Apalutamide-induced severe hypothyroidism: case series and practice recommendations for thyroid management.

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.

Comparison of PSMA immunohistochemistry scoring systems to parametric [18F]PSMA-1007 PET/MRI in primary prostate cancer.

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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Risk of Cancer-related Death for Men with Biopsy Grade Group 1 Prostate Cancer and High-risk Features: A European Multi-institutional Study.

International Society of Urological Pathology grade group 1 (GG 1) prostate cancer (PCa) is generally considered insignificant, with recent suggestions that it should even be considered as "noncancerous". We evaluated outcomes for patients with GG 1 PCa on biopsy (bGG 1) and high-risk features (prostate-specific antigen [PSA] >20 ng/ml and/or cT3-4 stage) to challenge the hypothesis that every case of bGG 1 PCa has a benign disease course. We used the multi-institutional EMPaCT database, which includes data for 9508 patients with high-risk PCa undergoing surgery. We included patients with bGG 1 PCa (n = 848) in our analysis and divided them into three groups according to PSA >20 ng/ml, cT3-4 stage, or both. The estimated 10-yr cancer-specific survival (CSS) rate was 96% in the overall population, 88% in the group with both PSA >20 ng/ml and cT3-4 stage, 97% in the group with PSA >20 ng/ml alone, and 98% in the group with cT3-4 stage alone. Similar CSS outcomes were found in subgroups with GG 1 PCa on pathology (n = 502) and with GG 1 on biopsy diagnosed after 2005 (n = 253). Study limitations include the lack of magnetic resonance imaging (MRI) staging and MRI-targeted biopsies. In conclusion, patients with GG 1 and either PSA >20 ng/ml or cT3-4 stage have a low risk of dying from their cancer after surgery. However, patients with GG 1 PCa and both PSA >20 ng/ml and cT3-4 stage are at higher risk of cancer-specific mortality and active treatment should be discussed for this subgroup. Patient summary: We assessed outcomes for patients diagnosed with low-grade prostate cancer on biopsy who also had one or two factors associated with high risk disease. Men with both of those risk factors had a higher risk of dying from their prostate cancer. Active treatment should be discussed for this subgroup of patients.

Effect of Radical Prostatectomy on Survival for Men with High-risk Nonmetastatic Prostate Cancer Features Selected According to STAMPEDE Criteria: An EMPaCT Study.

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.

Effects of high- versus low-intensity lipid-lowering treatment in patients undergoing serial coronary computed tomography angiography: results of the multi-center LOCATE study.

AIM: To evaluate the effects of lipid-lowering medications of different intensities on total, calcified, and non-calcified plaque volumes in patients undergoing serial cardiac computed tomography angiography (CCTA). METHODS: Individuals with chronic coronary syndromes from 11 centers were included in a retrospective registry. Total, calcified, and non-calcified plaque volumes were quantified and the relative difference in plaque volumes between baseline and follow-up CCTA was calculated. The intensity of lipid-lowering treatment was designated as low, moderate, or high, based on current recommendations. RESULTS: Of 216 patients (mean age 63.1 ± 9.7 years), undergoing serial CCTA (median timespan = 824.5 [IQR = 463.0-1323.0] days), 89 (41.2%) received no or low-intensity lipid-lowering medications, and 80 (37.0%) and 47 (21.8%) moderate- and high-intensity lipid-lowering agents, respectively. Progression of total and non-calcified plaque was attenuated in patients on moderate-/high- versus those on no/low-intensity treatment and arrested in patients treated with high-intensity statins or PCSK9 inhibitors (p < 0.001). Halted increase of non-calcified plaque was associated with LDL-cholesterol reduction (p < 0.001), whereas calcified plaque mass and Agatston score increased irrespective of the lipid-lowering treatment (p = NS). The intensity of lipid-lowering therapy robustly predicted attenuation of non-calcified plaque progression as a function of the time duration between the two CCTA scans, and this was independent of age and cardiovascular risk factors (HR = 3.83, 95% CI = 1.81-8.05, p < 0.001). CONCLUSION: The LOCATE multi-center observational study shows that progression of non-calcified plaques, which have been previously described as precursors of acute coronary syndromes, can be attenuated with moderate-intensity, and arrested with high-intensity lipid-lowering therapy. GERMAN CLINICAL TRIALS REGISTER: DRKS00031954.

