Prediction of pathological up-staging after radical nephroureterectomy in patients with upper tract urothelial carcinoma.

PURPOSE: The diagnostic accuracy of computed tomography urography for upper tract urothelial carcinoma is high; however, difficulties are associated with precisely assessing the T stage. Preoperative tumor staging has an impact on treatment options for upper tract urothelial carcinoma. We herein attempted to identify preoperative factors that predict pathological tumor up-staging, which will facilitate the selection of treatment strategies. MATERIALS AND METHODS: We retrospectively identified 148 patients with upper tract urothelial carcinoma who underwent computed tomography urography preoperatively followed by radical nephroureterectomy without preoperative chemotherapy at our institution between 2000 and 2021. Preoperative factors associated with cT2 or lower to pT3 up-staging were examined using a multivariate logistic regression analysis. RESULTS: Ninety out of 148 patients were diagnosed with cT2 or lower, and 22 (24%) were up-staged to pT3. A multivariate analysis identified a positive voided urine cytology (HR 4.69, p = 0.023) and tumor length ≥ 3 cm (HR 6.33, p = 0.003) as independent predictors of pathological tumor up-staging. CONCLUSIONS: Patients diagnosed with cT2 or lower, but with preoperative positive voided urine cytology and/or tumor diameter ≥ 3 cm need to be considered for treatment as cT3.

Profiling Fibroblast Growth Factor Receptor 3 Expression Based on the Immune Microenvironment in Upper Tract Urothelial Carcinoma.

BACKGROUND: Although several studies have shown favorable outcomes in upper tract urothelial carcinoma (UTUC) with fibroblast growth factor receptor 3 (FGFR3) mutations and/or expression, the relationship between immune cell markers and FGFR3 expression remains unknown. OBJECTIVE: To clarify the FGFR3-based immune microenvironment and investigate biomarkers to predict the treatment response to pembrolizumab (Pem) in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS: We conducted immunohistochemical staining in 214 patients with UTUC. The expression levels of FGFR3, CD4, CD8, CD68, CD163, CD204, and programmed cell death ligand 1 (PD-L1) were examined. INTERVENTION: All UTUC patients underwent radical nephroureterectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the relationship between these immune markers and patient prognosis. RESULTS AND LIMITATIONS: A total of 109 (50.9%) patients showed high FGFR3 expressions and a favorable prognosis compared with the remaining patients. Among the six immune markers, CD8 high expression was an independent favorable factor, whereas CD204 expression was an independent prognostic factor for cancer death. From the FGFR3-based immune clustering, three immune clusters were identified. Cluster A showed low FGFR3 with tumor-associated macrophage-rich components (CD204+) followed by a poor prognosis due to a poor response to Pem. Cluster B showed low FGFR3 with an immune hot component (CD8+), followed by the most favorable prognosis owing to a good response to Pem. Cluster C showed high FGFR3 expression but an immune cold component, followed by a favorable prognosis due to the high FGFR3 expression, but a poor response was confirmed with Pem. CONCLUSIONS: Although most patients exhibit a poor response to Pem, individuals with low FGFR3 expression and immune hot status may benefit clinically from Pem treatment. PATIENT SUMMARY: We conducted immunohistochemical staining to evaluate fibroblast growth factor receptor 3 (FGFR3)-related immune microenvironment by evaluating the expressions of CD4, CD8, CD68, CD163, CD204, and PD-L1 in 214 upper tract urothelial carcinoma patients. We identified three distinct immune clusters based on FGFR3 expressions and found that patients with a low FGFR3 expression but immune hot status received the maximum benefit from an immune checkpoint inhibitor.

Vasohibin-1 Expression Can Predict Pathological Complete Remission of Advanced Bladder Cancer with Neoadjuvant Chemotherapy.

