PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI–Resistant Metastatic Clear Cell Renal Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism. @*Materials and Methods@#To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib. @*Results@#Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway. @*Conclusion@#These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

Construction of a Retrospective Cohort to Observe 10-Year Urologic Cancer Treatment Trends at the Biggest Medical Center of South Korea

Purpose@#To construct a urologic cancer database using a standardized, reproducible method, and to assess preliminary characteristics of this cohort. @*Materials and Methods@#Patients with prostate, bladder, and kidney cancers who were enrolled with diagnostic codes in the electronic medical record (EMR) at Asan Medical Center from 2007–2016 were included. Research Electronic Data Capture (REDCap) was used to design the Asan Medical Center-Urologic Cancer Database (AMC-UCD). The process included developing a data dictionary, applying branching logic, mapping clinical data warehouse structures, alpha testing, clinical record summary testing, creating “standards of procedure,” importing data, and entering data. Descriptive statistics were used to identify rates of surgeries and numbers of patients. @*Results@#Clinical variables (n=407) were selected to develop a data dictionary from REDCap. In total, 20,198 urologic cancer patients visited our institution from 2007–2016 (bladder cancer, 4,616; kidney cancer, 5,750; prostate cancer, 10,330). The overall numbers of patients and surgeries increased over time, with robotic surgeries rapidly growing over a decade. The most common treatment for urologic cancer was surgery, followed by chemotherapy and radiation therapy. @*Conclusions@#Using a standardized method, the AMC-UCD fosters multidisciplinary research. This constructed database provides access to clinical statistics to effectively assist research. Preliminary data should be refined through EMR chart review. The successful organization of data from 2007–2016 provides a framework for future periods of investigation and prospective models.

Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma

10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort.CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.

Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma

BACKGROUND@#Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated.@*METHODS@#We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases.@*RESULTS@#TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort.@*CONCLUSION@#TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.

Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma

BACKGROUND@#Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated.@*METHODS@#We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases.@*RESULTS@#TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort.@*CONCLUSION@#TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.

Urinary transglutaminase 2 as a potent biomarker to predict interstitial fibrosis and tubular atrophy of kidney allograft during early posttransplant period in deceased donor kidney transplantation

PURPOSE: Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. We tested whether quantification of urinary TG2 may represent a noninvasive method to estimate the severity of kidney allograft fibrosis. METHODS: We prospectively collected urine specimens from 18 deceased donor kidney transplant recipients at 1-day, 7-day, 1-month, 3-month, and 6-month posttransplant. In addition, kidney allograft tissue specimens at 0-day and 6-month posttransplant were sampled to analyze the correlation of urinary TG2 and kidney allograft fibrosis. RESULTS: Thirteen recipients had increased interstitial fibrosis and tubular atrophy (IFTA) scores at the 6-month protocol biopsy (IFTA group). The mean level of urinary TG2 in the IFTA group was higher compared to that of 5 other recipients without IFTA (no IFTA group). Conversely, the mean level of urinary syndecan-4 in the IFTA group was lower than levels in patients without IFTA. In the IFTA group, double immunofluorescent staining revealed that TG2 intensity was significantly upregulated and colocalizations of TG2/heparin sulfate proteoglycan and nuclear syndecan-4 were prominent, usually around tubular structures. CONCLUSION: Urinary TG2 in early posttransplant periods is a potent biomarker for kidney allograft inflammation or fibrosis.

Diverse Immunoprofile of Ductal Adenocarcinoma of the Prostate with an Emphasis on the Prognostic Factors

BACKGROUND: Ductal adenocarcinoma (DAC) of the prostate is an uncommon histologic subtype whose prognostic factors and immunoprofile have not been fully defined. METHODS: To define its prognostic factors and immunoprofile, the clinicopathological features, including biochemical recurrence (BCR), of 61 cases of DAC were analyzed. Immunohistochemistry was performed on tissue microarray constructs to assess the expression of prostate cancer-related and mammalian target of rapamycin (mTOR) signaling-related proteins. RESULTS: During the median follow-up period of 19.3 months, BCR occurred in 26 cases (42.6%). DAC demonstrated a wide expression range of prostate cancer-related proteins, including nine cases (14.8%) that were totally negative for pan-cytokeratin (PanCK) immunostaining. The mTOR signaling-related proteins also showed diverse expression. On univariate analysis, BCR was associated with high preoperative serum levels of prostate-specific antigen (PSA), large tumor volume, predominant ductal component, high Gleason score (GS), comedo-necrosis, high tumor stage (pT), lymphovascular invasion, and positive surgical margin. High expressions of phospho-mTOR (p-mTOR) as well as low expressions of PSA, phospho-S6 ribosomal protein (pS6) and PanCK were associated with BCR. On multivariable analysis, GS, pT, and immunohistochemical expressions of PanCK and p-mTOR remained independent prognostic factors for BCR. CONCLUSIONS: These results suggest GS, pT, and immunohistochemical expressions of PanCK and p-mTOR as independent prognostic factors for BCR in DAC. Since DAC showed diverse expression of prostate cancer–related proteins, this should be recognized in interpreting the immunoprofile of DAC. The diverse expression of mTOR-related proteins implicates their potential utility as predictive markers for mTOR targeted therapy.

