intermediate (46.4%, AOR = 0.58, 95% CI 0.41-0.81) RS were less likely than patients with a high RS (65.0%) to undergo BCS after NACT. Increasing ER% was associated with higher odds of BCS after NET (AOR = 1.09, 95% CI 1.01-1.17). Breast-conserving surgery rates increased by ~20 percentage points between ER <50% and >80%. In both cohorts, the odds of BCS were similar between 70-gene low-risk and high-risk groups. Asian or uninsured patients had lower odds of BCS., Conclusions: Neoadjuvant chemotherapy is unlikely to downstage tumors with a low-intermediate RS, higher ER%/PR%, or lower Ki-67%. Breast-conserving surgery after NET was most dependent on ER%. Findings could facilitate treatment decision-making based on tumor biology and racial/socioeconomic disparities and improve patient counseling on the likelihood of successful BCS., (© 2024. The Author(s).)

Background and Aims: Cervical intraepithelial neoplasia(CIN)and persistent high-risk human papillomavirus (HR-HPV)infection are associated with impaired local cellular immunity; however, the molecular mechanisms underlying these processes are not well understood. The involvement of the programmed death 1/programmed death 1 ligand (PD-1/PD-L1) pathway in the downregulation of T cell function has been demonstrated recently and it is believed to have a role in the onset and persistence of HPV infection and cervical cancer. Our aim is to analyze the role of PD-L1 in the CIN to identify a possible biomarker of HSIL (CIN2+) progression and persistence., Methods: We performed a systematic review, considering papers published from January 2000 to May 2024, according to PRISMA guideline, in order to obtain a Comprehensive analysis of the literature regarding the role of PD-L1 expression in CIN. The most important medical databases, such as PubMed, Cochrane Database of narrative Reviews, EMBASE, and Web of Science, were consulted. Articles documenting the characteristics and clinical implications of PDL-1 expression in cervical dysplasia were given special consideration., Results: HR-HPV lesions show a positive expression of PD-L1, which level increase from LSIL (CIN1) to cervical cancer. The expression of PD-L1 in both mononuclear and cervical epithelial cells also exhibit an elevation with the progression of the lesions followed by a overexpression of pro-inflammatory cytokines IFN-γ and IL-12 and downregulation of anti-inflammatory cytokine IL-10 indicating a role of PD-1/PD-L1 pathway in cervical immunity., Conclusions: PD-1 and PD-L1 may serve as diagnostic and prognostic biomarkers as well as valuable tools in immunotherapy for treating cancer and CIN., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

In this era of precision medicine, incorporating quantitative measures of estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 expressions and genomic assays could more precisely identify neoadjuvant systemic therapy with the highest likelihood of response and tumor downstaging. In our recent study, we quantified the likelihood of achieving breast-conserving surgery (BCS vs. mastectomy) after neoadjuvant chemotherapy or endocrine therapy as a function of demographics, quantitative ER/PR/Ki-67 expressions, 21-gene recurrence scores, or 70-gene risk scores in early-stage, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Using the 2010-2020 National Cancer Database, we found that the BCS rate after neoadjuvant chemotherapy was higher among patients with high 21-gene recurrence scores, lower ER/PR expression, or higher Ki-67 expression. Most patients who received neoadjuvant endocrine therapy underwent BCS, which was mostly dependent on ER expression. Asian women were less likely than white women to undergo BCS after neoadjuvant treatments. Lack of health insurance was associated with lower odds of BCS in both neoadjuvant settings. Although our study provides insight into the associations of BCS with quantitative biomarkers at a single time point, several questions remain unanswered. With the evolving landscape of neoadjuvant therapies in development for HR-positive/HER2-negative breast cancer, ongoing work using quantitative biomarkers and genomic assay scores is needed to select the right neoadjuvant systemic therapy for the right patient. Given the increasing amount of data available at the time of breast cancer diagnosis, novel computational approaches are needed to integrate patient demographic and tumor-specific factors to predict the optimal treatment strategy and likelihood of BCS., (© 2024. Society of Surgical Oncology.)

