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Antiandrogens were originally developed as therapeutic agents for prostate cancer but are also expected to be effective for breast cancer. However, the role of androgen signaling in breast cancer has long been controversial due to the limited number of experimental models. Our study aimed to comprehensively investigate the efficacy of antiandrogens on breast cancer. In the present study, a total of 18 breast cancer cell lines were treated with the agonist or antagonists of the androgen receptor (AR). Among the 18 cell lines tested, only T-47D cells proliferated in an androgen-dependent manner, while the other cell lines were almost irresponsive to AR stimulation. On the other hand, treatment with AR antagonists at relatively high doses suppressed the proliferation of not only T-47D cells but also some other cell lines including AR-low/negative cells. In addition, expression of the full-length AR and constitutively active AR splice variants, AR-V7 and ARV567es, was not correlated with sensitivity to AR antagonists. These data suggest that the antiproliferative effect of AR antagonists is AR-independent in some cases. Consistently, proliferation of AR-knockout BT-549 cells was inhibited by AR antagonists. Identification of biomarkers would be necessary to determine which breast cancer patients will benefit from these drugs.
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Neoplasias da Mama , Neoplasias da Próstata , Masculino , Humanos , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Próstata/metabolismo , Células MCF-7 , Linhagem Celular TumoralRESUMO
BACKGROUND: This study aims to investigate the relationship between comorbidities and survival in patients with mUC treated with pembrolizumab as a second-line treatment. METHODS: From February 2018 to October 2021, we analyzed the data of 185 consecutive patients with metastatic UC who received pembrolizumab as second-line therapy at The Jikei University Hospital and five affiliated hospitals. We used the Charlson Comorbidity Index (CCI) to assess the comorbidities. The outcomes of interest were progression-free survival (PFS) and overall survival (OS). To compare the survival differences, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and the IPTW-adjusted Cox regression hazards model were used. RESULTS: After IPTW adjustment, patient characteristics were well-balanced between patients with high CCI and those with low CCI. The IPTW-adjusted Kaplan-Meier curves of PFS and OS based on CCI revealed that the patients with high CCI (2 or more) had a shorter PFS (median, 1.6 vs. 2.8 months) and a shorter OS (median, 12.4 vs. 18.8 months) (0-1). Similarly, in the IPTW-adjusted Cox regression hazards model, patients with high CCI had significantly shorter PFS [HR, 1.84 (95% CI 1.26-2.68; p = 0.002)] and OS [HR, 1.98 (95% CI 1.20-3.27; p = 0.008)] than those with lower CCI. CONCLUSIONS: High CCI was associated with a higher risk of disease progression as well as overall mortality in mUC patients treated with second-line pembrolizumab.
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Anticorpos Monoclonais Humanizados , Comorbidade , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/uso terapêutico , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/secundário , Estimativa de Kaplan-Meier , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologiaRESUMO
OBJECTIVE: Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10 months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. METHODS: This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. RESULTS: No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10 months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. CONCLUSION: In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.