Staphylococcus-associated Glomerulonephritis / 대한내과학회지

A 64-year-old woman was admitted with vertebral osteomyelitis and polyarthritis (both knees and the right shoulder). She had had no health problems before these conditions developed. Joint culture grew methicillin-resistant Staphylococcus aureus. During hospitalization, hematuria, proteinuria, azotemia, and decreased C3 were reported. The renal biopsy showed mesangial proliferative glomerulonephritis with C3 and IgA co-dominant deposits on immunofluorescence staining. Following incision and drainage of the right shoulder and right knee, and intravenous vancomycin for 15 weeks, the C-reactive protein, proteinuria, hematuria, and C3 level all normalized. Here, we report a case of Staphylococcus-associated glomerulonephritis with a brief review of the literature.

Clinicopathological Features of Prostate Ductal Carcinoma: Matching Analysis and Comparison with Prostate Acinar Carcinoma

We evaluated the clinicopathological features and prognosis of 29 cases of prostate ductal carcinoma was considered to be an aggressive subtype of prostate acinar carcinoma. We selected 29 cases who were diagnosed prostate ductal carcinoma and had a radical prostatectomy (RP). The acinar group (n = 116) was selected among 3,980 patients who underwent a prostatectomy. The acinar group was matched to the ductal group for prostate specific antigen (PSA), clinical stage, Gleason score, and age. The mean (range) of the follow-up periods for the ductal and acinar group was 23.8 +/- 20.6 and 58 +/- 10.5 months, respectively. The mean age of the prostate ductal and acinar carcinoma patients was 67.3 and 67.0 yr and the mean PSA level was 14.7 and 16.2 ng/mL, respectively. No statistical differences were evident between groups in terms of the final pathologic stage or positive resection margin rate other than the postoperative Gleason score. A greater proportion of the ductal group demonstrated a postoperative Gleason score > or = 8 in comparison with the acinar group (P = 0.024). Additionally, we observed significant prognostic difference in our patient series in biochemical recurrence. The ductal group showed a poorer prognosis than the acinar group (P = 0.016). There were no differences significantly in terms of final pathology and rate of positive resection margin, but a greater proportion of the ductal group demonstrated a Gleason score > or = 8 than the acinar group after matching for PSA, Gleason score in biopsy and clinical stage. The ductal group also showed a poorer prognosis.

Clinical Significance of Substaging and HER2 Expression in Papillary Nonmuscle Invasive Urothelial Cancers of the Urinary Bladder

The study aimed to verify the prognostic utility, therapeutic application and clinical benefits of tumor substaging and HER2 status in papillary non-muscle invasive bladder cancer (NMIBC). Select NMIBC transurethral resection specimens from 141 patients were used to construct tissue microarrays for assessing the substaging, HER2 protein expression by immunohistochemistry (HER2-IHC) and gene amplification by dual-color silver in situ hybridization (HER2-SISH). Substages were identified by the differing depth of tumor invasion (pTa / pT1a / pT1b / pT1c). HER2 protein expression was semiquantitatively analyzed and grouped into negative (score 0, 1+) and positive (score 2+, 3+). Other clinicopathological variables were also investigated. For NMIBC, HER2-IHC and HER2-SISH showed positive results in 6/141 (4.3%) and 4/141 (2.8%) respectively, which correlated well with tumor substaging. In multivariate analysis, substaging, HER2-IHC, and HER2-SISH were found to be independent predictors of progression-free survival (P < 0.001, P < 0.001, P = 0.031). HER2-IHC was the sole independent predictor of recurrent free survival in NMIBC (P = 0.017). It is suggested that tumor substaging and HER2 status are independent predictive markers for tumor progression or recurrence, and thus could be included in diagnostic and therapeutic management for NMIBC.

