Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma.

BACKGROUND: Several clear cell renal cell carcinoma (ccRCC) cases harbour fibroblast growth factor receptor 4 (FGFR4) gene copy number (CN) gains. In this study, we investigated the functional contribution of FGFR4 CN amplification in ccRCC. METHODS: The correlation between FGFR4 CN determined via real-time PCR and protein expression evaluated using western blotting and immunohistochemistry was assessed in ccRCC cell lines (A498, A704, and 769-P), a papillary RCC cell line (ACHN), and clinical ccRCC specimens. The effect of FGFR4 inhibition on ccRCC cell proliferation and survival was assessed via either RNA interference or using the selective FGFR4 inhibitor BLU9931, followed by MTS assays, western blotting, and flow cytometry. To investigate whether FGFR4 is a potential therapeutic target, a xenograft mouse model was administered BLU9931. RESULTS: 60% of ccRCC surgical specimens harboured an FGFR4 CN amplification. FGFR4 CN was positively correlated with its protein expression. All ccRCC cell lines harboured FGFR4 CN amplifications, whereas ACHN did not. FGFR4 silencing or inhibition attenuated intracellular signal transduction pathways, resulting in apoptosis and suppressed proliferation in ccRCC cell lines. BLU9931 suppressed tumours at a tolerable dose in the mouse model. CONCLUSION: FGFR4 contributes to ccRCC cell proliferation and survival following FGFR4 amplification, making it a potential therapeutic target for ccRCC.

Single-center survey of prescription trends and appropriate use plans for macrolide antimicrobials.

INTRODUCTION: Macrolides (MCs) are broad-spectrum antimicrobials with activity against many microorganisms. They are widely used, and the development of MC-resistant bacteria is a serious problem in Japan. It is therefore necessary to clarify the purpose and duration of administration, with the aim of promoting appropriate use. METHODS: Patients of all ages, for whom oral MCs were prescribed between 2016 and 2020 were included. They were divided into four groups based on the number of days per prescription. In the long-term treatment group, patients treated with MCs for ≥1000 days were specifically investigated for the purpose of treatment. RESULTS: Macrolide prescriptions increased from 2019 to 2020. Most patients received ≥28 days of treatment based on one prescription. During the study period, 1212 patients (28.6%) received a total of ≥50 days and 152 patients (3.6%) received a total of ≥1000 days of treatment. Approximately a third of long-term administrations were for nontuberculous mycobacterial infections (NTMs), and 18.3% of patients with NTMs were treated with MCs alone. In addition, many MCs were administered for their anti-inflammatory effects on neutrophils. CONCLUSIONS: Owing to their pleiotropic effects, MCs may also be administered for the treatment of noninfectious diseases. In general, the long-term administration of antimicrobials contradicts the strategy for the suppression of resistant bacteria. It is thus important to understand the actual clinical utility of MCs and the purpose and duration of administration. In addition, strategies for the appropriate use of MCs are required for each medical institution.

Bacillus subtilis variant natto Bacteremia of Gastrointestinal Origin, Japan.

We report a case of bacteremia caused by Bacillus subtilis variant natto after a gastrointestinal perforation in a patient in Japan. Genotypic and phenotypic studies of biotin identified B. subtilis var. natto. This case and 3 others in Japan may have been caused by consuming natto (fermented soybeans).

Cardiac acoustic biomarkers as surrogate markers to diagnose the phenotypes of pulmonary hypertension: an exploratory study.

