Publications by authors named "Chin-Lee Wu"

179 Publications

TFEB Promotes Prostate Cancer Progression Regulating ABCA2-Dependent Lysosomal Biogenesis.

Front Oncol 2021 1;11:632524. Epub 2021 Mar 1.

Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.

Transcription factor EB (TFEB), a member of the MiT family, is dysregulated in different cancers and exerts specific biological functions within the tumor microenvironment. Downregulation of TFEB induces macrophage polarization in the TME and promotes tumor progression. However, the biological role and clinical significance of TFEB in prostate cancer (PCa) remain unknown. This study aimed to identify the role of TFEB in PCa and its potential clinical value. We explored TFEB expression in PCa using public databases and verified its prognostic value using immunohistochemistry in PCa tissue samples. The results revealed that TFEB expression was up-regulated in PCa tissues and was associated with cancer metastasis. Next, overexpression of TFEB promoted PCa cell malignant behavior in and experiments. RNA-sequencing and bioinformatics analysis showed high expression of TFEB promoted lysosomal biogenesis and knockdown of TFEB expression decreased the number of lysosomes. Furthermore, the ATP-binding cassette transporter A2 (ABCA2) was identified as a target gene of TFEB, which was verified using the cleavage under targets and release using nuclease (CUT&RUN) assay and qRT-PCR. Silencing of ABCA2 reduced lysosomal biogenesis and decreased matrix metalloproteinases expression, which reduced PCa cell invasion and migration in the tumor microenvironment. Our study suggests that TFEB promotes PCa progression by regulating ABCA2 through lysosomal biogenesis and may serve as a prognostic factor or as a potential therapeutic target of PCa.
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http://dx.doi.org/10.3389/fonc.2021.632524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959325PMC
March 2021

Novel CFD modeling approaches to assessing urine flow in prostatic urethra after transurethral surgery.

Sci Rep 2021 Jan 12;11(1):663. Epub 2021 Jan 12.

Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.

Assessment of the pressure and velocity of urine flow for different diameter ratios of prostatic urethra (RPU) after transurethral surgery using computational fluid dynamics (CFD). A standardized and idealized two-dimensional CFD model after transurethral surgery (CATS-1st) was developed for post-surgery mid-voiding. Using CATS-1st, 210 examples were amplified according to an array of size [3][5][14], which contained three groups of longitudinal diameters of prostatic urethra (LD-PU). Each of these groups contained five subgroups of transverse diameters of the bladder neck (TD-BN), each with 14 examples of transverse diameters of PU (TD-PU). The pressure and velocity of urine flow were monitored through flow dynamics simulation, and the relationship among RPU-1 (TD-PU/TD-BN), RPU-2 (RPU-1/LD-PU), the transverse diameter of the vortex, and the midpoint velocity of the external urethral orifice (MV-EUO) was determined. A total of 210 CATS examples, including CATS-1st examples, were analyzed. High (bladder and PU) and medium/low (the rest of the urethra) pressure zones, and low (bladder), medium (PU), and high (the rest of the urethra) velocity zones were determined. The rapid changes in the velocity were concentrated in and around the PU. Laminar flow was present in all the examples. The vortices appeared and then gradually shrank with reducing RPU on both the sides of PU in 182 examples. In the vortex examples, minimum RPU-1 and RPU-2 reached close to the values of 0.79 and 0.02, respectively. MV-EUO increased gradually with decreasing RPU. In comparison to the vortex examples, the non-vortex examples exhibited a significantly higher (p < 0.01) MV-EUO. The developed CFD models (CATS) presented an effective simulation of urine flow behavior within the PU after transurethral surgery for benign prostatic hyperplasia (BPH). These models could prove to be useful for morphological repair in PU after transurethral surgery.
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http://dx.doi.org/10.1038/s41598-020-79505-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804846PMC
January 2021

Standardization of reporting discontinuous tumor involvement in prostatic needle biopsy: a systematic review.

Virchows Arch 2021 Mar 6;478(3):383-391. Epub 2021 Jan 6.

