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Abstract Background The COVID-19 pandemic might have delayed cancer diagnosis and management. The aim of this systematic review was to compare the initial tumor stage of new cancer diagnoses before and after the pandemic. Methods We systematically reviewed articles that compared the tumor stage of new solid cancer diagnoses before and after the initial pandemic waves. We conducted a random-effects meta-analysis to compare the rate of metastatic tumors and the distribution of stages at diagnosis. Subgroup analyses were performed by primary tumor site and by country. Results From 2,013 studies published between January 2020 and April 2022, we included 58 studies with 109,996 patients. The rate of metastatic tumors was higher after the COVID-19 outbreak than before (pooled OR: 1.29 (95% CI, 1.06-1.57), I 2 : 89% (95% CI, 86-91)). For specific cancers, common ORs reached statistical significance for breast (OR: 1.51 (95% CI 1.07-2.12)) and gynecologic (OR: 1.51 (95% CI 1.04-2.18)) cancers, but not for other cancer types. According to countries, common OR (95% CI) reached statistical significance only for Italy: 1.55 (1.01-2.39) and Spain:1.14 (1.02-1.29). Rates were comparable for stage I-II versus III-IV in studies for which that information was available, and for stages I-II versus stage III in studies that did not include metastatic patients. Conclusions Despite inter-study heterogeneity, our meta-analysis showed a higher rate of metastatic tumors at diagnosis after the pandemic. The burden of social distancing policies might explain those results, as patients may have delayed seeking care.

Background: The COVID-19 pandemic might have delayed cancer diagnosis and management. The aim of this systematic review was to compare the initial tumor stage of new cancer diagnoses before and after the pandemic. Methods: We systematically reviewed articles that compared the tumor stage of new solid cancer diagnoses before and after the initial pandemic waves. We conducted a random-effects meta-analysis to compare the rate of metastatic tumors and the distribution of stages at diagnosis. Subgroup analyses were performed by primary tumor site and by country. Results: From 2,013 studies published between January 2020 and April 2022, we included 58 studies with 109,996 patients. The rate of metastatic tumors was higher after the COVID-19 outbreak than before (pooled OR: 1.29 (95% CI, 1.06-1.57), I2: 89% (95% CI, 86-91)). For specific cancers, common ORs reached statistical significance for breast (OR: 1.51 (95% CI 1.07-2.12)) and gynecologic (OR: 1.51 (95% CI 1.04-2.18)) cancers, but not for other cancer types. According to countries, common OR (95% CI) reached statistical significance only for Italy: 1.55 (1.01-2.39) and Spain:1.14 (1.02-1.29). Rates were comparable for stage I-II versus III-IV in studies for which that information was available, and for stages I-II versus stage III in studies that did not include metastatic patients. Conclusions: Despite inter-study heterogeneity, our meta-analysis showed a higher rate of metastatic tumors at diagnosis after the pandemic. The burden of social distancing policies might explain those results, as patients may have delayed seeking care. [ABSTRACT FROM AUTHOR]

Abstract Background The aim of study was to evaluate survival outcome and limb function in cancer patients with proximal limbs metastasis. Associated factors on survival outcome and limb function were identified. The comparative analysis between intramedullary nailing and prosthesis surgery in cancer patients with proximal limb metastasis was performed. Methods In this five-center retrospective study, patients diagnosed with limbs metastasis were collected. Descriptive statistics was used and log-rank test was performed to analyze the survival in subgroups. The Cox proportional hazards regression analysis was performed to identify the independent prognostic factors. The Musculoskeletal Tumor Society (MSTS) scoring system was used to evaluate limb function after surgery, and t test or analysis of variance (ANOVA) was utilized in subgroup analysis. Results A total of 316 patients with limb metastasis were included with mean age at 61.0 years. The most common primary tumor was breast, followed by renal cancer and lung cancer. The median overall survival was 24.0 months and the 1-, 3- and 5-year survival rates were 86.9%, 34.7% and 6.8%, respectively. Primary tumor type, visceral metastasis and chemotherapy were proved to be the independent prognostic factors. The mean Musculoskeletal Tumor Society (MSTS) score was 20.5, significant difference was observed in subgroup of solitary/multiple bone metastasis, with/without pathological fracture, and type of surgery. Conclusion The present study concluded that primary tumor type, visceral metastasis and chemotherapy were three factors affecting the survival of patients. Compared with intramedullary nailing, the patients underwent prosthesis surgery showed better limb function, this procedure should be encouraged in patients with indication.

BackgroundMetastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome.MethodsPNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121).ResultsThe CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene "metastasis" signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression.ConclusionsMeasuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis.

Background: The aim of study was to evaluate survival outcome and limb function in cancer patients with proximal limbs metastasis. Associated factors on survival outcome and limb function were identified. The comparative analysis between intramedullary nailing and prosthesis surgery in cancer patients with proximal limb metastasis was performed. Methods: In this five-center retrospective study, patients diagnosed with limbs metastasis were collected. Descriptive statistics was used and log-rank test was performed to analyze the survival in subgroups. The Cox proportional hazards regression analysis was performed to identify the independent prognostic factors. The Musculoskeletal Tumor Society (MSTS) scoring system was used to evaluate limb function after surgery, and t test or analysis of variance (ANOVA) was utilized in subgroup analysis. Results: A total of 316 patients with limb metastasis were included with mean age at 61.0 years. The most common primary tumor was breast, followed by renal cancer and lung cancer. The median overall survival was 24.0 months and the 1-, 3- and 5-year survival rates were 86.9%, 34.7% and 6.8%, respectively. Primary tumor type, visceral metastasis and chemotherapy were proved to be the independent prognostic factors. The mean Musculoskeletal Tumor Society (MSTS) score was 20.5, significant difference was observed in subgroup of solitary/multiple bone metastasis, with/without pathological fracture, and type of surgery. Conclusion: The present study concluded that primary tumor type, visceral metastasis and chemotherapy were three factors affecting the survival of patients. Compared with intramedullary nailing, the patients underwent prosthesis surgery showed better limb function, this procedure should be encouraged in patients with indication. [ABSTRACT FROM AUTHOR]

Abstract As the main isoforms of membranous glucose transporters (GLUT), GLUT1 involves tumorigenesis, metastasis and prognosis in a variety of cancers. However, its role in breast cancer metastasis remains to be elucidated. Here we examined its transcriptional and survival data in patients with breast cancer from several independent databases including the Oncomine, Gene Expression Profiling Interactive Analysis, Gene Expression across Normal and Tumor tissue, UALCAN, cBioPortal, Kaplan-Meier Plotter and PROGgeneV2. We found that its mRNA expression was significantly high in cancer tissues, which was associated with metastasis and poor survival. Transcription factor c-Jun might bind to GLUT1 promoter to downregulate its gene expression or mRNA stability, therefore to suppress glycolysis and metastasis. By qRT-PCR, we verified that GLUT1 was significantly increased in 38 paired human breast cancer samples while JUN was decreased. Furthermore, the protein level of GLUT1 was higher in tumor than in normal tissues by IHC assay. To explore underlying pathways, we further performed GO and KEGG analysis of genes related to GLUT1 and JUN and found that GLUT1 was increased by transcription factor c-Jun in breast cancer tissues to influence glycolysis and breast cancer metastasis.

