MMP1, IL-1ß, sTNFR-1, and IL-6 are prognostic factors for patients with unresectable or metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC. METHODS: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021. Blood samples were drawn before treatment, and 73 soluble factors in the plasma were analyzed using a bead-based multiplex assay. We examined factors associated with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE) using the Chi-squared test, Kaplan-Meier method, and the COX proportional hazards model. RESULTS: Patients exhibited a median PFS and OS of 212 and 783 days, respectively. Significant differences in both PFS and OS were observed for MMP1 (PFS, p < 0.001; OS, p = 0.003), IL-1ß (PFS, p = 0.021; OS, p = 0.008), sTNFR-1 (PFS, p = 0.017; OS, p = 0.005), and IL-6 (PFS, p = 0.004; OS, p < 0.001). Multivariate analysis revealed significant differences in PFS for MMP1 (hazard ratio [HR] 5.305, 95% confidence interval [CI], 1.648-17.082; p = 0.005) and OS for IL-6 (HR 23.876, 95% CI, 3.426-166.386; p = 0.001). Moreover, 26 patients experienced irAE, leading to ICI discontinuation or withdrawal. MMP1 was significantly associated with irAE (p = 0.039). CONCLUSION: MMP1 may be associated with severe irAE, and MMP1, IL-1ß, sTNFR-1, and IL-6 could serve as prognostic factors in unresectable or metastatic RCC treated with ICIs. MMP1 and IL-6 were independent predictors of PFS and OS, respectively. Thus, inhibiting these soluble factors may be promising for enhancing antitumor responses in patients with RCC treated with ICIs.

Retroperitoneal low-grade fibromyxoid sarcoma.

Introduction: Low-grade fibromyxoid sarcoma is an uncommon deep-seated soft-tissue sarcoma that occurs rarely in young adults and children. Although surgical resection provides a long-term prognosis, late local recurrence and metastasis may occur. Case presentation: A 44-year-old woman with no prior medical history presented with breathing and abdominal discomfort. Contrast-enhanced computed tomography scan revealed a retroperitoneal tumor protruding into the thoracic cavity and pleural effusion on the left side. Tumor biopsy revealed sarcoma. We performed complete resection of the tumor along with part of the diaphragm and replaced the diaphragm with a prosthetic patch. Histopathologic findings indicated low-grade fibromyxoid sarcoma. The patient experienced no postoperative complications and received no adjuvant therapy. Furthermore, she survived 4 years after surgery without recurrence. Conclusion: Complete surgical resection is effective for low-grade fibromyxoid sarcoma; therefore, it is important to plan appropriately for complete resection when biopsy reveals malignant findings.

Immune mediators as predictive biomarkers for anti-PD-1 antibody therapy in urothelial carcinoma.

Introduction: This study aimed to identify immune mediators, including cytokines, chemokines, and growth factors, in the plasma for predicting treatment efficacy and immune-related adverse events (irAEs) in advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs). Methods: We enrolled 57 patients with aUC who were treated with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab after the failure of platinum-based chemotherapy between February 2018 and December 2020. Plasma levels of 73 soluble immune mediators were measured before and 6 weeks after initiating pembrolizumab therapy. The association of estimated soluble immune mediators with clinical outcomes, including overall survival (OS), progression-free survival (PFS), anti-tumor responses, and irAEs, were statistically evaluated. Results: In the multivariate analysis, levels of 18 factors at baseline and 12 factors during treatment were significantly associated with OS. Regarding PFS, baseline levels of 17 factors were significantly associated with PFS. Higher levels of interleukin (IL)-6, IL-8, soluble tumor necrosis factor receptor 1 (sTNF-R1), and IL-12 (p40), both at baseline and post-treatment, were significantly associated with worse OS. Conversely, low IL-6 and high TWEAK levels at baseline were associated with irAEs. Among identified factors, interferon (IFN) γ and IL-12 (p40) were repeatedly identified; high baseline levels of these factors were risk factors for worse OS and PFS, as well as progressive disease. Notably, using correlation and principal component analysis, factors significantly associated with clinical outcomes were broadly classified into three groups exhibiting similar expression patterns. Discussion: Measuring plasma levels of soluble immune mediators, such as IL-6, IL-8, sTNF-R1, IFNγ, and IL-12 (p40), could be recommended for predicting prognosis and irAEs in ICI-treated patients with aUC.

