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Abstract This study aimed to develop a deep learning (DL) model for predicting the recurrence risk of lung adenocarcinoma (LUAD) based on its histopathological features. Clinicopathological data and whole slide images from 164 LUAD cases were collected and used to train DL models with an ImageNet pre-trained efficientnet-b2 architecture, densenet201, and resnet152. The models were trained to classify each image patch into high-risk or low-risk groups, and the case-level result was determined by multiple instance learning with final FC layer’s features from a model from all patches. Analysis of the clinicopathological and genetic characteristics of the model-based risk group was performed. For predicting recurrence, the model had an area under the curve score of 0.763 with 0.750, 0.633 and 0.680 of sensitivity, specificity, and accuracy in the test set, respectively. High-risk cases for recurrence predicted by the model (HR group) were significantly associated with shorter recurrence-free survival and a higher stage (both, p

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

Abstract We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7–10.4). The common treatment-related adverse events of grades 3–4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10−4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Background Pathologic diagnosis of antibody-mediated rejection (ABMR) in ABO-incompatible (ABOi) transplantation patients is often challenging because patients without ABMR are frequently immunopositive for C4d. The aim of this study was to determine whether C4d positivity with microvascular inflammation (MVI), in the absence of any detectable donor-specific antibodies (DSAs) in ABOi patients, could be considered as ABMR. Methods A retrospective study of 214 for-cause biopsies from 126 ABOi kidney transplantation patients was performed. Patients with MVI score of ≥2 and glomerulitis score of ≥1 (n = 62) were divided into three groups: the absolute ABMR group (DSA-positive, C4d-positive or C4d-negative; n = 36), the C4d-positive group (DSA-negative, C4d-positive; n = 22), and the C4d-negative group (DSA-negative, C4d-negative; n = 4). The Banff scores, estimated glomerular filtration rates (eGFRs), and graft failure rates were compared among groups. Results C4d-positive biopsies showed higher glomerulitis, peritubular capillaritis, and MVI scores compared with C4d-negative specimens. The C4d-positive group did not show significant differences in eGFRs and graft survival compared with the absolute ABMR group. Conclusion The results indicate that C4d positivity, MVI score of ≥2, and glomerulitis score of ≥1 in ABOi allograft biopsies may be categorized and treated as ABMR cases.

Purpose: Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. Materials and Methods: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Results: Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. Conclusions: These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.

Hematoxylin and eosin (H&E) staining has been widely used as a fundamental and essential tool for diagnosing diseases and understanding biological phenomena by observing cellular arrangements and tissue morphological changes. However, conventional staining methods commonly involve solution-based, complex, multistep processes that are susceptible to user-handling errors. Moreover, inconsistent staining results owing to staining artifacts pose real challenges for accurate diagnosis. This study introduces a solution-free H&E staining method based on agarose hydrogel patches that is expected to represent a valuable tool to overcome the limitations of the solution-based approach. Using two agarose gel-based hydrogel patches containing hematoxylin and eosin dyes, H&E staining can be performed through serial stamping processes, minimizing color variation from handling errors. This method allows easy adjustments of the staining color by controlling the stamping time, effectively addressing variations in staining results caused by various artifacts, such as tissue processing and thickness. Moreover, the solution-free approach eliminates the need for water, making it applicable even in environmentally limited middle- and low-income countries, while still achieving a staining quality equivalent to that of the conventional method. In summary, this hydrogel-based H&E staining method can be used by researchers and medical professionals in resource-limited settings as a powerful tool to diagnose and understand biological phenomena.

The impact of the coronavirus disease 2019 (COVID-19) vaccination on humoral and cellular immunity in transplant recipients remains unknown. We report the case of a 78-year-old kidney transplant recipient who experienced acute T cell-mediated rejection after receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioN-Tech). She had no history of acute rejection throughout the 13 years after deceased donor kidney transplantation. Fifteen days after receiving the second dose of the BNT162b2 vaccine, the recipient visited our center with a mild headache and fever. Her serum creatinine level had increased from 0.61 to 4.95 mg/dL. Kidney allograft biopsy indicated acute T cell-mediated rejection (grade IB) with no pathologic evidence of antibody-mediated rejection. Anti-severe acute respiratory syndrome coronavirus 2 spike-immunoglobulin G and -immunoglobulin M measurements were weak positive and negative, respectively. Careful monitoring of kidney allograft function is vital for transplant recipients undergoing COVID-19 vaccination.

