OGT and FLAD1 Genes Had Significant Prognostic Roles in Progressive Pathogenesis in Prostate Cancer.

PURPOSE: This study aimed to identify metabolic genes associated with non-metastatic prostate cancer progression using The Cancer Genome Atlas (TCGA) datasets and validate their prognostic role by assessing patients' immunohistochemical prostatectomy specimens. MATERIALS AND METHODS: Several metabolic candidate genes analyzed were highly correlated with cancer progression to biochemical recurrence (BCR) and deaths in 335 patients' genetic information from TCGA datasets. Those candidate genes and their expressions in tissue specimens were validated retrospectively by immunohistochemical analysis of radical prostatectomy specimens collected from 514 consecutive patients with non-metastatic prostate cancer between 2000 and 2015. The Cox proportional-hazards model was used to predict the prognostic role of each candidate gene expression in BCR and survival prognoses with a statistical significance of p-value <0.05. Twenty metabolic genes were identified by own developed software (Targa; https://github.com/cgab-ncc/TarGA), whose median expression levels consistently increased with cancer progression to the BCR and deaths. RESULTS: Five metabolic genes (MAT2A, FLAD1, UGDH, OGT, and RRM2) were found to be significantly involved in the overall survival in the TCGA dataset. The immunohistochemical validation and clinicopathological data showed that OGT (hazard ratio [HR], 1.002; 95% confidence interval [CI], 1.001-1.003) and FLAD1 (HR, 1.010; 95% CI, 1.003-1.017) remained significant factors for BCR and cancer-specific survival, respectively, in the multivariate analysis even after adjusting for confounding clinicopathological parameters (p<0.05). CONCLUSIONS: OGT and FLAD1 showed significant prognostic factors of disease progression, even after adjustment for confounding clinicopathological parameters in non-metastatic prostate cancer.

Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients With Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study.

PURPOSE: Intravesical mitomycin-C is recommended immediately after transurethral resection of bladder tumor for nonmuscle-invasive bladder cancer. However, a lack of compliance occurs due to the associated complications. Here, we aimed to assess the efficacy and safety of intravesical mitomycin-C before transurethral resection of bladder tumor in patients with nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This was a single-center, open-label, parallel-arm, randomized phase II clinical trial in patients with suspected nonmuscle-invasive bladder cancer before transurethral resection of bladder tumor. Participants were randomly assigned (1:1) to receive 2 doses of intravesical mitomycin-C (40 mg/20 mL) 1 day and 4 hours before transurethral resection of bladder tumor (n = 49) or no treatment (n = 50) with block randomization (size 2 and 4), stratified by bacillus Calmette-Guérin/intravesical mitomycin-C. The primary endpoint was recurrence-free survival and secondary endpoints were progression-free survival and adverse events in the per-protocol analysis. RESULTS: Seventy-one patients (33, intervention; 38, control) were well matched for baseline characteristics. Sixty-one had been followed without recurrence for at least 10.4 months; 3 and 8 patients showed recurrence in the intervention and control groups, respectively. The 1-year recurrence-free survival rate was 97% and 89% for the intervention and control groups, respectively. Neoadjuvant intravesical mitomycin-C resulted in a reduction (63%) in the relative recurrence risk (hazard ratio, 0.37; 80% 1-sided confidence interval, -∞-0.65, P = .11). Disease progression occurred in 3 patients in the control group (P = .051) but not in the intervention group. Neoadjuvant intravesical mitomycin-C was well tolerated, and adverse events were local and of grade 1/2. CONCLUSIONS: Two doses of neoadjuvant intravesical mitomycin-C are safe and effective in reducing nonmuscle-invasive bladder cancer recurrence and progression after transurethral resection of bladder tumor.

A retrospective single-centered, comprehensive targeted genetic sequencing analysis of prognostic survival using tissues from Korean patients with metastatic renal cell carcinoma after targeted therapy.