The efficacy of conventional anti-angiogenesis drugs is usually low in treating hepatocellular carcinoma (HCC). Therefore, there is an urgent need to find new precise therapeutic targets and to develop more effective drugs for the treatment of HCC. Vasculogenic mimicry (VM) is different from classic endothelium-dependent angiogenesis and is associated with a poor prognosis in patients with malignant tumor. However, the mechanism underlying VM is complex and not fully defined. Ig-like transcript (ILT)-4, as a negative regulator of immune response, is expressed in many solid tumors. However, whether and how ILT4 regulates VM remains unclear. This study found VM enriched in HCC tissues, especially in tissues from patients with relapse within 5 years after surgery. Similarly, ILT4 expression level was also higher in HCC tissues from patients with relapse within 5 years after surgery. Linear regression analysis revealed a positive correlation between the expression of ILT4 and VM density. Furthermore, overexpression/knockdown of ILT4 expression upregulated/down-regulated VM-related marker, three-dimensional tube formation, and migration and invasion in HCC cell lines in vitro. In mechanistic studies, ILT4 promoted VM formation via mitogen-activated protein kinase (MAPK)/ERK signaling. This study provides a rationale and mechanism for ILT4-mediated postoperative relapse via inducing VM in HCC. The related molecular pathways can be used as novel therapeutic targets for the inhibition of HCC angiogenesis and postoperative relapse., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: The incidence of recurrent gliomas is high, exerting low survival rates and poor prognoses. Transcription factor AP-2α has been reported to regulate the progression of primary glioblastoma (GBM). However, the function of AP-2α in recurrent gliomas is largely unclear., Methods: The expression of AP-2α and O6-methylguanine DNA-methyltransferase (MGMT) was detected in recurrent glioma tissues and cell lines by Western blots, the regulation mechanisms between AP-2α/MGMT promoter and RA/AP-2α promoter were studied by luciferase reporter assays, EMSA, and chIP assays. The effects of AP-2α and TMZ/RA treatment on cell viability in vitro and in vivo were investigated by MTT assays, γH 2 AX staining, comet assays and intracranial injection., Key Findings: AP-2α expression negatively correlates with the expression of MGMT in glioma samples. AP-2α could directly bind with the promoter of the MGMT gene, suppresses transcriptional levels of MGMT and downregulate MGMT expression in TMZ-resistant U87MG-R and T98G cells, but TMZ treatment decreases AP-2α expression and increases MGMT expression. The extended TMZ treatment and increased TMZ concentrations reversed these effects. Moreover, AP-2α overexpression combines with TMZ to decrease cell viability, concurrently with improved DNA damage marker γH 2 AX. Furthermore, retinoic acid (RA) activates RAR/RXR heterodimers, which bind to RA-responsive elements (RAREs) of the AP-2α promoter, and activates AP-2α expression in recurrent glioma cells. Finally, in intracranial relapsed glioma mouse model, both RA and TMZ could retard tumor development and prolong the mouse survival., Significance: AP-2α activation by gene overexpression or RA treatment reveals the suppressive effects on glioma relapse, providing a novel therapeutic strategy against malignant refractory gliomas., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Glioblastoma due to recurrence is clinically challenging with 10-15 months overall survival. Previously we showed that therapy-induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate the TIS reversal mechanism for potential therapeutic intervention to prevent glioblastoma (GBM) recurrence., Methods: Residual senescent (RS) and end of residual senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenarios. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays, and IHCs were performed for the mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model., Results: Transcriptome analysis showed co-expression of endoplasmic reticulum (ER) stress-unfolded protein response (UPR) and senescence-associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, Reactive oxygen specis (ROS), DNA damage, and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP, and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in ER, RS cells displayed stressed ER morphology, upregulated ER stress markers, and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21, and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival., Conclusion: We demonstrate that PERK-mediated UPR regulates senescence reversal and its inhibition can be exploited as a potential seno-therapeutic