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Benzamidas , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Tioidantoínas , Humanos , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Feniltioidantoína/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Tioidantoínas/uso terapêutico , Tioidantoínas/efeitos adversos , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Antígeno Prostático Específico/sangue , Resultado do TratamentoRESUMO
BACKGROUND: The KEYNOTE-045 trial showed that pembrolizumab therapy improved the survival of patients with advanced urothelial carcinoma (UC). However, its effectiveness in trial-ineligible patients remains unclear. MATERIALS AND METHODS: We conducted a multicenter retrospective study to evaluate the effectiveness of pembrolizumab in patients with metastatic UC who were trial-ineligible. The data of 164 consecutive patients with platinum-treated metastatic UC who received pembrolizumab as second-line therapy were analyzed. Trial eligibility was assessed using the KEYNOTE-045 criteria. Inverse probability of treatment weighting (IPTW) was used to balance patient characteristics. Overall survival (OS) and progression-free survival (PFS) were examined using the IPTW-adjusted Kaplan-Meier method. IPTW-adjusted restricted mean survival times (RMSTs) were compared between ineligible and eligible patients. RESULTS: Seventy-five patients (45.7%) were classified as ineligible based on the KEYNOTE-045 criteria. Baseline hemoglobin concentration of less than 9.0 g/dL was the most common reason for trial protocol violation (N = 23 [14.0%]). An IPTW-adjusted logistic regression model showed that the trial-eligibility was not significantly associated with objective response (OR: 0.65, 95% CI: 0.32 to 1.29, P = 0.22). Ineligible patients had similar RMST for PFS (difference: 3.8 months, 95% CI: -1.6 to 9.3, P = 0.17) and RMST for OS (difference: 1.4 months, 95% CI: -5.4 to 8.2, P = 0.93) compared with eligible patients. CONCLUSIONS: This study suggests that the effectiveness of pembrolizumab may be retained in ineligible patients with platinum-treated metastatic UC. Expanding trial eligibility criteria for these patients may be beneficial.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/patologia , Platina/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
OBJECTIVES: Radical cystectomy is the gold-standard treatment for muscle-invasive bladder cancer and aggressive non-muscle-invasive bladder cancer. To enhance clinical decision-making regarding patients with bladder cancer who underwent radical cystectomy, a recurrence prediction biomarker with high accuracy is urgently needed. In this study, we developed a model for the prediction of bladder cancer recurrence after radical cystectomy by combining serum microRNA and a pathological factor. METHODS: We retrospectively analyzed the clinical records of 81 patients with bladder cancer who underwent radical cystectomy between 2008 and 2016. The dataset was divided into two, and Fisher linear discriminant analysis was used to construct a prognostic model for future recurrence in the training set (n = 41). The performance of the model was evaluated in the validation set (n = 40). RESULTS: Thirty patients had recurrence after having undergone radical cystectomy. A prognostic model for recurrence was constructed by combining a pathological factor (i.e. positive pathological lymph node status) and three microRNAs (miR-23a-3p, miR-3679-3p, and miR-3195). The model showed a sensitivity of 0.87, a specificity of 0.80, and an area under the receiver operating characteristic curve of 0.88 (0.77-0.98) in the validation set. Furthermore, Kaplan-Meier analysis revealed that patients with a low prediction index have significantly longer overall survival than patients with a high prediction index (P = 0.041). CONCLUSION: A combination of serum microRNA profiles and lymph node statuses is useful for the prediction of oncological outcomes after radical cystectomy in patients with bladder cancer.
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MicroRNAs , Neoplasias da Bexiga Urinária , Biomarcadores , Cistectomia , Humanos , Biópsia Líquida , Recidiva Local de Neoplasia/diagnóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
We compared brain metastasis of renal cell carcinoma (RCC) in patients who received tyrosine kinase inhibitors (TKIs) ; 17 received local therapy, while 16 did not. The median survival rate was 19 months in the local therapy group and 11 months in the tyrosine kinase inhibitor alone group, showing no significant difference (pï¼0.52). Symptoms such as paralysis, headache, and dysarthria occurred due to brain metastasis. These symptoms improved in 8 out of 10 patients in the local therapy group. There were no cases of grade 3 or higher complications due to local therapy. Although local therapy did not prolong the overall survival, an improvement in symptoms was observed, suggesting that it is acceptable as palliative treatment.
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Neoplasias Encefálicas , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Metástase Neoplásica , Inibidores de Proteínas Quinases , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Extracellular vesicles (EVs) are small lipid membrane vesicles that are secreted from almost all kinds of cells into the extracellular space. EVs are widely accepted to be involved in various cellular processes; in particular, EVs derived from cancer cells have been reported to play important roles in modifying the tumor microenvironment and promoting tumor progression. In addition, EVs derived from cancer cells encapsulate various kinds of tumor-specific molecules, such as proteins and RNAs, which contribute to cancer malignancy. Therefore, the unveiling of the precise mechanism of intercellular communication via EVs in cancer patients will provide a novel strategy for cancer treatment. Furthermore, a focus on the contents of EVs could promote the use of EVs in body fluids as clinically useful diagnostic and prognostic biomarkers. In this review, we summarize the current research knowledge on EVs as biomarkers and therapeutic targets and discuss their potential clinical applications.