Clinicopathological features of Xp11.2 translocation renal cell carcinoma

PURPOSE: Xp11.2 translocation renal cell carcinoma (RCC) is characterized by various translocations of the TFE3 transcription factor gene. These rare cancers occur predominantly in children and young adults. Here, we review the clinicopathological features of Xp11.2 translocation RCC. MATERIALS AND METHODS: We identified 21 patients with Xp11.2 translocation RCC. We retrospectively analyzed patient characteristics, clinical manifestations, and specific pathological features to assess definitive diagnosis, surgical and systemic treatments, and clinical outcomes. RESULTS: The mean age at diagnosis was 43.4+/-20.0 years (range, 8-80 years; 8 males and 13 females). Eleven patients were incidentally diagnosed, nine patients presented with local symptoms, and one patient presented with systemic symptoms. The mean tumor size was 6.2+/-3.8 cm (range, 1.9-14 cm). At the time of diagnosis, 11, 1, and 5 patients showed stage I, II, and III, respectively. Four patients showed distant metastasis. At analysis, 15 patients were disease-free after a median follow-up period of 30.0 months. Four patients received target therapy but not effectively. CONCLUSIONS: Xp11 translocation RCC tends to develop in young patients with lymph node metastasis. Targeted therapy did not effectively treat our patients. Surgery is the only effective therapy for Xp11 translocation RCC, and further studies are needed to assess systemic therapy and long-term prognosis.

Concurrent Thin Basement Membrane Disease and Minimal Change Disease: A Case Report / 대한내과학회지

Thin basement membrane disease is defined as diffuse thinning of the glomerular basement membrane, and is clinically characterized by persistent hematuria, minimal proteinuria, normal renal function, and a benign course. It can occur together with other glomerular diseases. We experienced a case of thin basement membrane disease concurrent with minimal-change disease. Treatment with corticosteroid resulted in improved proteinuria and peripheral edema during the follow-up period.

Practical Standardization in Renal Biopsy Reporting

BACKGROUND: To standardize renal biopsy reporting and diagnosis, The Renal Pathology Study Group of the Korean Society of Pathologists (RPSKSP) has developed a renal pathology reporting format for the native and allograft kidney. METHODS: A consensus checklist of a provisional renal biopsy format was sent to all members of the RPSKSP. Feed back opinions regarding the practical application of the checklist to the diagnostic work were received. RESULTS: Kidney biopsies require three essential examinations: by light microscopy, immunofluorescence (IF), and electron microscopy (EM). A final report of a renal biopsy should include information on specimen adequacy and a description of the morphologic change using a systematic semiquantitative method for each of the compartments, with optional separate IF and EM reports. CONCLUSIONS: A standard renal biopsy report format is important in establishing clinicopathologic correlations, making reliable prognostic considerations, comparing the findings in sequential biopsies and evaluating the effects of therapy.

A Case of Multiple Venous Thrombosis as the First Manifestation of Lupus Nephritis / 대한신장학회지

Kidney involvement in systemic lupus erythematosus (SLE) is common. The incidence of venous thrombosis in SLE ranges from 5-15%, and venous thrombosis in lupus nephritis associated with nephritic syndrome or antiphospholipid antibody syndrome is reported in 30-35%. Lupus nephritis with nephrotic syndrome is not infrequently encountered at the point of diagnosis of SLE, but venous thrombosis as the first manifestation of SLE is rare. Herein we present our clinical experience with a case of multiple venous thrombosis with nephrotic-range proteinuria as the first manifestation of lupus nephritis.

Intravenous Immunoglobulin Treatment in a Kidney Transplant Patient with Chronic Antibody-Mediated Rejection / 대한신장학회지

A 66-year-old male was admitted for increasing azotemia. He was diagnosed with chronic antibody- mediated rejection and had received a livingdonor renal transplant from his 32-year-old son prior to his admission. The peritubular capillaries of his kidney were diffusely positive on C4d immunostaining. It is known that there is an agreement between C4d staining and serological and histopathological data during rejection that is thought to have a humoral component. The role of alloantibodies in chronic renal allograft deterioration and the corresponding morphologic changes have been increasingly recognized during the recent years. However the treatment guidelines for chronic antibody-mediated rejection have not yet been established. Intravenous immunoglobulin (IVIG) has been shown to decrease the titers of anti-HLA antibodies in highly sensitized patients awaiting transplant. There are also numerous proposed mechanisms regarding how IVIG exerts its immunomodulatory action. As we have experienced chronic antibody-mediated rejection and how IVIG treatment improves renal function, we recognize that IVIG has the potential to be used for treating certain subgroups of chronic allograft nephropathy patients with positive C4d staining and anti-HLA antibodies.

A Case of Light Chain Deposition Disease Involving Kidney and Bone Marrow with Microangiopathic Hemolytic Anemia / 대한진단검사의학회지

We report a case of light chain deposition disease in a 59-yr-old female showing deposition of monoclonal light chain in the kidney and bone marrow accompanied with a schistocytosis, the morphologic finding of microangiopathic hemolytic anemia. The immunofluorescence examination of the kidney revealed strongly stained kappa-light chain deposits on the glomerular mesangium and capillary wall, tubules, and vessel wall. The electron microscopy demonstrated electron-dense deposits on the glomerular basement membrane and mesangium. Anemia was observed with schistocytosis and Howell-Jolly body in the peripheral blood smears. The immunohistochemical examination of the bone marrow showed the presence of kappa-light chain deposits in scattered plasma cells and thickened vessel wall in the absence of a prominent plasma cell proliferation. Although an immunofixation electrophoresis failed to detect a monoclonal gammopathy, the presence of monoclonal protein could be identified by an abnormal kappa/lambda ratio on the serum free light chain analysis.

