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Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Context.— Intraductal carcinoma of the prostate (IDC-P) is considered a distinct form of aggressive prostate cancer where comedonecrosis, a grade 5 pattern, is occasionally present. Meanwhile, assigning a Gleason grade to IDC-P remains controversial. Objective.— To assess the clinical significance of necrosis associated with IDC-P. Design.— We compared radical prostatectomy (RP) findings and oncologic outcomes in men with prostate cancer exhibiting IDC-P with (IDC-P+/N+) versus without (IDC-P+/N−) comedonecrosis. Results.— Of the 558 RPs examined, IDC-P was present in 213 cases (38.2%), including 167 (78.4%) with IDC-P+/N− and 46 (21.6%) with IDC-P+/N+. When comparing IDC-P+/N− versus IDC-P+/N+ cases, the presence of necrosis was significantly associated with higher tumor grade, higher incidence of pT3/pT3b or pN1 disease, and larger estimated tumor volume. Outcome analysis revealed a significantly higher risk of disease progression in IDC-P+/N+ patients than in IDC-P+/N− patients (P < .001). Significant differences in progression-free survival between IDC-P+/N− and IDC-P+/N+ patients were also seen in subgroups, such as those without (P = .01) or with (P = .03) adjuvant therapy immediately after RP, those with pN0 disease (P < .001), and, more interestingly, those exhibiting conventional Gleason pattern 5 component (P = .02). Multivariate analysis showed significance for IDC-P+/N+ when IDC-P (grade 4) and IDC-P+/N+ (grade 5) were (hazard ratio, 1.768; P = .049) or were not (hazard ratio, 2.000; P = .008) incorporated into the Gleason score. Conclusions.— IDC-P+/N+ was found to be associated with worse histopathologic features on RP and poorer prognosis as an independent predictor. Pathologists may thus need to report the presence or absence of not only IDC-P but also comedonecrosis within IDC-P.

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (

Context.— Grading small foci of prostate cancer on a needle biopsy is often difficult, yet the clinical significance of accurate grading remains uncertain. Objective.— To assess if grading of limited adenocarcinoma on prostate biopsy specimen is critical. Design.— We studied 295 consecutive patients undergoing extended-sextant biopsy with only 1-core involvement of adenocarcinoma, followed by radical prostatectomy. Results.— The linear tumor lengths on these biopsy specimens were: less than 1 mm (n = 114); 1 mm or more or less than 2 mm (n = 82); 2 mm or more or less than 3 mm (n = 35); and 3 mm or more (n = 64). Longer length was strongly associated with higher Grade Group (GG) on biopsy or prostatectomy specimen, higher risk of extraprostatic extension/seminal vesicle invasion and positive surgical margin, and larger estimated tumor volume. When cases were compared based on biopsy specimen GG, higher grade was strongly associated with higher prostatectomy specimen GG, higher incidence of pT3/pT3b disease, and larger tumor volume. Outcome analysis further showed significantly higher risks for biochemical recurrence after radical prostatectomy in patients with 1 mm or more, 2 mm or more, 3 mm or more, GG2-4, GG3-4, GG4, less than 1 mm/GG2-4, less than 1 mm/GG3-4, less than 2 mm/GG3-4, 3 mm or more/GG2-4, or 3 mm or more/GG3-4 tumor on biopsy specimens, compared with respective control subgroups. In particular, 3 mm or more, GG3, and GG4 on biopsy specimens showed significance as independent prognosticators by multivariate analysis. Meanwhile, there were no significant differences in the rate of upgrading or downgrading after radical prostatectomy among those subgrouped by biopsy specimen tumor length (eg, Conclusions.— These results indicate that pathologists still need to make maximum efforts to grade relatively small prostate cancer on biopsy specimens.