option in glioblastoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Among gynecological malignancies, ovarian cancer (OC) presents the most challenging diagnostic scenario. Despite exhaustive efforts, up to 90 % of patients treated with taxane/platinum-based chemotherapy experience relapse, leading to poor survival rates. Identifying new molecular markers that can characterize disease aggressiveness, chemoresistance, recurrence risk, and metastasis is crucial. This study aimed to assess the susceptibility of three ovarian tumor cell lines (TOV-21G, SKOV-3, and OV-90) to cisplatin and paclitaxel, and to investigate the influence of these treatments on the mRNA expression of TANK, RIPK1, NFKB1, TNFRSF10D, and TRAF2. Among the cell lines, SKOV-3 ovarian adenocarcinoma cells demonstrated the highest resistance to cisplatin treatment (0.125 mg/mL), followed by TOV-21G (0.076 mg/mL) and OV-90 cells (0.028 mg/mL). Regarding paclitaxel treatment, the SKOV-3 cell line exhibited the highest resistance (1.4 µg/mL), followed by OV-90 (1.3 µg/mL) and TOV-21G cells (0.9 µg/mL). Gene expression analysis after paclitaxel treatment remained unchanged; however, after cisplatin treatment, TNFRSF10D was observed to be upregulated nearly 100-fold in SKOV-3 compared to all other cell lines studied. SKOV-3 is described as cisplatin and tumor necrosis factor-resistant. Despite the defective signaling of the TNFRSF10D receptor for apoptosis, it can activate the NFKB transcription factor through non-canonical TRAIL signaling, contributing to a pro-inflammatory immune response. In light of this, damage associated with cisplatin increases TNFRSF10D expression and may promote cell survival through non-canonical NFKB pathway activation. This suggests that resistance to TRAIL-induced apoptosis in these cells could serve as a promising chemoresistance biomarker in OC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background/aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor's gene profile is crucial to avoid positive MSM., Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets., Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests., Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The mucosal epithelium of the head and neck region (including the oral cavity, nasal cavity, pharynx, nasopharynx, and larynx) is the primary site exposed to tobacco smoke, and its presence of nicotinic acetylcholine receptors (nAChRs) has been observed in the mucosal epithelial cells of this area. It remains unclear whether HNSC cells can migrate and invade through nAChR signaling. A model of HNSC cells exposed to nicotine is established. Cell proliferation following nicotine exposure is assessed using the CCK-8 assay, while migration and invasion are evaluated through wound healing and Transwell assays. The effects of CHRNA5 knockdown and overexpression are also investigated. Immunofluorescence staining is used to analyze CHRNA5 expression and localization, and clonogenic assays are performed to measure colony proliferation after CHRNA5 knockdown and overexpression. The interaction between CHRNA5 and CES1 is examined using molecular docking, co-immunoprecipitation, and immunofluorescence. Differentially expressed genes are subjected to pathway enrichment analysis, and MEK/ERK protein expression and phosphorylation are validated via western blot. Tumor formation assays are performed in nude mice using sh-CHRNA5 Cal27 cells, followed by western blot and immunohistochemical staining. Additionally, laryngeal and hypopharyngeal cancer tissues are analyzed through immunohistochemistry. Nicotine significantly enhanced the proliferation, migration, and invasion capabilities of head and neck tumor cells, including Cal27, Fadu, HN6, and Tu686 cells, through the expression of CHRNA5. Knockdown of CHRNA5 can reduce cell migration, invasion, and proliferation, whereas nicotine exposure can reverse this trend. Additionally, the mRNA and protein expression of CES1 decreases with the knockdown of CHRNA5, indicating a regulatory relationship between the two. Transcriptomics revealed that the knockdown of CHRNA5 is associated with the MEK/ERK signaling pathway. Further cellular- and tissue-level evidence confirmed that the levels of p-MEK/MEK, p-ERK/ERK, and CES1 decreased following knockdown of CHRNA5, a trend that nicotine can reverse. Nicotine promotes the proliferation, migration, and invasion of HNSC by upregulating CHRNA5 expression. Knockdown of CHRNA5 reduces these effects, which can be reversed by nicotine. Nicotine exposure activates CHRNA5, regulating CES1 expression via the MEK/ERK pathway, contributing to the recurrence and metastasis of head and neck squamous carcinoma., (© 2024. The Author(s).)

