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Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting. The prostate cancer tumour microenvironment in the context of treatment remains to be explored. Here, single-cell RNA-sequencing and spatial transcriptomics analysis of samples at multiple treatment points from 120 patients suggests that club-like cells may contribute to treatment resistance. [ABSTRACT FROM AUTHOR]

Background/Objectives: Type 2 diabetes mellitus (T2DM) represents a major risk factor for peripheral artery disease (PAD). We aimed to evaluate the impact of T2DM on lesion localization and complexity, clinical presentation by Rutherford categories, and limb outcomes in elderly patients with symptomatic PAD undergoing endovascular revascularization. Methods: Five hundred consecutive patients with symptomatic infra-inguinal PAD who underwent rotational atherectomy-assisted endovascular revascularization were included. PAD clinical presentation and lesion localization were recorded. The primary endpoints were clinically driven target lesion revascularization (CD-TLR) and major amputation rates during follow-up. Results: Overall, 245/500 (49.0%) patients had T2DM, whereas 179 (35.8%) presented with lifestyle limiting claudication and 321 (64.2%) with critical limb-threatening ischemia (CLTI). Median age was 78.0 (IQR = 70.0–84.0) years, and 201 (40.2%) patients were female. The presence of T2DM was significantly more frequent in patients with CLTI vs. those with claudication (58.6 vs. 31.8%; p < 0.001). Furthermore, the percentage of patients with below-the-knee (BTK) lesions was significantly higher in patients with vs. without T2DM (40.7 vs. 27.5%, p = 0.0002). During median follow-up of 21.9 (IQR = 12.8–28.8) months, CD-TLR rates were similar in patients with vs. without T2DM (HR = 1.2, 95%CI = 0.8–2.0, p = 0.39). However, patients with T2DM had a ~5.5-fold increased risk for major above-the-ankle amputation (HR = 5.5, 95%CI = 1.6–19.0, p = 0.007). After adjustment for age, gender, lesion complexity, and calcification, T2DM remained predictive for major amputation (p = 0.04). Conclusions: T2DM is more frequently associated with CLTI, BTK-PAD, and amputations despite successful endovascular revascularization. More stringent surveillance of patients with PAD and T2DM is warranted to prevent atherosclerosis-related complications. [ABSTRACT FROM AUTHOR]

Simple Summary: Many beneficial mechanisms of action are known from soy isoflavones, including in prostate and prostate cancer. Previous research was able to demonstrate a clear effect of PSA modulation, and this could potentially lead to better selection of patients at increased risk of occult prostate carcinoma. In low-grade localized prostate cancer, more and more active surveillance is being proposed and a lot of research is being carried out to see if certain factors or treatments may also act in this regard. This formed the basis to study the effect of soy isoflavones in patients under active surveillance. In this study, we were able to observe PSA modulation in a large proportion of patients, resulting in fewer follow-up examinations and fewer positive control biopsies. Potentially, in active surveillance, a soy supplement could be useful to help select patients who could continue to be followed up or who should be treated earlier. Background/Objectives: To investigate the effect of a fermented soy supplement during 18 months in patients under active surveillance (AS) for low-risk and selected favorable intermediate-risk prostate cancer (PCa), with an emphasis on PSA modulation. Methods: Low-risk patients with ISUP grade 1, clinical stage cT1 or cT2a, PSA < 10 ng/mL and favorable intermediate-risk patients with ISUP grade 2 (<10% pattern 4), clinical stage T2b-c, PSA 10–20 ng/mL. The primary outcome was PSA response defined as maximum PSA rise less than or equal to 0.87 ng/mL after 1 year, based on the weighted average of PSA velocity (PSAV) in previous studies in similar populations. Secondary outcomes were disease progression, adverse histology on repeat biopsy or switch to active therapy. In addition, primary and secondary outcomes with imputed data were also determined as sensitivity analyses, using Mann–Whitney U or Chi-squared tests. Results: Overall, 92 (61.3%) of 150 patients showed a PSA level response. This was more evident in ISUP 1 patients and resulted in fewer follow-up MRIs and fewer control biopsies, as well as a fewer number of positive control biopsies with statistical significance in the imputed dataset. Obtaining a PSA response was numerically associated with less initiated therapy. Conclusions: a fermented soy supplement in patients under AS for low-risk and selected favorable intermediate-risk PCa could be useful in selecting patients who may remain under AS or who may need to switch to active therapy. [ABSTRACT FROM AUTHOR]