Context.— Perineural invasion (PNI) by prostate cancer has been associated with adverse pathology, including extraprostatic extension. However, the significance of PNI quantification on prostate biopsy (PBx) remains unclear. Objective.— To compare radical prostatectomy (RP) findings and long-term outcomes in patients whose PBx had exhibited PNI. Design.— We assessed 497 consecutive patients undergoing sextant (6-site/≥12-core) PBx showing conventional adenocarcinoma followed by RP. Results.— PNI was found in 1 (n = 290)/2 (n = 132)/3 (n = 47)/4 (n = 19)/5 (n = 5)/6 (n = 4) of the sites/regions of PBx. Compared with a single PNI site, multiple PNIs were significantly associated with higher preoperative prostate-specific antigen, higher Grade Group (GG) on PBx or RP, higher pT or pN category, positive surgical margin, and larger estimated tumor volume. When compared in subgroups of patients based on PBx GG, significant differences in RP GG (GG1–3), pT (GG1–2/GG1–3/GG2/GG3), surgical margin status (GG1–3/GG3/GG5), or tumor volume (GG1–2/GG1–3/GG2/GG3) between 1 versus multiple PNIs were observed. Moreover, there were significant differences in prostate-specific antigen (PNI sites: 1–2 versus 3–6/1–3 versus 4–6/1–4 versus 5–6), RP GG (1–3 versus 4–6/1–4 versus 5–6), pT (1–2 versus 3–6/1–3 versus 4–6), pN (1–3 versus 4–6), or tumor volume (1–2 versus 3–6/1–4 versus 5–6). Outcome analysis revealed significantly higher risks of disease progression in the entire cohort or PBx GG1–2/GG1–3/GG2/GG3/GG5 cases showing 2 to 6 PNIs, compared with respective controls with 1-site PNI. In multivariate analysis, multisite PNI was an independent predictor for progression (hazard ratio = 1.556, P = .03). Conclusions.— Multiple sites of PNI on PBx were associated with worse histopathologic features in RP specimens and poorer prognosis. PNI may thus need to be specified, if present, in every sextant site on PBx, especially those showing GG1–3 cancer.

Context.— Seminal vesicle invasion (SVI) by prostate cancer (pT3b disease) has been considered as a key prognostic factor. Objective.— To assess the clinical impact of T3a lesions (ie, extraprostatic extension other than bladder neck invasion [BNI] or SVI [EPE], microscopic bladder neck invasion [mBNI]) in pT3b disease. Design.— We compared radical prostatectomy findings and long-term oncologic outcomes in 248 patients with pT3b disease, with versus without EPE/mBNI. Results.— Extraprostatic extension/mBNI was found in 219 (88.3%)/48 (19.4%) cases, respectively. Extraprostatic extension was significantly associated with higher preoperative prostate-specific antigen (PSA) level, higher rates of positive surgical margin (pSM) and lymphovascular invasion (LVI), and larger tumor volume. Similarly, mBNI was significantly associated with higher PSA level, higher rates of Grade Group(s) 4-5 or 5, pSM, LVI, and pN1, and larger tumor volume. Significant differences in all of these clinicopathologic features (except lymph node metastasis) between EPE−/mBNI+ or EPE+/mBNI− and EPE+/mBNI+ cases were also observed. Outcome analysis revealed that patients with EPE (P < .001) or mBNI (P < .001) had a significantly higher risk of disease progression than respective controls. Notably, there were significant differences in progression-free survival between EPE−/mBNI+ or EPE+/mBNI− cases and EPE−/mBNI− (P = .001) or EPE+/mBNI+ (P < .001) cases. In multivariate analysis, EPE (hazard ratio [HR] = 6.53, P = .009) and mBNI (HR = 2.33, P = .003), as well as EPE−/mBNI+ or EPE+/mBNI− (HR = 11.7, P = .01) and EPE+/mBNI+ (HR = 25.9, P = .002) versus EPE−/mBNI−, showed significance for progression. Conclusions.— From these significant findings, we propose a novel pT3b subclassification: pT3b1 (SVI alone without EPE or mBNI), pT3b2 (SVI with either EPE or mBNI), and pT3b3 (SVI with both EPE and mBNI).