BACKGROUND AND PURPOSE: Neoadjuvant chemotherapy (NAC) is a well-established standard practice in invasive bladder cancer (BCa), however patient selection remains challenging. High expression of vasohibin-1 (VASH1), an endogenous regulator of angiogenesis, has been reported in high-grade and advanced BCa; however, its prognostic value for chemotherapy outcomes remains unexplored. In this study, we sought to identify biomarkers of chemotherapy response focusing on the relationship between angiogenesis and tissue hypoxia. METHODS: Forty Japanese patients with BCa who underwent NAC and radical cystectomy were included in the present analysis. We compared the immunohistochemical expression of CD34, VASH1, and carbonic anhydrase 9 (CA9) between patients who achieved tumor clearance at operation (ypT0) and those with residual disease after cystectomy. RESULTS: There were 19 patients in the ypT0 group, while the remaining 21 patients had residual tumors at operation. Patients in the ypT0 group had high microvessel density (p = 0.031), high VASH1 density (p < 0.001), and stronger CA9 staining (p = 0.046) than their counterparts. Multivariate analysis identified microvessel and VASH1 density as independent predictive factors for pathological ypT0 disease (p = 0.043 and 0.002, respectively). The 5-year recurrence-free survival rate was higher in the high VASH1 density group than in the low VASH1 density group (66.3% vs. 33.3%, p = 0.036). CONCLUSION: VASH1 density is a potential therapeutic biomarker for chemotherapy response in BCa.

Sigmoid Colon Cancer Masked by Refractory Diverticulitis With Abscess.

Colorectal cancer (CRC) can occasionally coexist with diverticulitis, thereby complicating diagnosis and treatment. In cases of refractory diverticulitis, it is important to consider the possibility of malignancy and determine appropriate treatment strategies. An 85-year-old male presented with lower left abdominal pain; he was admitted for further examination and the treatment of suspected sigmoid diverticulitis. On examination, a firm mass was palpated in the lower left quadrant. Imaging revealed sigmoid diverticulitis, partial abscess formation, and the involvement of the small bowel and abdominal wall. Although malignancy was suspected, a definitive diagnosis was not made. Because of the refractory nature of the disease, early surgical intervention, sigmoid colectomy, partial small bowel resection, abdominal wall resection, and lymph node dissection, was performed in accordance with the malignancy protocol. Pathologic diagnosis revealed adenocarcinoma within the diverticulitis with negative resection margins, indicating curative surgery. The low preoperative diagnostic rate of CRC associated with diverticulitis highlights the need for vigilance. Refractory diverticulitis may indicate the presence of concealed malignancy requiring surgical intervention. In the management of refractory diverticulitis, it is important to consider the potential coexistence of cancer. Even if extensive investigations are performed and a definitive diagnosis remains elusive, surgery must be considered.

Locally recurrent prostate cancer with RB1/TP53 alterations successfully treated by salvage focal brachytherapy: a case report.

Retinoblastoma transcriptional corepressor 1 (RB1) and tumor protein p53 (TP53) are well-known tumor suppressor genes; their alterations are associated with poor prognosis in human malignancies and quite rare in locally recurrent cases. The patient was a 58-year-old man who was diagnosed with cT1cN0M0 prostate cancer with Gleason score of 3+3=6 and underwent brachytherapy as the initial treatment. Local recurrence was detected in the left lobe of the prostate 154 months later and whole-exome sequencing that was performed at the request of the patient revealed RB1 loss-of-heterozygosity and TP53 p.I162Rfs*27 mutations. He underwent salvage focal brachytherapy with 125I seeds and serum prostate-specific antigen levels has been stabilized without any genitourinary or gastrointestinal toxicity.

Solitary fibrous tumor of the breast: A case report.