Nutritional Supplement With Fermented Soy in Men With an Elevated Risk of Prostate Cancer and Negative Prostate Biopsies: General and Oncological Results From the Prospective PRAECAP Trial.

OBJECTIVE: To investigate the effect of a dietary supplement containing fermented soy on PSA, IPSS, changes in prostate volume and prostate cancer (PCa) development after a 6-month challenge in men at increased risk of PCa and negative previous biopsies. MATERIALS AND METHODS: Patients with an elevated risk of PCa, defined by either 1 of the following criteria: PSA >3 ng/mL, suspect lesion at digital rectal examination (DRE), suspect lesion at transrectal ultrasound (TRUS)/magnetic resonance imaging (MRI) and previous negative prostate biopsies (at least 8 cores) within 12 months before inclusion. Statistical analysis was carried out using a non-parametric 1-sided paired Wilcoxon rank sum test, chi-square test, and Fisher's exact test. RESULTS: In this trial, 94 patients were eligible for analysis. A PSA response was detected in 81% of the cases. In 25.8% (24/93) of patients, a decrease of at least 3 points on the IPSS was observed. The median prostate volume did not statistically change after 6 months (P = .908). Patients with PSA modulation required fewer investigations and had fewer positive biopsies (P <.001) and significantly fewer ISUP ≥3 lesions (P = .02). CONCLUSION: We observed a significantly lower PSA level after a 6-month challenge with a fermented soy-containing supplement, and an effect on IPSS in a subset of patients. Prescribing a fermented soy supplement in patients with an increased PCa risk could lead to a better selection of patients at real increased risk of having occult PCa.

Salvage vesiculectomy for local prostate cancer recurrence: surgical technique and early post-operative outcomes.

PURPOSE: Isolated recurrence in remnants of the seminal vesicles (SV) after treatment of primary prostate cancer (PCa) has become a more frequent entity with the widespread use of more sensitive next-generation imaging modalities. Salvage vesiculectomy is hypothesized to be a worthwhile management option in these patients. The primary goal of this study is to describe the surgical technique of this new treatment option. Secondary outcomes are peri- and post-operative complications and early oncological outcomes. METHODS: Retrospective multicenter study, including 108 patients with solitary recurrence in the SV treated between January 2009 and June 2022, was performed. Patients with local recurrences outside the SVs or with metastatic disease were excluded. Both SVs were resected using a robot-assisted or an open approach. In selected cases, a concomitant lymphadenectomy was performed. RESULTS: Overall, 31 patients (29%) reported complications, all but one grade 1 to 3 on the Clavien-Dindo Scale. A median PSA decrease of 2.07 ng/ml (IQR: 0.80-4.33, p < 0.001), translating into a median PSA reduction of 92% (IQR: 59-98%) was observed. At a median follow-up of 14 months, freedom from secondary treatment was 54%. Lymphadenectomy had a significant influence on PSA reduction (p = 0.018). CONCLUSION: Salvage vesiculectomy for PCa recurrence limited to the SV is a safe procedure with excellent PSA response and is a potential curative treatment in a subset of patients. A concomitant lymphadenectomy can best be performed in all patients that did not underwent one at primary treatment.

Comparison of Two Contemporary Quantitative Atherosclerotic Plaque Assessment Tools for Coronary Computed Tomography Angiography: Single-Center Analysis and Multi-Center Patient Cohort Validation.