Department of Urology and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Discontinuous tumor involvement (DTI) is a not uncommon finding in the tumor in prostate needle core biopsies undertaken for diagnosis of prostate cancer (PCa). The objective of this review is to establish a clear definition of DTI in order to provide a standardized method of measurement which reliably reflects pathologic features and disease progression following radical prostatectomy (RP). A systematic literature search was performed using PubMed up to March 2020 to identify studies of PCa patients which included needle biopsies containing DTI and matched subsequent RP treatment with or without follow-up information. The methodology and quality of reporting of DTI are reviewed, compared, and summarized. DTI is a frequent finding in diagnostic biopsy for PCa (up to 30%). Six studies were compared by methods of measurement used for predicting pathologic features and outcomes which are observed in subsequent RP. In most cases with DTI (> 90%), intervening benign tissue in the tumor core was less than 5 mm. DTI found in the biopsy was likely to be associated with a single, irregular tumor nodule going in and out of the plane of the section, but DTI was not associated with multiple small foci of the tumor. Immunohistochemistry (IHC) also demonstrated that about 75% of cases of DTI shared an IHC profile which supports the concept that DTI most likely comes from a homogeneous tumor nodule. Furthermore, DTI was associated with positive surgical margin (PSM) and bilateral tumor in RP specimens. Compared to additive measurement (with the subtraction of intervening benign tissue), linear measurement (including intervening benign tissue) of DTI was more accurately predictive of aggressive disease in the RP including higher pT stage, PSM, and greater actual extent of the tumor. However, the advantage of linear measurement was lost in cases where there was an upgrade from the biopsy to the RP which may result from undersampling. For cases with either very small tumor foci or very extensive cancer volume, no difference was observed in these two methods of measurement. DTI in core biopsies may represent undersampling of a larger irregular nodule but likely does not result from multifocality and is similarly unlikely to represent multiclonality. Linear measurement of DTI was more accurately predictive of post-RP pathologic findings and oncologic prognosis. This method should be applied for patient selection for AS.
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http://dx.doi.org/10.1007/s00428-020-03009-xDOI Listing
March 2021

To stage or not to stage: determining the true clinical significance of the biopsy tract through perinephric fat in assessing renal cell carcinoma.

Histopathology 2020 Nov 25. Epub 2020 Nov 25.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Aims: Perinephric fat invasion (PFI) is a key component of renal cell carcinoma (RCC) staging, but there are limited data pertaining to biopsy tract seeding (BTS) resulting in perirenal tissue involvement [BTS with perinephric fat invasion (BTS-P)].The aim is to correlate clinical outcomes with pathologic stage to determine whether the presence of BTS-P should be considered a criterion to stage RCC as part of the pT3a category in the absence of any other upstaging variables.

Materials And Results: We identified 304 renal biopsies from patients with subsequent nephrectomies for RCC; 33 of the tumours contained PFI. Each case was reviewed to determine the presence of BTS-P and other forms of invasion [e.g. non-BTS-P PFI, sinus fat invasion (SFI), and/or renal vein invasion (RVI)], and these findings were compared with survival outcomes. Ten (30%) of 33 tumours with PFI showed BTS-P as the only finding, and were otherwise pT1 tumours; six (60%) patients were alive without disease (AWOD) (mean, 77.5 months), three were lost to follow-up (LTF), and one died of other disease (DOOD). Two patients showed true PFI plus BTS-P; one was LTF and one is AWOD at 107 months. Ten (43%) of 23 patients with tumours with true invasion (PFI ± SFI and/or RVI) are AWOD (mean, 97.7 months), eight (35%) died of disease (DOD), four were LTF, and one DOOD. Kaplan-Meier survival curves showed that the cancer-specific survival was significantly worse in patients with true invasion (P = 0.044) than in those with BTS-P as the sole finding.

Conclusion: Patients with tumours showing BTS-P only appear to have better outcomes than those with other non-PFI invasion, suggesting that this finding should not be upstaged to pT3a. Additional studies are needed to corroborate the significance of our observations.
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http://dx.doi.org/10.1111/his.14309DOI Listing
November 2020

Prostate and pancreas involvement are linked in IgG4-related disease.

Semin Arthritis Rheum 2020 12 15;50(6):1245-1251. Epub 2020 Sep 15.

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, United States; Rheumatology Unit, Clinical Epidemiology Unit, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. Electronic address:

Objective: Prostate involvement by IgG4-related disease (IgG4-RD) is a rarely described organ manifestation and knowledge regarding its frequency and clinical features is limited.

Methods: From a single-center cohort, 168 male patients were examined who satisfied the 2019 ACR/EULAR classification criteria or 2012 consensus histopathologic criteria for IgG4-RD.

