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Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, often discovered at an advanced stage at diagnosis. Nectin-4 is expressed in a broad range of patients with UTUC and is associated with poor progression-free survival. The receptors of the erythroblastosis oncogene B (ErbB) family are potential therapeutic targets for urothelial carcinoma. Herein, we aimed to investigate the relationship of nectin-4 and ErbB family receptors, namely epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in patients with UTUC. Targeted therapies for these receptors could be used in sequence or in combination for increasing treatment efficiency.We performed immunohisto-chemical analysis for HER2, EGFR, and nectin-4 using tissue microarrays. A total of 98 UTUC patients were included in the study. We investigated the impact of EGFR and HER2 expression status on recurrence-free survival (RFS) and cancer-specific survival (CSS) of all patients.The percentages of patients positive for HER2, EGFR, and nectin-4 were 97%, 70%, and 65%, respectively. The co-expression rates of HER2-EGFR, HER2-nectin-4, and EGFR-nectin-4 were 69%, 64%, and 47%, respectively. The number of patients positive for all three receptors was 47%. Higher HER2 levels were significantly associated with worse CSS and RFS. Higher EGFR levels were associated with a worse CSS.HER2, EGFR, and nectin-4 were highly expressed in UTUC. Combination of HER2-, EGFR-, and nectin-4-targeted therapy may be an effective option for the treatment of patients with UTUC.

In this study, we aimed to elucidate the pathophysiology of post-micturition dribble (PMD) through analyzing several variables including pressure flow study (PFS) findings and symptoms questionnaire.We retrospectively analyzed male patients who visited our department between 2010 and 2020. We used modified international prostate symptom score (m-IPSS), which consists of eight sub-score related to lower urinary tract symptoms (Incomplete Emptying, Frequency, Intermittency, Urgency, Weak Stream, Straining, Nocturia, and PMD) and one question related to quality of life (QOL). Multivariate regression analysis was conducted to evaluate the relationship between PMD and the variables, including age, prostate volume (PV), body mass index, bladder outlet obstruction index (BOOI), bladder contractility index, and bladder voiding efficiency, which were obtained by PFS.A total of 143 male patients were analyzed. The patients with PMD showed significantly larger PV and higher BOOI, and worse IPSS total and QOL score than those without PMD. Multivariate regression analysis showed that large PV and BOOI were significantly associated with PMD. In Spearman's correlation analysis, PMD and each m-IPSS sub-score except nocturia had significant positive correlation. Furthermore, Spearman's correlation analysis showed that PMD and QOL had significant strong positive correlation.PMD was significantly associated with large PV and BOO evaluated by PFS. Furthermore, PMD significantly exacerbated QOL. The severity of PMD and the other m-IPSS sub-score except nocturia could have intercorrelation with each other.

Several therapeutic agents are available for metastatic castration-resistant prostate cancer (CRPC). However, prognosis is still not well developed. The Gleason score (GS) is a prognostic factor available for patients with metastatic CRPC. GSs ranging from 6 to 10 and GSs ≥8 are usually categorized as single prognostic factors. In this study, we evaluated the prognosis of high-GS metastatic CRPC in Japanese men.Overall, 105 patients with metastatic CRPC with a GS ≥8 were retrospectively analyzed. Multivariate analyses of patient age, GS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) were performed using Cox proportional hazards analysis to predict overall survival (OS).GS 8 had all Gleason patterns of 4+4. Thirty patients (28.6%) had GS of 8, and 75 (71.4%) had GS of 9 or 10. As a first-line treatment for metastatic CRPC, 42 patients (40%) received abiraterone, 35 (33.3%) received enzalutamide, and 26 (24.8%) received docetaxel. The 5-year OS in patients with GS of 8 was 65.0% [95% confidence interval (CI): 43.07-86.82%], while the 5-year OS in patients with GS of 9 or 10 was 37.0% (95% CI: 24.41-56.11%). There was a significant difference in OS between the GS 8 and GS 9-10 groups (log-rank test, P=0.038). Multivariate analysis showed that GS and ECOG-PS were significant prognostic factors for OS.Patients with metastatic CRPC with GS 9-10 had poor prognoses, suggesting the need for additional treatment options.