Background Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in Western countries. However, it is relatively rare in Asia. This study examined epidemiologic characteristics of FL in South Korea, with an emphasis on recent trends of increase in cases. Methods We retrospectively examined 239 cases of newly diagnosed FL at a large tertiary institution in Korea (Asan Medical Center, Seoul, Republic of Korea) between 2008 and 2017. Age-adjusted incidence rates and clinicopathological variables were analyzed, and joinpoint regression analysis was used to identify the changes. Results The age-adjusted incidence of FL significantly increased during the study period (p = .034), and the ratio of (relative incidence) patients with FL to patients with NHL increased from 4.28% to 9.35% in the same period. Over the 10-year study assessment duration, the proportion of patients with stage III/IV FL (p = .035) and expression of BCL2 (p = .022) or BCL6 (p = .039) significantly increased. From 2013–2017, the proportion of patients with highrisk Follicular Lymphoma International Prognostic Index (FLIPI) score increased (21.5% to 28.7%), whereas that of low-risk FLIPI decreased (55.4% to 38.6%), although those results were not statistically significant (p = .066). Conclusions We found an increasing incidence of FL, with a disproportionate increase in the incidence of high-stage disease and recent changes in the clinicopathologic features of the Korean patient population.

Psoriasis: Regulatory protein linked to chronic inflammation An immune-regulating protein that mediates chronic inflammation in the skin offers a new therapeutic target for the autoimmune disorder psoriasis. A research team from South Korea led by Chang-Woo Lee from Sungkyunkwan University School of Medicine in Suwon and Heounjeong Go from the University of Ulsan College of Medicine in Seoul have discovered that Pellino1, a protein known to modulate immune responses to pathogens, is also found in abundance in the skin lesions of people with psoriasis. Using mouse models, the researchers showed how Pellino1 induces the proliferation of certain skin cells and triggers an inflammatory state through the activation of small proteins and immune cells normally involved in defense against infection. Targeting strategy that inactivate Pellino1 could help blunt the inflammatory signaling in the skin that drives the development of psoriatic lesions.

Abstract Background Infiltration of immune cells into the kidney is one of the key features of lupus nephritis (LN). The presence of immune cells in the urine may be used as a non-invasive biomarker of LN. Here, we aimed to analyze the clinicopathologic significance of urinary CD11c+ macrophages in patients with LN. Methods The numbers and proportions of CD11c+ macrophages in the urine samples of patients with LN at the time of kidney biopsy were examined using flow cytometry. We also examined the association between the levels of urinary CD11c+ macrophages and the clinical and pathologic features of patients with LN. Results Compared with patients without LN or those with non-proliferative LN, patients with proliferative LN had significantly higher numbers and proportions of urinary CD11c+ macrophages, which were strongly correlated with the serum anti-dsDNA antibody titer. The numbers and proportions of urinary CD11c+ macrophages were significantly associated with the values of chronicity indices such as tubular atrophy and interstitial fibrosis. No significant relationships were found between the levels of urinary CD11c+ macrophages and the activity scores, degree of proteinuria, or lupus disease activity. Urinary CD11c+ macrophages were more abundant in patients who did not achieve renal response to induction treatment with immunosuppressants than in those who achieved complete or partial response. The receiver operating characteristic (ROC) curve analysis showed that the number of urinary CD11c+ macrophages was the most powerful predictor of renal response at 6 months (ROC-AUC = 1.00, p = 0.0004). Conclusion The urinary levels of CD11c+ macrophages were closely associated with the chronic pathologic changes of LN and renal response and may thus be used as a novel biomarker in LN.

Digital pathology (DP) is no longer an unfamiliar term for pathologists, but it is still difficult for many pathologists to understand the engineering and mathematics concepts involved in DP. Computer-aided pathology (CAP) aids pathologists in diagnosis. However, some consider CAP a threat to the existence of pathologists and are skeptical of its clinical utility. Implementation of DP is very burdensome for pathologists because technical factors, impact on workflow, and information technology infrastructure must be considered. In this paper, various terms related to DP and computer-aided pathologic diagnosis are defined, current applications of DP are discussed, and various issues related to implementation of DP are outlined. The development of computer-aided pathologic diagnostic tools and their limitations are also discussed.