PURPOSE: To identify candidate gene mutations to significantly predict the risk of survival prognosis after treatment with systemic first-line targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) patients. MATERIALS AND METHODS: Between 2005 and 2017, 168 triplet-tissue block samples from 56 mRCC patients were selected for targeted gene sequencing (TGS). Fifty-six patients' medical records including overall survival (OS) and progression-free survival (PFS) at the time of mRCC diagnosis were evaluated. The patients were grouped into favorable (>12 months/>3 years), intermediate (3-12/12-36 months), and poor groups according to their PFS/OS (<3 months/<12 months). We identified any significant therapeutic targeted genes relating to the survival with a significance at p<0.050. RESULTS: The first line therapeutic response showed 1.8% complete remission, 14.2% partial response, 42.9% stable disease, and 41.1% progressive disease. Among the overall TGS results, the cumulative effect of CDH1, and/or PTK2 genes significantly reflected the therapeutic responses in terms of PFS/OS; CDH1 and PTK2 mutations were associated with poor prognostic outcomes (p<0.050). Among only triplet-quality check passed tissues, the SGO2, BRAF, URB1, and NEDD1 mutated genes significantly correlated with OS. Regarding metastasis, patients with liver metastasis had the worst OS (p=0.050). The combinational mutation number from these two candidate genes in the liver metastatic samples with mutated EGFR2 and FABP7 also showed a significantly worse OS than those with other metastatic lesions (p<0.050). CONCLUSIONS: This study reports several significant mutated genes related to the survival prognosis in mRCC patients treated with first-line TT.

Rapid Androgen-Responsive Proteome Is Involved in Prostate Cancer Progression.

Androgen exerts its functions by binding with an androgen receptor (AR). It can activate many signaling pathways that are important to the progression of castration-resistant prostate cancer (CRPC). Here, we characterized the rapid proteomic changes seen at 5, 15, 30, and 60 min after the androgen treatment of VCaP cells via the tandem mass tag (TMT) labeling strategy. A total of 5529 proteins were successfully identified and quantified. Dynamic time profiling of protein expression patterns allowed us to identify five protein clusters involved in various stages of androgen-initiated signal transmission and processing. More details of protein functions and localization patterns, and our elucidation of an AR-interacting protein network, were obtained. Finally, we validated the expression level of AR-regulated proteins known to be significantly regulated in CRPC patients using the mouse xenograft model and patient samples. Our work offers a systematic analysis of the rapid proteomic changes induced by androgen and provides a global view of the molecular mechanisms underlying CRPC progression.

RRM1 Expression as a Prognostic Biomarker for Unresectable or Recurrent Biliary Tract Cancer Treated with Gemcitabine plus Cisplatin.

The combination of gemcitabine plus cisplatin (GP) is regarded as a first-line treatment for patients with unresectable or recurrent biliary tract cancer (BTC). Several proteins including human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (DCK), cytidine deaminase (CDA), and ribonucleotide reductase subunit 1 (RRM1) are known to be involved in gemcitabine uptake and metabolism. This study was aimed to identify the predictive and prognostic values of these biomarkers in patients who treated with GP for advanced BTC. Tumor samples were obtained from 34 patients with unresectable or recurrent BTC who were treated with GP between August 2015 and February 2018. Intratumoral expression of hENT1, DCK, CDA and RRM1 was determined by immunohistochemistry and analyzed for association with chemotherapy response, progression-free survival (PFS) and overall survival (OS). Median OS was significantly longer in the RRM1-negative group than in the RRM1-positive (9.9 months vs. 5.9 months, p = 0.037). Multivariate adjustment analyses also demonstrated RRM1 expression as an independent prognostic factor for OS in patients treated with GP chemotherapy. Increased intratumoral expression of RRM1 on immunohistochemical staining may be a biomarker predicting poor survival in patients with GP chemotherapy for advanced BTC. Large-scale well-predefined prospective research is needed to validate the utility of biomarkers in clinical practice.

Association Between Antibiotic Treatment and the Efficacy of Intravesical BCG Therapy in Patients With High-Risk Non-Muscle Invasive Bladder Cancer.