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Chemotherapies against gastric cancer often fail, with cancer recurrence due potentially to the persistence of cancer stem cells. This unique subpopulation of cells in tumors possesses the ability to self-renew and dedifferentiate. These cancer stem cells are critical for initiation, maintenance, metastasis, and relapse of cancers; however, the molecular mechanisms supporting cancer stemness remain largely unknown. Increased kinase and decreased phosphatase activity are hallmarks of oncogenic signaling. Protein phosphatase 2A (PP2A) functions as a tumor-suppressor enzyme, and elevated levels of SET/I2PP2A, an endogenous PP2A protein inhibitor, are correlated with poor prognosis of several human cancers. Here, it was determined that SET expression was elevated in tumor tissue in a gastric cancer mouse model system, and SET expression was positively correlated with poor survival of human gastric cancer patients. Mechanistically, SET knockdown decreased E2F1 levels and suppressed the stemness of cancer cell lines. Immunoprecipitations show SET associated with the PP2A–B56 complex, and the B56 subunit interacted with the E2F1 transcription factor. Treatment of gastric cancer cells with the SET-targeting drug OP449 increased PP2A activity, decreased E2F1 protein levels, and suppressed stemness of cancer cells. These data indicate that a SET/PP2A/E2F1 axis regulates cancer cell stemness and is a potential target for gastric cancer therapy.Implications: This study highlights the oncogenic role of SET/I2PP2A in gastric cancer and suggests that SET maintains cancer cell stemness by suppressing PP2A activity and stabilizing E2F1. Mol Cancer Res; 16(3); 554–63. ©2018 AACR.

This file contains detailed material and methods, and supplemental data related with Fig. 1g, Fig. 2a, b, Fig. 3c, d, Fig. 4a, b, c, Fig. 5c

Recently, combination therapy including immune checkpoint inhibition (ICI) has proven to be effective as first-line therapy for patients with metastatic renal cell carcinoma. Although the first-line combination therapies with ICI have shown clinical benefit, a number of patients require second-line treatment. We report a 60-year-old man with metastatic renal cell carcinoma who was treated with pazopanib soon after nivolumab plus ipilimumab combination therapy. He experienced Grade 3 disseminated intravascular coagulation (DIC). We suspect that this was caused by an interaction between pazopanib and nivolumab even though ICI therapy was discontinued. He was treated with thrombomodulin and platelet transfusion and recovered from DIC. Treatment with pazopanib was subsequently restarted. No evidence of DIC was observed thereafter. This severe adverse reaction may have been induced by an interaction between activated proinflammatory immune cells and cytokines from an exacerbated inflammatory state and pazopanib. This report highlights the need to perform careful monitoring of patients who receive molecular targeted therapy after ICI-based immunotherapy.

The therapeutic landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has changed dramatically. Here, we provide the current status and future prospective of the management of mHSPC.We reviewed recent literature of landmark studies on the managements of mHSPC.Upfront docetaxel or androgen receptor signaling inhibitor (ARSi) in addition to ADT has improved survival in mHSPC patients and has become the new standard of care. Triplet therapy with docetaxel, ARSi and ADT also improved survival. In the future, triplet therapy may become the standard of care. Oligometastatic mHSPC patients could benefit from local therapy. The inclusion of risk factors or the genetic biomarkers will provide the best treatment for individual mHSPC patients.Strong systemic therapy in the first-line treatment of mHSPC has been shown to improve survival and quality of life. Currently, several clinical trials are evaluating novel compounds such as PARP inhibitor, AKT inhibitor, and immune checkpoint inhibitor. The therapeutic landscape of mHSPC management will change dramatically.

There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period.Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT.OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients.The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

Enzalutamide, apalutamide, and darolutamide are currently recommended for patients with non-metastatic castration-resistant prostate cancer (nmCRPC), but cross-resistance of androgen receptor-axis-targeted therapies (ARAT) occurs. Because darolutamide has a distinct chemical structure to other non-steroidal antiandrogens, it may be effective for nmCRPC patients resistant to enzalutamide or apalutamide. We retrospectively evaluated the efficacy of switching to darolutamide in patients with nmCRPC. We included nine nmCRPC patients who experienced biochemical progression on enzalutamide or apalutamide and were switched over to darolutamide. Five patients (55.5%) had a PSA response50% decline after starting darolutamide, with an average of 73% PSA decline. Median progression-free survival was 6 months. In conclusion, an ARAT switch from enzalutamide or apalutamide to darolutamide might be effective for nmCRPC. Although the validation in a large-scale cohort is necessary, the switch to darolutamide could be a promising therapeutic option after the progression of 1st line ARAT in nmCRPC patients.

