Can Pelvic Lymph Node Dissection in Prostate Cancer Patients with a 5% Briganti Nomogram Cut-off Value Provide an Oncological Benefit? A Large Multi-Institutional Cohort Study in Japan.

The Briganti nomogram (cut-off value 5%) is commonly used to determine the indications for pelvic lymph node dissection (PLND) in patients with prostate cancer. We retrospectively analyzed the potential oncological benefit of PLND based on the 5% cut-off value on the Briganti nomogram. We obtained the data from the Medical Investigation Cancer Network (MICAN) Study, which included 3,463 patients who underwent a radical prostatectomy (RP) at nine institutions in Japan between 2010 and 2020. We included patients with Briganti scores ≥ 5% and a follow-up period ≥6 months and excluded patients categorized in the very high-risk group (based on NCCN categories); a final total of the cases of 1,068 patients were analyzed. The biochemical recurrence (BCR)-free survival was significantly worse in the patients who underwent PLND compared to those who did not (p=0.019). A multivariate analysis showed that high prostate-specific antigen (PSA) levels (p<0.001) and an advanced T-stage (p=0.018) were significant prognostic factors for BCR, whereas PLND had no effect on BCR (p=0.059). Thus, PLND in patients with prostate cancer whose Briganti score was 5% did not provide any oncological benefit. Further research is necessary to determine the indication criteria for conducting PLND.

Unveiling the Genomic Landscape of Intraductal Carcinoma of the Prostate Using Spatial Gene Expression Analysis.

Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.

Senescent CD8+ T cells acquire NK cell-like innate functions to promote antitumor immunity.

It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8+ T cells. Furthermore, Menin-deficient CD8+ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.

Spatial Gene Expression Analysis Reveals Characteristic Gene Expression Patterns of De Novo Neuroendocrine Prostate Cancer Coexisting with Androgen Receptor Pathway Prostate Cancer.

Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.

PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. METHODS: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived CM using a tube formation assay that mimics angiogenesis. RESULTS: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP-derived CM containing PSMA-positive membranes, such as microvesicles transformed HUVECs "PSMA-negative" into "PSMA-positive." Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP-derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. CONCLUSIONS: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues.

DNA maintenance methylation enzyme Dnmt1 in satellite cells is essential for muscle regeneration.

Epigenetic transcriptional regulation is essential for the differentiation of various types of cells, including skeletal muscle cells. DNA methyltransferase 1 (Dnmt1) is responsible for maintenance of DNA methylation patterns via cell division. Here, we investigated the relationship between Dnmt1 and skeletal muscle regeneration. We found that Dnmt1 is upregulated in muscles during regeneration. To assess the role of Dnmt1 in satellite cells during regeneration, we performed conditional knockout (cKO) of Dnmt1 specifically in skeletal muscle satellite cells using Pax7CreERT2 mice and Dnmt1 flox mice. Muscle weight and the cross-sectional area after injury were significantly lower in Dnmt1 cKO mice than in control mice. RNA sequencing analysis revealed upregulation of genes involved in cell adhesion and apoptosis in satellite cells from cKO mice. Moreover, satellite cells cultured from cKO mice exhibited a reduced number of cells. These results suggest that Dnmt1 is an essential factor for muscle regeneration and is involved in positive regulation of satellite cell number.

Sequential immune-targeted surgical therapy resulted in disease-free survival in a case with advanced renal cell carcinoma.

BACKGROUND: Currently, immunotherapy is indicated for patients with metastatic RCC or unresectable RCC, but there is no indication for immunotherapy in the neoadjuvant setting. We report a case in which the combined use of nivolumab and ipilimumab and sequential TKI therapy enabled surgical treatment. CASE PRESENTATION: A 71-year-old female was diagnosed with a metastatic clear-cell renal cell carcinoma with a level IV tumor thrombus. She was started on nivolumab-ipilimumab therapy, and was switched to pazopanib monotherapy because the tumor thrombus progressed within the right atrium. The tumor shrank to resectable status with sequential therapy. She then underwent right nephrectomy and thrombectomy. Pathological analysis showed 10-20% residual tumor in the primary tumor, but no viable cells in tumor thrombus. She remains clinically disease-free 1 year after surgery. CONCLUSION: This case suggests the utility of sequential immune-targeted therapy as neoadjuvant therapy in advanced renal cell carcinoma.