Bone marrow adipocytes induce cancer-associated fibroblasts and immune evasion, enhancing invasion and drug resistance.

Bone metastasis occurs frequently in cancer patients. Conventional therapies have limited therapeutic outcomes, and thus, exploring the mechanisms of cancer progression in bone metastasis is important to develop new effective therapies. In the bone microenvironment, adipocytes are the major stromal cells that interact with cancer cells during bone metastasis. However, the comprehensive functions of bone marrow adipocytes in cancer progression are not yet fully understood. To address this, we investigated the role of bone marrow adipocytes on cancer cells, by focusing on an invasive front that reflects the direct effects of stromal cells on cancer. In comprehensive histopathological and genetic analysis using bone metastasis specimens, we examined invasive fronts in bone metastasis and compared invasive fronts with adipocyte-rich bone marrow (adipo-BM) to those with hematopoietic cell-rich bone marrow (hemato-BM) as a normal counterpart of adipocytes. We found morphological complexity of the invasive front with adipo-BM was significantly higher than that with hemato-BM. Based on immunohistochemistry, the invasive front with adipo-BM comparatively had a significantly increased cancer-associated fibroblast (CAF) marker-positive area and lower density of CD8+ lymphocytes compared to that with hemato-BM. RNA sequencing analysis of primary and bone metastasis cancer revealed that bone metastasized cancer cells acquired drug resistance-related gene expression phenotypes. Clearly, these findings indicate that bone marrow adipocytes provide a favorable tumor microenvironment for cancer invasion and therapeutic resistance of bone metastasized cancers through CAF induction and immune evasion, providing a potential target for the treatment of bone metastasis.

Cribriform pattern and intraductal carcinoma of the prostate can have a clinicopathological impact, regardless of their percentage and/or number of cores.

Cribriform pattern and intraductal carcinoma of the prostate (IDC-P) are widely accepted as poor prognostic factors in prostate cancer. However, it remains unclear to what extent the presence of these morphological features in prostate biopsy specimens, as diagnosed by hematoxylin-eosin-stained specimens only, affects the clinicopathological impact. In this study, we summarized the characteristics of the cribriform pattern and IDC-P in 850 prostate biopsy cases. The results showed a statistically significant increase in the incidence of cribriform pattern and IDC-P as grade group (GG) increased (especially in cases ≥ GG4, Chi-square test P < 0.001). The independent risk factors for cribriform pattern and IDC-P in biopsy specimens in the multivariate logistic regression analysis were the former GG, presence of IDC-P, lesion length of the highest GG core, latter GG, presence of the cribriform pattern, number of biopsies obtained, and number of highest GG core. Overall, 125 cases in which radical prostatectomy was conducted after biopsy were selected for further analysis. Multivariate logistic regression analysis using biopsy and surgical specimens confirmed that the presence of the cribriform pattern and IDC-P in biopsy specimens were independent risk factors for lymph node metastasis (odds ratios [95% confidence interval] were 6.54 [1.15-37.05] for the cribriform pattern and 23.71 [1.74-322.42] for IDC-P). The presence of the cribriform pattern and/or IDC-P in a biopsy specimen was a significant factor, even if only partially present, indicating lymph node metastasis. However, further validation is required to predict poor prognostic factors more accurately.

Chronological Change in EPHA2 Protein Expression Is Associated With Recurrence of Bladder Cancer.