Purpose We evaluated the predictive factors for completion of all six cycles of radium-223 (Ra-223) treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). We also developed a novel prediction model for Ra-223 treatment completion using these predictors. Methods We retrospectively reviewed data from 122 patients with mCRPC who were treated with Ra-223. The predictive factors for the completion of six cycles of Ra-223 treatment were evaluated. Statistically significant predictive factors were then used to develop a prediction model for treatment completion. Finally, using this prediction model, we classified the overall survival (OS) of the entire cohort into three groups. Results We identified three significant variables as the predictive factors for treatment completion: baseline alkaline phosphatase (ALP) level, baseline hemoglobin (Hb) level, and baseline pain. The three groups generated using the prediction model were: group 1 (patients with three predictive factors, i.e., ALP Conclusion Our study suggested that the baseline ALP level, baseline Hb level, and baseline pain were the predictive factors of completion of all six cycles of Ra-223 treatment in patients with mCRPC. Our prediction model consisting of these factors could predict not only the completion of Ra-223 treatment, but also the post-treatment survival. This model can thus be useful for selection of patients for Ra-223 treatment.

The tumor microenvironment (TME) is a dynamic milieu comprised of various cell types and molecular complexes that eventually evolves to promote cancer cell proliferation, metastasis, and immune evasion. Myeloid cells are a key component of the TME and play key roles in initiating antitumor responses and coordinating with cells of the adaptive immune system. However, these cells are eventually hijacked by tumors and provoke local inflammation that results in chronic cancer-associated inflammation and immune escape. Extracellular adenosine (ecADO) is an immunosuppressive metabolite that is produced in tumors that binds the adenosine 2a receptor (A2aR) which is widely expressed in immune cells. Studies have shown that blocking A2aR signaling has the potential to enhance antitumor immunity by boosting T and NK cell immune responses. However, the relationship between ecADO and tumor-associated myeloid cells is less characterized. We previously reported on the antitumor activity of A2aR and CD73 blockade in preclinical models of Pten-null prostate cancer and their impact on T cell mediated responses. Here, we examine tumor-associated myeloid cell infiltration in models of castration-naïve (CNPC) and castration-resistant prostate cancer (CRPC) the impact of A2aR and CD73 blockade. Transcriptomic, flow cytometric, and immunohistochemical (IHC) profiling studies of CNPC and CRPC from conditional Pten-knockout (KO) and Pten/Trp53-double knockout (DKO) showed that tumor-infiltrating myeloid cells constituted a significant proportion of the prostate tumor microenvironment. CD11b+/Ly6G+ cells representing tumor associated neutrophils (TANs) and myeloid derived suppressor cells (MDSCs) were the most abundant immune cell type comprising 14.9% and 32.1% of the total population, and 46.5% and 69.7% of infiltrating leukocytes in in CNPC and CRPC, respectively. Furthermore, CD11b+/Ly6G+ expressed high levels of CD73. Pte-null prostate tumors were characterized with enriched adenosine signaling signatures which were greater in CRPC compared to CNPC. Treatments with the A2aR inhibitor AZD4635 alone and in combination with CD73 antibody blockade reduced adenosinergic genes as well as genes associated with TAN/MDSC immunosuppressive functions. Additionally, tumors from treated mice exhibited improved T cell mediated cytotoxicity. Together, our findings indicate that tumor associated myeloid cells are an additional source of ecADO contributing to immune suppression which can be targeted with A2aR and CD73 inhibitors. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Kazuko Sakai, Alwin G. Schuller, Kris F. Sachsenmeier, Masahiro Nozawa, Eri Banno, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Targeting tumor infiltrating myeloid cells in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5155.

Gut microbes are intricately involved in maintaining normal physiology and homeostasis and have become a major area of study to determine their relevance in human disease. In cancer, alterations to gut microbiota has been associated to resistance to chemo- and immuno-therapy, whereas supplementation with specific taxa improves antitumor treatment responses. Mouse models have been essential to study disease biology and drug discovery. However, mice are fundamentally quite different from humans, thus, questions have arisen regarding their utility as pertinent tools to study microbial influences and their impact on human disease. To address these questions, we have performed a cross-species comparative analysis of the fecal microbiota from a human cohort of prostate cancer patients and a preclinical mouse model of prostate cancer. Microbiota composition was determined by 16s RNA gene sequencing on stool samples from tumor-bearing prostate-specific conditional Pten-knockout and disease-free wildtype mice and 16s RNA gene sequencing data from a human cohort of patients with suspected prostate cancer was used. Human cases were assigned to no cancer and cancer groups based on diagnosis from prostate biopsy and as low-risk (negative biopsy of Gleason grade Citation Format: Chisato Wakamori, Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Kazuko Sakai, Makoto Matsushita, Eri Banno, Yasunori Mori, Masahiro Nozawa, Mitsuhisa Nishimoto, Kazuhiro Yoshimura, Norio Nonomura, Kazuto Nishio, Hirotsugu Uemura. Integrative gut microbiome analysis of human and mouse prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3044.