OBJECTIVE: To investigate the association between antibiotic therapy and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). METHODS: This study involved the retrospective review of medical records of patients who underwent transurethral resection of bladder tumors for high-risk NMIBC followed by intravesical BCG therapy between 2008 and 2017. Patients were categorized as none, short- (2-6 days), and long-course use (≥7 days) based on the duration of antibiotic treatment concurrent with or initiated ≤30 days before BCG therapy. Oncologic outcomes, including recurrence-free survival and progression-free survival, were analyzed. RESULTS: Of the 276 patients enrolled in the study, 162 (58.7%) had pathologic T1 disease and 206 (80.2%) had high-grade disease. Concurrently with or prior to BCG therapy, 114 patients had (41.3%) received short-course antibiotic therapy, and 96 (34.8%) patients had received long-course antibiotics. The 5-year recurrence-free survival (62.2% vs 26.9%; log rank, p <0.001) and progression-free survival (79.6% vs. 53.3%; log rank, p=0.001) rates were significantly higher in patients who did not receive antibiotic therapy than in those treated with long-course antibiotics. Multivariable analysis revealed that antibiotic treatment for more than 7 days was independently associated with increased risks of recurrence (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.49-4.05; p < 0.001) and progression (HR, 3.68; 95% CI, 1.65-8.22 p = 0.001). CONCLUSION: Long-course antibiotic treatment concurrently with or prior to intravesical BCG adversely influenced disease recurrence and progression outcomes in patients with high-risk NMIBC. Careful use of antibiotics may be required to enhance the efficacy of intravesical BCG therapy. Further mechanistic and prospective studies are warranted.

High level of pre-treatment C-reactive protein to albumin ratio predicts inferior prognosis in diffuse large B-cell lymphoma.

The C-reactive protein-to-albumin ratio (CAR) has not been assessed in diffuse large B cell lymphoma (DLBCL, the most common non-Hodgkin lymphoma). This retrospective study evaluated the prognostic value of CAR in 186 DLBCL patients. A CAR value of 0.158 was selected as the most discriminative cut-off for identifying patients with high CAR values (73/141 patients, 51.8%). During a median follow-up of 32.5 months, the high CAR group had significantly poorer complete response to induction therapy (64.4% vs. 92.6%; p < 0.001), 3-year overall survival (OS) (68.3% vs. 96.2%; p < 0.0001), and 3-year progression-free survival (PFS) (53.5% vs. 88.0%; p < 0.0001). After adjusting for the International Prognostic Index components, a high CAR value independently predicted poor OS (HR: 6.02, 95% CI 1.19-30.38; p = 0.030) and PFS (HR: 3.62, 95% CI 1.40-9.36; p = 0.008). In an independent validation cohort (n = 50), patients with CAR > 0.158 also showed worse 3-year OS (47.9% vs. 87.2%, p = 0.0035) and 3-year PFS (36.1% vs. 82.1%, p = 0.0011). A high CAR remained significantly associated with poor outcomes for > 60-year-old patients (OS: p = 0.0038, PFS: p = 0.0015) and younger patients (OS: p = 0.0041, PFS: p = 0.0044). Among older patients, a high CAR value also predicted non-relapse mortality (p = 0.035). Therefore, the CAR might complement the International Prognostic Index in DLBCL cases.

Epithelial Splicing Regulatory Protein (ESPR1) Expression in an Unfavorable Prognostic Factor in Prostate Cancer Patients.

BACKGROUND: To evaluate the role of epithelial splicing regulatory protein 1 (ESRP1) expression in survival prognoses and disease progression for prostate cancer (PC) using The Cancer Genome Atlas (TCGA) dataset and to validate it using patients' prostatectomy specimens. METHODS: A preliminary investigation into the clinical significance of ESRP1 in PC was conducted using TCGA PC PRAD dataset and then using immunohistochemistry in 514 PC patients' tissue microarrays of radical prostatectomy specimens. The interpretation of immunohistochemistry was done using its intensity (high vs. low) or the semi-quantitative expression value (H-score, 0-300). The prognostic significance of ESRP1 expression was analyzed for biochemical recurrence (BCR), recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) using the Cox proportional-hazards model (p < 0.05). RESULTS: In the publicly available prostate adenocarcinoma dataset, ESRP1 expression was significantly higher in the tumor samples compared to the normal samples (p < 0.001). Survival analysis showed that the tumor samples in the ESRP1-high group had significantly worse BCR-free survival and RFS compared to the ESRP1-low group (p < 0.05), whereas OS was not (p=0.08). These results were largely consistent with the 514 patients' clinical data during a median 91.2 months of follow-up. After adjusting for significant prognostic clinicopathological factors, the multivariable models showed that the ESRP1 was a significantly risk factor for CSS (Hazard ratio 3.37, p = 0.034) and for BCR (HR 1.34, p=0.049) without any significance for OS (p=0.464). CONCLUSIONS: The higher ESRP1 expression appeared increased risk of disease progression and cancer-specific death in PC.

