Age-related Changes of the Prostate on Magnetic Resonance Imaging: Quantitative and Qualitative Evaluation in a Screening Cohort of BRCA Mutation Carriers.

BACKGROUND: Age-related changes in multiparametric magnetic resonance imaging (mpMRI) of the prostate have been reported in the general population but not in screening cohorts. OBJECTIVES: To evaluate age-related changes on prostatic mpMRI in a screening cohort of BRCA1/2 mutation carriers. METHODS: Asymptomatic BRCA1/2 mutation carriers underwent mpMRI as part of a screening program. All included patients were followed for 3 years with no evidence of prostate cancer. mpMRIs were retrospectively evaluated by two abdominal radiologists for peripheral zone (PZ) patterns on T2 (homogenous hyperintensity, wedge-shaped hypointensities, patchy hypointensities, or diffuse hypointensity), and transition zone (TZ) pattern on T2 (homogenous, heterogeneous, nodular). Apparent diffusion coefficient (ADC) values of PZ and TZ were measured. Statistical analysis was performed using a predefined age cutoff of 50 years old. RESULTS: Overall, 92 patients were included: 38 in the younger age group (40-49 years) and 54 in the older age group (50-69 years). PZ homogenous hyperintensity and wedge-shaped hypointensities were more common in the older patients, whereas diffuse hypointensity was more common in younger patients (P < 0.001 for both readers) with substantial inter-reader agreement between the readers (kappa=0.643). ADC values were lower in young patients in the PZ (P < 0.001) and TZ (P = 0.003). CONCLUSIONS: Age-related differences in mpMRI were validated in BRCA mutation carriers. As some features overlap with prostatic carcinoma, awareness is crucial, specifically to diffuse T2 hypointensities of the PZ and lower ADC values in the PZ and TZ, which are more common in younger patients.

Diagnostic Performance of 68Ga Prostate-specific Membrane Antigen PET/MRI Compared with Multiparametric MRI for Detecting Clinically Significant Prostate Cancer.

Background Gallium 68 (68Ga) prostate-specific membrane antigen (PSMA) PET/MRI may improve detection of clinically significant prostate cancer (CSPC). Purpose To compare the sensitivity and specificity of 68Ga-PSMA PET/MRI with multiparametric MRI for detecting CSPC. Materials and Methods Men with prostate specific antigen levels of 2.5-20 ng/mL prospectively underwent 68Ga-PSMA PET/MRI, including multiparametric MRI sequences, between June 2019 and March 2020. Imaging was evaluated independently by two radiologists by using the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. Sensitivity and specificity for CSPC (International Society of Urological Pathology grade group ≥ 2) were compared for 68Ga-PSMA PET/MRI and multiparametric MRI by using the McNemar test. Decision curve analysis compared the net benefit of each imaging strategy. Results Ninety-nine men (median age, 67 years; interquartile range, 62-71 years) were included; 79% (78 of 99) underwent biopsy. CSPC was detected in 32% (25 of 78). For CSPC, specificity was higher for 68Ga-PSMA PET/MRI than multiparametric MRI (76% [95% CI: 62, 86] vs 49% [95% CI: 35, 63], respectively; P < .001). Sensitivity was similar (88% [95% CI: 69, 98] vs 92% [95% CI: 74, 99], respectively; P > .99). For PI-RADS 3 lesions, specificity was also higher for 68Ga-PSMA PET/MRI than for multiparametric MRI: 86% (95% CI: 73, 95) versus 59% (95% CI: 43, 74), respectively (P = .002). Decision curve analysis showed that biopsies targeted to PSMA uptake increased the net benefit of multiparametric MRI only among PI-RADS 3 lesions. The net benefit of targeted biopsy for a PI-RADS 3 lesion with PSMA uptake was higher across all threshold probabilities over 8%. The net benefit of targeted biopsy was similar for PI-RADS 4 and 5 lesions, regardless of PSMA uptake. Conclusions Gallium 68 prostate-specific membrane antigen PET/MRI improved specificity for clinically significant prostate cancer compared with multiparametric MRI, particularly in Prostate Imaging Reporting and Data System grade 3 lesions. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Williams and Estes in this issue.

[BLADDER PAIN SYNDROME - DOES DETRUSOR MASTOCYTOSIS PREDICT SYMPTOMATIC IMPROVEMENT FOLLOWING BLADDER HYDRODISTENTION UNDER ANESTHESIA?]