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature immune cells that expand during cancer and can induce potent immune suppression. These cells play critical roles in supporting tumor growth and progression and their induction has been associated with the inactivation of PTEN. To date, few therapies targeting these cells are available which is partly due to their increasingly complex nature and context-dependent functions. Moreover, there is no clear definition to identify these cells. Enhancing our understanding of this cell population will aid in developing more effective cancer therapies. Here, we used gene expression profiling, flow cytometry, and quantitative immunohistochemistry to characterize tumor-infiltrating and circulating MDSCs in prostate carcinogenesis and progression in transgenic mouse models of prostate cancer driven by the conditional inactivation of Pten and Trp53. Transcriptomic profiling revealed enrichment of various myeloid-derived cell signatures in the early stages of prostate cancer including MDSCs, macrophages, and neutrophils. Flow cytometric analysis confirmed the increased infiltration of CD11b+/Ly6G+ (polymorphonuclear MDSCs (pMDSCs)) and CD11b+/Ly6C+ (monocytic MDSCs (mMDSCs)) cells in prostate tumors. The temporal dynamics of tumor-infiltrating myeloid cells were further profiled and showed that pMDSC and mMDSC abundances were 1.6 and 5.7-fold higher, respectively, in older mice with late-stage locally invasive adenocarcinomas (AdCa) compared to younger mice with early-stage prostatic intraepithelial neoplasia (PIN). In both instances, pMDSCs comprised most of the leukocyte infiltrate, however, mMDSCs tended to be positively correlated with tumor burden in AdCa but not PIN. In peripheral blood, CD44+/CD62L+ immature neutrophils were associated with high tumor burden in aged mice. Treatments targeting the androgen receptor (AR) signaling further exacerbated pMDSC infiltration in tumors and was associated with resistance to second androgen receptor-targeted agent (ARTA) therapy in a model of castration resistant prostate cancer. Our findings indicate that MDSCs are a prominent population in Pten-null prostate cancer and are implicated with resistance to prostate cancer treatment. MDSCs constitute a potentially targetable population and these models serve as viable platforms to further investigate their biological activity and further evaluate novel MDSC-directed therapies. Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazuko Sakai, Eri Banno, Shogo Adomi, Mitsuhisa Nishimoto, Takafumi Minami, Yasunori Mori, Kazutoshi Fujita, Masahiro Nozawa Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Profiling of myeloid-derived suppressor cells in Pten-deficient in prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2877.

Studies suggest that certain immune-mediated diseases may be associated with cancer risk beyond local organs. Prolonged systemic inflammation from inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn’s disease (CD) pose a greater risk to colorectal cancer (CRC) and accumulating data suggests that prostate cancer (PCa) risk is higher in patients with UC but not CD and that patients with PCa may be at a greater risk for CRC. A better understanding of the biological interactions between these conditions could have important implications for cancer screening, detection, and prevention in high-risk populations. However, data to establish the relationships and relative contributions of these diseases are lacking. Here, we explored these relationships using preclinical mouse models of dextran sulfate sodium (DSS)-induced colitis (DSS-UC) and DSS/azoxymethane (AOM)-induced CRC (DSS/AOM-CRC) in young and aged healthy wildtype mice and transgenic mice harboring Pten-deficient PCa. In the DSS/AOM-CRC model, aged PCa-bearing conditional Pten-knockout (KO) mice experienced poorer overall survival compared to age-matched wildtype (WT) without PCa because of CRC. DSS/AOM-CRC incidence was not affected by the presence of PCa, however tumor burden was higher in KO mice compared to WT and in KO mice, DSS/AOM-CRC accelerated PCa growth and progression. Prostates from WT DSS/AOM-CRC mice showed higher incidence of hyperplasia and greater myeloid cell infiltration compared to healthy controls. Systemic changes associated with DSS/AOM-CRC in both WT and KO mice included splenomegaly, lymphadenopathy, and immune cell composition. The impact of DSS-UC was investigated conditional Pten/Trp53-double knockout (DKO) mice with DDS only treatments starting at an age prior to the development of PCa. In this setting, cycling DSS led to the development of UC after 10 weeks of treatment and accelerated prostate tumor development characterized by high grade prostatic intraepithelial neoplasia (PIN) grade dysplasia and increased cell proliferation. Prostate tumors from mice with DSS-UC exhibited an altered tumor immune microenvironment characterized by a higher degree of inflammatory cell infiltrate. Changes in immune cell composition were also observed in peripheral blood and secondary lymphoid organs. These preclinical models recapitulated disease relationships observed in humans and provide a platform to further investigate biological mechanisms and therapeutic interventions. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Shogo Adomi, Eri Banno, Yasunori Mori, Takafumi Minami, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Exploring the relationships between prostate cancer, colorectal cancer, and ulcerative colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 640.