Purpose: Tumor recurrence after radiofrequency ablation (RFA) affects the survival rate of patients and limits its clinical application. Tumor recurrence around the ablation area may be related to the thermal injury of hepatocytes (HCs) around the tumor, but the specific mechanism is still unclear., Methods: A liver cancer thermal injury mouse model was established via RFA in the C57BL/6 mice. Primary HCs and Kupffer cells (KCs) were isolated and cultured to assess their sensitivity to thermal injury via the MTT assay. Flow cytometry was used to assess macrophage polarization. Furthermore, Western blotting and co-immunoprecipitation (co-IP) were utilized to evaluate the protein expression of intracellular signaling pathway. Finally, Transwell and wound healing assays was conducted to evaluate the invasion potential of liver cancer cells., Results: Our findings revealed that RFA-induced liver thermal injury promoted the upregulation and secretion of HMGB1 in HCs. HMGB1 had a protective effect on HCs thermal injury, potentially mediated through autophagy regulation. Heat-injured HCs release HMGB1, which activates the TREM1/JAK2/STAT3 signaling pathway in KCs, thus fostering an immunosuppressive tumor microenvironment (TME). Moreover, HMGB1 secretion by heat-injured HCs exacerbates the migration and invasion of HCC cells by influencing macrophage polarization., Conclusion: RFA-induced thermal injury triggers HMGB1 release from HCs, driving macrophage M2 polarization and increasing the invasion ability of liver cancer cells. These findings reveal a potential therapeutic target for combating liver cancer recurrence following thermal ablation., (© 2024. The Author(s).)

PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer., (© 2024. The Author(s).)

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin's multiaxial role in breast cancer progression and recurrence., (© 2024. The Author(s).)

Cancer dormancy followed by recurrence remains an enigma in cancer biology. Since both local and systemic recurrences are thought to emanate from dormant micrometastasis which take origin from lymphovascular tumor emboli we wondered whether the process of dormancy might initiate within lymphovascular emboli. This study combines experimental studies with a patient-derived xenograft (PDX) of inflammatory breast cancer (Mary-X) that spontaneously forms spheroids in vitro and budding lymphovascular tumor emboli in vivo with observational studies utilizing tissue microarrays (TMAs) of human breast cancers. In the experimental studies, Mary-X during both lymphovascular emboli formation in vivo and spheroidgenesis in vitro exhibited decreased proliferation, a G 0 /G 1 cell cycle arrest and decreased mTOR signaling. This induction of dormancy required calpain-mediated E-cadherin proteolysis and was mediated by decreased P13K signaling, resulting in decreased mTOR activity. In observational human breast cancer studies, increased E-cadherin immunoreactivity due to increased E-cad/NTF-1 but both decreased Ki-67 and mTOR activity was observed selectively and differentially within the lymphovascular tumor emboli. Both our experimental as well as observational studies indicate that in vivo lymphovascular tumor emboli and their in vitro spheroid equivalent initiate dormancy through these pathways.