We aimed to discover and validate urinary exosomal proteins as biomarkers for antibody−mediated rejection (ABMR) after kidney transplantation. Urine and for-cause biopsy samples from kidney transplant recipients were collected and categorized into the discovery cohort (n = 36) and a validation cohort (n = 65). Exosomes were isolated by stepwise ultra-centrifugation for proteomic analysis to discover biomarker candidates for ABMR (n = 12). Of 1820 exosomal proteins in the discovery cohort, four proteins were specifically associated with ABMR: cystatin C (CST3), serum paraoxonase/arylesterase 1, retinol-binding protein 4, and lipopolysaccharide−binding protein (LBP). In the validation cohort, the level of urinary exosomal LBP was significantly higher in the ABMR group (n = 25) compared with the T-cell-mediated rejection (TCMR) group and the no major abnormality (NOMOA) group. Urinary exosomal CST3 level was significantly higher in the ABMR group compared with the control and NOMOA groups. Immunohistochemical staining showed that LBP and CST3 in the glomerulus were more abundant in the ABMR group compared with other groups. The combined prediction probability of urinary exosomal LBP and CST3 was significantly correlated with summed LBP and CST3 intensity scores in the glomerulus and peritubular capillary as well as Banff g + ptc scores. Urinary exosomal CST3 and LBP could be potent biomarkers for ABMR after kidney transplantation.

Background Single staining is commonly performed for practical pathologic diagnoses. However, this method is limited in its ability to specify cellular morphology and immunophenotype and often requires consumption of limited tissue. This study aimed to describe an optimized protocol for multiple in situ hybridization (ISH) and immunohistochemistry (IHC). Methods The quality of multistaining was evaluated by carefully changing each step of ISH and IHC in an angioimmunoblastic T-cell lymphoma (AITL) case on a Ventana BenchMark XT automated immunostainer. The optimized protocols were also performed using another immunostainer and in 15 cases of five Epstein-Barr virus (EBV)–associated malignancies using formalin-fixed paraffin-embedded tissue. Results The quality of various ISH-IHC staining protocols was semi-quantitatively evaluated. The best EBV-encoded RNA (EBER)-ISH/double IHC staining quality, equivalent to single staining, was obtained using the following considerations: initial EBER-ISH application, use of protease and antigen retrieval reagent (cell conditioning 1 [CC1] treatment time was minimized due to impact on tissue quality), additional baking/ deparaffinization not needed, and reduced dilution ratio and increased reaction time for primary antibody compared with single immunostaining. Furthermore, shorter second CC1 treatment time yielded better results. Multiple staining was the best quality in another immunostainer and for different types of EBV-associated malignancies when it was performed in the same manner as for the Ventana BenchMark XT as determined for AITL. Conclusions EBER-ISH and double IHC could be easily used in clinical practice with currently available automated immunostainers and adjustment of reagent treatment time, dilution ratio, and antibody reaction time.

Abstract Background Although immunoglobulin A nephropathy (IgAN) is associated with an increased risk of renal allograft failure, evidences for its treatment, including renin-angiotensin-aldosterone system blockade (RAASB) usage, remain limited. Methods In this bi-center retrospective cohort study, we included patients who were recently diagnosed with IgAN through allograft biopsies. We identified their 6-month antihypertensive medication prescriptions and investigated the association between the medication types, albuminuria changes, and risk of 5-year death-censored-graft-failure (DCGF). The mixed effect model and cox regression analysis were used. Results A total of 464 allograft IgAN patients were included: 272, 38, 33, and 121 patients in the no antihypertensive medication, single agent RAASB, single agent beta blocker (BB)/calcium channel blocker (CCB), and combination therapy groups, respectively. High-degree albuminuria after 6 months of allograft IgAN diagnosis was an important prognostic parameter and a partial mediator for the association between the subgroups and 5-year DCGF. The usage of single RAASB was associated with decrement of albuminuria from allograft IgAN diagnosis (P for interaction = 0.03). The single BB/CCB group demonstrated significantly worse prognosis than the single RAASB group (adjusted hazard ratio, 2.76 [1.09–6.98]; P = 0.03). Conclusions In conclusion, RAASB may be beneficial for graft prognosis in early allograft IgAN patients who require single antihypertensive medication therapy, by means of reducing albuminuria. Further investigation of treatment strategy in allograft IgAN is warranted.