A low RENAL Nephrometry Score can avoid the need for the intraoperative insertion of a ureteral catheter in robot-assisted partial nephrectomy.

BACKGROUND: Intraoperative urinary collecting system entry (CSE) in robot-assisted partial nephrectomy (RAPN) may cause postoperative urinary leakage and extend the hospitalization. Therefore, identifying and firmly closing the entry sites are important for preventing postoperative urine leakage. In RAPN cases expected to require CSE, we insert a ureteral catheter and inject dye into the renal pelvis to identify the entry sites. We retrospectively analyzed the factors associated with intraoperative CSE in RAPN and explored the indications of intraoperative ureteral catheter indwelling in RAPN. METHODS: Of 104 Japanese patients who underwent RAPN at our institution from August 2016 to March 2020, 101 were analyzed. The patients were classified into CSE and non-CSE groups. The patients' background characteristics, RENAL Nephrometry Score (RNS), and surgical outcomes were analyzed. RESULTS: Intraoperative CSE was observed in 41 patients (41%). The CSE group had a significantly longer operative time, console time, ischemic time, and hospital stay than the non-CSE group. In a multivariable analysis, the N-score (odds ratio [OR] = 3.9, P < 0.05) and RNS total score excluding the L-score (OR = 3.1, P < 0.05) were associated with CSE. In a logistic regression analysis, CSE showed a moderate correlation with the RNS total score excluding the L-score (AUC 0.848, cut-off 5, sensitivity 0.83, specificity 0.73). CONCLUSION: A ureteral catheter should not be placed in patients with an RNS total score (excluding the L-score) of ≤ 4.

Predictors of Hypotension after Adrenalectomy for Pheochromocytoma.

The management of blood pressure is a significant concern for surgeons and anesthesiologists performing adrenalectomy for pheochromocytoma. We evaluated clinical factors in pheochromocytoma patients to identify the predictors of postoperative hypotension. The medical records of patients who underwent adrenalectomy for pheochromocytoma between 2001 and 2017 were retrospectively reviewed and clinical and biochemical data were evaluated. Of 29 patients, 13 patients needed catecholamine support in the perisurgical period while 16 patients did not. There were significant differences in median age, tumor size, and blood pressure drop (maxmin) between the 2 groups (68 vs 53 years old, p=0.045; 50 vs 32 mm diameter, p=0.022; 110 vs 71 mmHg, p=0.015 respectively). In univariate logistic analysis, age > 65.5 years, tumor size > 34.5 mm, urine metanephrine > 0.205 mg/day and urine normetanephrine > 0.665 mg/day were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urine metanephrine and urine normetanephrine levels were correlated with postoperative hypotension. These predictors may help in the safe perioperative management of pheochromocytoma patients treated with adrenalectomy.

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer.

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan-Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.

Feasibility of Laparoscopic Radical Cystectomy in Elderly Patients: A Comparative Analysis of Clinical Outcomes in a Single Institution.

Laparoscopic radical cystectomy (LRC) is a standard surgical treatment for muscle-invasive bladder cancer and high-risk non-muscle-invasive bladder cancer. LRC is a less invasive modality than conventional open surgery. Therefore, even elderly patients with invasive bladder cancer may be candidates for LRC. In this study, a comparative analysis of perioperative/oncological outcomes between elderly patients and younger patients who underwent LRC was performed to assess the feasibility of LRC in elderly patients. Sixty-eight consecutive patients who underwent LRC between October 2013 and March 2018 were enrolled and stratified into those younger than 75 years (n=37) and those ≥ 75 years old (n=31). The median follow-up period was 28.2 months. The preoperative and operative parameters and complications were similar in both groups. The 2-year overall survival (OS) was 64.4% in the younger vs. 76.4% in the elderly group (p=0.053), cancer-specific survival (CSS) was 79.3% vs. 81.7% (p=0.187), and recurrence-free survival (RFS) was 58.2% vs. 75.7% (p=0.174), respectively. No significant differences were observed in OS, CSS, or RFS between the groups. No significant differences were found between the groups with respect to peri-surgical/oncological outcomes. We conclude that LRC is feasible in elderly patients.