Abstract Background Only a limited proportion of patients with metastatic colorectal cancer (mCRC) receives metastatic surgery (including local ablative therapy). The aim was to investigate whether hospital volume and hospital level were associated with the chance of metastatic surgery. Methods This national cohort retrieved from the CRCBaSe linkage included all Swedish adult patients diagnosed with synchronous mCRC in 2009–2016. The association between annual hospital volume of incident mCRC patients and the chance of metastatic surgery, and survival, were assessed using logistic regression and Cox regression models, respectively. Hospital level (university/non-university) was evaluated as a secondary exposure in a similar manner. Both uni- and multivariable (adjusted for sex, age, Charlson comorbidity index, year of diagnosis, cancer characteristics and socioeconomic factors) models were fitted. Results A total of 1,674 (17%) out of 9,968 mCRC patients had metastatic surgery. High hospital volume was not associated with increased odds of metastatic surgery after including hospital level in the model, whereas hospital level was (odds ratio (OR) (95% confidence interval (CI)): 1.94 (1.68–2.24)). All-cause mortality was lower in university versus non-university hospitals (hazard ratio (95% CI): 0.83 (0.78–0.88)). Conclusions Patients with mCRC initially cared for by a university hospital experienced a greater chance to receive metastatic surgery and had superior overall survival. High hospital volume in itself was not associated with a greater chance to receive metastatic surgery nor a greater survival probability. Additional efforts should be imposed to provide more equal care for mCRC patients across Swedish hospitals.

Abstract Background The prognostic values of preoperative aspartate aminotransferase (AST), monocyte-to-lymphocyte ratio (MLR), AST·MLR index (AMLRI) and operation injury condition in patients with colorectal cancer liver metastases (CRLM) remains unclear. This retrospective study assessed the relationship between these markers, progression-free survival (PFS), and overall survival (OS) in CRLM patients undergoing resection. Methods AMLRI was defined as AST × MLR. Operation injury condition was defined according to operation time and blood loss. Cox regression analyses were used to identify risk factors and to develop nomograms. C-indexes, time-dependent receiver operating characteristic (time-ROC) curves and calibration curves were used to assess the models. Results A total of 379 patients were enrolled. The optimal cut-off value of the AMLRI was 3.33. In the multivariable analysis, AMLRI > 3.33 (hazard ratio [HR] = 2.162, p = 0.002) and serious operation injury condition (HR = 1.539, p = 0.012) were predictive for unfavourable OS, and AMLRI > 3.33 (HR = 1.462, p = 0.021) was predictive for unfavourable PFS. The nomograms were superior to Fong’s Clinical Risk Score (CRS) according to the C-indexes (PFS: 0.682 vs. 0.600; OS: 0.730 vs. 0.586) and time-ROCs. Conclusions Preoperative AMLRI and operation injury condition are easily accessible predictors for prognosis. The nomograms performed better than CRS for the prediction of recurrence and survival.

As the main isoforms of membranous glucose transporters (GLUT), GLUT1 involves tumorigenesis, metastasis and prognosis in a variety of cancers. However, its role in breast cancer metastasis remains to be elucidated. Here we examined its transcriptional and survival data in patients with breast cancer from several independent databases including the Oncomine, Gene Expression Profiling Interactive Analysis, Gene Expression across Normal and Tumor tissue, UALCAN, cBioPortal, Kaplan-Meier Plotter and PROGgeneV2. We found that its mRNA expression was significantly high in cancer tissues, which was associated with metastasis and poor survival. Transcription factor c-Jun might bind to GLUT1 promoter to downregulate its gene expression or mRNA stability, therefore to suppress glycolysis and metastasis. By qRT-PCR, we verified that GLUT1 was significantly increased in 38 paired human breast cancer samples while JUN was decreased. Furthermore, the protein level of GLUT1 was higher in tumor than in normal tissues by IHC assay. To explore underlying pathways, we further performed GO and KEGG analysis of genes related to GLUT1 and JUN and found that GLUT1 was increased by transcription factor c-Jun in breast cancer tissues to influence glycolysis and breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: To investigate the clinicopathological characteristics, diagnoses, treatments, and outcomes of a special type of gestational trophoblastic neoplasia (GTN) which only has extrauterine metastases without uterine primary lesions.Methods: The medical records and pathological sections of the patients who were pathologically diagnosed as GTN, only had extrauterine metastatic lesions but lacked uterine primary lesions, in Women's Hospital of Zhejiang University School of Medicine from February 2014 to March 2021 were collected and reviewed.Results: Thirteen patients with pathologically confirmed GTN presenting with extrauterine metastases from a missing primary site were included in the past 7 years. The median age was 31.2 years old. 76.9% of patients had a non-hydatidiform pregnancy last time. The intervals between the antecedent pregnancy were > 12 months in 61.5% of patients. Pretreatment serum human chorionic gonadotropin(hCG) levels ranged from 118.7 to 807,270 IU/L. Six patients were misdiagnosed as ectopic pregnancy at initial diagnosis, and 4 as primary tumors at metastatic sites. All of them were diagnosed definitely by surgical pathology including 8 choriocarcinomas (CC), 4 epithelioid trophoblastic tumors (ETTs), and 1 mixed GTN (CC mixed with ETT). All patients achieved complete remission (CR) after treatments. Three patients relapsed; no patient died by the end of follow-up.Conclusion: GTN presenting with extrauterine metastases from a missing primary site is easily misdiagnosed. Detection of serum hCG in these patients can reduce misdiagnosis. Chemotherapy combined with individualized surgery should be considered for these special GTN patients. Immune checkpoint inhibitors might be potential remedial measures for refractory and recurrent patients. [ABSTRACT FROM AUTHOR]

Abstract Background To investigate the clinicopathological characteristics, diagnoses, treatments, and outcomes of a special type of gestational trophoblastic neoplasia (GTN) which only has extrauterine metastases without uterine primary lesions. Methods The medical records and pathological sections of the patients who were pathologically diagnosed as GTN, only had extrauterine metastatic lesions but lacked uterine primary lesions, in Women’s Hospital of Zhejiang University School of Medicine from February 2014 to March 2021 were collected and reviewed. Results Thirteen patients with pathologically confirmed GTN presenting with extrauterine metastases from a missing primary site were included in the past 7 years. The median age was 31.2 years old. 76.9% of patients had a non-hydatidiform pregnancy last time. The intervals between the antecedent pregnancy were > 12 months in 61.5% of patients. Pretreatment serum human chorionic gonadotropin(hCG) levels ranged from 118.7 to 807,270 IU/L. Six patients were misdiagnosed as ectopic pregnancy at initial diagnosis, and 4 as primary tumors at metastatic sites. All of them were diagnosed definitely by surgical pathology including 8 choriocarcinomas (CC), 4 epithelioid trophoblastic tumors (ETTs), and 1 mixed GTN (CC mixed with ETT). All patients achieved complete remission (CR) after treatments. Three patients relapsed; no patient died by the end of follow-up. Conclusion GTN presenting with extrauterine metastases from a missing primary site is easily misdiagnosed. Detection of serum hCG in these patients can reduce misdiagnosis. Chemotherapy combined with individualized surgery should be considered for these special GTN patients. Immune checkpoint inhibitors might be potential remedial measures for refractory and recurrent patients.