Pulmonary hypertension (PH) is commonly associated with left heart disease. In this retrospective study, using the database of a clinical study conducted between January 2008 and July 2008, the phenotypes of PH were classified using non-invasive cardiac acoustic biomarkers (CABs) and compared with classification by echocardiography. Records with same-day measurement of acoustic cardiography and right heart catheterization (RHC) parameters were included; cases with congenital heart disease were excluded. Using the RHC measurements, PH was classified as pre-capillary PH (Prec-PH), isolated post-capillary PH (Ipc-PH), and combined pre-capillary and post-capillary PH (Cpc-PH). The first, second, third, and fourth heart sounds (S1, S2, S3, and S4) were quantified as CABs (intensity, complexity, and strength). Forty subjects were selected: 5 had Prec-PH, 5 had Ipc-PH, 8 had Cpc-PH, and 22 had No-PH. CABs were significantly correlated with RHC measurements, with significant differences among phenotypes. Phenotype classification was performed using various CABs, and the diagnostic performance as assessed by the area under the receiver operating characteristic curve was 0.674-0.720 for Prec-PH, 0.657-0.807 for Ipc-PH, and 0.742 for Cpc-PH. High negative and low positive predictive values for phenotype identification were observed. CABs may provide an ambulatory measurement method with home-monitoring friendliness which is more convenient than standard examinations to identify presence of PH and its phenotypes.

Surgical and focal treatment for metastatic renal cell carcinoma: A literature review.

Accompanied by the development of systemic therapy for metastatic renal cell carcinoma, the concept of focal treatment, including surgical treatment, has been changing. Although immediate cytoreductive nephrectomy was essentially considered for synchronous metastatic renal cell carcinoma patients, the CARMENA trial and SURTIME trial revealed the negative impact of immediate cytoreductive nephrectomy. Therefore, immediate cytoreductive nephrectomy is currently considered only for a limited number of patients. Besides, deferred cytoreductive nephrectomy seems to have efficacy for overall survival in prior retrospective studies. Two randomized controlled trials, the PROBE trial (NCT04510597) and the NORDIC-SUN trial (NCT03977571), are underway to elucidate deferred cytoreductive nephrectomy. Metastasectomy is also considered in metastatic renal cell carcinoma patients because previous studies demonstrated the overall survival benefit of metastasectomy. However, since all reports were retrospective studies, physicians could exclude the patients who were not expected to show the efficacy of metastasectomy. Therefore, an adequate patient selection for metastasectomy is important. A common factor predicting better overall survival was complete resection. Radiotherapies for metastatic lesions during systemic therapy showed approximately 90% local disease control rate at 1 year. However, no report has demonstrated that radiotherapy improves survival so far. Since surgical and focal treatments for metastatic renal cell carcinoma patients generally have minimal evidence, further investigations are needed.

Immunogenicity and safety of two doses of SARS-CoV-2 mRNA vaccine in kidney transplant recipients with low-dose rituximab.

OBJECTIVES: We evaluated whether the treatment history of low-dose rituximab affected safety profiles, and humoral and cellular responses induced by severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine in healthy controls and kidney transplant recipients. METHODS: We enrolled 10 healthcare workers as controls, 22 kidney transplant recipients with rituximab, and 36 kidney transplant recipients without rituximab without history of coronavirus disease 2019 who received two doses of vaccine. We assessed anti-severe acute respiratory syndrome coronavirus 2 spike antibody and the antigen-specific T cells using enzyme-linked immunospot against spike protein at baseline and after two doses of vaccine. RESULTS: All controls showed anti-severe acute respiratory syndrome coronavirus 2 antibody seroconversion and enzyme-linked immunospot positivity. Only 19/58 (33%) kidney transplant recipients experienced anti-severe acute respiratory syndrome coronavirus 2 antibody seroconversion and 31/58 (53%) kidney transplant recipients developed enzyme-linked immunospot assay positivity after vaccination. The anti-severe acute respiratory syndrome coronavirus 2 antibody seroconversion rate and enzyme-linked immunospot assay positivity rate after vaccination were not significantly different between kidney transplant recipients with or without rituximab. Multivariate regression analysis demonstrated rituximab was not associated with a lack of humoral and cellular responses to the vaccine. CONCLUSIONS: Low-dose rituximab in kidney transplant recipients did not affect humoral or cellular responses to the severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine without severe systemic adverse events including the deterioration of kidney function.

Effect of Extracellular Signal-Regulated Protein Kinase 5 Inhibition in Clear Cell Renal Cell Carcinoma.