Objectives The clinical impact of the laterality of perineural invasion (PNI) by prostate cancer remains poorly understood. We herein compared radical prostatectomy (RP) findings and long-term oncologic outcomes in patients with prostate cancer with PNI in two prostate biopsy (PBx) sites. Methods We retrospectively assessed 170 consecutive patients undergoing systematic sextant PBx where PNI had been detected in two of six PBx sites, followed by RP. Results PNI occurred unilaterally in 140 (82.4%) cases and bilaterally in 30 (17.6%) cases. Compared with unilateral PNI, bilateral PNI was significantly associated with a higher number of cancer-positive sites and longer total tumor length on PBx. However, there were no significant differences in RP findings, including tumor grade/stage and tumor volume, between unilateral and bilateral PNI cohorts. Kaplan-Meier analysis revealed that patients with bilateral PNI had a significantly higher risk of disease progression after RP than those with unilateral PNI (P = .038). In multivariate analysis, bilateral PNI (vs unilateral PNI) showed significance for progression (hazard ratio, 2.281; P = .023). Conclusions In PBx specimens exhibiting PNI in two sextant sites, bilateral PNI was found to be associated with poorer prognosis as an independent predictor but not worse histopathologic features in RP specimens compared with unilateral PNI.

The prognosis of prostate cancers exhibiting extraprostatic extension [other than bladder or seminal vesicle invasion (EPE)] and/or microscopic bladder neck invasion (mBNI) is variable, and further risk stratification is required. We herein assessed radical prostatectomy findings and long-term oncologic outcomes in consecutive 957 patients with pT3a disease. The patient cohort was divided into 4 groups, focal EPE (F-EPE) only (n=177; 18.5%), nonfocal/established (E-EPE) only (n=634; 66.2%), mBNI only (n=51; 5.3%). The rate of positive surgical margin and estimated volume of tumor were significantly higher in patients with both EPE and mBNI than in those with either. In addition, compared with F-EPE or mBNI only, E-EPE only was significantly associated with higher Grade Group, lymph node metastasis, and larger tumor volume. Kaplan-Meier analysis revealed a comparable prognosis after prostatectomy between those showing F-EPE only versus mBNI only ( P =0.986), and these 2 cohorts were combined for further analysis. Then, patients showing E-EPE only had a significantly higher or lower risk of progression compared with those showing F-EPE or mBNI only ( P0.001) or both EPE and mBNI ( P0.001), respectively. These significant differences in progression-free survival were also seen in subgroups, including those with or without undergoing adjuvant therapy before recurrence and those showing no lymph node metastasis. In multivariate analysis, F-EPE or mBNI only (hazard ratio=0.524, P =0.003) or both EPE and mBNI (hazard ratio=1.465, P =0.039) (vs. E-EPE only) showed significance for progression. Based on these findings, we propose a novel pT3a subclassification, pT3a1 (F-EPE or mBNI alone), pT3a2 (E-EPE alone), and pT3a3 (both EPE and mBNI).

Background: Cribriform-predominant adenocarcinoma of the lung (Cribri-ADC) is a recently described tumor growth pattern. However, its prognostic impact has not been clearly determined. We analyzed the data of a series of 1, 057 Japanese patients with resected lung adenocarcinoma to identify the clinical significance of Cribri-ADC. Methods: Cribriform pattern (Cribri-p) is defined as invasive back-to-back fused tumor glands with poorly formed glandular spaces or invasive tumor nests comprising tumors cells that produced glandular lumina. We investigated the correlations of Cribri-p and Cribri-ADC with clinicopathological factors as well as disease-free survival (DFS) and overall survival (OS). Results: Cribri-p was present in 217 patients (20.5%) and Cribri-ADC was determined in 25 patients (2.4%). Cribri-p was associated with larger tumor size, pleural invasion, vascular invasion, lymphatic invasion, and spreading through air spaces (STAS) (all, P

BACKGROUND: Androgen receptor (AR) activation has been implicated in the pathogenesis of urothelial cancer. However, it remains controversial whether 5α-reductase inhibitors (5α-RIs), which are known for blocking the conversion of testosterone to the more potent androgen dihydrotestosterone and often prescribed for the treatment of, for instance, benign prostatic hyperplasia, contribute to preventing the development of bladder cancer. OBJECTIVE: To determine the role of 5α-RI therapy in urothelial tumorigenesis and tumor progression, using cell line models. METHODS: In a human non-neoplastic urothelial SVHUC subline stably expressing a full-length wild-type human AR (SVHUC-AR) with carcinogen/MCA challenge and human bladder cancer lines, we assessed the effects of three 5α-RIs, dutasteride (up to 100 nM), finasteride (up to 500 nM), and epristeride (up to 5μM), on neoplastic/malignant transformation and cell growth, respectively. RESULTS: In AR-positive bladder cancer UMUC3 and 5637-AR cells, an AR antagonist bicalutamide significantly inhibited their proliferation, whereas three 5α-RIs failed to do. Similarly, these 5α-RIs did not significantly inhibit the migration of bladder cancer cells induced by the treatment of testosterone which could be metabolized into dihydrotestosterone in culture medium. In MCA-SVHUC-AR cells, induction of their neoplastic transformation by testosterone, which was prevented by bicalutamide, was confirmed. However, no significant inhibitory effects of 5α-RIs on the neoplastic transformation of AR-positive urothelial cells treated with or without testosterone were observed. CONCLUSIONS: Using in vitro models for urothelial cancer, 5α-RI treatment even at supra-pharmacological doses was thus found to have no significant impact on the prevention of both tumorigenesis and tumor progression.