Abstract Background Survival times differ among patients with advanced gastric carcinoma. A precise and universal prognostic evaluation strategy has not yet been established. The current study aimed to construct a prognostic scoring model for mortality risk stratification in patients with advanced gastric carcinoma. Methods Patients with advanced gastric carcinoma from two hospitals (development and validation cohort) were included. Cox proportional hazards regression analysis was conducted to identify independent risk factors for survival. A prognostic nomogram model was developed using R statistics and validated both in bootstrap and external cohort. The concordance index and calibration curves were plotted to determine the discrimination and calibration of the model, respectively. The nomogram score and a simplified scoring system were developed to stratify patients in the two cohorts. Results Development and validation cohort was comprised of 401 and 214 gastric cancer patients, respectively. Mucinous or non-mucinous histology, ECOG score, bone metastasis, ascites, hemoglobin concentration, serum albumin level, lactate dehydrogenase level, carcinoembryonic antigen level, and chemotherapy were finally incorporated into prognostic nomogram. The concordance indices were 0.689 (95% CI: 0.664 ~ 0.714) and 0.673 (95% CI: 0.632 ~ 0.714) for bootstrap and external validation. 100 and 200 were set as the cut-off values of nomogram score, patients in development cohort were stratified into low-, intermediate- and high-risk groups with median overall survival time 15.8 (95% CI: 12.2 ~ 19.5), 8.4 (95% CI: 6.7 ~ 10.2), and 3.9 (95% CI: 2.7 ~ 5.2) months, respectively; the cut-off values also worked well in validation cohort with different survival time in subgroups. A simplified model was also established and showed good consistency with the nomogram scoring model in both of development and validation cohorts. Conclusion The prognostic scoring model and its simplified surrogate can be used as tools for mortality risk stratification in patients with advanced gastric carcinoma.

Abstract Background We investigated the clinicopathological characteristics and survival of breast cancer lung metastases (BCLM) patients at initial diagnosis of metastatic breast cancer (MBC) in the Han population. Methods We attained clinical data of 3155 MBC patients initially diagnosed between April 2000 and September 2019 from the China National Cancer Center and finally included 2263 MBC patients in this study, among which 809 patients presented with lung metastases at first MBC diagnosis. The risk factors for BCLM were determined using multivariate logistic regression analysis and the prognostic factors of BCLM patients were assessed by univariate and multivariate Cox regression analyses. Results Patients with triple-negative subtype (42.3%) harbored the highest incidence proportions of lung metastases. Age ≥ 50 years, Eastern Cooperative Oncology Group (ECOG) 2, M1, hormone receptor-negative (HR-)/human epidermal growth factor receptor 2-positive (HER2) + subtype, triple-negative subtype and disease-free survival (DFS) > 2 years were remarkably associated with higher incidence of lung metastases, while invasive lobular carcinoma (ILC) and bone metastases were significantly correlated with lower odds of lung metastases at diagnosis. The median survival of BCLM patients was 41.7 months, with triple-negative subtype experiencing the worst prognosis of 26.8 months. ECOG 2, triple-negative subtype, liver metastases, multi-metastatic sites and DFS ≤ 2 years were significantly correlated with poor survival of BCLM patients. Conclusions Our study provides essential information on clinicopathological features and survival outcomes of BCLM patients at initial diagnosis of MBC in China.

Background: For some patients with advanced cancer not knowing prognosis is essential. Yet, in an era of informed decision-making, the potential protective function of unawareness is easily overlooked. We aimed to investigate 1) the proportion of advanced cancer patients preferring not to know prognosis; 2) the reasons underlying patients' prognostic information preference; 3) the characteristics associated with patients' prognostic information preference; and 4) the concordance between physicians' perceived and patients' actual prognostic information preference.Methods: This is a cross-sectional study with structured surveys (PROSPECT). Medical and thoracic oncologists included patients (n = 524), from seven Dutch hospitals, with metastatic/inoperable cancer and an expected median overall survival of ≤ 12 months. For analysis, descriptive statistics and logistic regression models were used.Results: Twenty-five to 31% of patients preferred not to know a general life expectancy estimate or the 5/2/1-year mortality risk. Compared to patients preferring to know prognosis, patients preferring unawareness more often reported optimism, avoidance and inability to comprehend information as reasons for wanting limited information; and less often reported expectations of others, anxiety, autonomy and a sense of control as reasons for wanting complete information. Females (p < .05), patients receiving a further line of systemic treatment (p < .01) and patients with strong fighting spirit (p < .001) were more likely to prefer not to know prognosis. Concordance between physicians' perceived and patients' actual prognostic information preference was poor (kappa = 0.07).Conclusions: We encourage physicians to explore patients' prognostic information preferences and the underlying reasons explicitly, enabling individually tailored communication. Future studies may investigate changes in patients' prognostic information preferences over time and examine the impact of prognostic disclosure on patients who prefer unawareness. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the second most common cancer among men worldwide. Mortality is highest among patients in resource-limited settings (RLS), in part due to late-stage disease. Among patients with metastatic prostate cancer (mPCa), studies have shown significant improvement in overall survival with the use of androgen deprivation therapy (ADT) and taxane-based chemotherapy. However, outcome data among patients treated with chemo-endocrine therapy are scarce in many resource-limited settings. The aim of this study was to determine the clinical characteristics and 5-year overall survival (OS) of patients with de novo mPCa treated at the Uganda Cancer Institute (UCI)., Methods: A retrospective chart review study was conducted between 2015 and 2019, and the data of patients with histologically confirmed prostate cancer and radiological evidence of metastasis were reviewed. Sample size was estimated for Cox Proportion Hazard regression. Data on clinical and laboratory characteristics, overall survival, and predictors of survival were extracted. P < 0.05 was considered to indicate statistical significance., Results: A total of 300 patients were enrolled over the 5-year study period. The median age was 68 (IQR 61.5-74) years. At presentation, lower urinary tract symptoms were reported in nearly all patients (96.7%, n = 290), median total prostate specific antigen (PSA) was 414.75 ng/ml and 40% (n = 120) of patients had grade 5 histological scores. In addition to receiving ADT, majority of patients (70.3%, n = 211) received at least 6 cycles of chemotherapy. Overall survival at one year was 92.4% (95% CI: 88.6-94.9%), but it declined to 45.2% (95% CI: 36.8-53.2%) at 5 years. A high Gleason score, the presence of visceral metastasis and receiving less than 6 cycles of chemotherapy were predictors of poor outcomes., Conclusion: Patients with de novo mPCa in Uganda present with high histologic grades and high baseline Prostate Specific Antigen (PSA) levels but have improved 5-year overall survival with a combination of chemotherapy and ADT as a first-line treatment. We recommend interventions to reduce late presentation and prospective studies to evaluate treatment efficacy in this population., Competing Interests: Declarations Ethics approval and consent to participate This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The Uganda Cancer Institute Research and Ethics Committee approved the study protocol and provided waiver of consent (approval number UCI-2021-15). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Vasculogenic mimicry (VM) is an alternative intratumoral microcirculation system that depends on the capacity of tumor cells to reorganize and grow in three-dimensional (3D) channel architectures like the capillaries formed by endothelial cells. Both VM and angiogenesis may coordinately function to feed cancer cells, allowing tumor growth. Long noncoding RNAs (lncRNAs) regulate critical cellular functions in cancer cells, including cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. The lncRNA, known as actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1), has been described as an oncogene in diverse types of cancers. However, its role in VM and metastasis in triple-negative breast cancer (TNBC) is unknown., Methods: Reverse transcription and quantitative polymerase chain reaction (RT‒qPCR) experiments were performed to evaluate the expression of 10 selected lncRNAs from literature in metastatic and nonmetastatic biopsies from TNBC patients. The expression of AFAP1-AS1 was analyzed in Genotype-Tissue Expression Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. The AFAP1-AS1 expression was knocked in TNBC Hs578T cells by transfection of specific siRNAs. Channel-like formation assays were performed using 3D cultures over Matrigel in hypoxia-treated Hs578T cancer cells with diminished expression of AFAP1-AS1. The angiogenesis tests were conducted using human umbilical vein endothelial cells (HUVECs) and AFAP1-AS1- silenced Hs578T cells on 3D cell cultures. The presence of VM (CD31-/PAS+) in tumor tissues from TNBC patients with and without metastasis was assessed through immunohistochemistry using endothelial marker CD31 antibodies and periodic acid-Schiff (PAS) staining., Results: Compared with normal mammary tissues, AFAP1-AS1 expression was higher in breast cancer tissues. Moreover, AFAP1-AS1 expression was upregulated in the TNBC subtype compared to receptor-positive breast tumors. In addition, the expression of AFAP1-AS1 was correlated with the expression of the thirteen genes characteristic of a previously reported hypoxia signature. Interestingly, AFAP1-AS1 was upregulated in primary TNBC tumors from patients who developed metastasis compared with the nonmetastatic group. Functional analysis revealed that the knockdown of AFAP1-AS1 in Hs578T cells significantly impaired the hypoxia-induced VM, accompanied by a decrease in the development of 3D channel networks. Similarly, AFAP1-AS1 knockdown counteracts the angiogenic potential of cancer cells, as indicated by a reduction in the number of polygons, sprouting cells, and nodes in HUVEC cells. Remarkably, an increase in CD31-/PAS + staining of 3D channel networks in primary breast tumors from metastatic patients was found compared with the nonmetastatic group. Finally, we found that the number of blood vessels increased in the nonmetastatic group more than in the metastatic cohort., Conclusions: Our data suggested that AFAP1-AS1 controls both VM and angiogenesis in Hs578T breast cancer cells and that increased metastasis is associated with VM in TNBC patients., (© 2024. The Author(s).)