(1) Background: Extracellular signal-regulating kinase 5 (ERK5) has been implicated in many cellular functions, including survival, proliferation, and vascularization. Our objectives were to examine the expression and effect of ERK5 in clear cell renal cell carcinoma (ccRCC). (2) Methods: The expressions of ERK5 and its regulating micro-RNA miR-143 were investigated using immunohistochemistry and quantitative reverse transcriptase PCR in surgical specimens of ccRCC patients. With invitro and in vivo studies, we used pharmacologic ERK5 inhibitor XMD8-92, RNA interference, pre-miR-143 transduction, Western blotting, MTS assay, apoptosis assay, and subcutaneous xenograft model. (3) Results: A strong ERK5 expression in surgical specimen was associated with high-grade (p = 0.01), high-recurrence free rate (p = 0.02), and high cancer-specific survival (p = 0.03). Expression levels of ERK5 and miR-143 expression level were correlated (p = 0.049). Pre-miR-143 transduction into ccRCC cell A498 suppressed ERK5 expression. ERK5 inhibition enhanced cyclin-dependent kinase inhibitor p21 expression and decreased anti-apoptotic molecules BCL2, resulting in decreased cell proliferation and survival both in ccRCC and endothelial cells. In the xenograft model, ERK5 inhibitor XMD8-92 suppressed tumor growth. (4) Conclusions: ERK5 is regulated by miR-143, and ERK5 inhibition is a promising target for ccRCC treatment.

Adjuvant heparinization before manipulation of artery reduces early failure in primary arteriovenous fistula for end-stage renal disease patients.

BACKGROUND: Arteriovenous fistula (AVF) is the most preferred vascular access for hemodialysis patients, and early failure of AVF is one of the most avoidable complications of this procedure. We retrospectively evaluated whether adjuvant systemic heparinization just before arterial manipulation could reduce early failure of primary AVF. METHODS: Three hundred and fifty-six patients with end-stage renal failure who underwent primary AVF surgery from April 2009 to September 2020 were enrolled in this study. The patients were divided into two groups based on whether they received adjuvant heparinization or not. Patient backgrounds, frequency of early AVF failure, and bleeding events were compared between the two groups. Multivariate Cox regression analysis identified risk factors for early AVF failure. RESULTS: Early failure of AVF was observed in only 2 of 157 patients (1.2%) in the adjuvant group, and the incident was significantly lower than observed in the non-adjuvant group, i.e., 17 of 199 patients (8.5%) (p = 0.002). Bleeding events were not significantly different between the two groups. Seven of 157 patients (4.5%) in the adjuvant group and 7 of 199 patients (3.5%) in the non-adjuvant group experienced bleeding events (p = 0.785). Female sex, use of steroids, hypoalbuminemia, venous stenosis in pre-surgical evaluation, arterial spasm in the perioperative period, new-onset venous stenosis after AVF anastomosis, technical failure of surgery, no early cannulation after surgery, and non-adjuvant heparinization were related to early AVF failure in the multivariate regression analysis. CONCLUSION: Adjuvant systemic heparinization therapy just before arterial manipulation reduced early failure of primary AVF without increasing bleeding events.

The effectiveness of prescription support and treatment reporting system on the appropriate usage of oral third-generation cephalosporins.

INTRODUCTION: Preauthorization and prospective audit and feedback system are reported to be effective for the achievement of appropriate use of intravenous antimicrobials, but few reports on oral antimicrobials are available, especially for adults. METHODS: The prescription of oral third-generation cephalosporins (oral 3rd Ceph) for inpatients and outpatients from 2013 to 2018 was investigated. The study period was divided into three phases. First, prescription support to suggest discontinuation of antimicrobials for unnecessary prescriptions, and alternative antimicrobials for inappropriate prescriptions were provided. Next, we continued prescription monitoring, and observed the trends of antimicrobial prescription without support. Finally, we have introduced prescription reporting system to promote the appropriate use of oral 3rd Ceph. In each phase, we evaluated days of therapy per 1000 patient-days and prescriptions per 1000 visits as an index of effectiveness of our interventions. RESULTS: The total annual amount of oral 3rd Ceph usage decreased significantly over time between phases, respectively. During the same period, the incidence rate of methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum ß-lactamase (ESBL)-producing bacteria, and AmpC ß-lactamase (AmpC)-producing bacteria was not changed significantly, indicating that oral 3rd Ceph usage was reduced without a concomitant increase of the drug-resistant bacteria. Simultaneously, the annual usage of other broad-spectrum antimicrobial agents such as oral fluoroquinolones and oral macrolides also decreased, which indicated these antimicrobials were not prescribed as an alternative for oral 3rd Ceph. CONCLUSIONS: The combination of prescription support activity and treatment reporting system for oral antimicrobial agents is an effective method for promoting appropriate oral antimicrobial use.