Ras homolog gene family member C (RhoC) is a GTPase involved in cell migration, implicated in epithelial-mesenchymal transition and treatment resistance and metastasis of cancer. For example, RhoC has been shown to be involved in resistance to radiation in cervical carcinoma. Here, the effect of X-ray irradiation on RhoC expression in prostate cancer (PCa) xenografts was investigated in both xenografts in regression and relapse. Male BALB/cAnNRj-Foxn1 nu/nu mice were inoculated with 4-6 million LNCaP-FGC cells and established xenografts were irradiated with X-rays (200 kV, 1 Gymin -1 ), 5, 10 or 15 Gy using a Gulmay Medical X-ray system. Expression of RhoC and Ki67, a known proliferation marker, was investigated in xenografts, given 15 Gy, 7 days (midst response as measured by size) or 3 weeks (relapse) post irradiation. Staining was quantified using the Halo software (v2.3.2089.34) with the Indica Labs - cytonuclear v1.6 algorithm. RhoC and Ki67 staining was divided into weak, medium, and strong staining and the percentage of cells stained, single and dual staining, was quantified. The HALO software was further used to classify the tissue in each section so that analysis of RhoC and Ki67 expression in cancer cells, stroma and necrotic areas could be done separately. The results showed that RhoC expression in cancer and stroma cells was significantly higher in relapsed xenografts than in those in regression. This was not seen for Ki67 staining, where the percentage of stained cells were the same in regressing and relapsing tumors. RhoC could be a useful biomarker to confirm relapse following external beam radiation therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Oskar Vilhelmsson Timmerand reports financial support was provided by RhoVac Aps. Jens Ceder reports financial support was provided by RhoVac Aps. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The insulin-like growth factor 1 receptor (IGF1R) has been associated with growth and metastasis in various cancers. However, its role in postoperative recurrence and prognosis in lung cancer lacks clear consensus. Therefore, this study aimed to investigate the potential relationship between IGF1R and postoperative recurrence as well as long-term survival in a large cohort. Additionally, we assessed the relationship between IGF1R and programmed death ligand 1 (PD-L1) expression. Our study encompassed 782 patients with non-small cell lung cancer (NSCLC). Immunostaining of surgical specimens was performed to evaluate IGF1R and PD-L1 expression. Among the patients, 279 (35.8%) showed positive IGF1R expression, with significantly worse relapse-free survival (RFS) and overall survival (OS). Notably, no significant differences in RFS and OS were observed between IGF1R-positive and -negative groups in stages 2 and 3. However, in the early stages (0-1), the positive group displayed significantly worse RFS and OS. In addition, PD-L1 expression was detected in 100 (12.8%) patients, with a significant predominance in the IGF1R-positive. IGF1R may serve as a prognostic indicator and a guide for perioperative treatment strategies in early-stage lung cancer. In conclusion, our findings underscore an association between IGF1R expression and poor survival and PD-L1 expression in NSCLC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nagamine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in the treatment of recurrent and/or metastatic (RM) head and neck squamous cell carcinoma (HNSCC) Keynote 048 highlighted the relevance of PD-L1 Combined Positive Score (CPS) as a predictive biomarker for ICIs treatment, but challenges persist regarding ideal assessment and concordance between primary and relapsing tumor has not been determined., Material and Methods: This is a retrospective multicentric study that included HNSCC patients with locoregional and/or metastatic relapses after curative treatment. Histological samples of primary tumors and corresponding relapses were collected. The primary objective was to evaluate PD-L1 CPS concordance between primary and recurrent tumors, with secondary objective of exploring the impact of clinical-pathological variables., Results: Out of 86 evaluated patients, 30 cases were excluded due to insufficient histological material, with a final enrollment of 56 patients. Concordance analysis revealed a 66.1% agreement in PD-L1 CPS between primary and recurrent tumors. Only 3.6% of cases exhibited a change from negative to positive PD-L1 CPS status, and 7.2% showed the reverse. Factors analyzed, including primary tumor site, treatment modality, and recurrence type, did not significantly influence PD-L1 CPS concordance level., Conclusion: While significant changes in PD-L1 CPS expression are rare, the study underscores the importance of confirmatory biopsies on relapse. However, reliance on archival tumor tissue for initial PDL1 assessment may be considered in cases where obtaining additional biopsies poses risks to patients or urgent therapeutic decisions are required., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [PB: participation to advisory board or conference honoraria for: Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini, Nestlè, Elevar. Other authors have nothing to declare]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background/aim: Elevated blood fibronectin (FN) levels have been observed in various cancers; however, their significance remains controversial. Herein, we measured the levels of sialyl-fibronectin (S-FN), a type of