INTRODUCTION: Solitary fibrous tumors (SFTs) are uncommon mesenchymal neoplasms that comprise <2 % of all soft tissue tumors. They are a diagnostically challenging group of neoplasms that can occur essentially anywhere. Molecular or genetic testing of soft tissue tumors will increasingly add to the foundation of distinctive histologic features, as accurate diagnosis is critical for appropriate treatment. CASE PRESENTATION: A 28-year-old woman was referred to our hospital for a left breast mass. Ultrasonography showed an oval hypoechoic mass with partially obscured boundaries. Surgical specimens revealed spindle tumor cells surrounding the mammary ducts and were immunoreactive for both CD34 and STAT6, suggesting SFTs. However, the infiltration of spindle tumor cells into the surrounding fat, and the storiform-like pattern made us consider dermatofibrosarcoma protuberans (DFSP) as a differential diagnosis. Lack of amplification of the COL1A1-PDGFB fusion gene, a characteristic feature of DFSP, led to our definitive diagnosis of breast SFT. DISCUSSION: The presence of STAT6 in tumor cell nuclei is a highly sensitive immunohistochemical marker for SFT. In our case, morphological features evoked the differential diagnosis of DFSP and we investigated the COL1A1-PDGFB fusion gene. The diagnostic process of reliably performing careful morphological examination and immunohistochemical marker test, and then obtain conviction by molecular cytogenetic technique is more and more important for soft tissue tumors. CONCLUSIONS: We report a quite uncommon case of breast SFT and excluded DFSP as a differential diagnosis. If it is difficult to distinguish between these diseases, molecular cytogenetic analysis would be required for accurate diagnosis.

Single-Cell Phenotyping of CD73 Expression Reveals the Diversity of the Tumor Immune Microenvironment and Reflects the Prognosis of Bladder Cancer.

The cutting edge of cancer immunotherapy extends to ecto-5'-nucleotidase (CD73), a cell membrane enzyme that targets the metabolism of extracellular adenosine. We herein focused on the expression of CD73 to clarify the state of CD73 positivity in cancer immunity and tumor microenvironment, thereby revealing a new survival predictor for patients with bladder cancer (BCa). We used clinical tissue microarrays of human BCa and simultaneously performed the fluorescent staining of cell type-specific markers (CD3, CD8, Foxp3, programmed cell death protein 1, and programmed death-ligand 1 [PD-L1]) and CD73 together with DAPI for nuclear staining. In total, 156 participants were included. Multiplexed cellular imaging revealed a unique interaction between CD73 expression and CD8+ cytotoxic T cells (CTLs) and Foxp3+ regulatory T (Treg) cells in human BCa, showing the high infiltration of CD8+CD73+ CTLs and Foxp3+CD73+ Treg cells in tumors to be associated with tumorigenesis and poor prognosis in BCa. Interestingly, from a biomarker perspective, the high infiltration of CD73+ Treg cells in tumors was identified as an independent risk factor for overall survival in addition to clinicopathologic features. Regarding the relationship between immune checkpoint molecules and CD73 expression, both CD73+ CTLs and CD73+ Treg cells tended to coexpress programmed cell death protein 1 as tumor invasiveness and nuclear grade increased. Additionally, they may occupy a spatial niche located distantly from PD-L1+ cells in tumors to interfere less with the cancerous effects of PD-L1+ cells. In conclusion, the present results on the status of CD73 in cancer immunity suggest that CD73 expression on specific T-cell types has a negative immunoregulatory function. These findings may provide further insights into the immunobiological landscape of BCa, which may be translationally linked to improvements in future immunotherapy practice.

Prognostic role of the innate immune signature CD163 and "eat me" signal calreticulin in clear cell renal cell carcinoma.