BACKGROUND: Coronary computed tomography angiography (CCTA) provides non-invasive quantitative assessments of plaque burden and composition. The quantitative assessment of plaque components requires the use of analysis software that provides reproducible semi-automated plaque detection and analysis. However, commercially available plaque analysis software can vary widely in the degree of automation, resulting in differences in terms of reproducibility and time spent. AIM: To compare the reproducibility and time spent of two CCTA analysis software tools using different algorithms for the quantitative assessment of coronary plaque volumes and composition in two independent patient cohorts. METHODS: The study population included 100 patients from two different cohorts: 50 patients from a single-center (Siemens Healthineers, SOMATOM Force (DSCT)) and another 50 patients from a multi-center study (5 different > 64 slice CT scanner types). Quantitative measurements of total calcified and non-calcified plaque volume of the right coronary artery (RCA), left anterior descending (LAD), and left circumflex coronary artery (LCX) were performed on a total of 300 coronaries by two independent readers, using two different CCTA analysis software tools (Tool #1: Siemens Healthineers, syngo.via Frontier CT Coronary Plaque Analysis and Tool #2: Siemens Healthineers, successor CT Coronary Plaque Analysis prototype). In addition, the total time spent for the analysis was recorded with both programs. RESULTS: The patients in cohorts 1 and 2 were 62.8 ± 10.2 and 70.9 ± 11.7 years old, respectively, 10 (20.0%) and 35 (70.0%) were female and 34 (68.0%) and 20 (40.0%), respectively, had hyperlipidemia. In Cohort #1, the inter- and intra-observer variabilities for the assessment of plaque volumes per patient for Tool #1 versus Tool #2 were 22.8%, 22.0%, and 26.0% versus 2.3%, 3.9%, and 2.5% and 19.7%, 21.4%, and 22.1% versus 0.2%, 0.1%, and 0.3%, respectively, for total, noncalcified, and calcified lesions (p < 0.001 for all between Tools #1 and 2 both for inter- and intra-observer). The inter- and intra-observer variabilities using Tool #2 remained low at 2.9%, 2.7%, and 3.0% and 3.8%, 3.7%, and 4.0%, respectively, for total, non-calcified, and calcified lesions in Cohort #2. For each dataset, the median processing time was higher for Tool #1 versus Tool #2 (459.5 s IQR = 348.0-627.0 versus 208.5 s; IQR = 198.0-216.0) (p < 0.001). CONCLUSION: The plaque analysis Tool #2 (CT-guided PCI) encompassing a higher degree of automated support required less manual editing, was more time-efficient, and showed a higher intra- and inter-observer reproducibility for the quantitative assessment of plaque volumes both in a representative single-center and in a multi-center validation cohort.

Which Patients with Prostate Cancer and Lymph Node Uptake at Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography/Computerized Tomography Scan Are at a Higher Risk of Prostate-specific Antigen Persistence After Radical Prostatectomy? Identifying Indicators of Systemic Disease by Integrating Clinical, Magnetic Resonance Imaging, and Functional Imaging Parameters.

BACKGROUND: The role of local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies on prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has scarcely been explored. Limited data are available to identify men who would benefit from RP; on the contrary, those more likely to benefit already have systemic disease. OBJECTIVE: We aimed to assess the predictors of prostate-specific antigen (PSA) persistence in surgically managed PCa patients with lymphadenopathies on a PSMA PET/CT scan by integrating clinical, magnetic resonance imaging (MRI), and PSMA PET/CT parameters. DESIGN, SETTING, AND PARTICIPANTS: We identified 519 patients treated with RP and extended lymph node dissection, and who received preoperative PSMA PET between 2017 and 2022 in nine referral centers. Among them, we selected 88 patients with nodal uptake at preoperative PSMA PET (miTxN1M0). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PSA persistence, defined as a PSA value of ≥0.1 ng/ml at the first measurement after surgery. Multivariable logistic regression models tested the predictors of PSA persistence. Covariates consisted of biopsy International Society of Urological Pathology (ISUP) grade group, clinical stage at MRI, and number of positive spots at a PET/CT scan. A regression tree analysis stratified patients into risk groups based on preoperative characteristics. RESULTS AND LIMITATIONS: Overall, lymph node invasion (LNI) was detected in 63 patients (72%) and 32 (36%) experienced PSA persistence after RP. At multivariable analyses, having more than two lymph nodal positive findings at PSMA PET, seminal vesicle invasion (SVI) at MRI, and ISUP grade group >3 at biopsy were independent predictors of PSA persistence (all p < 0.05). At the regression tree analysis, patients were stratified in four risk groups according to biopsy ISUP grade, number of positive findings at PET/CT, and clinical stage at MRI. The model depicted good discrimination at internal validation (area under the curve 78%). CONCLUSIONS: One out of three miN1M0 patients showed PSA persistence after surgery. Patients with ISUP grade 2-3, as well as patients with organ-confined disease at MRI and a single or two positive nodal findings at PET are those in whom RP may achieve the best oncological outcomes in the context of a multimodal approach. Conversely, patients with a high ISUP grade and extracapsular extension or SVI or more than two spots at PSMA PET should be considered as potentially affected by systemic disease upfront. PATIENT SUMMARY: Our novel and straightforward risk classification integrates currently available preoperative risk tools and should, therefore, assist physician in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography.

