Screening for prostate cancer in a city in Japan: age-specific prostate-specific antigen cutoff thresholds.

PURPOSE: Older men have higher prostate-specific antigen levels than younger men. However, the current Japanese Urological Association guidelines recommend secondary screening at a cutoff value of 4.0 ng/mL, even in older men. Here, we reexamined the cutoffs for older men using a prostate screening cohort in Japan and first performed an analysis to determine the indication cutoffs for detecting positive biopsies. METHODS: Data from 68,566 prostate cancer screenings in the city in 2018 were combined with cancer registration data. The optimal prostate-specific antigen levels to predict prostate cancer in different age groups were calculated using receiver operating characteristic curves after determining whether a cancer was registered within one year of screening. RESULTS: At the conventional prostate-specific antigen threshold of 4.0 ng/mL, the sensitivity, specificity, and negative predictive value were 94.9%, 91.7%, and 91.7%, respectively. The optimal prostate-specific antigen cutoff values for patients aged 50-59 years, 60-69 years, 70-79 years, and over 80 years were 3.900 ng/mL, 4.014 ng/mL, 4.080 ng/mL, and 4.780 ng/mL, respectively. CONCLUSIONS: The sensitivity and specificity of prostate cancer screening in the city were high, indicating a highly accurate screening. The prostate-specific antigen threshold was 4.78 ng/mL in patients older than 80 years. A higher prostate-specific antigen threshold may be useful in men over 80 years of age to avoid excess biopsy and reduce costs. Our results suggest that the current Japanese method of using PSA 4.0 ng/mL as a cutoff regardless of age may not be preferable for older men.

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.

Predictors of the development of febrile neutropenia in chemotherapy for advanced germ cell tumors.

OBJECTIVES: To identify the predictive factors for the development of febrile neutropenia (FN) in the course of chemotherapy for patients with germ cell tumors. METHODS: From January 2005 to December 2018, 80 patients were treated with induction chemotherapy for advanced germ cell tumors at Kanagawa Cancer Center Hospital, Japan. Of these, we retrospectively analyzed 267 cycles of chemotherapy. The incidence of FN was used as the objective variable. As predictive factors, we analyzed age, international germ cell consensus classification (IGCCC), laboratory data at the start of chemotherapy in each cycle, length of the largest metastatic lesion, number of cycles, and prophylactic use of granulocyte colony stimulating factor (G-CSF). RESULTS: We finally analyzed 267 cycles in 78 patients. The median age was 36 years (15-64). There was a total of 267 cycles. FN occurred in 40 cycles (15%) in 31 patients (40%). The first cycle was accompanied by a significantly higher FN than the subsequent cycles (p < 0.001). The univariate analysis identified age ≧36 years (p = 0.001), creatinine clearance (CCr) <70 (p < 0.001), serum albumin <3.3 (p = 0.002), maximum tumor diameter ≧60 mm (p = 0.036), and first cycle as significant risk factors. The multivariate analysis identified age, CCr, and first cycle as independent predictive factors of FN development. CONCLUSION: We identified older age, renal dysfunction, and first cycle of chemotherapy as predictive factors for FN. No statistically significant difference was shown in the usage of prophylactic G-CSF. Special attention should be given to FN in patients with high-risk factors.

Combination of Blood Adiponectin and Leptin Levels Is a Predictor of Biochemical Recurrence in Prostate Cancer Invading the Surrounding Adipose Tissue.

Biochemical recurrence is a process that progresses to castration-resistant prostate cancer (CRPC) and prediction of biochemical recurrence is useful in determining early therapeutic intervention and disease treatment. Prostate cancer is surrounded by adipose tissue, which secretes adipokines, affecting cancer progression. This study aimed to investigate the correlation between blood adipokines and CRPC biochemical recurrence. We retrospectively analyzed the clinical data, including preoperative serum adipokine levels, of 99 patients with pT3a pN0 prostate cancer who underwent proctectomy between 2011 and 2019. The primary outcome was biochemical recurrence (prostate-specific antigen: PSA > 0.2). We identified 65 non-recurrences and 34 biochemical recurrences (one progressed to CRPC). The initial PSA level was significantly higher (p = 0.006), but serum adiponectin (p = 0.328) and leptin (p = 0.647) levels and their ratio (p = 0.323) were not significantly different in the biochemical recurrence group compared with the non-recurrence group. In contrast, significantly more biochemical recurrences were observed in the group with adiponectin < 6 µg/mL and Leptin < 4 ng/mL (p = 0.046), initial PSA > 15 ng/mL, clinical Gleason pattern ≥ 4, and positive resection margin. A significant difference was also observed in the multivariate analysis (hazard ratio: 4.04, 95% confidence interval: 1.21-13.5, p = 0.0232). Thus, low preoperative serum adiponectin and high leptin levels were significantly associated with biochemical recurrence in adipose tissue-invasive prostate cancer, suggesting that they may be useful predictors of biochemical recurrence. Further studies with larger cases are needed to increase the validity of this study.