The effects of the innate immune status on patients with clear cell renal cell carcinoma (ccRCC) currently remain unknown. We herein provided more extensive information about the inner landscape of immunobiology of ccRCC. In total, 260 ccRCC samples from three different cohorts consisting of 213 primary tumors and 47 metastases were obtained. We focused on five representative innate immune signatures, CD68, CD163, the "eat me" signal calreticulin, the "don't eat me" signal CD47, and signal regulatory protein α, and examined the role of each signature by quantitative immunohistochemistry. We then conducted an integrated genome mutation analysis by next-generation sequencing. Among the five markers, high CD163 and low calreticulin expression levels were prognostic in ccRCC. The application of a new risk model based on CD163 and calreticulin levels, named the innate immune risk group (high risk: high-CD163/low calreticulin, intermediate risk: high-CD163/high calreticulin or low CD163/low calreticulin, low risk: low-CD163/high calreticulin), enabled the sequential stratification of patient prognosis and malignancy. Although organ-specific differences were observed, metastases appeared to have a higher innate immune risk, particularly in the lungs, with 50% of ccRCC metastases being classified into the high-risk group according to our risk score. An analysis of genomic alterations based on the innate immune risk group revealed that alterations in the TP53/Cell cycle pathway were highly prevalent in high-risk ccRCC patients according to two innate immune signatures CD163 and calreticulin. The present results provide insights into the immune-genomic biology of ccRCC tumors for innate immunity and will contribute to future therapies focused on the innate immune system in solid cancers.

IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer.

Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma.

Diagnostic Value of the Vesical Imaging-Reporting and Data System in Bladder Urothelial Carcinoma with Variant Histology.

The value of the Vesicle Imaging-Reporting and Data System (VI-RADS) in the diagnosis of muscle-invasive bladder cancer (MIBC) for urothelial carcinoma with variant histology (VUC) remains unknown. We retrospectively evaluated 360 consecutive patients with bladder cancer (255 pure urothelial carcinoma [PUC] and 69 VUC) who underwent multiparametric magnetic resonance imaging between 2011 and 2019. VI-RADS scores assigned by four readers were significantly higher for the VUC group than for the PUC group (p < 0.05). In the cohort of 122 pair-matched patients, there was no significant difference in VI-RADS score distribution between the PUC and VUC groups for all readers (p > 0.05). The area under the receiver operating characteristic curve for MIBC diagnosis via overall VI-RADS score was 0.93-0.94 for PUC and 0.89-0.92 for VUC, with no significant difference between the PUC and VUC groups (p = 0.32-0.60). These data suggests that VI-RADS scores achieved high diagnostic performance for detection of muscle invasion in both PUC and VUC. PATIENT SUMMARY: The Vesical Imaging-Reporting and Data System (VI-RADS) is a standardized system for reporting on detection of muscle-invasive bladder cancer via magnetic resonance imaging (MRI) scans. Our study shows that VI-RADS is also highly accurate for diagnosis for different variants of muscle-invasive bladder cancer, with good inter-reader agreement.

Immune profile analysis of peripheral blood and tumors of lung cancer patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have become central to lung cancer drug therapy, and establishing biomarkers that can predict effects and adverse events (AEs) is awaited. We prospectively analyzed the association between the immune-related molecular expression in peripheral blood mononuclear cells (PBMCs) and lung cancer tissues, and the effects of ICI monotherapy. Methods: Twenty-one patients with advanced non-small cell lung cancer (NSCLC) who received ICI monotherapy were included. Changes in the expression of immune-related molecules in PBMCs before and after the administration of ICI were analyzed by flow cytometry. The major histocompatibility complex (MHC) class I and programmed cell death-ligand 1 (PD-L1) expression of cancer cells, and the PD-L1, CD8 and CD103 expression of tumor infiltrating immune cells in lung cancer tissue before the administration of ICI were confirmed by immunohistochemistry (IHC). Results: Twenty-one patients were investigated, including 11 adenocarcinoma and 10 squamous cell carcinoma cases. Anti-programmed cell death protein-1 (PD-1) antibody (n=18) and anti-PD-L1 antibody (n=3) were administered. The clinical responses were graded as follows: complete response (CR) (n=1), partial response (PR) (n=7), stable disease (SD) (n=10) and progressive disease (PD) (n=3). Among immune-related molecules expressed in PBMCs, the CD103+ CD39+ CD8+ T cell change after administration closely correlated with the clinical response. In the univariate analyses of the factors associated with progression-free survival (PFS), CD103+ CD39+ CD8+ cell change after administration was identified as a significant prognostic factor, while the CD103+ CD39+ CD8+ cell change after administration and Brinkman index were independent prognostic factors in a multivariate analysis of the factors associated with PFS. Conclusions: The CD103+ CD39+ CD8+ cell change after administration may predict the efficacy of ICIs.