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Hemofiltração , Terapia de Alvo Molecular , Neoplasias/terapia , Animais , Biomarcadores Tumorais/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Valor Preditivo dos Testes , Transdução de SinaisRESUMO
Targeting extracellular vesicle (EV) secretion can have potential clinical implications for cancer therapy, however the precise regulatory mechanisms of EV secretion are not fully understood. Recently, we have shown a novel pathway of EV biogenesis in PCa cell lines, PC3 and PC3M. However, as the characteristics of EVs are divergent even among PCa cell lines, we hypothesized that other pathways or common regulatory pathways of EV biogenesis still exist. Here, we performed quantitative high-throughput screening to determine the key regulatory genes involved in EV biogenesis in 22Rv1 cells, which secrete a different type of EVs. In total, 1728 miRNAs were screened and miR-1908 was selected as the potential miRNA regulating EV biogenesis in 22Rv1 cells. Subsequently, we investigated target genes of miR-1908 using siRNA screening and identified that spermidine synthase (SRM) was the key regulator of EV secretion in 22Rv1 cells. Attenuation of SRM expression significantly inhibited secretion of EVs in 22Rv1 cells, and overexpression of SRM was confirmed in PCa tissues. Furthermore, we found that the number of endosome compartments was increased in cellular cytoplasm after knockdown of the SRM gene. In conclusion, our results showed that miR-1908-mediated regulation of SRM can control secretion of EVs in PCa. In addition, these data suggested that the EV secretion pathway was dependent on cellular characteristics.
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Vesículas Extracelulares/metabolismo , MicroRNAs/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Espermidina Sintase/genética , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Modelos Biológicos , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: Docetaxel (DOC) has been widely accepted as a therapeutic option for castration-resistant prostate cancer (CRPC). Evidence-based clinical guidelines have stipulated its use up to 10 cycles in most health care systems. There has been a paucity of information regarding potential benefits of its use over 10 cycles. The purpose of this study is to re-examine the rationale for the clinical guidelines concerning cycles of DOC in CRPC. METHODS: Between July 2007 and July 2016, a total of 122 CRPC patients received at least five cycles of DOC at Jikei University and its affiliate hospitals. Doses of DOC (75 mg/m 2 ) were administered every 3 to 4 weeks. Clinical outcomes between patients receiving extended cycles of DOC (≥11 cycles, extended [ex]-DOC group) were compared to those receiving fewer (≤10 cycles, short-DOC group). A subgroup of patients who had discontinued DOC owing to adverse events, but whose disease did not progress, were also considered for comparison (adverse events [AE] group). Overall survival from the induction of DOC was the primary outcome measure. Univariate and multivariate analyses were conducted to analyze variables associated with overall survival. RESULTS: The ex- and short-DOC groups included 80 and 42 patients, respectively. Most baseline demographics did not differ between groups. However, in the short-DOC group more patients had received abiraterone acetate and/or enzalutamide before chemotherapy, age at DOC induction was younger, and lactate dehydrogenase at DOC induction was higher. Overall survival was significantly longer in the ex-DOC group compared to the short-DOC group (median, 53 and 27 months, respectively; P = .04). A subgroup of 22 patients in AE group was compared to compensate for potential bias. Overall survival from the induction of DOC was comparable between AE group and ex-DOC groups (median, 53 vs 53 months, respectively; P = 0.87). Univariate and multivariate analyses did not show any advantage of extended use of DOC on patient survival. CONCLUSIONS: The results of this study failed to show the survival benefit of extended use of DOC over 10 cycles in CRPC patients in the era of innovative drugs such as abiraterone acetate, enzalutamide, and cabazitaxel. Further prospective studies are required to confirm our findings.
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Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Resultado do Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Taxa de SobrevidaRESUMO
BACKGROUND: Guidelines define docetaxel as a first-line therapeutic option for metastatic castration-resistant prostate cancer (mCRPC). However, the role of docetaxel in non-metastatic castration-resistant prostate cancer (nmCRPC) has not been fully investigated. The aim of this retrospective study was to evaluate the potential role of docetaxel in nmCRPC. Clinical outcomes including overall survival were compared between CRPC patients who had docetaxel introduced while in nonmetastatic versus metastatic diseases. METHODS: A total of 98 CRPC patients had docetaxel therapy. Of these 46 patients received docetaxel for nmCRPC, and 52 had distant metastases. Clinical outcomes from the time of diagnosis of CRPC were compared retrospectively between groups. RESULTS: The median observation period after the diagnosis of CRPC in these patients was 42 months (range, 3-166). Overall survival (OS) was significantly longer in the nmCRPC group than in the mCRPC group (not reached vs 52.2 months, respectively, P = 0.006). Multivariate analysis showed that longer time to CRPC, docetaxel use in nmCRPC, and use of abiraterone acetate and/or enzalutamide were significant predictors for improved OS (P = 0.04, 0.019 and 0.002, respectively). The incidence and profile of adverse events did not differ significantly between groups. CONCLUSIONS: Earlier induction of docetaxel in nmCRPC patients may prolong OS. Further prospective studies in more patients will be required to confirm our findings.