Results: Prostate involvement were identified in 25 (15%) of these cases. The majority of patients with IgG4-RD involving the prostate gland (80%) were symptomatic at presentation with incomplete voiding (64%), urinary frequency (52%), and urinary hesitancy (48%) being the most common complaints. The radiologic presentation of prostate disease is most often a focal abnormality suggesting inflammation rather than a mass lesion. While most patients with IgG4-related prostate disease (89%) experienced recurrence after or during glucocorticoid tapering, patients treated with B cell targeted therapy in this series experienced clinical improvement and were tapered off of glucocorticoids. Additionally, patients with IgG4-RD involving the pancreas (p = < 0.001) were more likely to have prostate involvement than were those with other types of organ involvement.

Conclusion: This report provides the first comprehensive clinical description of IgG4-RD involving the prostate gland and links this manifestation with pancreatic involvement.
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http://dx.doi.org/10.1016/j.semarthrit.2020.09.002DOI Listing
December 2020

Genome-wide profiling of BK polyomavirus integration in bladder cancer of kidney transplant recipients reveals mechanisms of the integration at the nucleotide level.

Oncogene 2021 01 13;40(1):46-54. Epub 2020 Oct 13.

Division of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Chronic BK polyomavirus (BKPyV) infection is recognized as a potential oncogenic factor of urothelial carcinoma (UC) in renal transplant recipients. Recent studies have reported a positive correlation among BKPyV integration, persistent overexpression of viral large T antigen (TAg), and malignancy, yet little is known about the specific integration mechanisms and the impacts of viral integration. Here, we performed whole-genome sequencing (WGS) and viral capture-based sequencing on high-grade immunohistochemically TAg-positive UCs in two renal transplant recipients. A total of 181 integration sites, including the three found by WGS, were identified by viral capture-based sequencing, indicating its enhanced sensitivity and ability in identifying low-read integration sites in subpopulations of the tumor cells. The microhomologies between human and BKPyV genomes were significantly enriched in the flanking regions of 84.5% the integration sites, with a median length of 7 bp. Notably, 75 human genes formed fusion sequences due to viral insertional integration. Among them, the expression of 15 genes were statistically associated with UC based on GEO2R expression analysis. Our results indicated a multisite and multifragment linear integration pattern and a potential microhomology or nonhomologous end joining integration mechanism at the single-nucleotide level. We put forward a potential selection mechanism driven by immunity and centered on viral integration in the carcinogenesis of BKPyV.
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http://dx.doi.org/10.1038/s41388-020-01502-wDOI Listing
January 2021

Long-term Oncologic Impact of Positive Anterior and Posterior Surgical Margins After Radical Prostatectomy.

Am J Clin Oncol 2020 12;43(12):872-879

Departments of Urology.

Objective: The objective of this study was to evaluate the impact of the anterior/posterior status of positive surgical margin (PSM) on long-term outcomes after radical prostatectomy for prostate cancer.

Patients And Methods: We included 391 consecutive PSM patients after radical prostatectomy between 1993 and 2007 excluding cases with multiple location PSM or lack of anterior/posterior status data. The oncologic impact of anterior-PSM and posterior-PSM were examined by Kaplan-Meier analysis and the Cox proportional hazards model.

Results: There were 115 cases (29.4%) with apex-PSM, 257 cases (65.7%) with peripheral PSM, and 19 cases (4.9%) with bladder neck PSM. Among the 257 peripheral PSM cases, 58 cases (22.6%) were with anterior-PSM, 174 cases (67.7%) were with posterior-PSM, and 25 cases (9.7%) were with both anterior and posterior PSM. Over a median follow-up of 12.6 years, patients with anterior-PSM, especially those with low to intermediate Gleason score (≤7), showed a biochemical recurrence (BCR) prognosis similar to those with apex-PSM. In contrast, patients with posterior-PSM showed significantly higher BCR risk on both univariate and multivariate analyses when compared with those with apex-PSM. No impact on metastasis-free survival or overall survival was observed.

Conclusions: In our study, we found that prostate cancer patients with anterior-PSM showed a more favorable BCR prognosis similar to those with apex-PSM when comparing to patients with posterior-PSM. Our study results may help physicians to choose different treatment options for patients diagnosed with different PSM status including considering further adjuvant treatment for patients with posterior-PSM.
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http://dx.doi.org/10.1097/COC.0000000000000765DOI Listing
December 2020

Biopsy Cell Cycle Proliferation Score Predicts Adverse Surgical Pathology in Localized Renal Cell Carcinoma.

Eur Urol 2020 11 14;78(5):657-660. Epub 2020 Sep 14.

Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. Electronic address:

Active surveillance (AS) is an accepted management strategy for some patients with renal cell carcinoma, but limited tools are available to identify optimal AS candidates. While renal mass biopsy provides diagnostic information, risk stratification based on biopsy is limited. In a retrospective, multi-institutional cohort that underwent renal mass biopsy followed by surgery, we assessed the ability of the cell cycle proliferation (CCP) score from clinical biopsy specimens to predict adverse surgical pathology (ie, grade 3-4, pT stage ≥3, metastasis at surgery, or papillary type II). Of 202 patients, 98 (49%) had adverse surgical pathology. When added to a baseline model including age, sex, race, lesion size, biopsy grade, and histology, CCP score was significantly associated with adverse pathology when modeled as a binary (odds ratio [OR]: 2.44 for CCP score >0, p = 0.02) and a continuous (OR: 1.72 per one unit increase, p = 0.04) variable. Discriminative performance measured by the area under the curve (AUC) improved from 0.73 in the baseline model to 0.75 and 0.76 in models including the CCP score. In the subgroup of patients with nephrectomy CCP score available (n = 67), the biopsy-based model outperformed the nephrectomy-based model (AUC 0.78 vs 0.75). These data support prospective assessment of biopsy CCP score to confirm clinical validity and assess potential utility in AS-eligible patients. PATIENT SUMMARY: In patients with localized renal cell carcinoma who underwent renal mass biopsy followed by surgery, the cell cycle proliferation score from clinical biopsy specimens could predict adverse surgical pathology.
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http://dx.doi.org/10.1016/j.eururo.2020.08.032DOI Listing
November 2020

Impact of biopsy perineural invasion on younger prostate cancer patients after radical prostatectomy.

Scand J Urol 2020 Dec 15;54(6):475-480. Epub 2020 Sep 15.

Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Objectives: To identify the potential indicators for higher-risk disease and poor outcome in younger prostate cancer (PCa) patients (age ≤ 50) who had undergone radical prostatectomy (RP) in the prostate-specific antigen (PSA) era.

Materials And Methods: A total of 186 PCa cases of age ≤ 50 who underwent RP between 2003 and 2010 at our center were included for study. High-risk disease after RP was defined as cases with pre-PSA ≥ 20 ng/ml and/or Gleason score (GS) ≥ 4 + 3 and/or pT stage ≥ 3. The poor outcome group was defined as cases with biochemical recurrence (BCR) and/or metastasis (Mets) and/or all-cause death. Multivariate logistic regression models were performed to identify independent risk factors for both high-risk disease and poor outcome.

Results: Among 186 younger PCa patients aged ≤ 50, 36 cases (19.5%) had high-risk disease and 24 cases (12.9%) had poor outcome. The presence of biopsy perineural invasion (BxPNI) was significantly associated with high-risk disease and showed a trend to correlate with worse outcome in univariate analysis. On multivariate logistic regression analysis, BxPNI was shown to be a significant independent risk factor with covariate of D'Amico for poor outcome ( = 0.047) and an independent risk factor with covariate of BxGPC for high-risk PCa excepting the variables to define high-risk disease ( = 0.013). Prognostically, cases with BxPNI showed a poor BCR-free survival in univariate analysis but did not reach significance ( = 0.063).

Conclusion: Our results show that BxPNI could be considered as a risk classification factor to identify the best candidates among younger PCa patients for further treatment and may also be used for developing active surveillance (AS) selection criteria for younger PCa patients.
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http://dx.doi.org/10.1080/21681805.2020.1817143DOI Listing
December 2020

Resolution of a High Grade and Metastatic BK Polyomavirus-Associated Urothelial Cell Carcinoma Following Radical Allograft Nephroureterectomy and Immune Checkpoint Treatment: A Case Report.

Transplant Proc 2020 Nov 30;52(9):2720-2725. Epub 2020 Jul 30.

Department of Surgery/Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA.

Background: BK viral infection in the posttransplant setting continues to cause serious morbidity with effects ranging from allograft nephropathy and dysfunction to urothelial malignancy.

Results: In this report, we present a patient that developed BK-associated nephropathy and, 6 years later, locally advanced urothelial malignancy in the renal allograft with nodal, muscle, and extremity involvement. Following radical allograft nephroureterectomy, he was treated with palliative radiation and the immune checkpoint inhibitor atezolizumab. Follow-up imaging at 1 year demonstrated radiographic complete response.