BACKGROUND/AIM: Bladder cancer is the most common urinary tract cancer. Patients diagnosed with advanced T-stage/muscle-invasive bladder cancer through transurethral resection of bladder tumors (TURBT) are treated with total radical cystectomy; however, there is a high chance of recurrence. Nevertheless, markers for predicting this recurrence are not currently available. Here, we evaluated the chronological change of ephrin type-A receptor 2 (EPHA2) expression, a molecule known for its role in cell adhesion, to predict bladder cancer recurrence after cystectomy, using TURBT and cystectomy specimens. MATERIALS AND METHODS: An immunostaining evaluation method that combines whole-slide images and image analysis software was developed to quantify and evaluate stainability objectively. We assessed the correlation between EPHA2 expression and bladder cancer recurrence using this novel immunostaining method and chronological changes in target protein expression in TURBT and radical cystectomy samples. RESULTS: In TURBT specimens, the number of cases with a high N-terminal/C-terminal EPHA2 ratio in the group with recurrence was significantly higher than in the non-recurrent group (p=0.019). The number of cases with a high level of C-terminal EPHA2 positivity in the radical cystectomy specimen when compared to the TURBT specimen obtained from the same patient was significantly higher in the recurrent group than in the non-recurrent group (p=0.0034). CONCLUSION: EPHA2 appears to be a promising marker for bladder tumor recurrence after cystectomy and its evaluation may enable the selection of appropriate cases for adjuvant therapy among patients undergoing radical cystectomy. Further studies, including mass-scale analysis, are required to confirm these results.

Significance of non-standardized magnetic resonance imaging abnormalities and subsequent targeted prostate cancer biopsy for pathologists: A retrospective observational study.

Prostate biopsy is essential in diagnosing prostate cancer. The Prostate Imaging-Reporting and Data System (PI-RADS) and magnetic resonance imaging (MRI)-transrectal ultrasound fusion-guided biopsy are also useful for diagnosis. However, the burden of implementing and maintaining these techniques should be considered. Therefore, we investigated the significance of non-standardized pre-biopsy MRI abnormalities (conditions not in accordance with PI-RADS) and subsequent targeted biopsy. We collected clinicopathological data, including the presence or absence of MRI abnormalities, through biopsies from January 2017 to February 2022 at the Kanagawa Cancer Center and performed statistical analyses. We enrolled in 1086 cases: MRI abnormalities were observed in 861 cases (79.3%). In these 861 cases, the adenocarcinoma detection rate, number of positive cores, and length of the highest Grade Group (GG) lesions were significantly higher. In the multivariate analysis, MRI abnormalities were the most significant factor for detecting adenocarcinoma of ≥GG 2 (odds ratio: 4.52, 95% confidence interval: 3.08-6.63). Targeted biopsy showed a higher percentage of positive cores with ≥GG2 and longer highest GG lesion lengths than systematic biopsy. Furthermore, the highest GG was upgraded in 109 of 788 cases by targeted biopsy. However, several adenocarcinomas (125/788; 15.9%) could not be detected using only targeted biopsy. Non-standardized MRI abnormalities are powerful predictors of cancer and grading. Targeted biopsies based on MRI abnormalities provide several benefits. Owing to the relatively low implementation hurdle, these biopsies may serve as a bridge until the ideal approaches are popularized if the limitations are well understood.

[ADENOCARCINOMA OF THE RETE TESTIS WITH METASTASIS OF THE PENILE AND LUNG: A CASE REPORT].

Adenocarcinoma of the rete testis is a rare malignant tumor with poor prognosis. We report a case of adenocarcinoma of the rete testis. A 55-year-old man became aware of discomfort in the right scrotum. Negative results were obtained for the serum markers AFP, ß-human chorionic gonadotropin (ß-HCG), and LDH. Computed tomography (CT) showed enhancement of the right testis. Radical orchiectomy was performed. Immunohistochemical examination of the resected specimen showed positive results for CEA, and adenocarcinoma of the rete testis was diagnosed. Serum CEA level was elevated. CT showed swelling of the para-aortic lymph nodes. Retroperitoneal lymph node dissection (RPLND) was performed, and serum CEA then normalized. The patient developed penile metastases 4 months after RPLND, and serum CEA level again increased. Total penile resection was performed. TIP (Paclitaxel, Ifosfamide, Cisplatin) therapy was started after lung metastasis and increased serum CEA were identified. CT after 2 cycles of TIP therapy revealed disappearance of lung metastasis and normalization of serum CEA. Five months later, CT showed recurrence of lung metastases.

[A Case of Renocolic Fistula Caused by Infected Renal Cyst].