To evaluate the real-world data on the efficacy and safety of a combination therapy with radium-223 (Ra-223) and second-generation androgen-receptor targeting agents (ARTAs), including abiraterone acetate (ABI) and enzalutamide (ENZ), among Japanese patients with bone metastatic castration-resistant prostate cancer (CRPC).We retrospectively reviewed 79 patients with bone metastatic CRPC who were treated with Ra-223. The number of patients with concurrent ARTA use was 24:17 receiving ABI and 7 receiving ENZ. We evaluated the overall survival (OS) according to ARTA use and compared the survival of patients treated with Ra-223 with or without ARTA using multivariate analysis.The median survival in the entire cohort was 23.5 months. The patients receiving Ra-223 combined with ARTA showed a tendency of better OS than patients treated with Ra-223 alone, although no significant difference was observed (median OS, 26.5 vs 23.5 months;Our real-world data analysis suggested that Ra-223 combined with a second-generation ARTA is well tolerated in Japanese patients. The EOD score and pain at baseline are significant prognostic factors for OS, but the concurrent use of second-generation ARTA has no influence on OS among men treated with Ra-223. The concurrent use of BMA yields a marginally favorable OS.

BACKGROUND: Altered prostate-specific antigen (PSA) glycosylation patterns can be useful biomarkers in detecting high-grade prostate cancer (HGPC). The microfluidic immunoassay system can analyse α2,3-linked sialylated PSA (α2,3-Sia-PSA) and α1,6-linked fucosylated PSA (α1,6-Fuc-PSA) using different lectins, Mackkia amurensis agglutinin and Pholiota squarrosa lectin, respectively. Here, we investigated the diagnostic value of simultaneous analysis of α2,3-Sia-PSA and α1,6-Fuc-PSA for the detection of HGPC. METHODS: Men with serum PSA levels of 4–20 ng/mL who underwent prostate biopsy were included. The model to predict HGPC (Gleason grade ≥2) was constructed by multivariate logistic regression analysis, in combination with α2,3-Sia-PSA and α1,6-Fuc-PSA (SF index). RESULTS: In the development cohort (n = 150), the SF index showed good discrimination for HGPC (area under the receiver-operating curve (AUC) 0.842; 95% confidence interval (CI) 0.782–0.903), compared to the single PSA test (AUC 0.632, 95% CI 0.543–0.721), α2,3-Sia-PSA (AUC 0.711, 95% CI 0.629–0.793) and α1,6-Fuc-PSA (AUC 0.738, 95% CI 0.657–0.819). Decision-curve analysis showed the superior benefit of the SF index. In the validation cohort (n = 57), the SF index showed good discrimination for HGPC (AUC 0.769, 95% CI 0.643–0.895). CONCLUSIONS: The SF index could differentiate HGPC, providing useful information for decision making for prostate biopsy in men with abnormal PSA levels.

INTRODUCTION AND OBJECTIVE:The gut microbiota is involved in a variety of diseases that affect the entire body. Diet and body size influence the gut microbiota and are important risk factors for pr...

INTRODUCTION AND OBJECTIVE:Locally advanced or metastatic upper tract urothelial carcinoma (UTUC) is a lethal disease with limited treatment options for patients who do not positively respond to pl...