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, debilitating syndrome involving bladder pain and lower urinary tract symptoms (LUTS), with a substantial effect on patients' quality of life. IC/BPS poses a diagnostic challenge, and its available treatment options remain only moderately effective. Bladder-wall biopsies from IC/BPS patients commonly uncover mastocytosis. While mast-cells are suspected as pivotal in disease pathogenesis, the clinical significance of their presence remains unclear. Clinical guidelines differ on whether or not bladder biopsies should be a part of routine IC/BPS workup. AIMS: To determine whether detrusor mastocytosis can serve as a prognostic marker for treatment response and improvement duration. METHODS: We retrospectively collected patient data for IC/BPS patients who underwent bladder hydrodistension under anesthesia. We used statistical modelling to determine the effect of mastocystosis and other possible predictive factors - age, comorbidity, Hunner lesions - on the presence and duration of symptom improvement. RESULTS: A total of 35 patients (89% female, median age 63.5 [IQR 48.8-73.6] years) underwent hydrodistension, of whom 28 (89% female, median age 63.0 [44.8-73.1] years) had bladder biopsies; 11 (39%) of them had mastocystosis. Within a median follow-up of 8.8 [1.7-24.2] months, 11 (100%) of the patients with mastocytosis and 9 (53%) of the patients without it, experienced symptomatic improvement (p=0.007). Improvement duration was 8 months longer (p=0.006) in those with mastocystosis. Univariate logistic regression models were used to estimate odds ratios (OR). Mastocytosis (p=0.004) and Charlson Comorbidity score were the only variables with a statistically significant OR. Univariate survival models were fitted, and improvement duration was estimated to be longer in patients with mastocystosis (p=0.01). A multivariate Cox regression model found no variable to be statistically significant, though mastocystosis was borderline significant (p=0.055). CONCLUSIONS: Mastocystosis defines a discernible phenotype of IC/BPS, which exhibits higher rates and longer duration of hydrodistention treatment response. DISCUSSION: Notwithstanding limitations of sample size and retrospective study design, we were able to demonstrate that mastocystosis can serve as a prognostic factor for symptom improvement after hydrodistension in IC/BPS patients. Prospective studies are required to validate this finding and to investigate the mechanisms involved.

Hodgkin lymphoma and hypothermia: case report and review of the literature.

We report the development of hypothermia in a patient with Hodgkin lymphoma which resolved with chemotherapy administration. A review of the literature revealed 16 previous reports of hypothermia in patients with Hodgkin lymphoma. Overall prognosis seems to be unfavorable. To the best of our knowledge this is the first report of hypothermia in a patient with Hodgkin lymphoma transforming from chronic lymphocytic leukemia (Richter's syndrome). A possible pathophysiology could be paraneoplastic autonomic neuropathy. Physicians should be aware that Hodgkin lymphoma can present with hypothermia and should carefully monitor newly diagnosed patients with advanced disease for this complication. Likewise, patients with Hodgkin lymphoma who develop hypothermia should be screened for signs of autonomic neuropathy.

Effect of erythropoietin on healing of corneal epithelial defects in rabbits.

BACKGROUND/AIM: Corneal epithelial defects may heal slowly in patients with diabetes, limbal stem cell deficiency, extensive chemical burns or anesthetized corneas. Studies have shown that erythropoietin, a glycoprotein hormone that promotes red blood cell proliferation and inhibits apoptosis of erythroid progenitors, may also exert a cytoprotective, antiapoptotic effect on nonhematopoietic cells. The aim of the study was to examine the effect of erythropoietin on the healing process of corneal epithelial erosions in rabbit eyes. METHODS: Fifteen New Zealand albino rabbits were divided into 3 groups following induction of unilateral uniform corneal epithelial erosions. The first group received local treatment with erythropoietin-containing cellulose-based gel 4 times daily; the second group received treatment with cellulose-based gel without erythropoietin 4 times daily, and the third group received no treatment. The healing process was monitored twice daily using cobalt-blue-filtered slit lamp photography and digital images of fluorescein-stained corneas until complete re-epithelization was achieved. Following re-epithelization, corneas were removed for histologic processing. One-way analysis of variance and Mann-Whitney tests were used for statistical analysis. RESULTS: Mean ± SD time to complete re-epithelization was 55 ± 2.19 h in the group treated with erythropoietin-containing cellulose-based gel, 66.5 ± 14.25 h in the group treated with gel only and 62.2 ± 9.09 h in the untreated group (p = 0.16, not significant). There was no significant difference among the groups in the time to complete re-epithelization or the rate of epithelial healing. Histologic corneal evaluation revealed stromal vascularization in 2 of the 6 erythropoietin-treated rabbits and in neither of the control groups. CONCLUSION: Erythropoietin has no beneficial effect on the rate of healing of corneal epithelial erosions in rabbit eyes, and corneal stroma neovascularization seems to be a significant adverse effect.