Prognosis of Japanese metastatic renal cell carcinoma patients in the targeted therapy era.

BACKGROUND: The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. METHODS: We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. RESULTS: The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9-46.8), not reached (63.5 to not estimable), 46.8 months (37.1-52.9), and 10.4 months (8.9-14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4-56.5), and 11.5 (9.9-16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. CONCLUSION: While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.

Clinical utility of head computed tomography scan during systemic therapy for metastatic renal cell carcinoma.

OBJECTIVES: The utility of brain metastasis screening in asymptomatic metastatic renal cell carcinoma is controversial. Our study evaluated the utility of routine head computed tomography during systemic therapy. METHODS: We retrospectively investigated 152 metastatic renal cell carcinoma patients who did not initially have brain metastasis at Yamagata University Hospital from January 2008 to July 2019. Patients who routinely received head computed tomography scan together with routine contrast-enhanced chest/abdominal/pelvic computed tomography scan every 2-4 months during systemic therapy ("Routine head computed tomography" group, n = 95) and patients without routine head computed tomography ("No routine head computed tomography" group, n = 57) were compared. RESULTS: Brain metastasis occurred in 16 patients in the "Routine head computed tomography" group and six patients in the "No routine head computed tomography" group. There was no statistical difference in overall survival after metastatic renal cell carcinoma diagnosis between groups (53.4 vs 37.3 months, respectively, P = 0.357) and neurological symptom-free survival after metastatic renal cell carcinoma diagnosis (53.4 vs 36.6 months, P = 0.336). Although there was no statistical difference on incidence of unrecovered neurological symptom (25.0% vs 50.0%, P = 0.334), fewer patients in the "Routine head computed tomography" group required craniotomy (0% vs 66.7%, P = 0.002). In the "No routine head computed tomography" group, the neurological symptom resolved for all patients without craniotomy. CONCLUSIONS: Routine head computed tomography during systemic therapy for metastatic renal cell carcinoma is not significantly associated with improved brain metastasis prognosis. However, routine head computed tomography enables brain metastasis diagnosis in the asymptomatic phase, which can avoid craniotomy.

GPI-80 Augments NF-κB Activation in Tumor Cells.

Recent studies have discovered a relationship between glycosylphosphatidylinositol (GPI)-anchored protein 80 (GPI-80)/VNN2 (80 kDa GPI-anchored protein) and malignant tumors. GPI-80 is known to regulate neutrophil adhesion; however, the action of GPI-80 on tumors is still obscure. In this study, although the expression of GPI-80 mRNA was detectable in several tumor cell lines, the levels of GPI-80 protein were significantly lower than that in neutrophils. To clarify the function of GPI-80 in tumor cells, GPI-80-expressing cells and GPI-80/VNN2 gene-deleted cells were established using PC3 prostate cancer cells. In GPI-80-expressing cells, GPI-80 was mainly detected in vesicles. Furthermore, soluble GPI-80 in the conditioned medium was associated with the exosome marker CD63 and was also detected in the plasma obtained from prostate cancer patients. Unexpectedly, cell adhesion and migration of GPI-80-expressing PC3 cells were not modulated by anti-GPI-80 antibody treatment. However, similar to the GPI-80 family molecule, VNN1, the pantetheinase activity and oxidative state were augmented in GPI-80-expressing cells. GPI-80-expressing cells facilitated non-adhesive proliferation, slow cell proliferation, NF-κB activation and IL-1ß production. These phenomena are known to be induced by physiological elevation of the oxidative state. Thus, these observations indicated that GPI-80 affects various tumor responses related to oxidation.

Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101.

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.

Effect of general self-efficacy on promoting health-related quality of life during recovery from radical prostatectomy: a 1-year prospective study.

BACKGROUND: The decline of health-related quality-of-life (QOL) during the year after radical prostatectomy is severe. General self-efficacy (GSE) is an effective psychological factor for long-term regulation of patient behavior and emotions. GSE is expected to facilitate enhanced health-related quality of life. We evaluated changes in GSE and analyzed the relationship between GSE and prostate cancer-specific and general health-related QOL. METHODS: We conducted a longitudinal survey with 104 patients who underwent radical prostatectomy and administered the General Self-efficacy Scale (GSES), Expanded Prostate Cancer Index Composite (EPIC), and SF8 Health Survey (SF-8). ANCOVA was performed to compare EPIC and SF-8 between GSES high and low-medium groups. RESULTS: GSES scores increased significantly after 6 months. Regarding EPIC urinary summary scores, high GSES group was significantly higher than low-medium group at 1 month (mean score difference [MSD], 7.3; 95% CI 1.1-13.2, P = 0.016), 3 months (MSD, 6.8; 95% CI 0.7-12.8, P = 0.028), and 6 months (MSD, 6.3; 95% CI 0.9-11.7, P = 0.022). High GSES group had significantly higher SF-8 physical component summary score at 6 months (MSD, 3.2; 95% CI 1.4-5.0, P = 0.001), and significantly higher SF-8 mental component summary score at 1 month (MSD, 2.6; 95% CI 0.4-4.9, P = 0.022), 3 months (MSD, 2.7; 95% CI 0.8-4.6, P = 0.007), and 6 months (MSD, 2.8; 95% CI 1.0-4.6, P = 0.003). CONCLUSION: This study suggests that high GSE was associated with better prostate cancer-specific and general health-related QOL after radical prostatectomy.

New prognostic model for synchronous metastatic renal cell carcinoma.

OBJECTIVES: To create a new model for the prediction of overall survival in synchronous metastatic renal cell carcinoma. METHODS: Medical records of 158 patients with metastatic renal cell carcinoma diagnosed at the Yamagata University Hospital from August 2007 to February 2018 were reviewed. Among them, 77 with synchronous metastatic renal cell carcinoma were retrospectively analyzed using the univariate and multivariate analyses. A new prognostic model was constructed, followed by a bootstrap validation to estimate the model fitting. In addition, these prognostic factors were estimated in 67 metachronous metastatic renal cell carcinoma patients. RESULTS: Five independent prognostic factors were identified in synchronous metastatic renal cell carcinoma: cT3/4, cN1, high corrected calcium, >3.6 neutrophil-to-lymphocyte ratio and central nerve system metastasis. The number (%) and overall survival (95% confidence interval) in the favorable- (0 or 1 risk factor), intermediate- (2 risk factors) and poor-risk (≥3 risk factors) groups were 29 (45.3%) and 67.4 (31.8-NA), 21 (32.8%) and 16.8 (10.0-27.6), and 14 (21.9%) and 9.1 (7.3-13.7) months, respectively. The C-index was 0.72. Patients in the favorable-risk group had better overall survival with nephrectomy than without nephrectomy (hazard ratio 0.29, 95% confidence interval 0.09-0.91 with nephrectomy). In metachronous metastatic renal cell carcinoma, these prognostic factors showed no statistical differences in the overall survival. CONCLUSIONS: Prognostic factors are completely different between synchronous and metachronous metastatic renal cell carcinoma. The new model for synchronous metastatic renal cell carcinoma can predict a good candidate for cytoreductive nephrectomy.

Wavelength conversion using fiber cross-phase modulation driven by two pump waves.