Mamoru Hashimoto,1 Nobutaka Shimizu,1 Mitsuhisa Nishimoto,1 Takafumi Minami,1 Kazutoshi Fujita,1 Kazuhiro Yoshimura,1 Akihide Hirayama,2 Hirotsugu Uemura1 1Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; 2Department of Urology, Kindai Nara Hospital, Osaka-Sayama, JapanCorrespondence: Nobutaka ShimizuDepartment of Urology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, JapanTel +81-72-366-0221Fax +81-72-365-6273Email shimizun@med.kindai.ac.jpPurpose: This study aimed to elucidate the relationship of psoas muscle atrophy and visceral obesity with lower urinary tract symptoms in geriatric female patients.Patients and Methods: We retrospectively reviewed the medical records of female patients aged ≥ 65 years. The psoas muscle index was defined, using computed tomography, as the cross-sectional area of the psoas muscle at the third lumbar vertebral level divided by the body surface area. We also measured visceral fat area at the umbilical level using computed tomography. We used logistic regression analysis to examine the relationships between the International Prostate Symptom Score (total score, voiding subscore, and storage subscore) and variables, such as age, body mass index, psoas muscle index, and visceral fat area. The International Prostate Symptom Score was categorized as mild, moderate, or severe.Results: One hundred thirty-nine patients were included in our study. In the logistic regression analysis, we found statistically significant relationships between severe (versus mild-to-moderate) International Prostate Symptom Score storage subscore and variables, including low and high levels of psoas muscle index and visceral fat area, respectively. We could not find any significant relationships between the International Prostate Symptom Score total score and voiding subscore and the variables.Conclusion: Psoas muscle atrophy and visceral fat accumulation are potential risk factors for severe storage symptoms in female patients aged ≥ 65 years.Keywords: female, International Prostate Symptom Score, overactive bladder symptom, psoas muscle, visceral fat

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents, however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Simple Summary Next-generation antiandrogens have transformed the therapeutic landscape for castration-resistant prostate cancer. Their utility in other indications, such as high-risk castration-sensitive cancers and as combination therapy, are being investigated. Our aim was to profile the in vivo antitumor activity of apalutamide in phenotypically distinct mouse models of Pten-deficient castration-naïve and castration-resistant prostate cancer, using both early- and late-stage disease models, and to profile the molecular responses. We also evaluated the therapeutic potential and characterized the molecular responses of the combined targeted AR/AKT blockade and showed that while this approach was promising in vitro, it was mostly ineffective in vivo, particularly in the castration-resistant setting. Our findings provide evidence that links therapeutic resistance to STAT3 and PIM-1 in the castration-resistant setting and provide insights into the context-specific antitumor activity of apalutamide. Abstract Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Background The effect of intra-arterial infusion of fasudil hydrochloride in patients with post-traumatic cerebral vasospasm remains unclear. Here we report a case of intra-arterial infusion of fasudil hydrochloride for post-traumatic cerebral vasospasm. Case presentation A 47-year-old man was transferred to our hospital with a fractured skull and traumatic subarachnoid hemorrhage. As rhinorrhea of cerebrospinal fluid had not improved, repair surgery was carried out on day 4. Aphasia appeared on day 13. Magnetic resonance imaging and angiography showed an ischemic region in the left temporal lobe and vasospasm of the left middle cerebral artery. We immediately carried out angiography and diagnosed severe vasospasm of the M1 region of the left middle cerebral artery. After placing a microcatheter into the proximal middle cerebral artery, we injected fasudil hydrochloride intra-arterially. Vasospasm improved and aphasia resolved. Conclusion In this case, intra-arterial infusion of fasudil hydrochloride was effective against post-traumatic cerebral vasospasm.

Prostate tumors are characterized with constitutively activated AKT signaling primarily through the loss of PTEN. Second generation antiandrogens such as abiraterone acetate have improved the survival of prostate cancer patients, however, resistance remains a problem and patients with PTEN-deficient tumors have poorer outcomes to abiraterone treatments. Moreover, PTEN-deficient tumors are also characterized with immunosuppressive tumor microenvironments. In this study we investigate the benefit of adding capivasertib, a potent pan-Akt inhibitor, to abiraterone therapy in a preclinical model of Pten-deficient prostate cancer and examine the antitumor efficacy and its influence on antitumor immunity. The temporal effects of abiraterone and capivasertib alone and as combination therapy were evaluated after one and four weeks of dosing in conditional transgenic mice harboring Pten-deficient prostate tumors. While abiraterone therapy alone reduced genitourinary tract weights, which contain both AR-sensitive normal accessory sex organs and prostate tumor, the treatment had no overall effect on prostate tumor burden. Mice treated with capivasertib monotherapy experienced tumor burden reductions of 8.2% and 15.6% at week 1 and 8, respectively, moreover, the treatment combination of abiraterone + capivasertib significantly improved the therapeutic effect with tumor burden reductions of 35.6% and 37.8% at weeks 1 and 4, respectively versus vehicle control. qRT-PCR analysis of Ar target genes showed decreased expression in mice treated with abiraterone. All treatment combinations showed increased gene expression levels of Casp3 in tumors from mice at week one but were greatest in those treated with abiraterone alone or in combination and increased expression levels were sustained only in the combination cohort at week four. Immunological profiling of tumors from mice treated with abiraterone + capivasertib using qRT-PCR-based panel of immune-related genes revealed enrichments in genes associated with phagocytosis, antigen processing and dendritic cell function. Examination of the tumor draining lymph nodes by flow cytometric analysis showed ~1.5-fold-increases in the abundance of migratory dendritic cells (CD11b+\CD11c+\XCR1+) in all pharmacologically treated mice (versus vehicle control) and remained elevated only in mice receiving capivasertib as monotherapy or combination at week four. Additionally, mice treated with combination therapy also had enrichments in genes sets associated to T cell, NK cell and as well as T cell activation, cytotoxicity, and interferon gamma signature. The findings from this study provide preclinical evidence for the efficacy of combination therapy with abiraterone plus capivasertib and provides insights into its immunomodulatory effects and influence on antitumor immunity. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Keiko Kuroka, Kazutoshi Fujita, Eri Banno, Kazuko Sakai, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Preclinical efficacy of abiraterone plus capivasertib in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5282.