New classification of hydronephrosis on 18F-FDG-PET/CT predicts post-operative renal function and muscle-invasive disease in patients with upper urinary tract urothelial carcinoma.

OBJECTIVES: To evaluate the value of a classification of hydronephrosis on 18F-flurodeoxyglucose (FDG)-PET/CT in predicting post-operative renal function and pathological outcomes among patients with upper urinary tract urothelial carcinoma. METHODS: We retrospectively reviewed 71 patients treated with nephroureterectomy (NU) for upper urinary tract urothelial carcinoma after FDG-PET/CT between 2010 and 2016. Eight patients treated with ureteral stent or nephrostomy at the time of FDG-PET/CT were excluded. We classified hydronephrosis based on renal excretion of FDG as follows: Type 0, no hydronephrosis; Type 1, hydronephrosis with FDG excretion; and Type 2, hydronephrosis without FDG excretion. eGFR was recorded before pre-operataive FDG-PET/CT examination and after nephroureterectomy. RESULTS: Thirty-three patients (52%) had hydronephrosis, classified as Type 1 in 19 patients (30%) and Type 2 in 14 (22%). Type 2 hydronephrosis was associated with ureteral cancer and severe hydronephrosis on CT. Median changes in eGFR before and after nephroureterectomy in patients classified as Type 0, 1 and 2 were -23.9, -18.8 and 2.0 ml/min/1.73 m2, respectively. On multivariate analysis, Type 2 hydronephrosis was a significant predictor of change in eGFR (P = 0.001). Rates of muscle-invasive upper urinary tract urothelial carcinoma among Type 0, 1 and 2 patients were 37, 42 and 86%, respectively. On multivariate analysis, Type 2 hydronephrosis was a significant predictor of muscle-invasive upper urinary tract urothelial carcinoma (P = 0.032, OR 6.491). CONCLUSIONS: This classification of hydronephrosis from FDG-PET/CT is simple and useful for predicting post-operative renal function and muscle-invasive disease in patients with upper urinary tract urothelial carcinoma, especially with ureteral cancer. This classification can help in deciding eligibility for lymphadenectomy or perioperative cisplatin-based chemotherapy.

Role of robot-assisted radical prostatectomy in locally advanced prostate cancer.

Locally advanced prostate cancer is regarded as a very high-risk disease with a poor prognosis. Although there is no definitive consensus on the definition of locally advanced prostate cancer, radical prostatectomy for locally advanced prostate cancer as a primary treatment or part of a multimodal therapy has been reported. Robot-assisted radical prostatectomy is currently carried out even in high-risk prostate cancer because it provides optimal outcomes. However, limited studies have assessed the role of robot-assisted radical prostatectomy in patients with locally advanced prostate cancer. Herein, we summarize and review the current knowledge in terms of the definition and surgical indications of locally advanced prostate cancer, and the surgical procedure and perisurgical/oncological outcomes of robot-assisted radical prostatectomy and extended pelvic lymphadenectomy for locally advanced prostate cancer.

Low-Dose Docetaxel Combined with Dexamethasone Is Feasible for Patients with Castration-Resistant Prostate Cancer.

AIM: Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. METHODS: Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014. RESULTS: Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment-related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis. CONCLUSION: Low-dose docetaxel in combination with dexamethasone is feasible in Japanese CRPC patients. Hematological toxicity is less than that seen with standard docetaxel therapy, but it is necessary to monitor patients for severe nonhematological toxicities, particularly very elderly patients.