A 76-year-old male was previously found to have a renal cyst at the center of the right kidney, on a computed tomography (CT)scan for examination of another disease. The patient was admitted to the hospital because of fever. The CT scan showed an enlarged mass at the center of the right kidney and an increase in the density of peripheral fat tissue, suggesting an infection of the right renal cyst. In spite of conservative treatment with antibiotics, CT scan on the sixth day of admission revealed an increase in the size of the mass, and penetration in the ascending colon was suspected. An ultrasound-guided abscess puncture was performed, and a pigtail catheter (PC)was placed. Injection of contrast agent through the PC showed communication with the colon. The fistula site was identified using colon fiberscopy, and it was clipped. PC was removed after the closure of the fistula was confirmed by imaging. This is a rare case of renocolic fistula caused by an infected renal cyst, which was diagnosed by colon fiberscopy, and was treated by clipping the fistula.

[A Case of Purulent Penile Cavernitis with Emphysema].

An 82-year-old man visited our department with a chief complaint of penile pain and swelling. He was receiving maintenance dialysis for chronic renal failure and was catheterized because of urinary retention associated with prostatic hypertrophy. The penis was reddened with swelling extending to the root and marked tenderness. Blood tests indicated inflammation and imaging revealed an abscess with emphysematous changes in the cavernous region of the penis. The diagnosis was purulent penile cavernitis. His symptoms improved after decompression with incision and drainage. There has been no recurrence of the abscess in the 4 months since treatment.

[Post-Operative Immediate Single Instillation of Chemotherapy as Prevention of Recurrence after Transurethral Resection of Intermediate-High Risk Non-Muscle-Invasive Bladder Cancer].

We retrospectively evaluated the efficacy of immediate single instillation (SI) of pirarubicine hydrochloride (THP) in the chemoprevention of intermediate and high risk patients with non-muscle-invasive bladder cancer (NMIBC). The study population consisted of 256 intermediate and high risk patients with NMIBC who underwent Bacillus Calmette-Guerin (BCG) induction therapy or delayed intravesical chemotherapy between 1999 and 2014. We introduced SI of 30 mg THP in 30 ml normal saline for all cases in 2010, and thus earlier cases could be considered as historical controls. As BCG induction therapy, patients received 80 mg of BCG Tokyo strain 2 weeks after transurethral resection of bladder tumor (TURBT), and the instillations were repeated weekly for 8 weeks. On the other hand, as delayed intravesical chemotherapy, patients received 30 mg THP in 30 ml normal saline over a period of 6 months starting 2 weeks after TURBT. The instillation schedule was once a week for 1 month, every other week for 1 month and once a month for 4 months. The patients were followed with cystoscopy and urine cytology every 3 months for the first 2 years and every 6 months thereafter. The 3-, and 5-year non-recurrence rates were 80. 3 and 80.3%, respectively, in the single immediate instillation group and 69.7 and 64.5%, respectively, in the control group. Univariate analysis revealed a significant difference between the SI group and the control group (P=0. 025). Multivariate analysis showed that there was an independent and significant recurrence risk factor in selecting chemotherapy instead of BCG in additional intravesical instillation therapy and not to perform SI. Limitations of our study are its retrospective and nonrandomized nature with a limited number of patients.

[Post-Operative Single Immediate Intravesical Instillation Chemotherapy as Prophylaxis for Reccurence after Transurethral Resection of Low Risk Non-Muscle-Invasive Bladder Cancer].

We evaluated the efficacy of single-dose instillation of pirarubicine hydrochloride (THP) in the chemoprophylaxis of non-muscle-invasive bladder cancer(NMIBC). In a retrospective study, 135 evaluable patients were assigned to three groups after transurethral resection of bladder tumors (TURBT). In group 1, patients received no adjuvant therapy after TURBT. In group 2, patients received a single-dose of 30 mg THP in 30 ml normal saline immediately after TURBT. In group 3, patients received 30 mg THP in 30 ml normal saline 2 weeks after TURBT , and the instillations were repeated for 4 weeks, then every other week twice and successively monthly for 6 months. Patients were followed with cystoscopy and urine cytology every 3 months for the first 2 years and every 6 months thereafter. The 3- and 5-year non-recurrence rates were 66.9%, and 66.0%, respectively, in group 1, 85.6%, and 85.6%, respectively, in group 2, and 93.6%, and 77.9%, respectively, in group 3. There was a significant difference only between group 1 and group2 (P ＝0.048). With respect to the recurrence per month, there was a significant difference between the 3 groups (P＝0.014) for the first 2 years. However, there was no significant difference thereafter. Limitations of our study are its retrospective and nonrandomized nature with a limited number of patients.

