Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and ...G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.
Background
Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) is a newly defined subtype that is unlikely to benefit from BCG rechallenge. Radical cystectomy is ...currently recommended for BCG-unresponsive NMIBC; however, a certain proportion of these patients can be managed with treatments other than that. Herein, we conducted a multicenter retrospective study to analyze the clinical outcomes of BCG-unresponsive NMIBC patients who did not receive radical cystectomy.
Methods
Of the 141 BCG-unresponsive NMIBC patients, 94 (66.7%) received treatment except radical cystectomy. Survival outcomes were calculated from the date of diagnosis using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors were identified using the multivariate Cox regression model. This group was further classified into three groups according to the number of risk factors, and survival outcomes were compared.
Results
Multivariate analyses identified low estimated glomerular filtration rate (< 45 ml/min/1.73 m
2
) and large tumor size (≥ 30 mm) before BCG induction as independent poor prognostic factors for progression-free survival and overall survival, while the latter was also an independent factor for cancer-specific survival. The presence of variant histology was an independent poor prognostic factor for overall survival. The high-risk non-cystectomy group showed a significantly poor prognosis for progression-free survival (hazard ratio: 7.61, 95% confidence interval: 2.11–27.5), cancer-specific survival (10.4, 0.54–70.02), and overall survival (8.28, 1.82–37.7).
Conclusions
Our findings suggest that patients with renal impairment and large tumors should undergo radical cystectomy if the complications and intentions of the patients allow so.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
3.
Perioperative therapies for urological cancers Inokuchi, Junichi; Yokomizo, Akira; Nishiyama, Naotaka ...
Japanese journal of clinical oncology,
2020-Apr-07, Volume:
50, Issue:
4
Journal Article
Peer reviewed
Open access
Although surgery with curative intent is critical for management of many localized cancers, multimodal therapy including neoadjuvant and adjuvant therapy has been introduced to increase the ...effectiveness of local control of surgery and prolong survival. However, strong evidence supporting the utility of such multimodal therapy is limited. The utility of perioperative chemotherapy has been extensively investigated in bladder cancer, and several randomized controlled trials have indicated the benefit of neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Regrettably, perioperative therapy for other urological cancers is controversial; therefore, no definitive conclusions have been drawn. Recently, the number of trials has rapidly increased due to the development of immune checkpoint inhibitors, used alone or in combination with other modalities. In this review, we summarize the current status and supporting evidence for perioperative therapies such as neoadjuvant and adjuvant therapies for urological cancers, including prostate cancer, urothelial cancer and renal cell carcinoma.
Background
This study investigated the clinical impact of carcinoma in situ (CIS) in intravesical Bacillus Calmette-Guérin (BCG) therapy for patients with non-muscle-invasive bladder cancer (NMIBC).
...Methods
This study retrospectively evaluated 3035 patients who were diagnosed with NMIBC and treated by intravesical BCG therapy between 2000 and 2019 at 31 institutions. Patients were divided into six groups according to the presence of CIS as follows: low-grade Ta without concomitant CIS, high-grade Ta without concomitant CIS, high-grade Ta with concomitant CIS, high-grade T1 without concomitant CIS, high-grade T1 with concomitant CIS, and pure CIS (without any papillary lesion). The endpoints were recurrence- and progression-free survival after the initiation of BCG therapy. We analyzed to identify factors associated with recurrence and progression.
Results
At a median follow-up of 44.4 months, recurrence and progression were observed in 955 (31.5%) and 316 (10.4%) patients, respectively. Comparison of six groups using univariate and multivariate analysis showed no significant association of CIS. However, CIS in the prostatic urethra was an independent factors associated with progression.
Conclusion
Concomitant CIS did not show a significant impact in the analysis of Ta and T1 tumors which were treated using intravesical BCG. Concomitant CIS in the prostatic urethra was associated with high risk of progression. Alternative treatment approaches such as radical cystectomy should be considered for patients with NMIBC who have a risk of progression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although neoadjuvant chemotherapy provides survival benefits in muscle-invasive bladder cancer, the impact of neoadjuvant chemotherapy on health-related quality of life has not been investigated by a ...randomized trial. The purpose of this study is to compare health-related quality of life in patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy followed by radical cystectomy or radical cystectomy alone based on patient-reported outcome data.
Patients were randomized to receive two cycles of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin followed by radical cystectomy or radical cystectomy alone. Health-related quality of life was measured using the Functional Assessment of Cancer Therapy-Bladder (version 4) questionnaire before the protocol treatments, after neoadjuvant chemotherapy, after radical cystectomy and 1 year after registration.
A total of 99 patients were analysed. No statistically significant differences in postoperative health-related quality of life were found between the arms. In the neoadjuvant chemotherapy arm, the scores after neoadjuvant chemotherapy were significantly lower than the baseline scores in physical well-being, functional well-being, Functional Assessment of Cancer Therapy-General total, weight loss, diarrhoea, appetite, body appearance, embarrassment by ostomy appliance and total Functional Assessment of Cancer Therapy-Bladder. However, there was no difference in scores for these domains, except for embarrassment by ostomy appliance, between the two arms after radical cystectomy and 1 year after registration.
Although health-related quality of life declined during neoadjuvant chemotherapy, no negative effect of neoadjuvant chemotherapy on health-related quality of life was apparent after radical cystectomy. These data support the view that neoadjuvant chemotherapy can be considered as a standard of care for patients with muscle-invasive bladder cancer regarding health-related quality of life.
Objectives
Pembrolizumab, an anti‐PD‐1 monoclonal antibody, revolutionized the treatment for advanced urothelial carcinoma. However, the standard treatment for patients after disease progression with ...pembrolizumab had not been established until the recent approval of enfortumab vedotin. We analyzed the treatment of these patients in the real world, and the patient background and outcomes.