Outcomes of Cytoreductive Radical Prostatectomy for Oligometastatic Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography: Results of a Multicenter European Study.

BACKGROUND: De novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown. OBJECTIVE: To analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET. DESIGN, SETTING, AND PARTICIPANTS: Overall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET. INTERVENTION: Cytoreductive radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Thirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed. RESULTS AND LIMITATIONS: Overall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5-93.7%) and 98.9% (95% CI 96.8-100%), respectively. The limitations include retrospective design and short-term follow-up. CONCLUSIONS: Cytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy. PATIENT SUMMARY: We found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications.

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients.

Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as "BRCA-ness". Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.

Pericoronary adipose tissue attenuation is associated with non-calcified plaque burden in patients with chronic coronary syndromes.

BACKGROUND: Pericoronary adipose tissue attenuation (PCAT) is a marker of inflammation of the pericoronary fat tissue, which can be assessed by coronary computed tomography angiography (CCTA). Its prognostic value was reported in previous studies. Nevertheless, the relationship between PCAT, plaque burden and coronary artery disease (CAD) severity, are not well defined. AIM: We sought to evaluate the relationship between PCAT, CAD severity based on the CAD-RADS 2.0 score and plaque burden in patients with chronic coronary syndrome (CCS). METHODS: Consecutive patients with a clinical indication for CCTA due to suspected or known CCS were included in our study. PCAT was measured in the proximal 4 â€‹cm of each of the right coronary artery (RCA), left anterior descending artery (LAD), and the left circumflex artery (LCX). The CAD-RADS 2.0 score was assessed in all patients and total, calcified, and non-calcified plaque burden was quantitatively measured. RESULTS: 868 patients (median age of 67.0 (IQR â€‹= â€‹58.0-75.0)yrs., 400 (46.1%) female) underwent CCTA between September 2020 and August 2022 due to CCS. Weak correlations were found between PCAT and the total plaque burden, as well as with the Agatston score, whereas no correlations were found between PCAT and CAD-RADS 2.0 score. Associations were also observed between the PCAT of the LAD, RCA and LCX with non-calcified plaque burden (Odds ratios of 1.22 (95%CI â€‹= â€‹1.15-1.29), 1.11 (95%CI â€‹= â€‹1.07-1.17) and 1.14 (95%CI â€‹= â€‹1.08-1.14), respectively, p â€‹< â€‹0.001 for all) which were independent of age, the Agatston score, and the CAD-RADS 2.0 score). In addition, higher PCAT were noticed with increasing number of plaques, exhibiting high-risk features per patient (p â€‹< â€‹0.05 by ANOVA for all). CONCLUSION: PCAT exhibits significant associations with non-calcified plaque burden and plaques with high-risk features in patients undergoing CCTA for CCS. Thus, PCAT may identify high-risk patients who could benefit from more aggressive preventive therapy, which merits further investigation in future studies.

Case report: Strong low-density-cholesterol reduction accompanied by shrinkage of low-attenuation coronary plaque during lipid-lowering treatment with bempedoic acid-serial evaluation by coronary computed tomography angiography.