Primary adrenal leiomyosarcoma with lymph node metastasis: a case report.

BACKGROUND: Leiomyosarcomas typically originate in smooth muscle cell. Leiomyosarcoma potentially arising from the adrenal gland is an extremely rare mesenchymal tumors associated with delayed diagnosis and poor prognosis. CASE PRESENTATION: A 34-year-old man visited our department complaining of right hypochondriac pain. Computed tomography demonstrated a solid mass measuring 5.2 cm in diameter above the right kidney, corresponding to the right adrenal gland, and a lymph node mass, which appeared to have invaded the IVC wall. Right adrenalectomy and lymphadenectomy were performed. A microscopic examination revealed primary adrenal leiomyosarcoma with lymph node metastasis. No adjuvant therapy was performed, and the patient remains recurrence-free at 10 months postoperatively. CONCLUSIONS: We experienced a very rare case of primary adrenal leiomyosarcoma. Aggressive surgical resection including vascular reconstruction may be associated with improved survival.

Fluorodeoxyglucose positron emission tomography/computed tomography for diagnosis of upper urinary tract urothelial carcinoma.

BACKGROUND: The purpose of this study was to assess the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to detect upper urinary tract urothelial carcinomas (UTUC) compared with pathological examination of tissues obtained by ureteroscopic biopsy and split cytologic analysis of urine obtained after retrograde pyelography. METHODS: Clinicopathological records of patients at our institution were retrospectively reviewed. Fifty patients with clinically suspected UTUC, who were histologically diagnosed by nephroureterectomy, partial ureterectomy, or endoscopic biopsy, were included. The patient cohort included 42 men and 8 women, with a median age of 73 (range 54-92) years. RESULTS: Only 27 % of 49 patients with UTUC had positive voided urine cytology, and 33 % of 40 patients had positive split urine cytology. In addition, 40 % of 10 patients had a positive endoscopic biopsy. However, 83 % of 48 patients with UTUC had positive results from FDG-PET/CT examination. The positive predictive value of FDG-PET/CT was 95 %. There were no correlations between sensitivity and tumor stage or tumor grade. Sensitivity of FDG-PET/CT for patients with and without diabetes mellitus was 60 and 89 %, respectively. CONCLUSIONS: These preliminary results from a small number of patients revealed that FDG-PET/CT enabled effective detection of UTUC.

[Clinicopathologic characteristics and prognosis of patients with adrenocortical carcinoma].

PURPOSE: Adrenocortical carcinoma (ACC) is a rare condition associated with poor prognosis. This study aimed to evaluate the clinicopathologic characteristics and prognosis of 7 patients with ACC. PATIENTS AND METHODS: The clinicopathologic characteristics, treatment, and survival of 7 patients with pathologically confirmed ACC treated at our institution between January 2002 and December 2012 were retrospectively examined. RESULTS: The study cohort comprised 4 male and 3 female patients (median age at diagnosis, 63 years [range, 36-71 years]). The median tumor size was 7.0 cm (range, 4.0-13.0 cm), and the median follow-up duration was 22 months (range, 9-107 months). One patient had stage I ACC, 4 had stage III, and 2 showed metastasis. The patient with stage I disease underwent laparoscopic adrenorectomy and those with stage III disease underwent adrenorectomy with the excision of adjacent organs. Four of these 5 patients are alive without recurrence at a median of 55 months (range, 22-107 months) after surgery. Of the 2 patients with metastases, 1 received combined chemotherapy with etoposide, adriamycin, and cisplatin plus mitotane without surgical resection but died 19 months later, and the other, with a solitary lung metastasis, underwent adrenorectomy and metastatectomy followed by adjuvant treatment with mitotane and is alive without recurrence at 9 months after treatment. The 3-year cause-specific survival rate was 56%. CONCLUSIONS: Patients with advanced-stage tumors showed long-term survival with complete tumor resection at diagnosis; hence, this seems to be most beneficial treatment option for patients with ACC.