Prostate cancers depend on androgens and the androgen receptor (AR) to drive androgen signaling pathways. Androgen-deprivation therapy (ADT) and second-generation antiandrogens have become the new standard of care for men with prostate cancer. However, resistance to these therapies remains a problem. TP53 mutations and PTEN loss have been associated with patients who fail to respond to anti-androgen therapies and complex interactions between AR signaling and the immune system means that these therapies have the potential to affect antitumor immune responses. Here, we characterize treatment responses of ADT alone and in combination with antiandrogen therapy using apalutamide (Apa) in a mouse model of Pten/Trp53-deficeint castrate-resistant prostate cancer (CRPC). Twenty-eight-week-old conditional Pten/Trp53-double knockout mice were randomized as untreated control or treated with ADT via orchidectomy for four weeks followed by vehicle or Apa therapy for an additional four weeks. While both treatments reduced tumor burden, there was no difference between treatments. Treatment responses in were further evaluated and were judged as favorable or non-favorable, relative to median tumor burden. Analysis of individual treatment responses indicated that 31.3% (5/16) of mice treated with ADT+Apa had tumor burden reductions >20% (relative to the median) compared to 6.3% (1/16) in ADT, and in both instances, 37.5% (6/16) of mice treated with ADT or ADT+Apa had tumor burden increases >20%. IHC showed lower nuclear/cytoplasm expression of AR in ADT+Apa treated mice and the reduction was more pronounced in favorable responders. ADT+Apa treated mice had lower gene expression levels of Ar than ADT alone and AR target genes (Fkbp5, Tmprss2, Timp4 and Nkx3.1) were decreased in ADT+Apa favorable responders whereas these target genes as well as AR-regulating genes (Myc and Igf1r, Igf1) were higher in ADT+Apa non-favorable responders. Cancer cell proliferation did not differ between treatments, but cancer glands in ADT+Apa treated mice had significantly greater IHC expression levels of cleaved caspase 3, a marker for apoptosis, and were greatest in ADT+Apa favorable responders. Levels of p-S6 ribosomal protein, a downstream target of Akt, were higher in the cancer glands of ADT+Apa but were reduced in stromal and infiltrating immune cells. Immune profiling by gene expression and flow cytometry showed enhanced macrophage involvement and reduced MDSC/granulocyte activity in ADT+Apa treated mice. There were no differences in CD8 T cell and NK cell abundance between the two cohorts, but greater cytotoxic activity was noted in all favorable responders. This study provides preclinical data that links therapeutic resistance to anti-AR signal pathways therapies in Pten/Trp53-deficeint CRPC to compensatory pathway activation and immune suppression. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazuko Sakai, Kazutoshi Fujita, Eri Banno, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Therapeutic resistance to anti-AR signal pathway therapies is related to compensatory pathway activation and immune suppression in mouse Pten/Trp53-deficient CRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5211.