Background: Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes., Methods: International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS., Results: Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer., Conclusions: Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further., (© 2024. The Author(s).)

Background: Breast cancer is the most commonly diagnosed cancer worldwide. Although major treatments represented by chemotherapy have shown effectiveness at the initial period, recurrence and metastasis still occur later after treatments. The alternation of the tumor microenvironment by chemotherapy is confirmed as a trigger of the elevated proliferation and migration of the remaining tumor cells., Methods: Using bioinformatic methods, differential gene expression analysis was used to determine DEGs between post-chemotherapy and pre-chemotherapy samples of breast cancer patients, followed by survival analysis and ELISA analysis of the potential key genes. An in vitro model of 2 breast cancer cells lines was used to demonstrate the role of VWF in the evasion and migration of breast cancer cells, using cell migration, evasion and wound healing assays, PCR and molecular docking analysis., Results: 19 hub genes were further identified using GO and KEGG pathway analyses and WGCNA. The 5 secreted protein-coding genes with reported carcinogenesis effects (VWF, SVEP1, DPT, ADIPOQ, and LPL) were further analyzed in breast cancer patients and VWF was identified as a potential key regulator in the anthracycline-based chemotherapy-exacerbated metastasis. It was further confirmed that anthracycline-based chemotherapeutics doxorubicin exacerbated VWF upregulation and the evasion and migration of breast cancer cells. Based on molecular docking analysis and previous study, berberine was used as an inhibitor of VWF, and showed an effective inhibition of the doxorubicin-exacerbated VWF upregulation, migration and evasion in breast cancer., Conclusions: Doxorubicin-exacerbated evasion and migration through VWF upregulation. Berberine as an inhibitor of VWF was able to reversed the doxorubicin-exacerbated VWF upregulation and evasion and migration in breast cancer cells., (© 2024. The Author(s).)

Background: Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC., Patients and Methods: This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated., Results: From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 - mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 - subtype. The median treatment was 6 cycles (range, 2 - 8 cycles). In the full cohort, TNBC, and HR + HER2 - subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed., Conclusion: ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment., (© 2024. The Author(s).)

The response of patients with colorectal cancer to chemotherapy is tightly correlated with their genomic variation. Among these, APC, TP53, KRAS, PIK3CA are the most frequently mutated genes in advanced colorectal cancer patients. However, the precise correlation between these mutations and the therapeutic effects of chemotherapy remains elusive. Here, we conducted genome sequencing to identify commonly mutated genes in colorectal cancer patients and comprehensively assessed their sensitivity to chemotherapy drugs by monitoring computer tomography (CT) scans and carcinoembryonic antigen (CEA) levels. Surprisingly, we discovered that the objective response rate to the standard first-line chemotherapy among patients harboring combined KRAS and TP53 mutations is dismal, and these patients are predisposed to recurrence and metastasis. Furthermore, advanced-stage patients with concurrent KRAS and TP53 mutations are susceptible to developing cancer-associated cachexia due to chemotherapy resistance or forced cessation of treatment. Our findings underscore the urgent need for the development of innovative and novel chemotherapeutic strategies to effectively manage colorectal cancer patients harboring combined KRAS and TP53 mutations., (© 2024. The Author(s).)

Background: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib., Methods: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/μL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression., Results: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0-9) and 1 (range, 0-7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019)., Conclusion: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer., (© 2024. The Author(s).)

Background: Exercise is associated with improved survival, physical functioning, treatment tolerability, and quality of life in early-stage breast cancer. These same endpoints matter in metastatic breast cancer (MBC). Prior trials in MBC have found exercise to be not feasible or of limited benefit, possibly due to inclusion of patients with heterogeneous disease trajectories. Patients with MBC have variable disease trajectories and supportive care needs; those with indolent MBC have longer life expectancy, lower symptom burden and distinct priorities, and are well-positioned to participate in and benefit from an exercise program. The EMBody trial aims to determine the impact of a multimodal exercise intervention on cardiorespiratory fitness, physical function, body composition, and patient-reported outcomes, specifically in patients with stable, indolent MBC., Methods: Eligible patients have MBC with no evidence of disease progression on current therapy in the prior 12 months and cannot be receiving cytotoxic chemotherapy. The trial aims to enroll 100 patients, randomized 1:1 to the exercise intervention versus usual care, stratified by baseline function. The virtually-delivered exercise intervention arm achieves moderate intensity exercise with exercise physiologists 3 days/week for 16 weeks. The 60-minute sessions include aerobic, resistance, balance and stretching exercises. The exercise arm receives informational sessions on the role of exercise in cancer and principles of habit and self-efficacy. The primary endpoint is 16 week change in fitness on a ramp treadmill test between the exercise and control arms. Secondary endpoints include change in a physical function, muscle mass assessed by CT scans, and PROs of fatigue and quality of life. Exploratory analysis includes behavioral modifiers of exercise adherence and effectiveness and serologic measures of inflammatory, metabolic, and immune pathway biomarkers., Discussion: The EMBody trial evaluates exercise in a unique patient population with indolent, non-progressive MBC. Patients living with MBC experience similar symptom burden to those undergoing therapy for early-stage disease and the benefits achieved with exercise could be similarly impactful. This trial will contribute evidence to support expansion of exercise recommendations, among other survivorship care efforts, to those living with metastatic disease., Clinical Trial Information: NCT05468034., Trial Registration: NCT05468034. Date of registration: 7/12/2022., (© 2024. The Author(s).)