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.

Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs.

Recent evidence indicates that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in tumor formation in a telomere-independent manner. Non-canonical function of hTERT has been considered as a therapeutic target for cancer therapy. We have previously shown that hTERT phosphorylation at threonine 249 (p-hTERT), which promotes RdRP activity, is an indicator of an aggressive phenotype and poor prognosis in liver and pancreatic cancers, using two cohorts with small sample sizes with polyclonal p-hTERT antibody. To clarify the clinical relevance of p-hTERT, we developed a specific monoclonal antibody and determined the diagnostic and prognostic value of p-hTERT in cancer specimens using a large cohort. A monoclonal antibody for phosphorylated hTERT (p-hTERT) at threonine 249 was developed and validated. The antibody was used for the immunohistochemical staining of formalin-fixed, paraffin-embedded specimens from 1523 cases of lung, colon, stomach, pancreatic, liver, breast, and kidney cancers. We detected elevated p-hTERT expression levels in cases with a high mitotic activity, high pathological grade, and high nuclear pleomorphism. Elevated p-hTERT expression was an independent prognostic factor for lung, pancreatic, and liver cancers. Furthermore, p-hTERT expression was associated with immature and aggressive features, such as adenosquamous carcinoma (lung and pancreas), invasive type of cancer (lung), high serum alpha-fetoprotein level (liver), and triple-negative status (breast). In conclusion, RdRP activity indicated by p-hTERT expression predicts aggressive cancer phenotypes in various types of cancer. Thus, p-hTERT is a novel biomarker for the diagnosis of aggressive cancers with a poor prognosis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Plasma circulating tumor DNA profiling in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Molecular analysis of tumor tissues has been extensively analyzed in germ cell tumors. However, genetic analysis of plasma circulating tumor DNA has been limited. Our objective was to analyze genetic alterations in circulating tumor DNA as well as its impact on prognosis in patients with chemo-refractory germ cell tumors. METHODS: We included 13 patients with chemo-refractory germ cell tumors who relapsed after second-line or higher previous chemotherapy and performed targeted sequencing of plasma cell-free DNA using an AVENIO Expanded kit. RESULTS: Tumor-specific genetic alterations were identified in all patients. The most frequently mutated gene was TP53 (53.4%), followed by PTEN (23.1%), GNAS (15.4%) and MTOR (15.4%). Moreover, EGFR amplification (38.5%) and MET amplification (15.4%) were also identified. We defined two or more single nucleotide variants detected in plasma cell-free DNA as circulating tumor DNA-positive. Kaplan-Meier analysis revealed that overall survival was significantly shorter in circulating tumor DNA-positive patients than circulating tumor DNA negative-patients (median overall survival 3.13 vs. 8.73 months; p = 0.042). CONCLUSION: Analysis of plasma circulating tumor DNA could detect genetic alterations in patients with chemo-refractory GCT. Moreover, detectable circulating tumor DNA in plasma was associated with poor prognosis in those patients. These results suggest that liquid biopsy using analysis of plasma circulating tumor DNA may be clinically useful for germ cell tumor patients.

Sexual function using the EORTC QLQ-TC26 in testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate sexual function after treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 (EORTC QLQ-TC26) questionnaire in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants completed the EORTC QLQ-TC26 questionnaires. We evaluated sexual function after treatment for TC using the EORTC QLQ-TC26 and analyzed the impact of treatment on sexual function in TC survivors. RESULTS: A total of 567 TC survivors responded to the EORTC QLQ-TC26. Median age at the time of response was 43 years (interquartile range [IQR] 35-51 years), and median follow-up period after treatment was 5.2 years (IQR 2.2-10.0 years). Sexual function, particularly ejaculatory function, was significantly lower after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) than after Surveillance or Chemotherapy groups (p < 0.05). In the PC-RPLND group, nerve-sparing procedure preserved postoperative ejaculatory function after RPLND compared with the non-nerve-sparing and offered improved ejaculatory function with time. On multivariate analysis, RPLND was a significant predictor of post-treatment ejaculatory dysfunction, particularly without nerve-sparing (odds ratio 3.0, 95% CI 1.2-7.7, p < 0.05). In addition, TC survivors with nerve-sparing RPLND had higher sexual activity than those without. CONCLUSION: This survey of the EORTC QLQ-TC26 showed that sexual function and activity in TC survivors after RPLND was reduced in the absence of nerve-sparing techniques.

Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma.

Urothelial carcinoma (UC) is an umbrella term for bladder cancers (BCa) and upper-tract urothelial carcinoma (UTUC), with BCa and UTUC sometimes detected concomitantly. The methods of detection for UC are often inaccurate or highly invasive, and, therefore, are thought to be unsatisfactory. Previously, we reported seven serum miRNAs as diagnostic markers for BCa. Here, we re-evaluated potential diagnostic miRNAs in different institutions. We prospectively analyzed serum samples obtained from 126 UC patients (BCa: 106 samples; UTUC: 14 samples; UTUC with BCa: six samples) and 50 noncancer controls by microarray analysis. We randomly assigned these samples into a training or a validation set. Biomarker candidate miRNAs were selected based on cross-validation scores in the training set of samples, with diagnostic power confirmed in the validation set. Among the diagnostic miRNAs identified in this way, miR-1343-5p and miR-6087 had been identified as potential diagnostic miRNAs in our previous study. In addition, we evaluated the association between the serum levels of identified miRNAs and the presence of UC risk conditions. The expression levels of several miRNAs correlate with the risk factors in participants without UC, which may be explained by the presence of a microscopic tumor or a precancerous lesion. In conclusion, we identified two robust miRNA diagnostic markers for UC detection. Further functional analysis is required to elucidate the mechanism by which alterations in the expression of these miRNAs occur.

Association of financial toxicity with quality of life in testicular cancer survivors.

OBJECTIVES: Most testicular cancer (TC) survivors have long-term survival. However, the association between financial toxicity (FT), which is an economic side effect of cancer treatment, and the quality of life (QOL) of TC survivors is still unclear. Thus, the impact of FT on the QOL of TC survivors was examined in a multi-institutional cross-sectional study. METHODS: We recruited TC survivors from eight high-volume institutions in Japan between January 2018 and March 2019. A total of 562 participants completed the EORTC QLQ-C30, EORTC QLQ-TC26 and the questionnaires on demographics, including annual income. Financial difficulty in the EORTC QLQ-C30 and low income were used to assess financial distress (FD) and financial burden (FB), respectively. FT was defined as FD and FB. The QOL scores were compared, and a multivariate logistic regression analysis for FT was performed. RESULTS: With severe FD, TC survivors had more treatment side effects, physical limitations, and anxiety concerning employment and future. The TC survivors who reported low income were worried about their jobs and the future. The QOL of the survivors with FT exhibited high impairment, except for sexual activity. In particular, the TC survivors with FT were physically limited and anxious concerning the future. The multivariate logistic regression analysis revealed that four or more chemotherapy cycles were substantial risk factors for FT (4 cycles, odds ratio (OR) = 4.17; ≥5 cycles, OR = 6.96). CONCLUSIONS: TC survivors who received multi-cycle chemotherapy were prone to experience FT, resulting in a decline in their health-related QOL.

Phase II trial of nivolumab monotherapy and biomarker screening in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor. METHODS: Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second-line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate. RESULT: We performed a biomarker analysis of programmed death ligand-1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high-dose chemotherapy. The median number of nivolumab doses was 3 (range 2-46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well-tolerated, with only two Grade 3 adverse events observed. Programmed death ligand-1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand-1 is unreliable to measure response. CONCLUSIONS: Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response.

Fertility and reproductive technology use in testicular cancer survivors in Japan: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate fertility and use of reproductive technology of testicular cancer survivors in a multi-institutional, cross-sectional study. METHODS: This study recruited testicular cancer survivors who were followed after treatment for testicular cancer at eight high-volume institutions between 2018 and 2019. The participants completed the questionnaires on marital status, fertility and use of reproductive technology. RESULTS: A total of 567 testicular cancer survivors, with a median age of 43 years, responded to the questionnaire. Chemotherapy was given to 398 survivors, including three cycles of cisplatin-based chemotherapy in 106 patients and four cycles in 147 patients. Among 153 survivors who attempted sperm cryopreservation, 133 (87%) could preserve sperm. Of the 28 survivors whose cryopreserved sperm was used, 17 (61%) fathered children. Of the 72 survivors who fathered children without the use of cryopreserved sperm, 59 (82%) fathered naturally. Whereas 33 (20%) of 169 survivors treated without chemotherapy fathered children without using cryopreserved sperm, 39 (10%) of 398 treated with chemotherapy fathered children (P < 0.05). Furthermore, the paternity rate was 12% and 5% in testicular cancer survivors with three and four cycles of cisplatin-based chemotherapy, respectively (P < 0.05). However, of 121 survivors who wanted to have children, 14 (12%) received counseling about infertility treatment. CONCLUSIONS: Testicular cancer survivors preserving their sperm have a higher paternity rate after chemotherapy, especially after four cycles, than those not using cryopreserved sperm. Physicians who give chemotherapy for testicular cancer need to take particular care not only with respect to recurrence of testicular cancer, but also to post-treatment fertility.