Curcumin is a naturally occurring compound found in turmeric and is well-known for its anticancer and anti-inflammatory properties, however, low solubility, poor absorption and fast clearance resulting in low systemic bioavailability has hindered therapeutic applications for free curcumin and has prompted the development of curcumin-based formulations with improved bioavailability. Curcumin monoglucuronide (CMG) is a water-soluble injectable prodrug that shows improved bioavailability over oral free curcumin and has demonstrated anticancer activity. In this study, we examine the therapeutic efficacy and immunomodulatory effects of CMG in mouse prostate cancer models driven by the conditional inactivation of Pten. The acute immunomodulatory effects of CMG were profiled in tumors from 28-week-old conditional Pten/Trp53 double knockout mice one-week after intraperitoneal dosing with CMG and were evaluated using a focused panel of qRT-PCR-based immune related genes, flow cytometry and immunohistochemistry (IHC). Overall, mice receiving CMG showed a higher inflammation profile compared to vehicle controls and was characterized with enrichments in macrophage, dendritic cell, and T cell gene signatures. CMG treated mice showed enhanced dendritic cell activity in tumors including an increased abundance of activated of migratory dendritic cells (CD11b+\CD11c+\XCR1+\MHC-II+\CD80+). Tumors from CMG-treated mice also contained increased T cell infiltration (including CD8+ and CD4+ T cells) as well as enrichment of genes related to T cell differentiation and activation and an increased abundance of CD4+\CD25+ regulatory T cells. While one week of dosing did not result in a significant reduction of tumor burden for CMG-treated mice, there was a 1.9-fold increase in cancer cell apoptosis as measures by cleaved caspase-3 IHC expression (P=0.004) and was correlated to leukocyte infiltration particularly in the ventral lobes of the prostate. The antitumor efficacy and long-term immunomodulatory effects of CMG were further evaluated in 16-week-old conditional Pten knockout after four weeks of dosing. In this model, tumor from mice treated with CMG showed a 10% reduction of tumor burden compared to vehicle controls (P=0.065). Tumors from CMG treated mice also had a 1.7-fold increase in apoptosis compared to vehicle treated mice (P=0.009) and tended to have reduced cancer cell proliferation compared to vehicle controls (P=0.148). Gene expression and flow cytometry analyses showed that tumors from mice treated with CMG for four weeks maintained improved tumor inflammation and showed an increased T cell infiltration over vehicle treated controls including effector cytotoxic T cells (CD8+\Granzyme B+). These findings provide preclinical evidence for the antitumor and immune modulatory activity of CMG in mouse hormone sensitive Pten-deficient prostate cancer. Citation Format: Yurie Kura, Marco A. De Velasco, Naomi Ando, Kazuko Sakai, Kazutoshi Fujita, Eri Banno, Yoshihiko Fujita, Mamoru Hashimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Curcumin monoglucuronide modulates the tumor microenvironment of Pten-null prostate tumors and exhibits antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5952.

Androgen deprivation therapy (ADT) remains the standard care for men with advanced prostate cancer. Although initially effective, many patients fail to maintain durable responses and progress to lethal castration-resistant prostate cancer. Commensal bacteria play important role in maintaining homeostasis and proper immune function. However, ADT alters gut bacterial compositions and the ramifications being investigated. In this study, we used a mouse model of Pten-deficient prostate cancer to characterize differences in bacterial composition of gut bacteria in mice with castration naïve-prostate cancer (CNPC) and gut microbiota from mice three and six weeks after treatment ADT via surgical castration representing castration-sensitive prostate cancer (CSPC) and CRPC, respectively. Fecal samples were collected and processed for 16s rRNA amplicon sequencing. ADT resulted in significant changes to biological diversity and local diversity was highest in CSPC (Shannon index, P=0.04). Community composition also differed significantly different between the groups (Adonis OTU Bray-Curtis, P=0.001, NMDS stress=0.07). Despite dissimilarities between bacterial communities among the groups, CNPC and CRPC shared a greater similarity. Taxa associated with CNPC included Unclassified S247, Prevotella L. reuteri, unclassified Rikenellaceae and unclassified Bacteroidales; taxa associated with CSPC included R. gnavus, Dorea, unclassified Desulfovibrionaceae, Dehalobacterium, A. muciniphilia, Bifidobacterium, and B. producta; and taxa associated with CRPC included Turicibacter, R. flavefaciens, L. garvieae, unclassified Peptostreptococcaceae and unclassified Bacilli. Mice with CSPC and CRPC had an increased abundance genes associated with of catabolic metabolic pathways associated with aromatic compound, steroid Benzoate, and toluene degradation as well as genes associated to pathways corresponding to methane metabolism, phosphonate and phosphinate metabolism, and nitrogen metabolism. Genes enriched in fecal taxa from CNPC and CRPC mice were associated with folate biosynthesis, galactose metabolism, amino sugar and nucleotide sugar metabolism, and carbon fixation pathways in prokaryotes. This study provides preclinical evidence to support the association between the gut microbiome and prostate cancer phenotypes associated with sensitivity to ADT. Citation Format: Chisato Wakamori, Marco A. De Velasco, Kazuko Sakai, Yurie Kura, Naomi Ando, Kazutoshi Fujita, Eri Banno, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuto Nishio, Hirotsugu Uemura. Transformation of the gut microbiome in response to androgen deprivation and the transition to castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5637.