Introduction: MicroRNAs (miRNAs) are single RNA molecules that act as global regulators of gene expression in mammalian cells and thus constitute attractive targets in treating cancer. Here we aimed to investigate the possible involvement of miRNA-141 (miR-141) in cervical cancer and to identify its potential targets in cervical cancer cell lines., Methods: The level of miR-141 in HeLa and C-33A cells has been assessed using the quantitative real-time PCR (qRT-PCR). A new miR-141 construct has been performed in a CMV promoter vector tagged with GFP. Using microarray analysis, we identified the potentially regulated genes by miR-141 in transfected HeLa cells. The protein profile of killer-like receptor C1 (KLRC1), KLRC3, carcinoembryonic antigen-related cell adhesion molecule 3 (CAM3), and CAM6 was investigated in HeLa cells transfected with either an inhibitor, antagonist miR-141, or miR-141 overexpression vector using immunoblotting and flow cytometry assay. Finally, ELISA assay has been used to monitor the produced cytokines from transfected HeLa cells., Results: The expression of miR-141 significantly increased in HeLa and C-33A cells compared to the normal cervical HCK1T cell line. Transfection of HeLa cells with an inhibitor, antagonist miR-141, showed a potent effect on cancer cell viability, unlike the transfection of miR-141 overexpression vector. The microarray data of HeLa cells overexpressed miR-141 provided a hundred of downregulated genes, including KLRC1, KLRC3, CAM3, and CAM6. KLRC1 and KLRC3 expression profiles markedly depleted in HeLa cells transfected with miR-141 overexpression accompanied by decreasing interleukin 8 (IL-8), indicating the role of miR-141 in avoiding programmed cells death in HeLa cells. Likewise, CAM3 and CAM6 expression reduced markedly in miR-141 transduced cells accompanied by an increasing level of transforming growth factor beta (TGF-β), indicating the impact of miR-141 in cancer cell migration. The IntaRNA program and miRWalk were used to check the direct interaction and potential binding sites between miR-141 and identified genes. Based on this, the seeding regions of each potential target was cloned upstream of the luciferase reporter gene in the pGL3 control vector. Interestingly, the luciferase activities of constructed vectors were significantly decreased in HeLa cells pre-transfected with miR-141 overexpression vector, while increasing enormously in cells pre-transfected with miR-141 specific inhibitor., Conclusion: Together, these data uncover an efficient miR-141-based mechanism that supports cervical cancer progression and identifies miR-141 as a credible therapeutic target., (© 2024. The Author(s).)

Background: The prognostic values of preoperative aspartate aminotransferase (AST), monocyte-to-lymphocyte ratio (MLR), AST·MLR index (AMLRI) and operation injury condition in patients with colorectal cancer liver metastases (CRLM) remains unclear. This retrospective study assessed the relationship between these markers, progression-free survival (PFS), and overall survival (OS) in CRLM patients undergoing resection.Methods: AMLRI was defined as AST × MLR. Operation injury condition was defined according to operation time and blood loss. Cox regression analyses were used to identify risk factors and to develop nomograms. C-indexes, time-dependent receiver operating characteristic (time-ROC) curves and calibration curves were used to assess the models.Results: A total of 379 patients were enrolled. The optimal cut-off value of the AMLRI was 3.33. In the multivariable analysis, AMLRI > 3.33 (hazard ratio [HR] = 2.162, p = 0.002) and serious operation injury condition (HR = 1.539, p = 0.012) were predictive for unfavourable OS, and AMLRI > 3.33 (HR = 1.462, p = 0.021) was predictive for unfavourable PFS. The nomograms were superior to Fong's Clinical Risk Score (CRS) according to the C-indexes (PFS: 0.682 vs. 0.600; OS: 0.730 vs. 0.586) and time-ROCs.Conclusions: Preoperative AMLRI and operation injury condition are easily accessible predictors for prognosis. The nomograms performed better than CRS for the prediction of recurrence and survival. [ABSTRACT FROM AUTHOR]

Background: Only a limited proportion of patients with metastatic colorectal cancer (mCRC) receives metastatic surgery (including local ablative therapy). The aim was to investigate whether hospital volume and hospital level were associated with the chance of metastatic surgery.Methods: This national cohort retrieved from the CRCBaSe linkage included all Swedish adult patients diagnosed with synchronous mCRC in 2009-2016. The association between annual hospital volume of incident mCRC patients and the chance of metastatic surgery, and survival, were assessed using logistic regression and Cox regression models, respectively. Hospital level (university/non-university) was evaluated as a secondary exposure in a similar manner. Both uni- and multivariable (adjusted for sex, age, Charlson comorbidity index, year of diagnosis, cancer characteristics and socioeconomic factors) models were fitted.Results: A total of 1,674 (17%) out of 9,968 mCRC patients had metastatic surgery. High hospital volume was not associated with increased odds of metastatic surgery after including hospital level in the model, whereas hospital level was (odds ratio (OR) (95% confidence interval (CI)): 1.94 (1.68-2.24)). All-cause mortality was lower in university versus non-university hospitals (hazard ratio (95% CI): 0.83 (0.78-0.88)).Conclusions: Patients with mCRC initially cared for by a university hospital experienced a greater chance to receive metastatic surgery and had superior overall survival. High hospital volume in itself was not associated with a greater chance to receive metastatic surgery nor a greater survival probability. Additional efforts should be imposed to provide more equal care for mCRC patients across Swedish hospitals. [ABSTRACT FROM AUTHOR]

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab - however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody-liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations.Methods/designHERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab.DiscussionThe HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage.Trial registrationClinicaltrials.gov identifier: NCT02213744 . Registration date: 06AUG2014.

Abstract Background Nomograms are currently used in predicting individualized outcomes in clinical oncology of several cancers. However, nomograms for evaluating occult nodal metastasis of patients with squamous cell carcinoma of lateral tongue (SCCLT) have not been widely investigated for their functionality. This retrospective cohort study was designed to address this question. Methods This study was divided into primary and validation cohorts. The primary cohort comprised 120 patients diagnosed between 2012 and 2017, whereas the validation cohort included 41 patients diagnosed thereafter. The diagnostic value of multiparametric MRI, including radiologic tumor thickness threshold (rTTT) in three-dimensions, paralingual distance, and sublingual distance were investigated. A nomogram was developed based on stepwise logistic regression of potential predictors associated with nodal metastasis in the primary cohort and then tested for predictive accuracy in the validation cohort using area under the curve (AUC) and goodness-of-fit tests. Results Multivariate analysis, tumor size (odd ratio [OR] 15.175, 95% confidence interval [CI] 1.436–160.329, P = 0.024), rTTT (OR 11.528, 95% CI 2.483–53.530, P = 0.002), paralingual distance (OR 11.976, 95% CI 1.981–72.413, P = 0.005), and tumor location (OR 6.311, 95% CI 1.514–26.304, P = 0.011) were included in the nomogram to predict the likelihood of having cervical metastasis. A nomogram cutoff value of 210 points (sensitivity 93.8%, specificity 87.5%) was significantly different to classify the patients metastasis risk group (P 210 points.