Prognostic Implication of SOX2 Expression Associated with p16 in Oropharyngeal Cancer: A Study of Consecutive Tissue Microarrays and TCGA.

For oropharyngeal squamous cell carcinoma (OPSCC), there are not enough additional robust biomarkers for subgrouping after the distinct classification using p16. As SOX2 is an emerging biomarker for cancer treatment, its clinical implication in OPSCC was evaluated using a consecutive tissue microarray (TMA) cohort consisting of 111 patients who underwent surgery as an initial treatment from May 2002 to December 2016 and 79 patients in The Cancer Genome Atlas (TCGA) dataset. In both datasets, p16+/SOX2High (HPV+/SOX2High in TCGA) showed the best prognosis among the four groups classified by SOX2 and p16 for 5-year overall survival (OS) and recurrence (all p < 0.05), but SOX2 did not make a significant difference in the prognosis of the p16- group. In the TMA cohort, SOX2High was significantly correlated with response to radiotherapy and lower pathologic T classification in the p16+ group (p = 0.001). In TCGA, correlations between SOX2 and tumor stage classification or radiotherapy were not observed; however, HPV+/SOX2High had a significantly low tumor mutation burden among the four groups (all p < 0.05). In summary, SOX2 was proven to be a potential marker to predict overall survival and recurrence in p16+ OPSCC. However, the role of SOX2 has not yet been confirmed in p16- OPSCC patients.

Analysis of the concordance of 20 immunohistochemical tissue markers in metastasectomy lesions in patients with metastatic renal cell carcinoma: A retrospective study using tissue microarray.

Purpose: This study aimed to characterize the different expressions of 20 tissue markers in multiple metastatic lesions and organs in patients with metastatic renal cell carcinoma (mRCC). Materials and Methods: Sixty-six patients with mRCC, harboring 162 metastasectomy tissue lesions (MTLs), were enrolled. Immunohistochemical analysis for the following tissue markers was performed: BAP1; CD31; CD 34; HIF1α and 2α; Ki67; pS6; PBRM1; PDGFRα and ß; PDL1; PSMA; PTEN; α-SMA; TGase2; VEGFR1, 2, and 3; VHL loss; and CA9. Cases were identified pathologically using the semi-quantitative H-score (0-300), including the intensity score (0, 1, 2, 3). The concordance rate was calculated as the number of patients with concordant binary score out of the total number of patients in that comparison. Results: The specimens from 66 patients were divided into those from the same organs and those from different organs. Forty-two patients (44 cases) with 96 MTLs and 39 with 83 MTLs were examined. Among the 20 tissue markers, only BAP1, PSMA, VEGFR3, PDGFRα, and pS6 tissue showed high concordance ratio (>0.7) regardless of different metastatic tissues and different metastatic lesions within the tumor. Conclusions: The study demonstrated the intratumoral heterogeneity of mRCC with a low-concordance index of most tissue markers. However, some had high concordance with a similar expression regardless of the metastatic organs, metastatic sites, or presence of recurrence.

Quantitative analysis of tumor-specific BCL2 expression in DLBCL: refinement of prognostic relevance of BCL2.

BCL2 overexpression has been reported to be associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL). However, currently there is no consensus on the evaluation of BCL2 expression and only the proportion of BCL2 positive cells are evaluated for the determination of BCL2 positivity. This study aimed to define BCL2 positivity by quantitative analysis integrating both the intensity and proportion of BCL2 expression. BCL2 expression of 332 patients (221 patients for the training set and 111 patients for the validation set) with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were analyzed using the tumor-specific automated quantitative analysis (AQUA) scoring method based on multiplex immunofluorescence. In the training set, high BCL2 AQUA score (N = 86, 38.9%) was significantly associated with poor prognosis (p = 0.01, HR 2.00; 95% CI [1.15-3.49]) independent of international prognostic index, cell of origin, and MYC expression. The poor prognostic impact of the high BCL2 AQUA score was validated in the validation set. AQUA scoring of BCL2 expression incorporating both the intensity and proportion of BCL2 positive cells was independently associated with survival outcomes of patients with primary DLBCL treated with R-CHOP.