Validation study of the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 for patients with testicular cancer.

OBJECTIVE: To validate the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 in Japanese-speaking testicular cancer survivors. METHODS: A total of 200 testicular cancer survivors were recruited at eight high-volume institutions in Japan. The participants completed the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and the International Index of Erectile Function 15 questionnaires. A total of 40 participants completed a retest of the questionnaires 2 weeks after the first response. The psychometric properties of the Japanese version including test-retest reliability, internal consistency and concurrent validity were evaluated. RESULTS: The mean age at response was 43 years (range 22-74 years), and the mean period after treatment was 77 months (range 0-416 months). The response rate for each item, except sexual function, was high, and the percentage of missing values was less than 3.5%. For test-retest reliability, seven of 12 scales met the criteria (intraclass correlation 0.70-0.86). For internal consistency, four of seven scales met the criteria (Cronbach's alpha 0.62-0.91). For concurrent validity, treatment side effects of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 were related to some domains of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. The sex-related subscales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 were moderately correlated with some International Index of Erectile Function 15 domains. CONCLUSIONS: The psychometric properties of the Japanese version are equivalent to the properties of the original European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26. The Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 questionnaire is a useful tool to assess the health-related quality of life of testicular cancer patients.

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.

Galectin-9 expression as a poor prognostic factor in patients with renal cell carcinoma.

Recently, the effectiveness of anti-programmed death 1 (PD-1) antibody therapy in the treatment of renal cell carcinoma (RCC) has been established. Nevertheless, efficacy has been reported to be limited to only 10-30% of patients. To develop more effective immunotherapy for RCC, we analyzed the immunological characteristics in RCC tissues by immunohistochemistry (IHC). We prepared a tissue microarray that consisted of tumor tissue sections (1 mm in diameter) from 83 RCC patients in Kanagawa Cancer Center between 2006 and 2015. IHC analysis was performed with antibodies specific to immune-related (CD8 and Foxp3) and immune checkpoint (programmed death ligand 1 (PD-L1) and 2 (PD-L2), B7-H4 and galectin-9) molecules. The numbers and proportions of positively stained tumor cells or immune cells were determined in each section. From multivariate analysis of all 83 patients, higher galectin-9 expression was detected as a factor associated with worse overall survival (OS) (P = 0.029) and that higher stage and higher B7-H4 expression were associated with worse progression-free survival (PFS) (P < 0.001 and P = 0.021, respectively). Similarly, in multivariate analysis of 69 patients with clear cell RCC, though not statistically significant, there was a trend for association between higher galectin-9 expression and worse OS (P = 0.067), while higher stage was associated with worse PFS (P < 0.001). This study suggests that higher galectin-9 expression is an independent adverse prognostic factor of OS in RCC patients. Therefore, to develop more effective personalized immunotherapy to treat RCC, it may be important to target not only PD-1/PD-L1, but also other immune checkpoint molecules such as galectin-9.

Clinical significance of programmed death-1 and programmed death-ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma.

Recently, immunotherapy based on blocking immune checkpoints with programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) Abs has been introduced for the treatment of advanced clear cell renal cell carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor-infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF-TKI-treated primary ccRCC tissues. Upregulated expression of PD-1 and PD-L1 by TIIC, and PD-L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD-1 and PD-L1 expression by TIIC was associated with a poorer response to VEGF-TKI, whereas PD-L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD-1-positive TIIC and PD-L1-positive TIIC were observed in tumors treated with VEGF-TKIs compared with those in untreated tumors. Our data suggest that PD-1 and PD-L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF-TKI treatment.

Diagnostic performance of 18F-fluciclovine PET/CT for regional lymph node metastases in patients with primary prostate cancer: a multicenter phase II clinical trial.