Introduction Simultaneous liver and kidney transplantation is a life-saving procedure for patients with liver failure and irreversible renal dysfunction. However, some studies have reported the recovery of native renal function after simultaneous liver and kidney transplantation. Case presentation A 33-year-old woman initially underwent living-donor liver transplantation for liver failure. When graft liver failure developed, she also sustained acute renal failure and required continuous hemodiafiltration for 6 weeks. Simultaneous liver and kidney transplantation from a brain-dead donor recovered her liver and renal function. A 1-year protocol graft kidney biopsy revealed acute cellular rejection despite stable serum creatinine levels. Renal scintigraphy showed functional native kidneys masking acute rejection of the graft kidney. The rejection was improved by pulse steroid therapy. Conclusion Acute rejection of the graft kidney may silently progress due to recovery of the native kidney function after simultaneous liver and kidney transplantation. Renal scintigraphy and graft kidney biopsy should be considered even if blood tests indicate stable total renal function.

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.

BACKGROUND: A micropapillary pattern (MP-p) is related to poor prognosis in patients with lung adenocarcinoma (L-ADC). In 2015, the WHO defined the MP-p as “papillary tufts forming florets that lack fibrovascular cores and may appear detached from alveolar walls”; however, the sizes of tumor clusters in air space were not mentioned in this classification. METHODS: We evaluated the MP-p dividing the cluster sizes in the air space by reviewing 1,062 cases of resected L-ADCs. We classified MP-p into two types according to cluster size as follows: typical floret MP-p, tumors with small-to-medium-sized clusters (1–20 tumor cells); and large nest MP-p, tumors with large-sized clusters (>20 tumor cells, large nest). We then recorded the frequency of each type and investigated the association between the MP-p type and clinicopathological factors. RESULTS: Twenty-nine percent of L-ADCs (n=308) were MP-p-positive. Typical floret MP-p and large nest MP-p were observed in 244 tumors (22.9%) and 64 tumors (6.0%), respectively. Only 7 additional micropapillary ADCs were detected when we reclassified ADCs in addition to large nest MP-p. Tumors with large nest MP-p showed the highest frequency of node metastasis and worse prognosis compared to those with typical floret MP-p and absent (P

Context.— Seminal vesicle invasion (SVI) as pT3b prostate cancer generally, but not uniformly, indicates poor prognosis. Objective.— To determine the clinical impact of pT3a lesions (ie, extraprostatic extension other than seminal vesicle or bladder invasion [EPE], microscopic bladder neck invasion [mBNI]), as well as unilateral (Uni) versus bilateral (Bil) SVI), in pT3b disease. Design.— We assessed radical prostatectomy findings and long-term oncologic outcomes in 248 consecutive patients with pT3b disease. Results.— Focal EPE, nonfocal EPE, mBNI, Uni-SVI, and Bil-SVI were identified in 13 (5.2%), 206 (83.1%), 48 (19.4%), 109 (44.0%), and 139 (56.0%) cases, respectively. Of possible combinations, we eventually divided our cases into 3 cohorts—Group 1: Uni/Bil-SVI and EPE−/mBNI− (n = 28; 11.3%); Group 2: Uni-SVI and EPE or mBNI (n = 103; 41.5%); and Group 3: Bil-SVI and EPE or mBNI (n = 70; 28.2%) or Uni/Bil-SVI and EPE+/mBNI+ (n = 47; 19.0%). Group 3 patients showed significant adverse histopathologic findings, compared with Group 1 or Group 2 patients. Kaplan-Meier analysis revealed that the prognosis was worse in the following order: Group 1, Group 2, and Group 3; and the differences in progression-free survival between any 2 groups were statistically significant. These significant differences were also seen in subgroups, such as those without or with adjuvant therapy before recurrence and those without lymph node metastasis. Additionally, Group 3 patients had a significantly higher risk of cancer-specific mortality than Group 2 patients. In multivariate analysis (Group 2 as a reference), Group 1 (hazard ratio [HR] = 0.169, P = .01) and Group 3 (HR = 1.620, P = .04) showed significance for progression. Conclusions.— From these significant findings, we propose a novel pT3b subclassification, namely pT3b1 (Group 1), pT3b2 (Group 2), and pT3b3 (Group 3), which more accurately stratifies its prognosis.