Neoadjuvant 177Lu-PSMA-I&T Radionuclide Treatment in Patients with High-risk Prostate Cancer Before Radical Prostatectomy: A Single-arm Phase 1 Trial.

BACKGROUND: High-risk localized prostate cancer (HRLPC) has a substantial risk of disease progression despite local treatment. Neoadjuvant systemic therapy before definitive local therapy may improve oncological outcomes by targeting the primary tumor and micrometastatic disease. OBJECTIVE: To evaluate whether a lutetium-177 prostate-specific membrane antigen radioligand (LuPSMA) can be safely administered to patients with HRLPC before robot-assisted radical prostatectomy (RARP) and to describe immediate oncological outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-arm clinical trial. Patients with HRLPC and elevated radioligand uptake on PSMA positron emission tomography/computed tomography were enrolled. Two or three LuPSMA radioligand doses (7.4 GBq) were given at 2-wk intervals. RARP with lymph node dissection was performed 4 wk after the last LuPSMA dose. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rate of surgical complications, operative parameters, changes in functional and quality-of-life measures, and immediate oncological outcomes (histological findings and biochemical response) were measured. Data were analyzed descriptively. RESULTS AND LIMITATIONS: Fourteen patients participated (median age 67 yr). Prostate-specific antigen decreased by 17% (interquartile range [IQR] 9-50%) after two LuPSMA doses and 34% (IQR 11-60%) after three doses. Thirteen patients underwent RARP with no identifiable anatomical changes or intraoperative complications. Four patients (30%) had postoperative complications (pneumonia, pulmonary embolism, urinary leak with urinary tract infection). At 3 mo postoperatively, 12 patients (92%) required one pad or less. Final whole-mount pathology showed positive surgical margins (PSMs) in seven patients (53%) and downgrading to International Society of Urological Pathology grade group 3 in three patients (23%). Treatment-related effects included a clear vacuolated cytoplasm and pyknotic nuclei. CONCLUSIONS: LuPSMA followed by RARP appears to be surgically safe. While oncological outcomes are pending, continence recovery seems to be unaffected by LuPSMA treatment. PATIENT SUMMARY: We evaluated outcomes for patients with aggressive localized prostate cancer who received treatment with a radioactive agent before surgical removal of their prostate. This approach appears to be safe and feasible, but its therapeutic efficacy is still unknown.

A systematic review and meta-analysis of artificial intelligence diagnostic accuracy in prostate cancer histology identification and grading.

BACKGROUND: Artificial intelligence (AI) is a promising tool in pathology, including cancer diagnosis, subtyping, grading, and prognostic prediction. METHODS: The aim of the study is to assess AI application in prostate cancer (PCa) histology. We carried out a systematic literature search in 3 databases. Primary outcome was AI accuracy in differentiating between PCa and benign hyperplasia. Secondary outcomes were AI accuracy in determining Gleason grade and agreement among AI and pathologists. RESULTS: Our final sample consists of 24 studies conducted from 2007 to 2021. They aggregate data from roughly 8000 cases of prostate biopsy and 458 cases of radical prostatectomy (RP). Sensitivity for PCa diagnostic exceeded 90% and ranged from 87% to 100%, and specificity varied from 68% to 99%. Overall accuracy ranged from 83.7% to 98.3% with AUC reaching 0.99. The meta-analysis using the Mantel-Haenszel method showed pooled sensitivity of 0.96 with I2 = 80.7% and pooled specificity of 0.95 with I2 = 86.1%. Pooled positive likehood ratio was 15.3 with I2 = 87.3% and negative - was 0.04 with I2 = 78.6%. SROC (symmetric receiver operating characteristics) curve represents AUC = 0.99. For grading the accuracy of AI was lower: sensitivity for Gleason grading ranged from 77% to 87%, and specificity from 82% to 90%. CONCLUSIONS: The accuracy of AI for PCa identification and grading is comparable to expert pathologists. This is a promising approach which has several possible clinical applications resulting in expedite and optimize pathology reports. AI introduction into common practice may be limited by difficult and time-consuming convolutional neural network training and tuning.

Dynamic 68Ga-PSMA-11 PET/CT for the Primary Evaluation of Localized Renal Mass: A Prospective Study.