FN secreted by tumor cells, and investigated whether blood S-FN secretion is associated with recurrent metastasis and epithelial-mesenchymal transition (EMT)., Patients and Methods: An ELISA system recognizing S-FN was constructed, and the amount of S-FN in blood samples from 63 patients with thyroid carcinoma was measured. The relationship between S-FN secretion and clinical prognosis was also examined. Vimentin immunostaining was performed to identify the mesenchymal status of the cells during EMT., Results: After 12 years of observation, 17/63 patients had recurrent metastases, including nine cases of lymph node recurrence (LNR) and eight cases of remote metastasis (RM). LNR occurred in 7/39 (17.9%) of S-FN-negative cases, where 4/7 (57.1%) had two or more repeat recurrences. In S-FN-positive cases, LNR was observed in 2/24 cases (8.3%), and no repeat recurrence was observed. For RM, 6/39 (15.4%) patients were S-FN-negative, of which 5/6 (83.3%) had progressive disease even during treatment at metastasis. Of the S-FN-positive cases, RM was observed in 2/24 (8.3%) patients; progressive disease was observed in 1/2 (50.0%) patients. In 9/11 S-FN-negative recurrent metastasis cases (81.8%) and 2/4 S-FN-positive cases (50.0%), many vimentin-positive, FN-secreting cells were found in the interstitial tissue around the tumor., Conclusion: S-FN-negative thyroid cancer has a poor prognosis because of the progression of EMT associated with increased paracrine FN levels in the stroma., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: To examine the prognostic value of F-18 fluorodeoxyglucose (FDG) uptake in the bone marrow (BM) for disease recurrence and survival in patients with oropharyngeal squamous cell carcinoma (OP-SCC). The secondary aims were to evaluate the prognostic value of PET/CT parameters for the primary oropharyngeal tumor and total tumor burden, and to assess the correlation between FDG uptake variables and serum inflammatory markers., Methods: This was an observational study of 91 patients with OP-SCC who underwent pretreatment FDG-PET/CT. The patients' blood samples were collected before treatment, and treatment was administered with the intention to cure. The median follow-up time was 40 months. The PET parameters measured were SUV mean BM for the assessment of BM FDG uptake, SUV mean , SUV max , total lesion glycolysis (TLG), and metabolic tumor volume (MTV) for the evaluation of primary oropharyngeal tumor and total tumor burden. Blood samples were analyzed to determine each patient's white cell, red cell, and platelet cell counts, hemoglobin, and C-reactive protein level. In a subgroup of 33 patients, blood serum was analyzed to evaluate the expression of serum immune proteins using a proximity extension assay (Olink Proteomics)., Results: The univariate analysis revealed that SUV mean BM and tumor-specific parameters (SUV max tumor, SUV mean total, SUV max total, MTVtotal, TLGtotal) were significantly associated with recurrence-free survival (RFS). After adjusting for age, sex, and stage only SUV mean BM remained significantly associated with RFS. Spearman's correlation identified several correlations between PET parameters and inflammatory markers., Conclusions: Our results show that several FDG-PET/CT parameters may have a prognostic value of treatment outcome in patients with OP-SCC. However, SUV mean BM was the only independent PET parameter that showed a prognostic value for RFS in the study cohort. Moreover, the study findings might suggest an association between systemic inflammation and the metabolic activity in the BM., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Comprehensive analysis of clinical evidence for breast cancer adipogenesis with prognosis is lacking. This study aims to consolidate the latest evidence on the relationship between adipogenesis and breast cancer outcomes., Data Sources: Medline, Web of Science, Embase, Scopus, Clinicaltrials.gov, Cochrane library., Methods: A systematic review was conducted according to the PRISMA guidelines. Studies that reported the correlation between tumor adipogenesis and cancer recurrence or empirical pathological markers were included for meta-analysis. The standard reference for pathological markers determination was set as histopathological examination. The PROSPERO ID was CRD489135., Results: Eleven studies were included in this systematic review and meta-analysis. Several adipogenesis biomarkers involved in the synthesis, elongation, and catabolism of fatty acids, such as FASN, Spot 14, pS6K1, lipin-1, PLIN2, Elovl6, and PPARγ, were identified as the potential biomarkers for predicting outcomes. Through meta-analysis, the predictive value of adipogenesis biomarkers for 5-year recurrence rate was calculated, with a pooled predictive risk ratio of 2.19 (95% CI: 1.11-4.34). In terms of empirical pathological markers, a negative correlation between adipogenesis biomarkers and ki-67 was observed (RR: 0.69, 95% CI: 0.61-0.79). However, no significant correlation was found between the adipogenesis and ER, PR, HER2, or p53 positivity., Conclusions: Biomarker of adipogenesis in breast cancer is a significant predictor of long-term recurrence, and this prediction is independent of HR, HER2, and ki-67. The diverse roles of adipogenesis in different breast cancer subtypes highlight the need for further research to uncover specific biomarkers that can used for diagnosis and prediction., Protocol Registration: PROSPERO ID: CRD489135., (© 2024. The Author(s).)