Perineural invasion (PNI) by prostate cancer detected on systematic sextant biopsy (S-Bx) has been considered as a key prognosticator. However, the clinical significance of PNI on magnetic resonance imaging-targeted biopsy (T-Bx) needs to be further investigated. We assessed 169 patients undergoing T-Bx with concurrent S-Bx, followed by radical prostatectomy (RP) from 2015 to 2019. In all cases where cancer was detected on T-Bx only (n = 34) or both S-Bx and T-Bx (B-Bx; n = 135), PNI was found in 33 (19.5%) T-Bxs. Compared with no PNI, PNI on T-Bx was associated with higher Grade Group on biopsy/RP, higher pT stage, and lymph node metastasis. Outcome analysis revealed a significant difference in the risk of biochemical recurrence after RP between cases with and without PNI on T-Bx (P = 0.021). Next, in the 135 B-Bx cases, PNI was found on S-Bx only (n = 31), T-Bx only (n = 15), or B-Bx (n = 16). Compared with PNI on S-Bx, B-Bx PNI was associated with higher preoperative prostate-specific antigen, higher biopsy GG, higher pT stage, and larger tumor volume. There were no significant differences in any of the clinicopathologic features examined between cases with PNI on T-Bx only vs. B-Bx. Moreover, in this subgroup of patients, PNI on B-Bx was associated with significantly higher risks of biochemical recurrence, compared with PNI on S-Bx only (P = 0.024) or T-Bx only (P = 0.033). In multivariate analysis, PNI on B-Bx showed significance for recurrence (hazard ratio = 2.787, P = 0.034). The presence of PNI on T-Bx, particularly B-Bx, associated with worse histopathologic features on RP and poorer outcomes might thus be useful for risk stratification.

Magnetic resonance imaging-targeted biopsy (T-Bx) has been shown to more accurately detect clinically significant prostate cancer. However, the clinical significance of cancer detection on T-Bx, followed by definitive treatment, needs to be further investigated. We herein investigated unique cohorts of patients with prostate cancer detected on systematic sextant biopsy (S-Bx) and/or T-Bx.We assessed consecutive patients who had undergone T-Bx with concurrent S-Bx (6 sites, ≥12 cores), followed by radical prostatectomy from 2015 to 2019. Within our Surgical Pathology database, we identified a total of 222 men who met the inclusion criteria for prostatic adenocarcinoma on either S-Bx or T-Bx, or both (B-Bx). Radical prostatectomy findings and oncologic outcomes were then compared among groups.Prostate cancer was detected on S-Bx only (n = 32; 14%), T-Bx only (n = 40; 18%), or B-Bx (n = 150; 68%). Compared to cases with cancer detected on S-Bx only, those on T-Bx only or B-Bx showed significantly higher tumor grade (highest Grade Group in each patient) on biopsy and significantly larger estimated tumor volume on prostatectomy. There were no significant differences in tumor volume on biopsy, tumor grade on prostatectomy (except S-Bx vs. B-Bx), pT or pN stage category, surgical margin status, or preoperative prostate-specific antigen level between cases where cancer was detected on S-Bx only vs. T-Bx only or B-Bx. There were also no significant differences in any of these clinicopathologic features between cancers detected on T-Bx only vs. B-Bx. Kaplan-Meier analysis revealed a significantly higher risk of biochemical recurrence after prostatectomy in patients whose cancer was detected on T-Bx only (P = 0.020) or B-Bx (P = 0.032) than in those on S-Bx only. No significant difference in recurrence-free survival between T-Bx only vs. B-Bx cases (P = 0.601) was seen. In multivariate analysis, cancer detection on T-Bx only (vs. S-Bx only) showed significance for recurrence (hazard ratio = 8.482, P = 0.045).Detection of prostate cancer on T-Bx, in addition to or instead of S-Bx, was found to be associated with larger tumor volume as well as worse prognosis. However, no significant clinicopathologic impact of simultaneous tumor detection on S-Bx was indicated in patients with prostate cancer present on T-Bx.