Squamous cell carcinoma of the prostate with SMARCA4 alteration in a Japanese patient.

Introduction: Squamous cell carcinoma of the prostate is very rare. Due to difficulty in diagnosis, it is often detected in advanced stages. Effective treatment of squamous cell carcinoma and the genetic profiling has not yet been established. Case presentation: We experienced the case of a 79-year-old man who was diagnosed with primary squamous cell carcinoma of the prostate. He had multiple lymph node metastases, liver metastases, and lung metastases, and he was treated with gemcitabine and carboplatin. However, he had poor patient status: it became difficult to continue after one course, and best supportive care was provided. We also performed targeted next-generation sequencing of 160 cancer-related genes and detected SMARCA4 mutation. Conclusion: This is the first study reporting the genomic profiling of squamous cell carcinoma of prostate in Japan.

Salvage focal brachytherapy in castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy.

Introduction: Treatment strategy for castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy has not been established. Case presentation: We described a case of castration-resistant prostate cancer with neuroendocrine differentiation after initial external beam radiotherapy followed by salvage androgen deprivation therapy. Magnetic resonance imaging detected recurrence of a suspicious lesion in the left lobe of the prostate, although the prostate-specific antigen level was <0.2 ng/mL. Transperineal prostate saturation needle biopsy detected adenocarcinoma with neuroendocrine differentiation. The patient underwent salvage focal brachytherapy and had a prostate-specific antigen progression-free survival of 20 months with no obvious adverse events. No recurrence has been detected on magnetic resonance imaging for 18 months. Conclusion: Salvage focal brachytherapy for prostate cancer after external beam radiotherapy can be one of the treatment strategies for local recurrence of castration-resistant prostate cancer with neuroendocrine differentiation.

ALK rearrangement-associated renal cell carcinoma morphologically mimicking mucinous tubular and spindle cell carcinoma: a case report.

BACKGROUND: Anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC) is an extremely rare tumor and ALK-RCC that mimics mucinous tubular and spindle cell carcinoma (MTSCC) has been very reported only in one instance. CASE PRESENTATION: A 42-year-old Japanese woman was admitted to our hospital for the treatment of a left renal tumor measuring 5 cm in maximum dimension. She underwent a laparoscopic left nephrectomy. Histologically, the tumor formed tubular or focally papillary structures with a small amount of spindle-shaped tumor cells against the background of prominent extracellular mucin. Although the tumor cells were negative for immunohistochemistry (IHC) of alpha-methylacyl-CoA racemase (AMACR) and lymph node metastasis was presented (these are atypical findings for MTSCC), we initially diagnosed the tumor as MTSCC based on its morphological characteristics with mucin deposition. However, an additional IHC analysis revealed that the tumor cells were diffusely positive for ALK-IHC. In addition, TPM3 exon 8 - ALK exon 20 fusion gene was detected by RNA sequencing. The tumor was thus correctly diagnosed as ALK rearrangement-associated renal cell carcinoma (ALK-RCC). CONCLUSIONS: Since the use of molecular targeted therapy with an ALK inhibitor for ALK-RCC is promising, the correct pathological diagnosis of ALK-RCC is quite important. We strongly recommend that ALK-IHC be routinely performed for renal tumors with negative AMACR staining that mimic MTSCC.

A Japanese case of castration-resistant prostate cancer with BRCA2 and RB1 co-loss and TP53 mutation: a case report.