The high rate of postoperative recurrence contributes to the poor outcome in hepatocellular carcinoma (HCC), and effective strategies for managing recurrence are currently lacking. Based on seven pairs of tumors and non-tumor adjacent tissues (NATs) proteomic datasets across five cancer types, this study systematically investigates the stratified and therapeutic value of tumors and NATs for tumor recurrence. NATs exhibited stable and irreplaceable independent prognostic capabilities for recurrence, complementing clinical indicators and tumor characteristics. In comparison to tumor tissues, NATs exhibit higher enrichment levels of recurrence-related proteins in pathways such as immunity, extracellular matrix, and angiogenesis. Taking HCC as an example, we identified SERPINH1 as a recurrent biomarker with drug-targeting potential that applied to both tumors and NATs and then validated them through independent immunohistochemistry cohorts and animal experiments. Patients with high SERPINH1 expression in both tumors and NATs have the highest 5-year recurrence rates, even among clinically low recurrence risk groups. Targeting SERPINH1 can effectively delay tumor occurrence and progression. This study highlights the significant importance of NATs in recurrence prediction and postoperative management, proposing a recurrence management strategy that focuses on both tumors and NATs. SERPINH1 emerges as a valuable biomarker and drug target for addressing postoperative recurrence in HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Glioblastoma (GBM) is a clinically challenging primary brain tumor with poor survival outcome despite surgical resection and intensive chemoradiation. The metabolic heterogeneity of GBM can become biomarkers for treatment response, resistance, and outcome prediction. The aim of the study is to investigate metabolic distinctions between primary and recurrent GBM tissue and patient plasma to establish feasibility for metabolic profiling., Methods: A single-center cohort study analyzed tissue and blood samples from 15 patients with GBM using untargeted metabolomic/lipidomic assays. Metabolomic, lipidomic, and biogenic amine analyses were conducted on GBM tissue and patient plasma at diagnosis and recurrence using untargeted mass spectrometry. The study utilized a small but longitudinally collected cohort to evaluate alteration in metabolites, lipids, and biogenic amines between specimens at diagnosis and recurrence., Results: Exploratory analysis revealed significant alteration in metabolites, lipids, and biogenic amines between diagnostic and recurrent states in both tumor and plasma specimens. Notable metabolites differed at recurrence, including N-alpha-methylhistamine, glycerol-3-phosphate, phosphocholine, and succinic acid in tissue, and indole-3-acetate, and urea in plasma. Principal component analysis revealed distinct metabolomic profiles between tumor tissue and patient plasma. Distinct metabolic profiles were observed in GBM tissue and patient plasma at recurrence, demonstrating the feasibility of using metabolomic methodologies for longitudinal studies. One patient exhibited a unique tumor resistance signature at diagnosis, possibly indicating a high-risk metabolomic phenotype., Conclusions: In this small cohort, the findings suggest the potential of metabolomic signatures of GBM tissue and patient plasma for risk stratification, outcome prediction, and the development of novel adjuvant metabolic-targeting therapies. The findings suggest metabolic discrepancies at diagnosis and recurrence in tissue and plasma, highlighting potential implications for evaluation of clinical response. The identification of significant changes in metabolite abundance emphasizes the need for larger studies using targeted metabolomics to validate and further explore these profiles., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Liu YA et al.)