Abstract Background Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare hereditary kidney cancer syndrome in which affected individuals are at risk of skin and uterine leiomyomatosis and kidney cancer. HLRCC-associated kidney cancer is a lethal disease with a highly aggressive behavior, and there is no standard treatment option for metastatic disease. Case presentation Here, we report a 29-year-old patient with a locally advanced HLRCC-assiciated RCC. He was administrated temsirolimus initially, then underwent surgical removal of kidney, retroperitoneal lymph nodes, inferior vena cava and tumor thrombi. Unfortunately, multiple liver metastases were confirmed 1 month after surgery, so axitinib was given but failed immediately. We tried bevacizumab plus erlotinib, which achieved long-term good response lasting more than 18 months. He is alive with disease and maintains bevacizumab plus erlotinib treatment. Conclusion The promising results obtained in this patient suggest that combined bevacizumab plus erlotinib may offer a valid treatment option for advanced HLRCC-associated kidney cancer, even after failures of mTOR inhibitor and/or VEGFR TKI based therapies.

Background: Fabry disease (FD) is a recessive X-linked lysosomal storage disorder caused by α-galactosidase A (GLA) deficiency. Although the mechanism is unclear, GLA deficiency causes an accumulation of globotriaosylceramide (Gb3), leading to vasculopathy. Methods: To explore the relationship between the accumulation of Gb3 and vasculopathy, induced pluripotent stem cells generated from four Fabry patients (FD-iPSCs) were differentiated into vascular endothelial cells (VECs). Genome editing using CRISPR-Cas9 system was carried out to correct the GLA mutation or to delete Thrombospondin-1 (TSP-1). Global transcriptomes were compared between wild-type (WT)- and FD-VECs by RNA-sequencing analysis. Findings: Here, we report that overexpression of TSP-1 contributes to the dysfunction of VECs in FD. VECs originating from FD-iPSCs (FD-VECs) showed aberrant angiogenic functionality even upon treatment with recombinant α-galactosidase. Intriguingly, FD-VECs produced more p-SMAD2 and TSP-1 than WT-VECs. We also found elevated TSP-1 in the peritubular capillaries of renal tissues biopsied from FD patients. Inhibition of SMAD2 signaling or knock out of TSP-1 (TSP-1−/−) rescues normal vascular functionality in FD-VECs, like in gene-corrected FD-VECs. In addition, the enhanced oxygen consumption rate is reduced in TSP-1−/− FD-VECs. Interpretation: The overexpression of TSP-1 secondary to Gb3 accumulation is primarily responsible for the observed FD-VEC dysfunction. Our findings implicate dysfunctional VEC angiogenesis in the peritubular capillaries in some of the complications of Fabry disease. Funding: This study was supported by grant 2018M3A9H1078330 from the National Research Foundation of the Republic of Korea. Keywords: Fabry disease, Human induced pluripotent stem cells (hiPSCs), Globotriaosylceramide (Gb3), Vascular dysfunction, Thrombospondin-1

Nephrotic syndrome in the first year of life, characterized by renal dysfunction and proteinuria, is associated with a heterogeneous group of disorders. These disorders are often related to genetic mutations, but the syndrome can also be caused by a variety of other diseases. We report an infant with nephrotic syndrome associated with a neuroblastoma. A 6-month-old girl was admitted with a 10% weight loss over 10 days and nephrotic-range proteinuria. She was ill-looking, and her blood pressure was higher than normal for her age. Her cystatin-C glomerular filtration rate was decreased, and levels of plasma renin, aldosterone, and catecholamines were elevated. Renal ultrasonography and abdominal computed tomography showed a retroperitoneal prevertebral mass encasing both renal arteries and the left renal vein. The mass was partially resected laparoscopically, and the pathologic diagnosis was neuroblastoma. Findings on a simultaneous renal biopsy were unremarkable. The patient was treated with chemotherapy and several anti-hypertensive drugs, including an alpha blocker. Two months later, the mass had decreased in size and the proteinuria and hypertension were gradually improving. In an infant with abnormal renin-angiotensin system activation, severe hypertension, and nephrotic-range proteinuria, neuroblastoma can be considered in the differential diagnosis.