OBJECTIVE: This multicenter, phase II clinical trial evaluated the diagnostic performance of 18F-fluciclovine, a novel amino acid for positron-emission tomography (PET), for detection of small lymph node metastases with short-axis diameters of 5-10 mm in patients with prostate cancer. METHODS: Patients with prostate cancer were eligible after screening of laboratory tests and pelvic contrast-enhanced computed tomography (CT). Pelvic region 18F-fluciclovine PET/CT was then acquired within 28 days and dissection of regional lymph nodes was performed within 60 days of pelvic contrast-enhanced CT. Diagnostic performance of 18F-fluciclovine-PET/CT was evaluated by comparison with standard histopathology of lymph nodes. RESULTS: In a total of 28 patients, 40 regional lymph nodes with short-axis diameters of 5-10 mm were eligible for efficacy evaluation; seven of these showed metastases confirmed by histopathology. The sensitivity of 18F-fluciclovine PET/CT was 57.1% (4/7). All four true positive lymph nodes detected by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm and a high proportion of cancer volume (60-100%) according to pathology evaluation. The specificity, diagnostic accuracy, positive predictive value, and negative predictive value of 18F-fluciclovine PET/CT in lymph node-based analysis were 84.8% (28/33), 80.0% (32/40), 44.4% (4/9), and 90.3% (28/31), respectively. No clinically significant adverse events occurred. CONCLUSIONS: 18F-fluciclovine PET/CT detected small lymph node metastases; however it also showed positive findings in benign lymph nodes. Refinement of the image assessment criteria may improve the diagnostic performance of 18F-fluciclovine PET/CT for small lymph node metastases in patients with prostate cancer.

Prognostic value of an automated bone scan index for men with metastatic castration-resistant prostate cancer treated with cabazitaxel.

BACKGROUND: A computer-assisted diagnostic system for analyzing bone scans (BONENAVI) calculates the automated bone scan index (aBSI). Here we evaluated the aBSI as a prognostic imaging biomarker for men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel. METHODS: We retrospectively analyzed 48 patients who received cabazitaxel for mCRPC and evaluated the ability of the aBSI to predict overall survival (OS). The Cox proportional hazards model was used to investigate the associations between baseline aBSI at cabazitaxel treatment and OS with the clinical variables as follows: age, number of cycles of docetaxel, serum prostate-specific antigen, hemoglobin (Hb), lactate dehydrogenase (LDH), and alkaline phosphatase. We determined the C-index to evaluate the discriminatory ability of our models when we included or excluded the aBSI from the analyses. RESULTS: The median OS after cabazitaxel treatment was 10.0 months, and patients with aBSI ≤1% achieved significantly longer OS compared with patients with aBSI ≥1%. Multivariate analysis showed that age, Hb, LDH, and aBSI were independent prognostic factors of OS. Adding aBSI to the base model increased the C-index from 0.78 to 0.80. CONCLUSIONS: The aBSI may serve as a useful imaging biomarker for predicting OS among men with mCRPC treated with cabazitaxel. Prospective studies are required to establish the value of aBSI as prognostic imaging biomarker.

Significant response to nivolumab for metastatic chromophobe renal cell carcinoma with sarcomatoid differentiation: a case report.

BACKGROUND: The treatment of advanced or metastatic renal cell carcinoma (RCC) has drastically changed since the approval of immune checkpoint therapy. Nivolumab is a treatment option for patients with metastatic RCC, previously treated with targeted antiangiogenic therapy. The efficacy of nivolumab for patients with RCC was established by the Checkmate 025 clinical trial. Chromophobe RCC (CRCC) represents around 5% of RCC cases, but non-clear cell RCC (non-ccRCC) subtypes were excluded from the Checkmate 025 clinical trial. We report a case in which the use of nivolumab as the seventh-line therapy elicited a significant response in the treatment of metastatic CRCC with sarcomatoid differentiation. CASE PRESENTATION: We report a case of a 41-year-old woman with metastatic CRCC with sarcomatoid differentiation. She was treated with sunitinib, pazopanib, everolimus, sorafenib, axtinib, and temsirolimus, but treatment was discontinued because of disease progression or strong adverse events. Seventh-line treatment with nivolumab was initiated and significant clinical improvement was noted after 4 cycles. The treatment was well-tolerated with no significant side effects and the patient continues with nivolumab treatment at present. CONCLUSIONS: Nivolumab may be an attractive treatment option for non-ccRCC patients with sarcomatoid differentiation that exhibited aggressive characteristics and poor prognosis. Further investigation is warranted.