Purpose: Quantification of PSMA expression via PSMA PET is well-established, however quantification of PSMA via immunohistochemistry (IHC) is not standardized. Our aim was to determine the most optimal PSMA IHC scoring system to quantify PSMA expression with PSMA PET as reference standard.Primary intermediate- and high-risk prostate cancer patients received an [18F]PSMA-1007 PET/MRI followed by radical prostatectomy. SUVmax, SUVmean and Ki of the prostate tumor was determined. Prostate tumors were stained with anti-PSMA antibodies and scored by 2 readers via 10 IHC scoring systems: histochemical score (H-score), immunoreactivity scorepredominant intensity (IRSpredominant intensity), IRS classificationpredominant intensity, IRSmean intensity, IRS classificationmean intensity, Allred score, predominant expression pattern, Shannon diversity index (SDI), percentage negatively stained cells and total percentage positively stained cells. Spearman’s rank correlation coefficients (ρ) were calculated between PET parameters and IHC scoring systems. Interreader agreement for the IHC scoring systems was measured by the intraclass correlation coefficient (ICC).Fifty tumors in 46 patients were analysed. H-score had the best correlation with SUVmax (ρ 0.615 p < 0.0001) and SUVmean (ρ 0.570, p < 0.0001) and the second best correlation with Ki (ρ 0.411, p = 0.0030). SDI had the best correlation with Ki (ρ -0.440, p = 0.0014) and the second best correlation with SUVmax (ρ -0.516, p = 0.0001) and SUVmean (ρ -0.490, p = 0.0003). A moderate interreader agreement was observed for H-score (ICC 0.663, 95% CI 0.495–0.797) and SDI (ICC 0.546, 95% CI 0.354–0.725).H-score had the best correlation with PSMA PET quantification and an acceptable interreader agreement. Therefore, we deem H-score the most optimal PSMA IHC scoring system.Methods: Quantification of PSMA expression via PSMA PET is well-established, however quantification of PSMA via immunohistochemistry (IHC) is not standardized. Our aim was to determine the most optimal PSMA IHC scoring system to quantify PSMA expression with PSMA PET as reference standard.Primary intermediate- and high-risk prostate cancer patients received an [18F]PSMA-1007 PET/MRI followed by radical prostatectomy. SUVmax, SUVmean and Ki of the prostate tumor was determined. Prostate tumors were stained with anti-PSMA antibodies and scored by 2 readers via 10 IHC scoring systems: histochemical score (H-score), immunoreactivity scorepredominant intensity (IRSpredominant intensity), IRS classificationpredominant intensity, IRSmean intensity, IRS classificationmean intensity, Allred score, predominant expression pattern, Shannon diversity index (SDI), percentage negatively stained cells and total percentage positively stained cells. Spearman’s rank correlation coefficients (ρ) were calculated between PET parameters and IHC scoring systems. Interreader agreement for the IHC scoring systems was measured by the intraclass correlation coefficient (ICC).Fifty tumors in 46 patients were analysed. H-score had the best correlation with SUVmax (ρ 0.615 p < 0.0001) and SUVmean (ρ 0.570, p < 0.0001) and the second best correlation with Ki (ρ 0.411, p = 0.0030). SDI had the best correlation with Ki (ρ -0.440, p = 0.0014) and the second best correlation with SUVmax (ρ -0.516, p = 0.0001) and SUVmean (ρ -0.490, p = 0.0003). A moderate interreader agreement was observed for H-score (ICC 0.663, 95% CI 0.495–0.797) and SDI (ICC 0.546, 95% CI 0.354–0.725).H-score had the best correlation with PSMA PET quantification and an acceptable interreader agreement. Therefore, we deem H-score the most optimal PSMA IHC scoring system.Results: Quantification of PSMA expression via PSMA PET is well-established, however quantification of PSMA via immunohistochemistry (IHC) is not