BACKGROUND: Abnormalities in homologous recombination contribute to the aggressive nature of castration-resistant prostate cancer. Retinoblastoma transcriptional corepressor 1 (RB1) and breast cancer 2 (BRCA2) exist close to each other in the same chromosome, and the significance of their concurrent loss has become a hot topic in the field of cancer research. CASE PRESENTATION: A 61-year-old man presented with a chief complaint of a mass on his head and was diagnosed as multiple bone metastases from prostate cancer. He was treated with standard medication, but he died 2 years 6 months after being diagnosed with prostate cancer. Simultaneous biallelic loss of RB1 and BRCA2 as well as a truncating mutation of tumor protein p53 (TP53) were revealed by genomic analysis. CONCLUSION: To our knowledge, this is the first report of castration-resistant prostate cancer (CRPC) with BRCA2 and RB1 co-loss and TP53 mutation. To establish a treatment strategy for highly malignant cases with such multiple genetic features is important.

Profiling the Biological Characteristics and Transitions through Upper Tract Tumor Origin, Bladder Recurrence, and Muscle-Invasive Bladder Progression in Upper Tract Urothelial Carcinoma.

To evaluate biological characteristics and transitions of upper tract urothelial carcinoma (UTUC) through metachronous bladder tumors after radical nephroureterectomy (RNU), we conducted immunohistochemical (IHC) staining of tumor specimens of UTUC tumor origin, non-muscle-invasive bladder cancer (NMIBC) and MIBC progressed after intravesical recurrence (IVR), and bladder primary MIBC. Fibroblast growth factor receptor 3 (FGFR3), p53, cytokeratin 5/6 (CK5/6), and CK20 were stained to examine expression rates. After expression assessment with heatmap clustering, the overexpression of four biomarkers from UTUC origin to metachronous MIBC progression was analyzed with clinicopathological variables. We found that high CK20 and low CK5/6 expression were both observed in UTUC tumor origin and subsequent NMIBC after RNU. By investigating molecular expression in the IVR specimen, we observed that low pT stage bladder recurrence occupied the majority of CK20 high CK5/6 low expression, but would change to CK20 low CK5/6 high expression as it progressed to MIBC. UTUC metachronous MIBC has different characteristics compared with bladder primary MIBC, which comprises favorable biological features such as high FGFR3 expression, and follows favorable prognosis compared to those without FGFR3 expression. The present study demonstrated that the biological characteristics of UTUC tumor origin shifts from luminal to basal-like features with progression to MIBC, but FGFR3 expression taken over from UTUC origin may comprise a favorable entity compared to primary MIBC.

Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer.

BACKGROUND: The aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer. METHODS: We performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens. RESULTS: Varying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer. CONCLUSION: The immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.

Castration-resistant prostate cancer patient presenting with whole genome doubling with CDK-12 mutation.

BACKGROUND: The use of whole-genome sequencing in clinical practice has revealed variable genomic characteristics across cancer types, one of which is whole-genome doubling (WGD), which describes the duplication of a complete set of chromosomes. Yet it is relatively rare in prostate cancer and no such case has ever been reported in Japanese patients. CASE PRESENTATION: A 54-year-old patient with prostatic adenocarcinoma with bone and lymph node metastases was started on androgen-deprivation therapy. As the prostate cancer turned castration-resistant, multimodal therapies including taxane- and platinum-based chemotherapy, androgen-receptor antagonist inhibitors, radiotherapy and radium-233 were introduced. Good controls of serum prostate-specific antigen (PSA) level and bone metastases were achieved for more than 13 years since after the initial treatment. During the treatment, a metastatic lymph node biopsy was performed to confirm the tumor histology, and spinal decompression surgery were performed for spinal compression due to lumber vertebral metastases. The immunohistochemical analysis identified PSA and androgen receptor positive tumor cells in both metastatic lesions, while no variable cancer cells were detected in the prostate on second biopsy. Whole-genome sequencing was performed on the biopsied metastatic lymph node in search for another possible treatment and it revealed that the tumor had WGD and CDK12 mutation. The WGD-positive tumor cells contained large and polymorphic nucleus, presumably reflecting on the ploidy abnormality of the chromosomes. CONCLUSIONS: This report is the first case of a Japanese patient presenting with WGD, who survived more than 13 years with multimodal chemotherapies and radiotherapies.