Here, we present a patient with coronary artery disease and prior percutaneous coronary interventions. This patient had to discontinue taking multiple statins and ezetimibe due to intolerance with musculoskeletal complaints and nausea. Monotherapy with bempedoic acid was well tolerated and was exceptionally effective at lipid lowering, enabling patients to achieve the low-density lipoprotein target of <55 mg/dl, as recommended by current guidelines. In addition, serial coronary computed tomography angiography performed upon clinical indications, during 20 months of lipid-lowering treatment with bempedoic acid, demonstrated signs of favorable plaque component modification, with shrinkage of the low-attenuation plaque component compared to baseline findings.

Identification of the Optimal Candidates for Nodal Staging with Extended Pelvic Lymph Node Dissection Among Prostate Cancer Patients Who Underwent Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography. External Validation of the Memorial Sloan Kettering Cancer Center and Briganti Nomograms and Development of a Novel Tool.

BACKGROUND: Although the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases. OBJECTIVE: To externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting. DESIGN, SETTING, AND PARTICIPANTS: Overall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Available tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools. RESULTS AND LIMITATIONS: Overall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation. CONCLUSIONS: Tools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population. PATIENT SUMMARY: Tools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases.

Successful Conservative Treatment of Mobile Aortic Thrombus Causing Acute Limb Ischemia.

In this clinical vignette, we present the case of an 83-year-old female patient with acute limb ischemia, resulting from a large (1.8 × 2.8 cm) mobile thrombus in the descending aorta. The peripheral obstruction was treated with mechanical thrombectomy, whereas the intra-aortic thrombus was treated conservatively with clopidogrel and fondaparinux. (Level of Difficulty: Beginner.).

Mitral Annular Dynamics in AF Versus Sinus Rhythm: Novel Insights Into the Mechanism of AFMR.

OBJECTIVES: This study aimed to investigate mitral annular dynamics in atrial fibrillation (AF) and after sinus rhythm restoration, and to assess the relationship between annular dynamics and mitral regurgitation (MR). BACKGROUND: AF can be associated with MR that improves after sinus rhythm restoration. Mechanisms underlying this atrial functional MR (AFMR) are ill-understood and generally attributed to left atrial remodeling. METHODS: Fifty-three patients with persistent AF and normal left ventricular ejection fraction were prospectively examined by means of 3-dimensional transesophageal echocardiography before, immediately after, and 6 weeks after electric cardioversion to sinus rhythm. Annular motion was assessed during AF and in sinus rhythm with the use of 3-dimensional analysis software, and the relationship with MR severity was explored. RESULTS: During AF and immediately after sinus rhythm restoration, the mitral annulus behaved relatively adynamically, with an overall change in annular area of 10.3% (95% CI: 8.7%-11.8%) and 12.2% (95% CI: 10.6%-13.8%), respectively. At follow-up, a significant increase in annular dynamics (19.0%; 95% CI: 17.4%-20.6%; P < 0.001) was observed, owing predominantly to an increase in presystolic contraction (P < 0.001). The effective regurgitant orifice area decreased from 0.15 cm2 (0.10-0.23 cm2) during AF to 0.09 cm2 (0.05-0.12 cm2) at follow-up (P < 0.001) in the total cohort, and from 0.27 (0.23-0.33) to 0.16 (0.12-0.29) in the subgroup with effective regurgitant orifice area (EROA) ≥0.20 cm2. The change in presystolic annular motion was the only independent determinant of the decrease in MR severity (P = 0.027), by optimizing annular-leaflet imbalance. Patients with more pronounced blunting of presystolic dynamics had a higher EROA (P < 0.001), because of a lower total-to-closed leaflet area ratio (P < 0.001) at each point in time. This ratio was the strongest independent determinant of AFMR severity (adjusted P = 0.003). CONCLUSIONS: Mitral annular dynamics are impaired in AF, with blunted presystolic narrowing that contributes to AFMR. Sinus rhythm restoration allows gradual recovery of presystolic annular dynamics. Improved annular dynamics decrease AFMR severity by optimizing annular-leaflet imbalance, regardless of LA remodeling.

Experimental and Computational Studies of the Structure of Sulfonimidoyl Vinyllithiums.

tBuCH=C(Li)S(O)(NSO2 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 Ph2 C=C(Li)S(O)(NSO2 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)(NSO2 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 LiCH2 S(O)(NSO2 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.