Lack of an Association between Neutrophil-to-Lymphocyte Ratio and PSA Failure of Prostate Cancer Patients Who Underwent Radical Prostatectomy.

Introduction. The neutrophil-to-lymphocyte ratio (NLR), which can be easily calculated from routine complete blood counts of the peripheral blood, has been suggested to serve as a prognostic factor for some solid malignancies. In the present study, we aimed to determine the relationship between NLR in prostate cancer patients undergoing radical prostatectomy (RP) and their prognosis. Materials and Methods. We assessed NLR in 73 men (patients) who received RP for their prostate cancer. We also performed immunohistochemistry for CD8 and CD66b in a separate set of RP specimens. Results. The median NLR in the 73 patients was 1.85. There were no significant correlations of NLR with tumor grade (p = 0.834), pathological T stage (p = 0.082), lymph node metastasis (p = 0.062), or resection margin status (p = 0.772). Based on the area under the receiver operator characteristic curve (AUROC) to predict biochemical recurrence after RP, potential NLR cut-off point was determined to be 2.88 or 3.88. However, both of these cut-off points did not precisely predict the prognosis. There were no statistically significant differences in the number of CD66b-positive neutrophils or CD8-positive lymphocytes between stromal tissues adjacent to cancer glands and stromal tissues away from cancer glands and between different grades or stages of tumors. Conclusions. There was no association between NLR and biochemical failure after prostatectomy.

[KIDNEY TRANSPLANTATION IN A PATIENT WITH AN INDIANA POUCH: A CASE REPORT].

Kidney transplantation with an Indiana pouch is very rare, and a case report about it has not been found. This is our report about a successful case of kidney transplantation in a patient with an Indiana pouch. A 32 year-old woman with end stage renal failure was referred to our hospital for living related kidney transplantation. She had undergone an Indiana pouch diversion, due to a neurogenic bladder with spina bifida and renal dysfunction, 11 years ago. However, her kidney function gradually deteriorated, and finally she was started on hemodialysis six months ago. We performed living related kidney transplantation from her mother. We transplanted a graft into her right fossa iliaca and made an anastomosis between a graft ureter and an Indiana pouch. Her postoperative course was uneventful with good graft function. Now 1 year after transplantation, she maintains good graft function without urinary tract infection dor rejection.

[Case of renal cell carcinoma with intertrabecular vertebral metastases detected f-18 fluorodeoxyglucose positron emission tomography and MRI].

We report a case of renal cell carcinoma with intertrabecular vertebral metastases detected by F-18 fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The patient was a 40-year-old female, referred to our hospital for fever of ＞ 38°C, and loss of body weight. Examination showed anemia and elevated C-reactive protein (CRP). Abdominal enchanced CT showed a mass 3 cm in diameter, located on left kidney. She was diagnosed with left renal cell carcinoma (cT1aN0M0). Laparoscopic radical nephrectomy with a transabdominal approach was performed. Histological findings showed clear cell renal cell carcinoma G2＞G3. Although after operation, she presented with fever of ＞38°C, anemia, and elevated CRP and alkaline phosphatase. Systemic bone scan could not detect any bone metastases, but FDG-PET/CT and lumber MRI revealed cancer invasion to the bone of the whole body. Histological findings at bone biopsy showed clear cell carcinoma infiltrating the marrow space. We diagnosed the case as bone metastases of intertrabecular vertebral type. She was treated with temsirolimus,but died about five months after her first visit. Intertrabecular vertebral metastases that infiltrate the marrow space without trabecular bone alteration are not visible on radiographs or bone scans. FDG-PET/CT and MRI are more useful for diagnosis of intertrabecular vertebral metastases such as in this case.