Modified FOLFOX6 chemotherapy in patients with metastatic urachal cancer.

BACKGROUND: To improve the prognosis of patients with urachal cancer and establish an effective chemotherapeutic regimen for distant metastases. METHODS: We conducted a retrospective study to evaluate the efficacy and safety of a modified combination of 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) therapy in patients with metastatic urachal cancer. RESULTS: Five patients were treated with mFOLFOX6. Their median age was 65 years (range 41-80). The median follow-up time was 42 months (range 18-46). Two of the 5 patients (40%) showed an objective response: 1 achieved a clinically complete response and 1 a partial response. The grade 3/4 toxicity associated with this regimen was primarily neutropenia, but febrile neutropenia was not observed. Oxaliplatin treatment was discontinued because of a grade 2 allergic reaction in 1 patient. Grade 2 peripheral sensory neuropathy caused by oxaliplatin was observed in 2 patients, and the OPTIMOX (stop and go) approach had to be adopted. CONCLUSIONS: mFOLFOX6 appears to be effective for the treatment of metastatic urachal cancer.

Combined chemotherapy with gemcitabine and carboplatin for metastatic urothelial carcinomas in patients with high renal insufficiency.

BACKGROUND: This was a retrospective study to evaluate the activity and toxicity of a combined chemotherapeutic regimen of gemcitabine and carboplatin (GCa) in patients with metastatic urothelial carcinomas (UCs) with special regard to patients with highly impaired renal function. METHODS: Eleven patients whose creatinine clearance was 30 ml/min or under and who had been diagnosed with metastatic UC were treated with GCa. The patient cohort comprised 4 males and 7 females, with a median age of 74 (range 67-84) years. The median follow-up was 19 (range 1-58) months. RESULTS: Five of the 11 patients (45%) showed an objective response, with 2 achieving a clinically complete response and 3 a partial response with GCa. The grade 3/4 toxicity of the regimen was primarily hematological, including anemia (55%), neutropenia (45%), and thrombocytopenia (45%). Four patients (36%) could not complete the treatment in total. Grade 3 pneumonitis was found in one patient, and the treatment was terminated. Grade 4 febrile neutropenia occurred in the patient on hemodialysis, and the patient was forced to discontinue the chemotherapy. Another 2 patients also called off the treatment due to a pulmonary adverse event and an elevation of serum creatinine, respectively. CONCLUSIONS: GCa appears to be effective for the treatment of metastatic UCs in patients with impaired renal function, but it is necessary to pay attention to the occurrence of severe adverse events.

CD21lo B Cells Could Be a Potential Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma.

Immune checkpoint inhibitor (ICI) therapy increases the risk of immune-related adverse events (irAEs). In particular, combination checkpoint blockade (CCB) targeting inhibitory CTLA-4 and PD-1 receptors could lead to irAEs at a higher rate than ICI monotherapy. Management of irAEs is important while using ICIs. However, there are no reliable biomarkers for predicting irAEs. The aim of this study was to elucidate early B cell changes after CCB therapy in patients with renal cell carcinoma (RCC) and verify whether B cells can be a predictor of irAEs. This prospective cohort study was conducted with 23 Japanese patients with metastatic RCC. An increase in the proportion of CD21lo B cells and CD21lo memory B cells was confirmed following CCB therapy. Although there were no differences in clinical outcomes between irAE and no-irAE groups, the proportion of CD21lo B cells at baseline was lower in the irAE group, with a significant increase after the first cycle of CCB therapy. Further analysis revealed a moderate correlation between irAEs and CD21lo B cell levels at baseline (area under the curve: 0.83, cut-off: 3.13%, sensitivity: 92.3, specificity: 70.0). This finding indicates that patients with low baseline CD21lo B cell levels warrant closer monitoring for irAEs. The clinical registration number by the Certified Review Board of Ehime University is No. 1902011.