Successful Sirolimus Treatment for Korean Patients with Activated Phosphoinositide 3-kinase δ Syndrome 1: the First Case Series in Korea.

Activated phosphoinositide 3-kinase δ syndrome (APDS)1 is caused by gain-of-function mutations in PIK3CD, which encodes the catalytic p110δ subunit of phosphoinositide 3 kinase. We describe three patients with APDS1, the first thereof in Korea. Therein, we investigated clinical manifestations of APDS1 and collected data on the efficacy and safety profile of sirolimus, a mammalian target of rapamycin inhibitor and pathway-specific targeted medicine. The same heterozygous PIK3CD mutation was detected in all three patients (E1021K). After genetic diagnosis, all patients received sirolimus and experienced an excellent response, including amelioration of lymphoproliferation and improvement of nodular mucosal lymphoid hyperplasia in the gastrointestinal tract. The median trough level of sirolimus was 5.5 ng/mL (range, 2.8-7.5) at a dose of 2.6-3.6 mg/m². Two patients who needed high-dose, short-interval, immunoglobulin-replacement treatment (IGRT) had a reduced requirement for IGRT after initiating sirolimus, and the dosing interval was extended from 2 and 3 weeks to 4 weeks. The IgG trough level after sirolimus treatment (median, 594 mg/dL; range, 332-799 mg/dL) was significantly higher than that before sirolimus treatment (median, 290 mg/dL; range, 163-346 mg/dL) (p<0.001). One episode of elevated serum creatinine with a surge of sirolimus (Patient 2) and episodes of neutropenia and oral stomatitis (Patient 1) were observed. We diagnosed the first three patients with APDS1 in Korea. Low-dose sirolimus may alleviate clinical manifestations thereof, including hypogammaglobulinemia.

Identification of Significant Prognostic Tissue Markers Associated with Survival in Upper Urinary Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy: A Retrospective Immunohistochemical Analysis Using Tissue Microarray.

PURPOSE: The purpose of this study was to identify prognostic tissue markers for several survival outcomes after radical nephroureterectomy among patients with upper urinary tract urothelial carcinoma using tissue microarray and immunohistochemistry. MATERIALS AND METHODS: Retrospectively, data of 162 non-metastatic patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy between 2004 and 2016 were reviewed to determine intravesical recurrence-free survival (IVRFS), disease-free survival (DFS), and overall survival (OS). The expression of 27 tissue markers on a tissue microarray of radical nephroureterectomy samples and prognostic values of clinicopathological parameters were evaluated using immunohistochemistry and Cox proportional hazard models after adjusting for significant prognostic clinicopathological variables. The expression of all tissue markers was categorized into a binary group with continuous H-scores (0-300). RESULTS: Median follow-up was 53.4 months (range, 3.6 to 176.5 months); and, 58 (35.8%), 48 (29.6%), and 19 (11.7%) bladder recurrence, disease progression, and all cause death, respectively, were identified. After adjusting for significant clinicopathological factors including intravesical instillation for bladder recurrence-free survival, pathologic T category and intravesical instillation for disease progression-free survival , and pathologic T category for OS (p < 0.05), IVRFS was associated with epithelial cadherin (hazard ratio [HR], 0.49), epidermal growth factor receptor/erythroblastosis oncogene B (c-erb) (HR, 2.59), and retinoblastoma protein loss (HR, 1.85); DFS was associated with cyclin D1 (HR, 2.16) and high-molecular-weight cytokeratin (HR, 0.42); OS was associated with E-cadherin (HR, 0.34) and programmed cell death 1 ligand (HR, 13.42) (p < 0.05). CONCLUSION: Several significant tissue markers were associated with survival outcomes in upper urinary tract urothelial carcinoma patients treated with radical nephroureterectomy.

Association between Postoperative Detection of Circulating Tumor Cells and Recurrence in Patients with Prostate Cancer.