INTRODUCTION AND OBJECTIVE:We and others have indicated that androgen receptor (AR) signaling plays a critical role in urothelial cancer outgrowth. Meanwhile, our DNA microarray data suggest that l...

Context.— Seminal vesicle involvement by prostate cancer has generally been considered as a key prognosticator. Objective.— To assess the clinical significance of unilateral (Uni) versus bilateral (Bil) seminal vesicle invasion (SVI). Design.— We compared radical prostatectomy findings and long-term oncologic outcomes in 248 patients showing Uni-SVI (n = 139) versus Bil-SVI (n = 109). Results.— Tumor grade was significantly higher in Bil-SVI cases than in Uni-SVI cases. Additionally, Bil-SVI was significantly associated with a higher incidence of lymphovascular invasion, lymph node metastasis, or positive surgical margin, and larger estimated tumor volume. When the histopathologic features at SVI foci were compared, Grade Group (GG) 3-5/4-5/5 and cribriform morphology were significantly more often seen in Bil-SVI. Outcome analysis revealed that patients with Bil-SVI had a significantly higher risk of disease progression (P < .001) than patients with Uni-SVI. Significantly worse progression-free survival in patients with Bil-SVI was also observed in all subgroups examined, including those with no immediate adjuvant therapy (IAT) (n = 139; P = .01), IAT (n = 109; P = .001), pN0 disease (n = 153; P = .002), or pN1 disease (n = 93; P = .006). In multivariate analysis, Bil-SVI (versus Uni-SVI) showed significance for progression in the entire (hazard ratio [HR] = 1.83, P = .01), IAT (HR = 2.90, P = .006), and pN0 (HR = 2.05, P = .01) cohorts. Meanwhile, tumor grade at SVI (eg, GG4, GG5), as an independent predictor, was significantly associated with patient outcomes. Conclusions.— Bil-SVI was found to be strongly associated with worse histopathologic features on radical prostatectomy and poorer prognosis. Pathologists may thus need to report Uni-SVI versus Bil-SVI, along with other histopathologic findings, such as Gleason score, at SVI in prostatectomy specimens.

The pulmonary artery (PA) in patients with pulmonary hypertension (PH) becomes dilated. We analyzed the postoperative changes of the main PA after lung transplantation (LuTx). The subjects of this retrospective study were 68 LuTx recipients, divided into a PH group (n = 36) and a non-PH group (n = 32), based on preoperative right heart catheterization findings. The PA diameter was measured on chest computed tomography. We evaluated the correlation between the mean pulmonary arterial pressure (mPAP) and the main PA diameter and compared the main PA diameters before and 3 months after LuTx. The main PA diameter was significantly correlated with the mPAP (r = 0.423, P