Conclusions: This report supports the growing body of evidence supporting the association of urothelial malignancy and BK virus infection in renal transplant recipients. Further, it highlights the novel application of immune checkpoint inhibitors in the treatment of advanced posttransplant malignancy, in particular when the allograft is removed and the tumor is possibly of donor origin.
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http://dx.doi.org/10.1016/j.transproceed.2020.06.012DOI Listing
November 2020

Viral integration in BK polyomavirus-associated urothelial carcinoma in renal transplant recipients: multistage carcinogenesis revealed by next-generation virome capture sequencing.

Oncogene 2020 08 28;39(35):5734-5742. Epub 2020 Jul 28.

Department of Organ Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China.

BK polyomavirus (BKPyV)-associated cancer after transplantation has gained increasing attention. However, the role of BKPyV integration on oncogenesis is still unclear. In this study, next-generation virome capture sequencing of primary and metastatic tumors were performed in three patients with BKPyV-associated urothelial carcinoma after renal transplantation. As a result, a total of 332 viral integration sites were identified in the six tumors. Integration of BKPyV in both primary and metastatic tumors followed the mechanism of microhomology-mediated end joining mostly, since microhomologies between human and BKPyV genomes were significantly enriched in flanking regions of 84% of the integration sites. Viral DNA breakpoints were nonrandom and tended to assemble in large T gene, small T gene and viral protein 2 gene. There were three, one and one consensus integration sites between the primary and metastatic tumors, which affected LINC01924, eIF3c, and NEIL2 genes in the three cases respectively. Thus, we concluded that integration of BKPyV was a continuous process occurring in both primary and metastatic tumors, generating heterogenous tumor cell populations. Through this ongoing process, certain cell populations might have gained growth advantage or metastatic potential, as a result of viral integration either affecting the cellular genes where the viral DNA integrated to or altering the expression or function of the viral genes.
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http://dx.doi.org/10.1038/s41388-020-01398-6DOI Listing
August 2020

Clinicopathological characteristics of localized prostate cancer in younger men aged ≤ 50 years treated with radical prostatectomy in the PSA era: A systematic review and meta-analysis.

Cancer Med 2020 09 22;9(18):6473-6484. Epub 2020 Jul 22.

Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Objectives: With the rapid increase in younger age prostate cancer (PCa) patients, the impact of younger age on decision-making for PCa treatment needs to be revaluated in the new era.

Materials And Methods: A systematic literature search was performed using PubMed, EMBASE, and Web of Science up to October 2019 to identify the eligible radical prostatectomy (RP) studies focusing on understanding the impact of age on clinicopathological features and oncological prognosis in patients with localized PCa in PSA era. Meta-analyses were conducted using available hazard ratios (HRs) from both univariate and multivariate analyses.

Results: Twenty-six studies including 391 068 patients with RP treatments from the PSA era were included. Of these studies, age of 50 years old (age50) is the most commonly used cut-off age to separate the younger patient group (including either age < 50 or age ≤ 50) from the older patient group. In these studies, the incidence of younger patients varied between 2.6% and 16.6% with a median of 8.3%. Younger patients consistently showed more favorable clinicopathological features correlated with better BCR prognosis. Meta-analyses showed a 1.38-fold improved BCR survival of younger patients in multivariate analysis. Among the high-risk PCa patients, younger age was independently associated with worse oncological outcomes in multivariate analyses.

Conclusion: In this study, we found younger age correlated with favorable clinicopathological characteristics and better BCR prognosis in low- to intermediate-risk patients. In high-risk group patients, younger patients often showed significantly worse oncological outcomes. Our study results suggest that age 50 could be used as a practical cut-off age to separate younger age patients from older age PCa patients.
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http://dx.doi.org/10.1002/cam4.3320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520296PMC
September 2020

Quantification of perineural invasion focus after radical prostatectomy could improve predictive power of recurrence.

Hum Pathol 2020 10 13;104:96-104. Epub 2020 Jul 13.

Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

Perineural invasion (PNI) after radical prostatectomy (RP) is a common feature of prostate cancer (PCa) and has been associated with unfavorable tumor characteristics. However, its prognostic relevance is controversial. In this study, we evaluated the impact of both PNI status (PNI+ versus PNI-) and quantified number of PNI focus on the long-term prognosis of biochemical recurrence (BCR) after RP. After reevaluating PNI of a total of 721 patients with localized PCa who underwent RP at our institution between 2000 and 2002, we examined associations between PNI status or PNI focus number and clinicopathological factors including tumor stage, Gleason score, margin status, tumor location, preoperative prostate specific antigen, age, prostate weight as well as BCR outcome. PNI was present in 530 of 721 cases (73.5%) of the RP specimens and was associated with more aggressive disease. BCR occurred in 19.4% of all patients within a median follow-up period of 8.5 years. PNI+ status was associated with poor BCR prognosis in univariate analysis but lost in multivariate analysis. Based on the number of PNI focus, PNI was further divided into 2 distinct group: PNI+ a (≤3) and PNI+ b (>3). In a multivariate Cox regression model, PNI+ b (>3) was identified as an independent BCR prognostic factor. Quantification of PNI focus number beside the dichotomized status recording will not only provide more detailed information but also be a novel prognostic indicator for risk stratification. Further external validation will be needed for an optimal cut-off value of the PNI focus number. Our findings will help further research on the relevance of PNI in the pretreatment setting and support ongoing efforts to understand its role of cancer progression.
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http://dx.doi.org/10.1016/j.humpath.2020.07.005DOI Listing
October 2020

ARNT-dependent CCR8 reprogrammed LDH isoform expression correlates with poor clinical outcomes of prostate cancer.

Mol Carcinog 2020 08 22;59(8):897-907. Epub 2020 Apr 22.

Department of Urology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.

Lactate dehydrogenase isozyme (LDH) is a tetramer constituted of two isoforms, LDHA and LDHB, the expression of which is associated with cell metabolism and cancer progression. Our previous study reveals that CC-chemokine ligand-18 (CCL18) is involved in progression of prostate cancer (PCa).This study aims to investigate how CCL18 regulates LDH isoform expression, and therefore, contributes to PCa progression. The data revealed that the expression of LDHA was upregulated and LDHB was downregulated in PCa cells by CCL18 at both messenger RNA and protein levels. The depletion of CCR8 reduced the ability of CCL18 to promote the proliferation, migration, and lactate production of PCa cells. Depletion of a CCR8 regulated transcription factor, ARNT, significantly reduced the expression of LDHA. In addition, The Cancer Genome Atlas dataset analyses revealed a positive correlation between CCR8 and ARNT expression. Two dimension difference gel electrophoresis revealed that the LDHA/LDHB ratio was increased in the prostatic fluid of patients with PCa and PCa tissues. Furthermore, increased LDHA/LDHB ratio was associated with poor clinical outcomes of patients with PCa. Together, our results indicate that the CCR8 pathway programs LDH isoform expression in an ARNT dependent manner and that the ratio of LDHA/LDHB has the potential to serve as biomarkers for PCa diagnosis and prognosis.
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http://dx.doi.org/10.1002/mc.23201DOI Listing
August 2020

Update on Renal Neoplasms: Clinicopathologic-Radiologic Correlation With Case-Based Examples.

AJR Am J Roentgenol 2020 06 14;214(6):1220-1228. Epub 2020 Apr 14.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Warren 831B, Boston, MA 02114.

This article provides a brief overview of the clinicopathologic and radiologic correlation of 12 renal neoplasms, encompassing the conventional subtypes of renal cell carcinoma and a few of the newly recognized subtypes from the 2016 World Health Organization classification of renal tumors. In addition, we touch upon infrequent neoplasms that may enter the differential diagnosis of a renal mass, with corresponding radiologic and gross images and histologic findings of case-based examples. Familiarity with the radiologic and pathologic characteristics of renal cell carcinoma and other renal neoplasms is important to correctly identify and treat these masses.
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http://dx.doi.org/10.2214/AJR.20.22816DOI Listing
June 2020

GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate.

Cancer Res 2020 06 16;80(11):2150-2162. Epub 2020 Mar 16.

Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

Metformin is an oral drug widely used for the treatment of type 2 diabetes mellitus. Numerous studies have demonstrated the value of metformin in cancer treatment. However, for metformin to elicit effects on cancer often requires a high dosage, and any underlying mechanism for how to improve its inhibitory effects remains unknown. Here, we found that low mRNA expression of glycerol-3-phosphate dehydrogenase 1 (GPD1) may predict a poor response to metformin treatment in 15 cancer cell lines. and , metformin treatment alone significantly suppressed cancer cell proliferation, a phenotype enhanced by GPD1 overexpression. Total cellular glycerol-3-phosphate concentration was significantly increased by the combination of GPD1 overexpression and metformin treatment, which suppressed cancer growth via inhibition of mitochondrial function. Eventually, increased reactive oxygen species and mitochondrial structural damage was observed in GPD1-overexpressing cell lines treated with metformin, which may contribute to cell death. In summary, this study demonstrates that GPD1 overexpression enhances the anticancer activity of metformin and that patients with increased GPD1 expression in tumor cells may respond better to metformin therapy. SIGNIFICANCE: GPD1 overexpression enhances the anticancer effect of metformin through synergistic inhibition of mitochondrial function, thereby providing new insight into metformin-mediated cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2852DOI Listing
June 2020

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy.