Abstract Background Stereotactic Body Radiation Therapy (SBRT) is an innovative modality based on high precision planning and delivery. Cancer with bone metastases and oligometastases are associated with an intermediate or good prognosis. We assume that prolonged survival rates would be achieved if both the primary tumor and metastases are controlled by local treatment. Our purpose is to demonstrate, via a multicenter randomized phase III trial, that local treatment of metastatic sites with curative intent with SBRT associated of systemic standard of care treatment would improve the progression-free survival in patients with solid tumor (breast, prostate and non-small cell lung cancer) with up to 3 bone-only metastases compared to patients who received systemic standard of care treatment alone. Methods This is an open-labeled randomized superiority multicenter phase III trial. Patients with up to 3 bone-only metastases will be randomized in a 1:1 ratio.between Arm A (Experimental group): Standard care of treatment & SBRT to all bone metastases, and Arm B (Control group): standard care of treatment. For patients receiving SBRT, radiotherapy dose and fractionation depends on the site of the bone metastasis and the proximity to critical normal structures. This study aims to accrue a total of 196 patients within 4 years. The primary endpoint is progression-free survival at 1 year, and secondary endpoints include Bone progression-free survival; Local control; Cancer-specific survival; Overall survival; Toxicity; Quality of life; Pain score analysis, Cost-utility analysis; Cost-effectiveness analysis and Budget impact analysis. Discussion The expected benefit for the patient in the experimental arm is a longer expectancy of life without skeletal recurrence and the discomfort, pain and drastic reduction of mobility and handicap that the lack of local control of bone metastases eventually inflicts. Trials registration ClinicalTrials.gov NCT03143322 Registered on May 8th 2017. Ongoing study

BackgroundThis retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.MethodsEighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.ResultsRetreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).ConclusionOur data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.

BackgroundCirculating biomarkers are urgently needed in hepatocellular carcinoma (HCC). The aims of this study were to determine the feasibility of detecting and isolating circulating tumor cells (CTCs) in HCC patients using enrichment for epithelial cell adhesion molecule (EpCAM) expression, to examine their prognostic value, and to explore CTC-based DNA sequencing in metastatic HCC patients compared to a control cohort with non-malignant liver diseases (NMLD).MethodsWhole blood was obtained from patients with metastatic HCC or NMLD. CTCs were enumerated by CellSearch then purified by immunomagnetic EpCAM enrichment and fluorescence-activated cell sorting. Targeted ion semiconductor sequencing was performed on whole genome-amplified DNA from CTCs, tumor specimens, and peripheral blood mononuclear cells (PBMC) when available.ResultsTwenty HCC and 10 NMLD patients enrolled. CTCs ≥ 2/7.5 mL were detected in 7/20 (35%, 95% confidence interval: 12%, 60%) HCC and 0/9 eligible NMLD (p = 0.04). CTCs ≥ 1/7.5 mL was associated with alpha-fetoprotein ≥ 400 ng/mL (p = 0.008) and vascular invasion (p = 0.009). Sequencing of CTC DNA identified characteristic HCC mutations. The proportion with ≥ 100x coverage depth was lower in CTCs (43%) than tumor or PBMC (87%) (p

Background: We investigated the clinicopathological characteristics and survival of breast cancer lung metastases (BCLM) patients at initial diagnosis of metastatic breast cancer (MBC) in the Han population.Methods: We attained clinical data of 3155 MBC patients initially diagnosed between April 2000 and September 2019 from the China National Cancer Center and finally included 2263 MBC patients in this study, among which 809 patients presented with lung metastases at first MBC diagnosis. The risk factors for BCLM were determined using multivariate logistic regression analysis and the prognostic factors of BCLM patients were assessed by univariate and multivariate Cox regression analyses.Results: Patients with triple-negative subtype (42.3%) harbored the highest incidence proportions of lung metastases. Age ≥ 50 years, Eastern Cooperative Oncology Group (ECOG) 2, M1, hormone receptor-negative (HR-)/human epidermal growth factor receptor 2-positive (HER2) + subtype, triple-negative subtype and disease-free survival (DFS) > 2 years were remarkably associated with higher incidence of lung metastases, while invasive lobular carcinoma (ILC) and bone metastases were significantly correlated with lower odds of lung metastases at diagnosis. The median survival of BCLM patients was 41.7 months, with triple-negative subtype experiencing the worst prognosis of 26.8 months. ECOG 2, triple-negative subtype, liver metastases, multi-metastatic sites and DFS ≤ 2 years were significantly correlated with poor survival of BCLM patients.Conclusions: Our study provides essential information on clinicopathological features and survival outcomes of BCLM patients at initial diagnosis of MBC in China. [ABSTRACT FROM AUTHOR]

Background: Survival times differ among patients with advanced gastric carcinoma. A precise and universal prognostic evaluation strategy has not yet been established. The current study aimed to construct a prognostic scoring model for mortality risk stratification in patients with advanced gastric carcinoma. Methods: Patients with advanced gastric carcinoma from two hospitals (development and validation cohort) were included. Cox proportional hazards regression analysis was conducted to identify independent risk factors for survival. A prognostic nomogram model was developed using R statistics and validated both in bootstrap and external cohort. The concordance index and calibration curves were plotted to determine the discrimination and calibration of the model, respectively. The nomogram score and a simplified scoring system were developed to stratify patients in the two cohorts. Results: Development and validation cohort was comprised of 401 and 214 gastric cancer patients, respectively. Mucinous or non-mucinous histology, ECOG score, bone metastasis, ascites, hemoglobin concentration, serum albumin level, lactate dehydrogenase level, carcinoembryonic antigen level, and chemotherapy were finally incorporated into prognostic nomogram. The concordance indices were 0.689 (95% CI: 0.664 ~ 0.714) and 0.673 (95% CI: 0.632 ~ 0.714) for bootstrap and external validation. 100 and 200 were set as the cut-off values of nomogram score, patients in development cohort were stratified into low-, intermediate- and high-risk groups with median overall survival time 15.8 (95% CI: 12.2 ~ 19.5), 8.4 (95% CI: 6.7 ~ 10.2), and 3.9 (95% CI: 2.7 ~ 5.2) months, respectively; the cut-off values also worked well in validation cohort with different survival time in subgroups. A simplified model was also established and showed good consistency with the nomogram scoring model in both of development and validation cohorts. Conclusion: The prognostic scoring model and its simplified surrogate can be used as tools for mortality risk stratification in patients with advanced gastric carcinoma. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) has been extensively studied and verified by the CellSearch® system. Varieties of microfluidic systems have been developed to improve capture efficiency with the lack of standardization and automation. This study systematically verified the positive threshold for prognosis and its guidance value in anti-HER2 therapy based on a novel automated microfluidic system OmiCell®., Methods: CTCs isolation, enumeration and labeling were performed using the OmiCell® system. CTCs identification and reporting were performed using the DeepSight® scanning system., Results: The capture efficiency and specificity of OmiCell® system was 91.9% and 90%, respectively. Then, 65 MBC patients with known HER2 status of their metastatic tumors were enrolled. In the cohort, we detected ≥ 1 CTCs in 59 patients (90.8%, range: 1-55 CTCs, median = 6), < 8 CTCs in 45 (69.2%) and ≥ 8 CTCs in 20 (30.8%) patients at baseline. The patients with < 8 CTCs had longer PFS than ≥ 8 CTCs (median, 7 vs. 4.4 months, p = 0.028). CTC enumeration was found to be an independent prognostic factor in our cohort. Moreover, we found a weak concordance between tissue HER2 (tHER2) status and the corresponding CTCs (k = 0.16, p = 0.266). The patients with tHER2 positive and cHER2 negative had better PFS compared with patients with both tHER2 and cHER2 positive (median, 8.2 vs. 3.3 months, p = 0.022)., Conclusions: This clinical study shows the prognosis value of a new threshold of CTC number and meanwhile the guidance value of cHER2 status in anti-HER2 therapy., (© 2024. The Author(s).)