Methods
We extracted data from 543 patients who experienced progressive disease after pembrolizumab initiation from a Japanese nation‐wide cohort of platinum‐refractory, metastatic urothelial carcinoma.
Results
The median overall survival of the 543 patients was 3.5 months (95% confidence interval 3.0–4.1). Of these, only 20.6% (n = 112) received chemotherapy as a subsequent systemic treatment after progressive disease. The regimen of chemotherapy was very diverse. The median overall survival was 11.9 months (95% confidence interval 9.2–14.7) for patients who received chemotherapy, compared to 2.4 months for those who did not receive chemotherapy (95% confidence interval 2.1–2.9; P < 0.0001). Patients who received subsequent chemotherapy were more likely to have better performance status, neutrophil‐to‐lymphocyte ratio <3, hemoglobin >11 mg/dL, and history of a single chemotherapeutic regimen at pembrolizumab initiation.
Conclusions
This report highlights the real‐world practice of the management after pembrolizumab treatment failure in the pre‐enfortumab vedotin era, characterized by infrequent use of subsequent anticancer therapy comprising various regimens, reflecting the lack of a standard treatment. Clinical introduction of enfortumab vedotin is expected to improve treatment outcomes in this setting. The present study will provide important baseline data for evaluating the influence of enfortumab vedotin on clinical practices and outcomes.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract A multicenter study of nonmetastatic castration-resistant prostate cancer (nmCRPC) was conducted to identify the optimal cut-off value of prostate-specific antigen (PSA) doubling time ...(PSADT) that correlated with the prognosis in Japanese nmCRPC. Of the 515 patients diagnosed and treated for nmCRPC at 25 participating Japanese Urological Oncology Group centers, 450 patients with complete clinical information were included. The prognostic values of clinical factors were evaluated with respect to prostate specific antigen progression-free (PFS), cancer-specific survival (CSS), and overall survival (OS). The optimal cutoff value of PSADT was identified using survival tree analysis by Python. The Median PSA and PSADT at diagnosis of nmCRPC were 3.3 ng/ml, and 5.2 months, respectively. Patients treated with novel hormonal therapy (NHT) showed significantly longer PFS (HR: hazard ratio 0.38, p < 0.0001) and PFS2 (HR 0.45, p < 0.0001) than those treated with vintage nonsteroidal antiandrogen agent (Vintage). The survival tree identified 4.65 months as the most prognostic PSADT cutoff point. Among the clinical and pathological factors PSADT of < 4.65 months remained an independent prognostic factor for OS (HR 2.96, p = 0.0003) and CSS (HR 3.66, p < 0.0001). Current data represented optimal cut-off of PSADT 4.65 months for a Japanese nmCRPC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
To assess real‐world oncological outcomes between the radical cystectomy (RC) group and non‐RC group for early relapse and refractory disease.
Methods
We retrospectively analyzed 953 ...patients with recurrent non‐muscle‐invasive bladder cancer (NMIBC) who received bacillus Calmette‐Guérin (BCG) at 31 affiliated hospitals from 2000 to 2019. Patients with missing data on the timing of failure were excluded and 871 patients remained eligible, of whom 447, 357, and 67 were classified as early relapse/refractory disease, intermediate/late relapse disease, and intolerant disease, respectively. For early relapse/refractory disease, patients were divided into two salvage treatment groups: RC and non‐RC. The clinicopathological variables of each group were examined using Kaplan–Meier plots and proportional Cox hazard ratios with matched score analyses to compare oncological outcomes between the two groups.
Results
Significantly worse progression‐free survival and cancer‐specific survival (CSS) were confirmed in the early relapse/refractory disease group compared to the intermediate/late relapse group. Of the 88 salvage patients in the RC group with early relapse/refractory disease, ≤pT1 was observed in 47, pT2 in 11, and ≥pT3 in 28 (two patients with unknown pT category). In early relapse/refractory disease, the RC group showed significantly high‐risk tumor compared to the non‐RC group. However, no significant difference was observed in CSS after matched score analyses (p = 0.45) between the RC and non‐RC groups.
Conclusions
This study found that the RC group showed no significant superiority compared to the non‐RC group in CSS for early relapse/refractory disease in terms of first salvage therapy.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Introduction
Metastases from renal cell carcinoma develop in various organs. However, the breadth of discrepancy in response to immune checkpoint inhibitors across tumor sites within the ...same individual remains unclear.
Patients and methods
We reviewed 50 patients with metastatic renal cell carcinoma who had target lesions at multiple sites and received nivolumab monotherapy (n = 36) or nivolumab plus ipilimumab (n = 14). When the best overall response in tumor burden increased at one site but decreased at other sites, the response was defined as a dissociated response. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1, and patients who met the definition of dissociated response were categorized as dissociated response. The rate of dissociated response and prognosis were evaluated.
Results
Eight of 36 (22%) and 4 of 14 (29%) patients treated with nivolumab and nivolumab plus ipilimumab were categorized as having dissociated response, respectively. The median overall survival of the patients treated with nivolumab was 20.2 months for those with a partial response, 6.8 months for those with stable disease, and 13.2 months for those with progressive disease, while dissociated response was not reached. There was no significant difference in the median overall survival between patients categorized as having progressive disease and those with dissociates response (P = 0.224).
Conclusion
A certain proportion of patients with metastatic renal cell carcinoma show dissociated response when treated with immune checkpoint inhibitors. The prognosis of patients with dissociated response and progressive disease was not shown to be significantly different.
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