Background Non–muscle-invasive bladder cancer (NMIBC) can be treated using transurethral resection (TUR), but high incidence of intravesical recurrence remains a clinical challenge. Single immediate postoperative instillation of chemotherapy (IPIOC) is controversial for NMIBC patients with intermediate recurrence risk. The aim of the present study was to report the efficacy and toxicity of IPIOC, particularly in intermediate-risk NMIBC patients, in the real-world setting. Patients and Methods We retrospectively analyzed 363 consecutive patients with primary NMIBC who underwent radical TUR at Kyoto University Hospital between 2007 and 2016. Results In low-risk patients, recurrence-free survival (RFS) was significantly better for IPIOC than non-IPIOC (2-year RFS: 89.3% vs. 59.4%; P = .001). In intermediate-risk patients, IPIOC was associated with significantly longer RFS compared with non-IPIOC (2-year RFS: 85.5% vs. 58.2%; P = .011). IPIOC and bacillus Calmette-Guerin (BCG) were independent predictors for post-TUR recurrence (non-IPIOC vs. IPIOC: hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.14-4.88; P = .02; non-BCG vs. BCG: HR, 2.22; P = .045, 95% CI, 1.02-5.30). In the high-risk group, only BCG was an independent prognostic factor of recurrence in a multivariate Cox proportional hazards model (HR, 2.55; P = .006, 95% CI, 1.32-4.87). There were no significant differences between the BCG-only group and the IPIOC with BCG group in Grade 3 or more local (16 patients [21%] vs. 21 patients [24%]; P = .61) or systemic (3 patients [4%] vs. 6 patients [7%]; P = .40) toxicity rates. Conclusion Our study showed the efficacy of IPIOC for the prevention of intravesical recurrence in primary intermediate-risk NMIBC patients regardless of BCG therapy.

Recipients of organ transplants are immunosuppressed and at high risk of oral infection. Oral diseases are often neglected compared with infections of other organs that typically confer higher morbidity. However, severe local symptoms hinder oral intake, decrease quality of life, and are sometimes lethal. Here we describe a case of a 57-year-old woman who developed recurrent aphthous stomatitis after kidney transplantation; the cause of the infection was complex and included cytomegalovirus, herpes simplex virus, and Candida species. Since misdiagnosis of oral diseases impairs patient quality of life and increases morbidity, clinicians should be aware of possible etiologies of oral infections in renal transplant recipients.

Bladder cancer usually forms a papillary structure. Progression along the cavity or membranous structures surrounding the bladder, rectum, or retroperitoneum without formation of a discrete mass is rare. We here present two patients with duodenal obstruction caused by retroperitoneal progression of bladder cancer, in both of whom computed tomography revealed bladder and rectal wall thickening with a malignant target sign, thickened mesorectal fascia with abnormal tissue stranding, and increased perirectal fat density. Both cancers progressed despite treatment, as indicated by faint abnormal tissue stranding and increased retroperitoneal fat density along the retromesenteric plane from the pelvis to the duodenum. Subsequently, both patients developed obstruction in the horizontal portion of the duodenum, still without formation of a mass lesion. These two patients highlight the challenges associated with retroperitoneal invasion by bladder cancer in the absence of a mass lesion and underscore the importance of considering cancer progression in patients with bowel obstruction, even when there is no obvious mass lesion and/or only minor retroperitoneal findings. Progression along the retromesenteric plane may be the key pathway via which progressive bladder cancer results in duodenal obstruction without or with a minor mass lesion.

Simple Summary It remains unclear why chemotherapy is often ineffective in patients with bladder cancer. Meanwhile, we previously reported that male sex hormones (i.e., androgens) could considerably reduce the efficacy of cisplatin, an anti-cancer drug used as the first-line treatment against advanced bladder cancer. The present study aimed to investigate how androgen receptor signaling, which is activated by binding of androgenic hormones, modulates sensitivity to cisplatin treatment in bladder cancer, using cell line models and surgical specimens. We found that the expression levels of the androgen receptor and a molecule (BXDC2) were inversely correlated and that loss of BXDC2 was associated with cisplatin resistance. We thus provide evidence to suggest an underlying molecular mechanism responsible for androgen receptor-induced chemoresistance in bladder cancer. Abstract Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease.

Vitamin-D receptor (VDR) mRNA is enriched in malignant lung, ovarian and pancreatic tissues and showed poor prognoses. Calcitriol and stable or CRISPR-directed VDR upregulation increased PD-L1mRNA and protein expression in cancer cells in-vitro. A ChIP assay showed the binding of VDR with VDREPD-L1. Stattic, a STAT3 phosphorylation inhibitor blocked calcitriol or VDR overexpression induced PD-L1 upregulation. MeTC7, a VDR antagonist developed by us, reduced PD-L1 expression on macrophages, ovarian, lung, breast, and pancreatic cancer cells in-vitro. In radiotherapy inducible PD-L1 model of orthotopic MC38 murine colon cancer, MeTC7 decreased PD-L1 surface expression, suppressed inflammatory monocytes (IMs) population and increased intra-tumoral CD69+PD1+CD8+T-cells. Intriguingly, MeTC7 reduced TH-MYCN transgenic neuroblastoma tumor growth without affecting PD-L1 and tumor immune milieu. In summary, Vitamin-D/VDR drives PD-L1 expression on cancer cells via STAT-3. Inhibiting VDR exhibited anti-checkpoint effects in orthotopic colon tumors, whereas PDL1-independent and anti-VDR/MYCN effects controlled growth of transgenic neuroblastoma and xenografted tumors.SummaryVitamin-D/VDR induces PD-L1 expression on cancer cells via STAT-3; and targeting VDR by a novel small molecule antagonist MeTC7 exhibits both anti-PD-L1 and anti-VDR/MYCN effects in tumor models.

Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent vasectomy vs. sham surgery performed at 4 weeks of age. One of the molecules identified by DNA microarray (i.e., ZKSCAN3) was then assessed in radical prostatectomy specimens and human prostate cancer lines. At 24 weeks, gross tumor (p = 0.089) and poorly differentiated adenocarcinoma (p = 0.036) occurred more often in vasectomized mice. Vasectomy significantly induced ZKSCAN3 expression in prostate tissues from C57BL/6 mice and prostate cancers from TRAMP mice. Immunohistochemistry showed increased ZKSCAN3 expression in adenocarcinoma vs. prostatic intraepithelial neoplasia (PIN), PIN vs. non-neoplastic prostate, Grade Group &ge, 3 vs. &le, 2 tumors, pT3 vs. pT2 tumors, pN1 vs. pN0 tumors, and prostate cancer from patients with a history of vasectomy. Additionally, strong (2+/3+) ZKSCAN3 expression (p = 0.002), as an independent prognosticator, or vasectomy (p = 0.072) was associated with the risk of tumor recurrence. In prostate cancer lines, ZKSCAN3 silencing resulted in significant decreases in cell proliferation/migration/invasion. These findings suggest that there might be an association between vasectomy and the development and progression of prostate cancer, with up-regulation of ZKSCAN3 expression as a potential underlying mechanism.

We recently demonstrated that silodosin, a selective α(1)-blocker often prescribed for the symptomatic treatment of benign prostatic hyperplasia (BPH), could inactivate a c-fos proto-oncogene regulator ELK1 in bladder cancer cells possessing a functional androgen receptor (AR). However, the clinical impact of α(1)-blockers on the development and progression of bladder cancer remained poorly understood. In the present study, we investigated if α(1)-blockers clinically used, including silodosin, tamsulosin, and naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with carcinogen/MCA challenge and bladder cancer lines, respectively. Bladder cancers in men treated with silodosin, tamsulosin, or naftopidil for their BPH were then compared. Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR, silodosin significantly reduced the expression levels of oncogenes (c-fos/NF-κB1) and induced those of tumor suppressors (p27/PTEN). However, tamsulosin (up to 1 µM) or naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive bladder cancer lines was considerably inhibited only by silodosin. Meanwhile, the incidence of bladder cancer in patients with silodosin [49/540 (9.1%)] was marginally lower, compared to those with tamsulosin [64/523 (12.2%); P=0.094] or tamsulosin or naftopidil [64+28/523+236 (12.1%); P=0.082]. There were no significant differences in tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for disease progression of non-muscle-invasive bladder tumors in the silodosin group than in the naftopidil group (P=0.011) or tamsulosin+naftopidil groups (P=0.035). Similarly, silodosin patients with muscle-invasive tumor had lower risks for disease progression, compared with tamsulosin (P=0.006) or tamsulosin+naftopidil (P=0.028) patients. Multivariate analysis further showed that silodosin treatment in those with non-muscle-invasive tumor was associated with improved progression-free survival, compared with naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; P=0.041) or tamsulosin/naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; P=0.054) treatment. Our in vitro studies thus indicate that both urothelial tumorigenesis and tumor growth are inhibited by silodosin, but not by tamsulosin or naftopidil. Clinical data further suggest that even pharmacological doses (e.g. 0.1 µM) of silodosin contribute to preventing bladder cancer progression.

The efficacy of cisplatin-based chemotherapy in patients with bladder cancer is often limited due to the development of therapeutic resistance. Our recent findings in bladder cancer suggested that activation of prostaglandin receptors (