Digital pathology systems (DPSs) have been globally implemented, and computer-assisted diagnosis (CAD) software has been actively developed in recent years. This study aimed to investigate perceptions of digital pathology and the demand for CAD. An online survey involving members of the Korean Society of Pathologists was conducted, and a demonstration clip of the diagnostic assistant software for a prostate needle biopsy was shown to them to provide a simple experience with CAD. One hundred sixty-four Korean pathologists (13.6% of 1210 Korean pathologists) participated. The majority (77.4%) answered affirmatively regarding the necessity of implementing a DPS, and 26.8% had plans to implement or increase the use of DPSs in the following 2–3 years at their medical institutions. Pathologists felt that multidisciplinary care or conference accessibility (56.7%), remote consultation (49.4%), and big data building (32.9%) were useful parts of DPSs. Most pathologists (81.7%) responded that CAD software would assist with the diagnostic process. In a prostate needle biopsy, pathologists used the software to improve the measurement of tumor volume and/or length and core length but not to suggest a diagnostic name or Gleason grade. Korean pathologists who participated in the survey had highly positive perceptions of digital pathology and maintained a positive attitude toward the use of CAD software.

Background Ductal adenocarcinoma (DAC) of the prostate is an uncommon histologic subtype whose prognostic factors and immunoprofile have not been fully defined. Methods To define its prognostic factors and immunoprofile, the clinicopathological features, including biochemical recurrence (BCR), of 61 cases of DAC were analyzed. Immunohistochemistry was performed on tissue microarray constructs to assess the expression of prostate cancer-related and mammalian target of rapamycin (mTOR) signaling-related proteins. Results During the median follow-up period of 19.3 months, BCR occurred in 26 cases (42.6%). DAC demonstrated a wide expression range of prostate cancer-related proteins, including nine cases (14.8%) that were totally negative for pan-cytokeratin (PanCK) immunostaining. The mTOR signaling-related proteins also showed diverse expression. On univariate analysis, BCR was associated with high preoperative serum levels of prostate-specific antigen (PSA), large tumor volume, predominant ductal component, high Gleason score (GS), comedo-necrosis, high tumor stage (pT), lymphovascular invasion, and positive surgical margin. High expressions of phospho-mTOR (p-mTOR) as well as low expressions of PSA, phospho-S6 ribosomal protein (pS6) and PanCK were associated with BCR. On multivariable analysis, GS, pT, and immunohistochemical expressions of PanCK and p-mTOR remained independent prognostic factors for BCR. Conclusions These results suggest GS, pT, and immunohistochemical expressions of PanCK and p-mTOR as independent prognostic factors for BCR in DAC. Since DAC showed diverse expression of prostate cancer–related proteins, this should be recognized in interpreting the immunoprofile of DAC. The diverse expression of mTOR-related proteins implicates their potential utility as predictive markers for mTOR targeted therapy.

There are many medical demands that still need to be resolved for prostate cancer (PCa), including better diagnosis and predictive medicine. For this to be accomplished, diverse medical data need to be integrated with the development of intelligent software (SW) based on various types of medical data. Various types of information technology have been used to address these medical demands of PCa. We initiated the PROstate Medical Intelligence System Enterprise-Clinical, Imaging, and Pathology (PROMISE CLIP) and a multicenter, big data study to develop PCa SW for patients with PCa and clinicians. We integrated the clinical data of 7257 patients, 610 patients’ imaging data, and 39,000 cores of pathology digital scanning data from four tertiary hospitals in South Korea. We developed the PROMISE CLIP registry based on integrated clinical, imaging, and pathology data. Related intelligent SW has been developed for helping patients and clinicians decide on the best treatment option. The PROMISE CLIP study directs guidelines for intelligent SW development to solve medical demands for PCa. The PROMISE CLIP registry plays an important role in advancing PCa research and care.