PLoS One 2020 5;15(3):e0229754. Epub 2020 Mar 5.

Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.

Purpose: To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC.

Patients And Methods: In a Local CRPC cohort, 42 prostatic specimens were collected from patients who were diagnosed as CRPC and underwent transurethral resection of the prostate (TURP) at Massachusetts General Hospital (MGH). In a metastatic CRPC (Met CRPC) cohort, 12 metastatic biopsies were collected from CRPC patients who would be treated with abiraterone plus dutasteride (Clinical Trial NCT01393730). As controls, 36 benign prostatic specimens were collected from patients undergoing prostate reduction surgery for symptoms of bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The methylation status of cytosine-phosphate-guanine (CpG) site(s) at SRD5A2 promoter regions was tested.

Results: Compared with benign prostatic tissue, CRPC samples demonstrated higher SRD5A2 methylation in the whole promoter region (Local CRPC cohort: P < 0.001; Met CRPC cohort: P <0.05). In Local CRPC cohort, a higher ratio of methylation was correlated with better OS (R2 = 0.33, P = 0.013). Hypermethylation of specific regions (nucleotides -434 to -4 [CpG# -39 to CpG# -2]) was associated with a better OS (11.3±5.8 vs 6.4±4.4 years, P = 0.001) and PFS (8.4±5.4 vs 4.5±3.9 years, P = 0.003) with cutoff value of 37.9%. Multivariate analysis showed that SRD5A2 methylation was associated with OS independently (whole promoter region: P = 0.035; specific region: P = 0.02).

Conclusion: Our study demonstrate that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to -2, is significantly associated with better survival for CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2 may affect the choices and sequence of available therapies for management of CRPC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229754PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058338PMC
June 2020

Updates in Histologic Grading of Urologic Neoplasms.

Arch Pathol Lab Med 2020 03;144(3):335-343

From the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Context.—: Tumor histology offers a composite view of the genetic, epigenetic, proteomic, and microenvironmental determinants of tumor biology. As a marker of tumor histology, histologic grading has persisted as a highly relevant factor in risk stratification and management of urologic neoplasms (ie, renal cell carcinoma, prostatic adenocarcinoma, and urothelial carcinoma). Ongoing research and consensus meetings have attempted to improve the accuracy, consistency, and biologic relevance of histologic grading, as well as provide guidance for many challenging scenarios.

Objective.—: To review the most recent updates to the grading system of urologic neoplasms, including those in the 2016 4th edition of the World Health Organization (WHO) Bluebook, with emphasis on issues encountered in routine practice.

Data Sources.—: Peer-reviewed publications and the 4th edition of the WHO Bluebook on the pathology and genetics of the urinary system and male genital organs.

Conclusions.—: This article summarizes the recently updated grading schemes for renal cell carcinoma, prostate adenocarcinomas, and bladder neoplasms of the genitourinary tract.
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http://dx.doi.org/10.5858/arpa.2019-0551-RADOI Listing
March 2020

Updates in Staging and Reporting of Genitourinary Malignancies.

Arch Pathol Lab Med 2020 03;144(3):305-319

From the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Context.—: The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual changed the tumor, node, metastasis (TNM) classification systems of genitourinary malignancies in 2017. However, some of the changes appear not well appreciated or recognized by practicing pathologists.

Objective.—: To review the major changes compared with the 7th edition in cancers of the prostate, penis, testis, bladder, urethra, renal pelvis/ureter, and kidney and discuss the challenges that pathologists may encounter.

Data Sources.—: Peer-reviewed publications and the 8th and 7th editions of the .

Conclusions.—: This article summarizes the updated staging of genitourinary malignancies, specifically highlighting changes from the 7th edition that are relevant to the pathologic staging system. Pathologists should be aware of the updates made in hopes of providing clarification and the remaining diagnostic challenges associated with these changes.
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http://dx.doi.org/10.5858/arpa.2019-0544-RADOI Listing
March 2020

Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland.