The potential role of prostate-specific membrane antigen (PSMA) PET/CT in non-prostate cancer tumors has shown promising results. We examined the performance of dynamic 68Ga-PSMA-11 PET/CT (DPSMA) for the evaluation of localized renal mass. Methods: A prospective case series of patients with a newly diagnosed renal mass who were referred for surgery was examined. DPSMA was performed in a standardized manner before surgery. The final surgical histology served as the standard of reference. PSMA expression in the tumor vasculature was assessed and staining intensity was scored. Tracer uptake and PSMA expression were compared between benign and malignant tissue. Results: Of 29 enhancing renal masses evaluated in 27 patients, 24 (83%) were malignant lesions. The median SUVmean of benign and malignant lesions was 2.3 (interquartile range [IQR], 2.2-2.7) and 6.8 (IQR, 4.2-10.1), respectively (P = 0.009). Median SUVmax of benign and malignant lesions was 3.8 (IQR, 3.3-4.5) and 9.4 (IQR, 5.4-15.8), respectively (P = 0.015). The median washout coefficient (K2) was significantly lower in malignant lesions than in benign lesions (0.17 vs. 0.70, P = 0.02). Positive PSMA staining was found in 20 of 24 malignant lesions and in 2 of 5 benign lesions (P = 0.04). Conclusion: This pilot study demonstrated DPSMA uptake and kinetics in localized renal masses. Increased 68Ga-PSMA-11 tracer uptake and intratumoral retention correlate with PSMA expression in malignant renal tumors compared with benign renal masses, supporting further assessment of DPSMA as a potential tool for evaluating localized renal masses.

The absence of spermatogenesis in radical orchiectomy specimen is associated with advanced-stage nonseminomatous testicular cancer.

BACKGROUND: To assess if clinical, pathological, and spermatogenesis factors are associated with clinical staging in patients with testicular germ cell tumors. PATIENTS AND METHODS: We retrospectively reviewed the pathology reports and slides from 267 men who underwent radical orchiectomy for testicular cancer at our institution during 1998-2019. Histologic slides were reviewed and the presence of mature spermatozoa was documented. Clinical, laboratory and radiographic characteristics were recorded. Logistic regression analyses were used to identify factors associated with advanced disease stage at diagnosis. RESULTS: Of 267 male patients, 115 (43%) patients had testicular non-seminomatous germ cell tumors (NSGCT) and 152 (57%) seminomatous germ cell tumors (SGCT). Among NSGCT patients, those presenting with metastatic disease had a higher proportion of predominant (>50%) embryonal carcinoma (64% vs. 43%, respectively, P = 0.03), and lymphovascular invasion (45.8% vs. 26.6%, respectively, P = 0.03) than non-metastatic patients. Spermatogenesis was observed in 56/65 (86.2%) and 36/49 (73.5%) of non-metastatic and metastatic NSGCT patients, respectively (P = 0.09). On semen analysis, severe oligospermia (<5 million/ml) was more common in metastatic than in non-metastatic NSGCT (26.5% vs. 8.3%, respectively, P = 0.04). On multivariate analysis, predominant embryonal carcinoma and lack of spermatogenesis in pathological specimens were associated with metastatic disease. CONCLUSION: The absence of spermatogenesis and a high proportion of embryonal carcinoma was associated with advanced disease in patients with NSGCT. Whether it may also translate as a predictor of oncologic outcome needs further evaluation.

A noninferiority within-person study comparing the accuracy of transperineal to transrectal MRI-US fusion biopsy for prostate-cancer detection.