Wavelength conversion using all-optical phase modulation in a fiber driven by two pump waves is investigated. The operation features are analyzed using an all-optical phase modulation model with two parallel-/cross-polarized pump waves to generate a phase-preserving copy of the optical signal at an exact frequency up-/down-shifted by the two-pump detuning. The conversion efficiency is experimentally verified using a 300-m highly-nonlinear fiber. The results agree well with a theoretical prediction. The conversion bandwidth over 4 THz is achieved and error-free wavelength conversion for a 32-GBd polarization-division multiplexed 16QAM signal is demonstrated. The technique's applicability to a large-capacity wavelength-division multiplexed signals is also discussed.

GPI-80 as a Useful Index for Myeloid Cell Heterogeneity and a Potential Prognostic Biomarker for Metastatic Renal Cell Carcinoma.

Myeloid-derived suppressor cells (MDSCs), which include neutrophilic MDSCs and monocytic MDSCs, exhibit high immunosuppressive activity. Glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) is selectively expressed on mature neutrophils in healthy individuals. Increased GPI-80 expression on monocytes and variations in GPI-80 expression on neutrophils indicate the appearance of MDSCs in the peripheral blood of cancer patients. However, it is still unclear whether GPI-80 expression on myeloid cells, neutrophilic MDSCs and monocytic MDSCs, is correlated with the clinical outcomes of patients with cancer. In this study, we investigated the characteristics of myeloid cells expressing GPI-80 and the implication of GPI-80 expression in the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), in which primary renal cell carcinoma spreads from the kidney to other organs. The study included 20 patients with mRCC (a mean age of 66.0 years) and 16 healthy volunteers (a mean age of 47.8 years). To determine the heterogeneity of myeloid cells in peripheral blood samples, we performed the three-dimensional principal component analysis using the combination of GPI-80, CD16, and latency-associated peptide-1 (LAP), derived from the N-terminal region of transforming growth factor-ß1 precursor. The results showed that myeloid cells in mRCC patients were widely distributed and clearly distinguishable from those in the healthy volunteers. The survival analysis revealed that GPI-80 expression on neutrophils and monocytes was correlated with poor prognostic outcomes of patients with mRCC. In conclusion, the expression of GPI-80 on myeloid cells, a useful index for the heterogeneity of MDSCs, serves as a potential prognostic biomarker for mRCC.

Augmentation of the expression of the eotaxin receptor on duodenal neutrophils by IL-21.

Inflammation can occur via different mechanisms, such as via acute and chronic responses, on numerous occasions and function accordingly through various roles. There are more than five subsets of neutrophils; neutrophilic heterogeneity is modulated by the inflammatory condition. To understand the characteristics of inflammation, identification of atypical neutrophils is important. In this study, we found that the expression of eotaxin receptor (CD193) on atypical neutrophils in the duodenum is augmented in IL-21 isoform transgenic (Tg) mice. In a series of studies, we have established a Tg mouse strain to further investigate the functions of IL-21 in vivo. Interestingly, Tg mice immunized with ovalbumin (OVA) were more sensitive to OVA-induced systemic anaphylaxis as compared with wild type mice with duodenal and splenic gross congestion. Further analysis conducted in the duodenum of Tg mice revealed that only the number of neutrophils migrating into the duodenum was significantly increased prior to immunization. Previous studies have shown that the gastrointestinal compartment and the spleen constantly produce eotaxin, which regulates basal levels of tissue eosinophils. Therefore, we analyzed CD193 expression on neutrophils and eosinophils. As expected, its expression by duodenal neutrophils was upregulated in Tg mice. Furthermore, the addition of IL-21 into bone marrow cell culture increased the number of CD193+ neutrophils, which easily migrated into the duodenum. These observations suggested that CD193+ neutrophils increase in number under inflammatory conditions due to chronic IL-21 production.

Pazopanib-induced crystal deposition in intestinal mucosa in a patient with retroperitoneal liposarcoma.

Pazopanib was administered to a 44-year-old man with local recurrence of retroperitoneal liposarcoma. Computed tomography showed an intestinal edema, which gradually progressed 15 months after pazopanib administration although he had no clinical symptoms. Upper gastrointestinal endoscopy implicated marked edematous hypertrophy of the Kerkling's fold. Pathological findings showed crystal deposition and fat accumulation, without a malignant component. All these abnormal findings resolved after pazopanib discontinuation.