PURPOSE: The clinical implications of postoperative detection of circulating tumor cells in prostate cancer are largely unknown. We investigated the association between postoperative circulating tumor cell detection after radical prostatectomy and disease recurrence in prospectively enrolled patients with prostate cancer. MATERIALS AND METHODS: A total of 203 patients with an undetectable prostate specific antigen who had undergone radical prostatectomy for prostate cancer were prospectively enrolled. Circulating tumor cell sampling was performed at a median of 4.5 months after surgery. The primary end point was biochemical recurrence-free survival. Detection of circulating tumor cells in the blood of patients was performed using a novel approach with a replication-competent adenovirus controlled by prostate specific antigen/prostate specific membrane antigen transcription regulatory elements (Ad5/35E1aPSESE4). RESULTS: Circulating tumor cells were detected in 73 (36.0%) patients with undetectable prostate specific antigen concentrations after surgery. The 3-year biochemical recurrence-free survival rate from the time of surgery was significantly higher in circulating tumor cell-negative than in circulating tumor cell-positive cases (81.6% vs 48.9%, log rank p <0.001). Multivariable analysis showed that postoperative circulating tumor cell detection was independently associated with an increased risk of biochemical recurrence (HR 5.42, 95% CI 3.24-9.06, p <0.001). C-index was increased in combinations of multivariable model and postoperative circulating tumor cell detection compared with the multivariable model alone. CONCLUSIONS: Circulating tumor cells in the blood were frequently detected in patients with undetectable prostate specific antigen levels after radical prostatectomy for localized prostate cancer. Furthermore, circulating tumor cell detection was associated with an increased risk of biochemical recurrence, suggesting that circulating tumor cell detection precedes prostate specific antigen rise after surgery in cases of prostate cancer recurrence. Large-scale validation is needed in the future.

Androgen-induced expression of DRP1 regulates mitochondrial metabolic reprogramming in prostate cancer.

Androgen receptor (AR) signaling plays a central role in metabolic reprogramming for prostate cancer (PCa) growth and progression. Mitochondria are metabolic powerhouses of the cell and support several hallmarks of cancer. However, the molecular links between AR signaling and the mitochondria that support the metabolic demands of PCa cells are poorly understood. Here, we demonstrate increased levels of dynamin-related protein 1 (DRP1), a mitochondrial fission mediator, in androgen-sensitive and castration-resistant AR-driven PCa. AR signaling upregulates DRP1 to form the VDAC-MPC2 complex, increases pyruvate transport into mitochondria, and supports mitochondrial metabolism, including oxidative phosphorylation and lipogenesis. DRP1 inhibition activates the cellular metabolic stress response, which involves AMPK phosphorylation, induction of autophagy, and the ER unfolded protein response, and attenuates androgen-induced proliferation. Additionally, DRP1 expression facilitates PCa cell survival under diverse metabolic stress conditions, including hypoxia and oxidative stress. Moreover, we found that increased DRP1 expression was indicative of poor prognosis in patients with castration-resistant PCa. Collectively, our findings link androgen signaling-mediated mitochondrial dynamics to metabolic reprogramming; moreover, they have important implications for understanding PCa progression.

Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30-Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial.

PURPOSE: The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30-expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit. MATERIALS AND METHODS: This phase II study (Clinicaltrials.gov: NCT02280785) enrolled relapsed or refractory high-CD30-expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ≥ 30% tumor cells positive for CD30 by immunohistochemistry. RESULTS: High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%). In a post-hoc analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1- negative patients showed a higher response (55.6%, 5/9) than MUM1-positive patients (13.3%, 2/15). CONCLUSION: BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.

A Retrospective Analysis of the Impact of Metastasectomy on Prognostic Survival According to Metastatic Organs in Patients With Metastatic Renal Cell Carcinoma.

This study evaluated the effects of metastasectomy on overall survival (OS) and progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC) according to metastatic organs. The medical records (2005-2017) of 273 patients with mRCC were analyzed retrospectively to evaluate OS and PFS according to metastatic organs and their metastasectomy states. The Cox proportional hazard model was used to determine the prognostic significance of metastasectomy. The Kaplan-Meier curve and log-rank test were used to compare groups with different modalities and metastatic organs at a statistical significance of p < 0.05. The overall median age was 57 years; 175 (64.3%) and 83 (30.4%) patients received cytoreductive nephrectomy and metastasectomy, respectively. The metastasectomy group was significantly younger and had a lower clinical T stage with significantly better PFS/OS (20.2/32.0 vs. 9.7/12.8 months) than that in the non-metastasectomy group (N = 190, p < 0.05). Liver with lung metastases were the worst metastatic combination for survivals in which liver metastasis was the only significant unfavorable risk factor for both PFS (HR 1.67) and OS (HR 1.74) (p < 0.05). Multivariable analysis confirmed that metastasectomy was a significant favorable risk factor for PFS (HR 0.70) and OS (HR 0.56) (p < 0.05) along with non-clear cell type (HR 0.61 for PFS), whereas the nuclear grade and poor Heng risk group were unfavorable risk factors (HR > 2.0) for both PFS and OS (p < 0.05). Metastasectomy and the affected metastatic organs significantly influenced prognostic survival in mRCC.