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Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Docetaxel/efeitos adversos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: To evaluate the role of androgen receptor-axis-targeted drugs (ARAT) in non-metastatic castration-resistant prostate cancer (nmCRPC) versus mCRPC. METHODS: Chemotherapy-naive patients (n = 114) with CRPC who had no metastasis at the time of diagnosis were included in this retrospective study. All patients were treated with ARAT at Jikei University and its affiliated hospitals from July 2014 to March 2017. The patients were stratified into nmCRPC (n = 81) and mCRPC (n = 33) groups according to their metastatic status at ARAT induction. The primary outcome measure was difference in overall survival (OS) between groups from the time of CRPC diagnosis. The patients were compared for progression-free survival (PFS) and prostate-specific antigen (PSA) response. The predictors of OS were explored by a multivariate Cox model. RESULTS: The baseline demographics did not differ significantly between the groups. The median observation period from the diagnosis of CRPC was 24.5 months (range: 3-135) and 20 months (range: 1-66) in nmCRPC and mCRPC groups, respectively. The nmCRPC group demonstrated better OS from the time of diagnosis of CRPC in Kaplan-Meier analysis than mCRPC group (86 months vs 40 months; P = 0.004), with similar results obtained for PFS (P = 0.048) and PSA response (P = 0.0014). Multivariate analysis demonstrated non-metastatic status, low PSA, and long PSA doubling time (PSADT) at ARAT induction as the significant predictors of longer OS (P = 0.044, 0.0001, and 0.026, respectively). CONCLUSIONS: Early use of ARAT may improve OS, PFS, and PSA response in CRPC. Larger, prospective studies will be required to confirm our findings.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/terapia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/efeitos dos fármacos , Adenocarcinoma/sangue , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/farmacologia , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/secundário , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment to benefit their own growth and survive in the patient's body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging. In this study, we applied a microRNA library to reveal the universal mechanisms of EV secretion from cancer cells. Here, we identified miR-891b and its direct target gene, phosphoserine aminotransferase 1 (PSAT1), which promotes EV secretion through the serine-ceramide synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of EV secretion from cancer cells. Interestingly, aberrant PSAT1 expression also regulated cancer metastasis via EV secretion. Our data link the PSAT1-controlled EV secretion mechanism and cancer metastasis and show the potential of this mechanism as a therapeutic target in multiple types of cancer.
Assuntos
Vesículas Extracelulares , MicroRNAs , Neoplasias , Serina , Transaminases , Humanos , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Serina/metabolismo , Animais , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Linhagem Celular Tumoral , Transaminases/metabolismo , Transaminases/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Camundongos , Ceramidas/metabolismo , Microambiente Tumoral , Metástase Neoplásica , Camundongos NusRESUMO
PURPOSE: Although docetaxel and ARSI are picked up as treatment options against chemo-naïve metastatic CRPC in clinical guidelines for prostate cancer, there is no clear evidence which agent should be introduced as first line treatment. Therefore, we investigated our CRPC cohort treated with docetaxel or ARSI as first-line agent against chemo-naïve CRPC to solve these clinical questions. PATIENTS AND METHODS: A total of 345 chemotherapy-naïve CRPC patients introduced to first-line docetaxel or ARSI (abiraterone or enzalutamide) between March 2006 and April 2017 at Jikei University Hospital and its affiliated institutions were included in this study. Propensity score matching method was used to minimize the patients' background. The outcome measures were PSA response rate, PSA decline ≥ 90%, cancer specific survival (CSS) and overall survival (OS). RESULTS: PSA decline correlated OS and CSS (p = 0.027, < 0.001, respectively) and median PSA decline rate was 60.4% in docetaxel group and 85.7% in ARSI group (p = 0.0311). Median OS was 33 m (95%CI: 27-53) in docetaxel group and 61 m (95%CI: 47-NA) in ARSI group (p = 0.0246). Median CSS was 34 m (95%CI: 27-53) in docetaxel group and NR (not reached) (95%CI: 61-NA) in ARSI group (p = 0.000133) in propensity score matching cohort. In multivariate analysis, ARSI induction first showed significantly better for OS and CSS (p = 0.0033 and < 0.001, respectively). CONCLUSION: In this study, better survival outcome with ARSI induction first than docetaxel against chemo-naïve CRPC. And the candidates who had survival benefit by induction docetaxel first could not be found in this study.