Background: In prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology., Methods: Acetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection., Results: Acetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin., Conclusion: PGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy., (© 2024. The Author(s).)

Objective: Transfer RNA-derived fragments (tRFs) are short non-coding RNA (ncRNA) sequences, ranging from 14 to 30 nucleotides, produced through the precise cleavage of precursor and mature tRNAs. While tRFs have been implicated in various diseases, including cancer, their role in lung adenocarcinoma (LUAD) remains underexplored. This study aims to investigate the impact of tRF-Val-CAC-010, a specific tRF molecule, on the phenotype of LUAD cells and its role in tumorigenesis and progression in vivo., Methods: The expression level of tRF-Val-CAC-010 was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Specific inhibitors and mimics of tRF-Val-CAC-010 were synthesized for transient transfection. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8), while cell invasion and migration were evaluated through Transwell invasion and scratch assays. Flow cytometry was utilized to analyze cell cycle and apoptosis. The in vivo effects of tRF-Val-CAC-010 on tumor growth and metastasis were determined through tumor formation and metastasis imaging experiments in nude mice., Results: The expression level of tRF-Val-CAC-010 was upregulated in A549 and PC9 LUAD cells (P < 0.01). Suppression of tRF-Val-CAC-010 expression resulted in decreased proliferation of A549 and PC9 cells (P < 0.001), reduced invasion and migration of A549 (P < 0.05, P < 0.001) and PC9 cells (P < 0.05, P < 0.01), enhanced apoptosis in both A549 (P < 0.05) and PC9 cells (P < 0.05), and increased G2 phase cell cycle arrest in A549 cells (P < 0.05). In vivo, the tumor formation volume in the tRF-inhibitor group was significantly smaller than that in the model and tRF-NC groups (P < 0.05). The metastatic tumor flux value in the tRF-inhibitor group was also significantly lower than that in the model and tRF-NC groups (P < 0.05)., Conclusion: This study demonstrates that tRF-Val-CAC-010 promotes proliferation, migration, and invasion of LUAD cells and induces apoptosis in vitro, however, its specific effects on the cell cycle require further elucidation. Additionally, tRF-Val-CAC-010 enhances tumor formation and metastasis in vivo. Therefore, tRF-Val-CAC-010 may serve as a novel diagnostic biomarker and potential therapeutic target for LUAD., (© 2024. The Author(s).)

Background: Metastatic prostate cancer is a leading cause of cancer-related morbidity and mortality in men, yet the underlying molecular mechanisms are poorly understood. Plexins are transmembrane receptors for semaphorins with divergent roles in many forms of cancer. We recently found that a single clinically relevant specific amino acid change (Proline1597Leucine, (P1597L)), found in metastatic deposits of prostate cancer patients, converts PlexinB1 from a metastasis suppressor to a gene that drives prostate cancer metastasis in vivo. However, the mechanism by which PlexinB1(P1597L) promotes metastasis is not known., Methods: Pull down assays using GST-RalGDS or -GSTRaf1-RBD were used to reveal the effect of mutant or wild-type PlexinB1 expression on Rap and Ras activity respectively. Protein-protein interactions were assessed in GST pulldown assays, Akt/ERK phosphorylation by immunoblotting and protein stability by treatment with cycloheximide. Rho/ROCK activity was monitored by measuring MLC2 phosphorylation and actin stress fiber formation. PlexinB1 function was measured using cell-collapse assays., Results: We show here that the single clinically relevant P1597L amino acid change converts PlexinB1 from a repressor of Ras to a Ras activator. The PlexinB1(P1597L) mutation inhibits the RapGAP activity of PlexinB1, promoting a significant increase in Ras activity. The P1597L mutation also blocks PlexinB1-mediated reduction in Rho/ROCK activity, restraining the decrease in MLC2 phosphorylation and actin stress fiber formation induced by overexpression of wild-type PlexinB1. PlexinB1(P1597L) has little effect on the interaction of PlexinB1 with small GTPases or receptor tyrosine kinases and does not inhibit PlexinB1-stimulated Akt or ERK phosphorylation. These results indicate that the mutation affects Rho signalling via the Rap/Ras pathway. The PlexinB1(P1597L) mutation inhibits morphological cell collapse induced by wild-type PlexinB1 expression, suggesting that the mutation induces a loss of an inhibitory tumour suppressor function., Conclusion: These results suggest that the clinically relevant P1597L mutation in PlexinB1 may transform PlexinB1 from a suppressor to a driver of metastasis in mouse models of prostate cancer by reducing the RapGAP activity of PlexinB1, leading to Ras activation. These findings highlight the PlexinB1-Rap-Ras pathway for therapeutic intervention in prostate cancer., (© 2024. The Author(s).)

Background: The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines., Methods: Patients with CRC in the Optum's de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group., Results: 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% (n = 66/310) to 45% (n = 178/393), the proportion who received standard dosing decreased from 79% (n = 244/310) to 55% (n = 215/393), the proportion who initiated their third treatment cycle increased from 36% (n = 113/310) to 46% (n = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1)., Conclusions: Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib., (© 2024. The Author(s).)

Objective: To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis., Methods: The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens., Results: A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs., Conclusion: In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs., (© 2024. The Author(s).)

Background: In the pivotal phase III RECOURSE trial, trifluridine/tipiracil (FTD/TPI) improved progression-free and overall survival (PFS, OS) of patients with pre-treated metastatic colorectal cancer (mCRC). Subsequently, the TALLISUR trial provided post-authorisation efficacy and safety data and patient-reported outcomes on quality of life (QoL) in a German patient cohort. The present analysis reports the final data on efficacy, safety and QoL and investigates the impact of baseline characteristics and associated prognostic subgroups on outcome., Methods: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). To assess the primary endpoint, QoL, EORTC QLQ-C30 questionnaires were employed. Secondary endpoints included QoL assessed through EQ-5D-5L questionnaires, OS, PFS and safety. Additionally, 3 subgroups were defined according to a post-hoc analysis of the RECOURSE trial: best, good and poor prognostic characteristics (BPC, GPC, PPC). Patients with < 3 metastatic sites at inclusion and/or ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC patients without liver metastasis at inclusion were considered to have BPC. All remaining patients were considered to have PPC., Results: Of 195 patients, 186 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. Treatment with FTD/TPI was associated with maintained QoL. For all patients, median OS was 6.9 months (95% CI 6.1 - 8.3) and for the defined subgroups (BPC n = 20 vs GPC n = 65 vs PPC n = 121) 12.2, 7.9 and 6.8 months (95% CI 6.0 - 18.2, 6.2 - 13.3, 5.4 - 8.1). The most frequent TEAEs were neutropenia (29.6%), anaemia (24.7%) and nausea (23.7%). Febrile neutropenia occurred in 1.1%., Conclusions: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression, but also with maintained QoL. Independent of other baseline characteristics such as ECOG performance status and age, low metastatic burden and indolent disease were factors associated with favourable outcome., Clinical Trial Registration: EudraCT-Number 2017-000292-83, first registration 19/06/2017., (© 2024. The Author(s).)

Objective: Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function., Methods: In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis., Results: After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma., Conclusions: Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis., (© 2024. The Author(s).)

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR., (© 2024. The Author(s).)

BackgroundAmplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients' experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC).Methods/designThe Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional.The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled.DiscussionSystHERs is expected to provide in-depth data on demographic, clinicopathological, and treatment patterns and their associations with clinical outcomes, PROs, and healthcare resource utilization. Tumor tissue and DNA repositories will also be established for use in future translational research.Trial registration numberNCT01615068 (ClinicalTrials.gov identifier).

BackgroundPatients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting.Methods/designPatients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m(2) once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed.DiscussionIf the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population.

Abstract Background We evaluated the clinical efficacy and prognosis of muscle-invasive bladder cancer according to the basal/squamous-like (BASQ) classification system based on immunohistochemical staining [CK5/6(+), CK14(+), GATA3(−), and FOXA1(−)]. Methods One hundred patients diagnosed with muscle-invasive bladder cancer (cT2-4 N0-3 M0) were included in the study. All patients underwent radical cystectomy after transurethral removal of bladder tumor. Immunostaining was performed for CK5/6, CK14, FOXA1, and GATA3 antibodies on tissue microarray slides, and expression patterns were quantitatively analyzed using a scanning program. Results The median follow-up time was 77.4 (interquartile range: 39–120.9) months. The mean age of the patients was 65.1 ± 11.2 years. FOXA1 or CK14 expression greater than 1% was respectively positively and negatively correlated with overall survival (OS; p = 0.011 and p = 0.042, respectively), cancer-specific survival (CSS; p = 0.050 for both), and recurrence-free survival (RFS; p = 0.018 and p = 0.040, respectively). For CK5/6+ and GATA3- or FOXA1- expression, 10% CK5/6+ cells were negatively correlated with OS (p = 0.032 and p = 0.039, respectively) and with RFS in combination with FOXA1- only (p = 0.050). Conclusions In this study, CK14 expression was associated with a poor prognosis. The new classification system of bladder cancer based on molecular characteristics is expected to helpful tool for the establishment of personalized treatment strategies and associated prediction of therapeutic responses.

Abstract Background Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 μm microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen. Methods The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration. Results Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and Cmax of plasma SN-38 per 1 mg injected irinotecan dose were significantly higher in irinotecan-loaded microspheres compared with FOLFIRI (P = 0.009 and P

Background: Nomograms are currently used in predicting individualized outcomes in clinical oncology of several cancers. However, nomograms for evaluating occult nodal metastasis of patients with squamous cell carcinoma of lateral tongue (SCCLT) have not been widely investigated for their functionality. This retrospective cohort study was designed to address this question.Methods: This study was divided into primary and validation cohorts. The primary cohort comprised 120 patients diagnosed between 2012 and 2017, whereas the validation cohort included 41 patients diagnosed thereafter. The diagnostic value of multiparametric MRI, including radiologic tumor thickness threshold (rTTT) in three-dimensions, paralingual distance, and sublingual distance were investigated. A nomogram was developed based on stepwise logistic regression of potential predictors associated with nodal metastasis in the primary cohort and then tested for predictive accuracy in the validation cohort using area under the curve (AUC) and goodness-of-fit tests.Results: Multivariate analysis, tumor size (odd ratio [OR] 15.175, 95% confidence interval [CI] 1.436-160.329, P = 0.024), rTTT (OR 11.528, 95% CI 2.483-53.530, P = 0.002), paralingual distance (OR 11.976, 95% CI 1.981-72.413, P = 0.005), and tumor location (OR 6.311, 95% CI 1.514-26.304, P = 0.011) were included in the nomogram to predict the likelihood of having cervical metastasis. A nomogram cutoff value of 210 points (sensitivity 93.8%, specificity 87.5%) was significantly different to classify the patients metastasis risk group (P < 0.001). Nomogram showed predictive accuracy with AUC 0.881 (95% CI 0.779-0.983, P < 0.001) and good calibration after the validation.Conclusions: A preoperative nomogram incorporating multiparametric MRI demonstrated good prediction and performed adequately in our study. Three-dimensional assessment of occult metastasis risk value obtained from this nomogram can assist in preoperative decision making for individual patients with early-stage SCCLT. The probability of nodal metastasis tended to be greater than 20% in patients with high metastasis risk or nomogram total score > 210 points. [ABSTRACT FROM AUTHOR]

Background: Stereotactic Body Radiation Therapy (SBRT) is an innovative modality based on high precision planning and delivery. Cancer with bone metastases and oligometastases are associated with an intermediate or good prognosis. We assume that prolonged survival rates would be achieved if both the primary tumor and metastases are controlled by local treatment. Our purpose is to demonstrate, via a multicenter randomized phase III trial, that local treatment of metastatic sites with curative intent with SBRT associated of systemic standard of care treatment would improve the progression-free survival in patients with solid tumor (breast, prostate and non-small cell lung cancer) with up to 3 bone-only metastases compared to patients who received systemic standard of care treatment alone.Methods: This is an open-labeled randomized superiority multicenter phase III trial. Patients with up to 3 bone-only metastases will be randomized in a 1:1 ratio.between Arm A (Experimental group): Standard care of treatment & SBRT to all bone metastases, and Arm B (Control group): standard care of treatment. For patients receiving SBRT, radiotherapy dose and fractionation depends on the site of the bone metastasis and the proximity to critical normal structures. This study aims to accrue a total of 196 patients within 4 years. The primary endpoint is progression-free survival at 1 year, and secondary endpoints include Bone progression-free survival; Local control; Cancer-specific survival; Overall survival; Toxicity; Quality of life; Pain score analysis, Cost-utility analysis; Cost-effectiveness analysis and Budget impact analysis.Discussion: The expected benefit for the patient in the experimental arm is a longer expectancy of life without skeletal recurrence and the discomfort, pain and drastic reduction of mobility and handicap that the lack of local control of bone metastases eventually inflicts.Trials Registration: ClinicalTrials.gov NCT03143322 Registered on May 8th 2017. Ongoing study. [ABSTRACT FROM AUTHOR]

Background: Despite increased use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma, little is known about patient experiences during this treatment. This study aimed to gain an in-depth understanding of experiences and unmet care needs of patients treated in the adjuvant or metastatic setting for advanced melanoma regarding their ICI treatment trajectory., Methods: Interviews and focus groups were conducted among 35 patients treated with ICIs in the adjuvant setting for completely resected stage III (n = 14), or in the metastatic setting for irresectable stage IV (n = 21) melanoma. A thorough thematic content analysis was conducted., Results: Three main themes were identified. When (1) dealing with uncertainty in the decision-making process, adjuvant patients explored the pros and cons, whereas metastatic patients considered immunotherapy their only viable option. Both groups expressed the need for additional guidance. In (2) navigating the immunotherapy course, both perceived the trajectory as intense, experienced a major impact on their and their (close) relatives' lives, and felt the need to (re)gain control. When (3) looking back on the immunotherapy experience, metastatic patients generally felt relieved, while among adjuvant patients, feelings of doubt regarding their choice for ICIs were also reported., Conclusions: ICI treatment is perceived as intensive for both patient groups, facing both comparable and distinct challenges throughout the treatment trajectory, underscoring the need for stage-specific, individualised guidance. Options regarding flexible follow-ups, low-threshold contact and psychosocial support throughout the treatment trajectory should be explored., (© 2024. The Author(s).)

Background: The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state., Methods: CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming's two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023., Discussion: The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases., Trial Registration: The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023., (© 2024. The Author(s).)

Background: HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I-II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression., Methods: This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+  locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes., Discussion: heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC., Trial Registration: ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022)., Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland., (© 2024. The Author(s).)