SETD2, GIGYF2, FGFR3, BCR, KMT2C, and TSC2 as candidate genes for differentiating multilocular cystic renal neoplasm of low malignant potential from clear cell renal cell carcinoma with cystic change.

Purpose: Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) and clear cell renal cell carcinoma with cystic change (MCRCC) have different prognoses despite similar histologic characteristics. The aim of this study was to identify differentially mutated genes in resected tumor specimens from patients diagnosed with MCRNLMP and MCRCC using a kidney cancer gene panel. Materials and Methods: Between 2009 and 2016, 13 MCRNLMP and 17 MCRCC cases were selected. Tumor tissues from 5 MCRNLMP and 16 MCRCC cases were subjected to gene sequencing to detect mutations among 88 genes selected from a kidney cancer gene panel after quality control. Fisher's exact test was used to compare gene mutation profiles between the two diseases. Genes were considered to be positive for mutation according to the presence of an in-frame/frameshift deletion or insertion, missense/nonsense mutation, or multi-hit mutation. Results: During a median follow-up period of 66.2 months, there was only one case of MCRCC recurrence among all 30 patients. Target gene sequencing showed that 35 genes tended to be more frequently positive in either disease group, with six genes showing a significantly different frequency of mutation between the groups: GIGYF2 (odds ratio [OR], 5.735), FGFR3 (OR, 6.787), SETD2 (OR, 4.588), BCR (OR, 6.266), KMT2C (OR, 8.167), and TSC2 (OR, 4.474). Conclusions: Six candidate genes showed significantly different mutation patterns between MCRNLMP and MCRCC, providing insight into their pathogenic mechanisms and differential prognoses.

Single-Center Analysis of Human Papillomavirus Infection and P16INK4A Expression among Korean Patients with Penile Cancer.

PURPOSE: This study aimed to evaluate the statuses of P16INK4A expression and human papillomavirus (HPV) infection among patients with penile cancer at a single Korean institution. PATIENTS AND METHODS: Fourteen patients with penile cancer at our center were retrospectively identified and their clinicopathological data were analyzed. The patients' HPV and P16INK4A expression status (a known tumor suppressor protein) were tested using genotyping with a DNA chip assay and immunohistochemical staining, respectively. The results regarding HPV status were compared to those from another Asian study. RESULTS: The mean age at diagnosis was 60 years (range: 34-86 years). The median tumor size was 3.0 cm (range: 0.6-4.7 cm). Ten tumors were located on the penile glans. Five patients tested positive for HPV DNA (5/14, 36%) and all cases involved HPV type 16 (5/5, 100%). Positive expression of P16INK4A was observed in 6 cases (6/14, 43%). Among the HPV positive cases, 80% of cases (4/5) were also positive for P16INK4A. The prevalence of HPV infection in our study (36%) was higher than in a previous Asian study (23%). CONCLUSIONS: This is the first study to evaluate the prevalence of HPV infection and P16INK4A expression among patients with penile cancer at a single Korean institution. The prevalence of HPV (36%) was slightly higher than the results from a previous Asian study. Additional multi-center studies are needed to better understand penile cancer in Korea and to identify biomarkers that can determine high-risk cases and predict their prognosis.

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study.

BACKGROUND: NUT carcinoma is a rare aggressive disease caused by BRD4/3-NUT fusion, and C-MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines. MATERIALS AND METHODS: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907). RESULTS: Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC50 of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7-8.2 nmol/L), also showed remarkable efficacies. CONCLUSION: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment. IMPLICATIONS FOR PRACTICE: NUT carcinoma (NC) is a disease caused by BRD-NUT fusion leading to C-MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.