standardized. Our aim was to determine the most optimal PSMA IHC scoring system to quantify PSMA expression with PSMA PET as reference standard.Primary intermediate- and high-risk prostate cancer patients received an [18F]PSMA-1007 PET/MRI followed by radical prostatectomy. SUVmax, SUVmean and Ki of the prostate tumor was determined. Prostate tumors were stained with anti-PSMA antibodies and scored by 2 readers via 10 IHC scoring systems: histochemical score (H-score), immunoreactivity scorepredominant intensity (IRSpredominant intensity), IRS classificationpredominant intensity, IRSmean intensity, IRS classificationmean intensity, Allred score, predominant expression pattern, Shannon diversity index (SDI), percentage negatively stained cells and total percentage positively stained cells. Spearman’s rank correlation coefficients (ρ) were calculated between PET parameters and IHC scoring systems. Interreader agreement for the IHC scoring systems was measured by the intraclass correlation coefficient (ICC).Fifty tumors in 46 patients were analysed. H-score had the best correlation with SUVmax (ρ 0.615 p < 0.0001) and SUVmean (ρ 0.570, p < 0.0001) and the second best correlation with Ki (ρ 0.411, p = 0.0030). SDI had the best correlation with Ki (ρ -0.440, p = 0.0014) and the second best correlation with SUVmax (ρ -0.516, p = 0.0001) and SUVmean (ρ -0.490, p = 0.0003). A moderate interreader agreement was observed for H-score (ICC 0.663, 95% CI 0.495–0.797) and SDI (ICC 0.546, 95% CI 0.354–0.725).H-score had the best correlation with PSMA PET quantification and an acceptable interreader agreement. Therefore, we deem H-score the most optimal PSMA IHC scoring system.Conclusion: Quantification of PSMA expression via PSMA PET is well-established, however quantification of PSMA via immunohistochemistry (IHC) is not standardized. Our aim was to determine the most optimal PSMA IHC scoring system to quantify PSMA expression with PSMA PET as reference standard.Primary intermediate- and high-risk prostate cancer patients received an [18F]PSMA-1007 PET/MRI followed by radical prostatectomy. SUVmax, SUVmean and Ki of the prostate tumor was determined. Prostate tumors were stained with anti-PSMA antibodies and scored by 2 readers via 10 IHC scoring systems: histochemical score (H-score), immunoreactivity scorepredominant intensity (IRSpredominant intensity), IRS classificationpredominant intensity, IRSmean intensity, IRS classificationmean intensity, Allred score, predominant expression pattern, Shannon diversity index (SDI), percentage negatively stained cells and total percentage positively stained cells. Spearman’s rank correlation coefficients (ρ) were calculated between PET parameters and IHC scoring systems. Interreader agreement for the IHC scoring systems was measured by the intraclass correlation coefficient (ICC).Fifty tumors in 46 patients were analysed. H-score had the best correlation with SUVmax (ρ 0.615 p < 0.0001) and SUVmean (ρ 0.570, p < 0.0001) and the second best correlation with Ki (ρ 0.411, p = 0.0030). SDI had the best correlation with Ki (ρ -0.440, p = 0.0014) and the second best correlation with SUVmax (ρ -0.516, p = 0.0001) and SUVmean (ρ -0.490, p = 0.0003). A moderate interreader agreement was observed for H-score (ICC 0.663, 95% CI 0.495–0.797) and SDI (ICC 0.546, 95% CI 0.354–0.725).H-score had the best correlation with PSMA PET quantification and an acceptable interreader agreement. Therefore, we deem H-score the most optimal PSMA IHC scoring system. [ABSTRACT FROM AUTHOR]

The androgen receptor signaling inhibitor apalutamide is used successfully for the treatment of prostate cancer. An increased risk of hypothyroidism, mostly subclinical, has been reported in the SPARTAN and TITAN trials. We present three cases of subacute deterioration of previously known but well-controlled hypothyroidism treated with levothyroxine, occurring shortly after the initiation of treatment with apalutamide, resulting in severe hypothyroidism. These cases highlight the importance of awareness of thyroid dysfunction during treatment with apalutamide, particularly in patients with pre-existing thyroid disease, common in the general population. We provide practice recommendations for thyroid management prior to and during apalutamide treatment as well as after the interruption of this therapy.