BACKGROUND: Magnetic resonance imaging (MRI) and ultrasound (US) fusion prostate-biopsies can be performed in a transrectal (TR-fusion) or transperineal (TP-fusion) approach. Prospective comparative evidence is limited. In this study we compared the detection rate of clinically-significant prostate-cancer (csPCa) within an index lesion between TR and TP-fusion. PATIENTS AND METHODS: This was a prospective, noninferiority, and within-person trial. Men scheduled for MRI-US-fusion with a discrete MRI PI-RRAD ≥ 3 lesion were included. A dominant index lesion was determined for each subject and sampled by TR and TP-fusion during the same session. The order of biopsies was randomized and equipment was reset to avoid chronological and incorporation bias. For each subject, the index lesion was sampled 4-6 times in each approach. All biopsies were performed using Navigo fusion software (UC-Care, Yokneam, Israel). csPCa was defined as: Grade Group ≥ 2 or cancer-core length ≥ 6 mm. We used a noninferiority margin of 10% and a one-sided alpha level of 5%. RESULTS: Seventy-seven patients completed the protocol. Median age was 68.2 years (IQR:64.2-72.2), median PSA was 8.9 ng/ml (IQR:6.18-12.2). Ten patients (13%) were biopsy naive, others (87%) had a previous biopsy. csPCa was detected in 32 patients (42%). All of these cases were detected by TP-fusion, while only 20 (26%) by TR-fusion. Absolute difference for csPCa diagnosis was 15.6 (CI 90% 27.9-3.2%) in favor of TP-fusion (p = 0.029). TP-fusion was noninferior to TR-fusion. The lower boundary of the 90% confidence-interval between TP-fusion and TR-fusion was greater than zero, therefore TP-fusion was also found to be superior. Exploratory subgroup analyses showed TP-fusion was consistently associated with higher detection rates of csPCa compared with TR-fusion in patient and index-lesion derived subgroups (size, location, PI-RADS, PSA, and biopsy history). CONCLUSIONS: In this study, TP-fusion biopsies were found to be noninferior and superior to TR-fusion biopsies in detecting csPCa within MRI-visible index lesion. Centers experienced in both TP and TR-fusion should consider these results when choosing biopsy method.

Predictors of spermatogenesis in radical orchiectomy specimen and potential implications for patients with testicular cancer.

OBJECTIVE: To assess the ability of semen analysis and other patients' characteristics to predict the presence of spermatozoa in radical orchiectomy pathological specimen, and describe potential implications for patients with azoospermia and testis cancer. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital. PATIENT(S): A total of 214 consecutive patients with testicular cancer who underwent radical orchiectomy between 1997 and 2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Histologic slides were reviewed and the presence of mature spermatozoa was documented. Clinical, laboratory, and radiographic characteristics were recorded. Logistic regression analyses were used to identify factors associated with the presence of spermatozoa in the noninvolved ipsilateral testicular parenchyma. RESULT(S): Spermatozoa were found in the pathological specimen of 145 patients (67.8%). At multivariate analysis, increased tumor size was the only factor associated with lower rates of spermatozoa in the specimen. Mean tumor diameter was 4.06 cm, and spermatozoa were found in 83% and 49% of testes with tumor diameters <4 and ≥4 cm, respectively. Preoperative semen analysis records were available for 107 patients. Oligozoospermia, severe oligozoospermia, azoospermia, and cryptozoospermia were observed in 17 (16%), 18 (17%), 9 (8%) and 3 (3%) patients, respectively. Sperm concentration and motility were not associated with complete spermatogenesis. Seven of 12 patients (58%) with either azoospermia or cryptozoospermia had mature sperm in their pathological sections. CONCLUSION(S): Larger testicular cancers are associated with lower rates of spermatozoa in the ipsilateral testis. Given the substantial likelihood (∼60%) of spermatozoa to be present in the cancerous testis of patients with azoospermia and cryptozoospermia, concomitant oncologic testicular sperm extraction (TESE) can be considered in these selected patients.

Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity.

BACKGROUND: The glucose regulated heat shock protein 78 (GRP78) is a central regulator of ER (endoplasmic reticulum) stress due to its pro-survival property. Up regulated GRP78 expression in tumor cells has been correlated with aggressive malignancies whereas some reports have predicted an improved prognosis. Over-expression of GRP78 in the ER promotes its localization to the cell surface on several cell types including tumor cells. METHODS: In order to elucidate whether GRP78 receptor positive and negative tumor cells manifest different properties in colorectal cancer, we first artificially separated GRP78 positive and negative sub-populations from HM7 and HCT116 cell lines using anti GRP78 antibody coated magnetic beads. RESULTS: Only GRP78 negative cells were highly proliferative, induced significant growth in tumor size in nude mice and metastasized to the liver in a human metastatic colorectal carcinoma model in mice. In contrast, GRP78 positive cells manifested reduced proliferation, colony formation, tumor growth and liver metastases. The reduced tumorigenicity of GRP78 positive subpopulation was abrogated by silencing GRP78 expression using siRNA oligomers. In our efforts to induce cell surface GRP78, we subjected the cells to doxorubicin and taxol that increased significantly the percent of GRP78 positive population. Cells pre-incubated with doxorubicin exhibited reduced proliferation and tumor growth in mice. CONCLUSION: This study demonstrates the significance of cell surface GRP78 in colon cancer, which may be used as a marker for reduced tumorigenicity.