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Background: Few studies have addressed the efficacy of nephroureterectomy for managing upper tract urothelial carcinoma (UTUC) in very elderly patients (those aged 85 years and older). We aimed to elucidate the association between age and clinical outcomes in patients with UTUC who underwent radical nephroureterectomy. Methods: We retrospectively analyzed data from 847 patients who underwent nephroureterectomy for UTUC. These patients were classified into four age brackets: young (≤64 years, n=177), intermediate (65-74 years, n=300), elderly (75-84 years, n=312), and very elderly (≥85 years, n=58). We applied logistic regression models to ascertain predictors of postoperative complications. Cox's proportional hazards models were used to evaluate key prognostic factors affecting non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). Results: In all, 56 patients reported postoperative complications. An Eastern Cooperative Oncology Group performance status ≥2 was identified as a significant predictor for postoperative complications whereas age did not show a noteworthy correlation. Kaplan-Meier survival analyses indicated that very elderly patients had notably poorer OS than younger groups. Nevertheless, the differences in NUTRFS and CSS across the age brackets were not statistically significant. In multivariable analyses, very elderly age was a substantial independent determinant of OS but not NUTRFS or CSS. Conclusions: The therapeutic benefits of surgical procedures are relatively consistent across age groups. This underscores the potential of considering surgical treatment for UTUC in patients aged 85 and above, provided they are deemed fit to withstand the surgical rigors and associated invasiveness.
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Bone metastases are still incurable and result in the development of clinical complications and decreased survival for prostate cancer patients. Recently, a number of studies have shown that extracellular vesicles (EVs) play important roles in tumour progression. Here, we show that EVs from metastatic prostate cancer cells promote osteoclast formation in the presence of receptor activator of NF-κB ligand (RANKL). EV characterization followed by functional siRNA screening identified CUB-domain containing protein 1 (CDCP1), a transmembrane protein, as an inducer of osteoclastogenesis. Additionally, CDCP1 expression on plasma-derived EVs was upregulated in bone metastatic prostate cancer patients. Our findings elucidate the effect of EVs from metastatic prostate cancer cells on osteoclast formation, which is promoted by CDCP1 located on EVs. Furthermore, our data suggested that CDCP1 expression on EVs might be useful to detect bone metastasis of prostate cancer.
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Vesículas Extracelulares , Neoplasias da Próstata , Masculino , Humanos , Osteogênese , Proteínas de Membrana , Osteoclastos , Antígenos de Neoplasias , Moléculas de Adesão CelularRESUMO
Clinically, the osteolytic phenotype is rare in prostate cancer (PCa), and the prognosis is generally worse than that of the osteoblastic phenotype. Osteoblastic prostate cancer (BPCa) is a major type of bone metastasis. Several factors responsible for osteogenesis have been identified, but the molecular mechanism of osteoblastic bone metastasis in PCa is not fully understood. Here, we show the osteogenic and tumor-suppressive roles of SERPINA3 and LCN2 in BPCa. In a co-culture of osteoblasts (OBs) and BPCa cells, SERPINA3 and LCN2 were remarkably upregulated in BPCa via OB-derived extracellular vesicles, while they were not in the co-culture of OBs and osteolytic prostate cancer (LPCa) cells. In both the co-culture system and mouse xenograft experiments with intracaudal injection, enhanced expression of SERPINA3 and LCN2 in PCa led to osteogenesis. Additionally, the addition of SERPINA3 and LCN2 to BPCa cells significantly suppressed the proliferative potential. Retrospective analysis also confirmed that high expression levels of SERPINA3 and LCN2 were significantly correlated with a better prognosis. Our results may partially explain how osteoblastic bone metastasis develops and why the prognosis for BPCa is relatively better than that for LPCa.