Background and Objective: A meta-analysis of two randomized STAMPEDE platform trials revealed that 3 yr of abiraterone acetate in addition to androgen deprivation therapy and radiation therapy significantly improved metastasis-free and overall survival (OS) in high-risk nonmetastatic prostate cancer (PCa) and should be considered a new standard of care. The aim of our study was to assess long-term cancer-specific survival (CSS) and OS for surgically treated patients with newly diagnosed nonmetastatic node-negative PCa meeting the STAMPEDE criteria for high risk., Methods: This was a retrospective, multicenter cohort study of patients with European Association of Urology (EAU) high-risk PCa who underwent radical prostatectomy and extended pelvic lymph node dissection. CSS was assessed using cumulative incidence curves and the Kaplan-Meier method was used to evaluate OS. We used a Fine and Gray model to evaluate the prognostic value of STAMPEDE high-risk factors (SHRFs) for CSS, and a Cox proportional-hazards model to assess the association of SHRFs with OS., Key Findings and Limitations: A total of 2994 patients with EAU high-risk PCa were divided into groups with 0, 1, 2, or 3 SHRFs. The 10-yr survival estimates for patients with 0-1 versus 2-3 SHRFs were 95% versus 82% for CSS and 81% versus 64% for OS (both p < 0.0001). In comparison to patients with 0 SHRFs, hazard ratios were 1.2 (p = 0.5), 3.9 (p < 0.0001), and 5.5 (p < 0.0001) for CSS, and 1.1 (p = 0.4), 2.2 (p < 0.0001), and 2.5 (p = 0.0004) for OS for patients with 1, 2, and 3 SHRFs, respectively., Conclusions and Clinical Implications: Our results confirm that the STAMPEDE high-risk criteria identify a subgroup of patients with highly aggressive PCa features and adverse long-term oncological outcomes. This population is likely to benefit most from aggressive multimodal treatment. Nevertheless, we have shown for the first time that surgery remains a viable treatment option for patients with STAMPEDE high-risk PCa., Patient Summary: Prostate cancer that meets the high-risk definitions from the STAMPEDE trial is an aggressive type of cancer. Our results for long-term cancer control outcomes indicate that surgery is a viable option for the subgroup of patients with this type of prostate cancer., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

tBuCH=C(Li)S(O)(NSO 2 Tol)Ph⋅L (L=2THF, TMEDA) (1⋅L) in THF solution is a monomer with a C-Li bond according to NMR spectroscopy and cryoscopy. It was identified as CIP through the scalar 13 C, 6 Li coupling and 6 Li,{ 1 H} NOE experiments. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure. 6 Li, 1 H FUCOUP and 6 Li, 1 H HMQC NMR experiments of 1⋅TMEDA revealed a scalar 6 Li, 1 H coupling across the Li-C=C-H bonds. According to the NMR data the π-bond of 1⋅L is polarized by the negative charge of the anionic C atom. tBuCH=C(Li)S(O)(NMe)Ph (2⋅L) is most likely also a monomer with a C-Li bond. According to 6 Li,{ 1 H} NOE experiments it has a four-membered C-Li-N-S chelate ring structure. 13 C NMR spectroscopy showed the C-Li bonds of 1⋅L and 2⋅L to be fluxional. 1 H NMR spectroscopy and 1D TOCSY experiments of Ph 2 C=C(Li)S(O)(NSO 2 Tol)Ph revealed topomerization of the phenyl groups, which is attributed to a fast positional exchange of the Li atom and the sulfonimidoyl group. The fluxionality of the C-Li bond and the interchange of the Li atom and the sulfonimidoyl group at the anionic C atom of sulfonimidoyl vinyllithiums, which result in a low configurational stability, most likely involve the formation of O,Li and N,Li CIPs through heterolysis of the C-Li bond. Ab initio calculation of MeCH=C(Li)S(O)(NMe)Ph yielded an energy minimum structure with a C-Li bond, a four-membered C-Li-N-S chelate ring and a strongly expanded C=C-Li bond angle. According to calculation of MeCH=C(Li)S(O)(NMe)Ph, [MeCH=CS(O)(NMe)Ph] - and MeCH=C(H)S(O)(NMe)Ph deprotonation is not accompanied by a shortening of the C-S bond. Ab initio calculation of MeCH=C(Li)S(O)(NSO 2 Me)Ph gave a structure with a C-Li bond and a six-membered C-Li-O-S-N-S chelate ring. 6 Li, 1 H NOE experiments and cryoscopy of LiCH 2 S(O)(NSO 2 Tol)Ph (3) revealed a monomeric CIP with a C-Li bond. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure found in polymeric 3 in the crystal., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)