Second Opinion Diagnoses of Cytologic Specimens on Consultation : Asan Medical Center Experience / 대한세포병리학회지

BACKGROUND: Second opinion diagnosis of outside pathology slides is a common practice for efficient and proper patient management. We analyzed cytology slides from outside hospitals submitted for a second opinion diagnosis to determine whether the second opinion diagnosis had any influence on patient care. METHODS: We reviewed 1,153 outside cytology slides referred to Asan Medical Center for second opinions from January, 2007, to December, 2007. All cases were categorized into three groups; no diagnostic discrepancy, minor diagnostic discrepancies (no impact on the management), and major diagnostic discrepancies (significant impact on the management and subsequent follow-up). RESULTS: The thyroid was the most common organ system (933 cases, 80.9%). Forty cases (3.6%) belonged to the major diagnostic discrepancy group and 149 cases (12.8%) to the minor discrepancy group. For validation of second opinion diagnoses in major discrepancy cases, subsequent biopsy or surgical resection specimens and clinical information were reviewed, which were available in 29 cases. The second opinion diagnoses resulted in alteration of clinical management in 21 of 29 cases. CONCLUSION: For all referred patients, second opinion diagnosis is important and mandatory for appropriate patient care.

Immunohistochemical Markers for Metastasis in Clear Cell Renal Cell Carcinoma

BACKGROUND: Renal cell carcinoma (RCC) is notorious for its high metastatic potential, and 30% of RCC patients present with metastatic disease at the initial presentation and 50% of them will develop metastasis or recurrence after radical surgery. METHODS: In an attempt to identify the best predictive marker(s) for metastasis in patients with clear cell RCCs (CRCCs), we examined the expression patterns of 7 metastasis/prognosis-related markers by constructing a tissue microarray including primary CRCC specimens from 30 metastatic and 60 nonmetastatic CRCCs. The markers we studied were Ki-67, MUC1, CD44s, PTEN, gelsolin, CA9 and p53. RESULTS: The expressions of Ki-67, PTEN, CD44s, gelsolin and p53 were increased, whereas those of MUC1 and CA9 were decreased in the metastatic CRCCs compared with the non-metastatic CRCCs. The receiver operating characteristic curve-area under the curve (AUC) value of Ki-67 was 0.671, which was the highest among the 7 markers. The optimal cut-off value, sensitivity and specificity of the Ki-67 expression were 1.67%, 86.7% and 41.7%, respectively. CONCLUSIONS: These results demonstrate that the Ki-67 expression was increased in metastatic CRCCs, and it had the highest predictive value among the 7 markers. This suggests that Ki-67 could be an excellent predictive marker for metastasis in CRCC patients.

Concurrent IgA Nephropathy and Minimal Change Disease in a Patient with Polycythemia Vera: A Case Report / 대한신장학회지

Polycythemia vera is a hematopoietic stem cell disease, characterized by sustained and excessive proliferation of erythrocytic, granurocytic and megakaryocytic cells in the bone marrow resulting in pancytosis in peripheral blood. There have been a few reports of glomerulonephritis with polycythemia vera, most of which were IgA nephropathy. We report a case of a polycythemia vera associated with proteinuria. We confirmed the polycythemia vera according to World Health Organization criteria. Renal pathology showed IgA nephropathy and minimal change disease. Periodic phlebotomy was done and hydroxyurea was administered without specific managements for renal disease. After 3-month treatment, hemoglobin level decreased and proteinurea disappeared.

A Case of Nephrotic Syndrome after Thymectomy due to Thymoma / 대한신장학회지

Thymoma is often accompanied by different paraneoplastic syndrome, such as myasthenia gravis, pure red-cell aplasia, systemic lupus erythematosus. Association of glomerulonephritis and thymic tumor is very rare, with only about 40 cases reported to date. The authors report here a case of nephrotic syndrome after thymectomy due to thymoma. A 68-year-old man presented with continuous coughing and mediastinal mass. The mass was found to be a thymoma of type AB and was resected completely. One month after removal of the thymoma, nephrotic syndrome appeared. Renal biopsy revealed diffuse foot process effacement, suggesting minimal change disease (MCD), with a focus of intraglomerular coagulation, suggesting thrombotic microangiopathy. There was no evidence of other autoimmune disease or causes of the nephropathy. Treatment with 500 mg methylprednisolone IV for three days followed by oral 60 mg prednisolone daily was started. After six weeks, his nephrotic syndrome was almost improved. To our knowledge, this is the second report of a patient with thymoma and MCD in Korea.