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BACKGROUND: The association of concurrent proton pump inhibitor (PPI) use with treatment outcome of metastatic urothelial carcinoma (UC) remains controversial. MATERIALS AND METHODS: We retrospectively analyzed the records of 227 patients with platinum-treated metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) and objective response per immune response evaluation criteria in solid tumors were also compared. Inverse probability of treatment weighting (IPTW)-adjusted multivariable Cox regression models and an IPTW-adjusted multivariable logistic regression model were used to evaluate the oncological outcomes. Furthermore, the heterogeneity of the treatment effect on OS was examined using interaction terms within the IPTW-adjusted univariate Cox regression models. RESULTS: Overall, 86 patients (37.9%) used PPIs. After weighting, no significant differences in patient characteristics were observed between PPI users and non-users. PPI use was significantly associated with a shorter OS (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.28-3.18, Pâ¯=â¯0.003) and iPFS (HR: 1.70, 95% CI: 1.23-2.35, Pâ¯=â¯0.001). Although not statistically significant, PPI use was associated with objective response as well (OR: 0.61, 95% CI: 0.36-1.02, Pâ¯=â¯0.06). The interaction analyses showed that the effect of PPI significantly decreased with age (HR: 0.97, 95% CI: 0.93-1.00, P[interaction]â¯=â¯0.048) and was increased in males (HR: 2.97, 95% CI: 1.10-8.05, P[interaction]â¯=â¯0.032). CONCLUSIONS: PPI use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Furthermore, the results suggested that its effects decreased with age and was increased in males.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais Humanizados , Carcinoma de Células de Transição/induzido quimicamente , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Masculino , Inibidores da Bomba de Prótons/efeitos adversos , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/induzido quimicamenteRESUMO
Clinically, the detection of bladder cancer (BCa) typically requires cystoscopy, which is potentially harmful and sometimes accompanied by adverse effects. Thus, new biomarkers are desirable for improving the management of BCa. Recently, "liquid biopsy" has received enormous attentions and has been extensively studied due to its promising clinical implication for precise medicine. Especially, extracellular vesicles (EVs) have attracted strong interest as a potential source of biomarkers. EVs have been reported to be found in almost all types of body fluids and are easy to collect. In addition, EVs tightly reflect the current state of the disease by inheriting specific biomolecules from their parental cells. Urinary EVs have gained great scientific interest in the field of BCa biomarker research since urine is in direct contact with BCa and can contain large amounts of EVs from the tumour microenvironment. To date, various kinds of biomolecules, including noncoding RNAs, mRNAs, and proteins, have been investigated as biomarkers in urinary EVs. In this narrative review, we summarize the recent advances regarding urinary EVs as non-invasive biomarkers in patients with BCa. The current hurdles in the clinical implications of EV-based liquid biopsy and the potential applications of EV research are also discussed.
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OBJECTIVE: To evaluate the risk factors of perioperative hemodynamic instability in pheochromocytoma, we conducted a systematic search of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-analysis. METHODS: In April 2021, we systematically searched PubMed, the Cochrane library, and Scopus for relevant studies on the risk factors of perioperative hemodynamic instability of adrenalectomy in patients with pheochromocytoma, and we subjected the findings from those studies to formal meta-analysis. RESULTS: Our systematic review identified 14 studies involving 1725 patients, of which nine studies with 967 patients were eligible for meta-analysis. The results of meta-analysis showed that tumor size (odds ratio (OR): 1.14 for each increased cm, 95% confidence interval (CI) 1.03-1.26, z = 2.57) and urinary norepinephrine (OR, 1.51: 95% CI 1.26-1.81; z = 4.50) were most closely associated with the occurrence of perioperative hemodynamic instability. CONCLUSION: These findings suggest that tumor size and urinary norepinephrine are important predictors and risk factors for perioperative hemodynamic instability in adrenalectomy for pheochromocytoma. Such findings may be of value to surgeons and anesthesiologists when considering or preparing for this procedure.