Prostate Cancer Prostatic Dis 2020 09 6;23(3):465-474. Epub 2020 Feb 6.

Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Background And Objective: Our patient cohort revealed that obesity is strongly associated with steroid-5α reductase type 2 (SRD5A2) promoter methylation and reduced protein expression. The underlying mechanism of prostatic growth in this population is poorly understood. Here we addressed the question of how obesity, inflammation, and steroid hormones affect the development of benign prostatic hyperplasia (BPH).

Material And Methods: We used preadipocytes, macrophages, primary human prostatic stromal cells, prostate tissues from high-fat diet-induced obese mice, and 35 prostate specimens that were collected from patients who underwent transurethral resection of the prostate (TURP). RNA was isolated and quantified with RT-PCR. Genome DNA was extracted and SRD5A2 promoter methylation was determined. Sex hormones were determined by high-performance liquid chromatography-tandem mass spectrometry. Protein was extracted and determined by ELISA test.

Results: In prostatic tissues with obesity, the levels of inflammatory mediators were elevated. SRD5A2 promoter methylation was promoted, but SRD5A2 expression was inhibited. Inflammatory mediators and saturated fatty acid synergistically regulated aromatase activity. Obesity promoted an androgenic to estrogenic switch in the prostate.

Conclusions: Our findings suggest that obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland, which may serve as an effective strategy for alternative therapies for management of lower urinary tract symptoms associated with BPH in select individuals.
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http://dx.doi.org/10.1038/s41391-020-0208-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938647PMC
September 2020

Microphthalmia family of transcription factors associated renal cell carcinoma.

Asian J Urol 2019 Oct 3;6(4):312-320. Epub 2019 May 3.

Department of Pathology and Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The microphthalmia (MiT) subfamily of transcription factors includes TFE3, TFEB, TFEC, and MITF. In the 2016 World Health Organization classification, MiT family translocation renal cell carcinoma (tRCC) including Xp11 tRCC and t(6;11) RCC, was newly defined as an RCC subtype. Xp11 and t(6;11) RCC are characterized by the rearrangement of the MiT transcription factors TFE3 and TFEB, respectively. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with TFEB amplification, melanotic MiT family translocation neoplasms, was identified may as a unique subtype of MiT family associated renal neoplasms, along with MITF associated RCC. In this review, we will collect available literature of these newly-described RCCs, analyze their clinicopathological and immunohistochemical features, and summarize their molecular and genetic evidences. We expect this review would be beneficial for the understanding of these rare subtypes of RCCs, and eventually promote clinical management strategies.
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http://dx.doi.org/10.1016/j.ajur.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872788PMC
October 2019

Novel and established EWSR1 gene fusions and associations identified by next-generation sequencing and fluorescence in-situ hybridization.

Hum Pathol 2019 11 17;93:65-73. Epub 2019 Aug 17.

Massachusetts General Hospital, Department of Pathology, and Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes in phenotypically identical tumors or partner with the same genes in morphologically and behaviorally different neoplasms. Our study set out to examine the EWSR1 fusions identified at our institution over a 3-year period, using various methods, their association with specific entities and possible detection of novel partners and associations. Sixty-three consecutive cases investigated for EWSR1 gene fusions between 2015 and 2018 at our institution were included in this study. Fusions were identified by either break-apart fluorescence in-situ hybridization (FISH), our clinical RNA-based assay for fusion transcript detection or both. Twenty-eight cases were concurrently tested by FISH and NGS, 24 were tested by FISH alone and 11 by NGS alone. Of the 28 cases with dual testing, 24 were positive by both assays for an EWSR1 gene fusion, 3 cases were discordant with a positive FISH assay and a negative NGS assay, and 1 case was discordant with a negative FISH assay but a positive NGS assay. Three novel fusions were identified: a complex rearrangement involving three genes (EWSR1/RBFOX2/ERG) in Ewing sarcoma, a EWSR1/TCF7L2 fusion in a colon adenocarcinoma, and a EWSR1/TFEB fusion in a translocation-associated renal cell carcinoma. Both colonic adenocarcinoma and renal cell carcinoma had not been previously associated with EWSR1 rearrangements to our knowledge. In a subset of cases, detection of a specific partner had an impact on the histological diagnosis and patient management. In our experience, the use of a targeted NGS-based fusion assay is superior to EWSR1 break-apart FISH for the detection of known and novel EWSR1 rearrangements and fusion partners, particularly given the emerging understanding that distinct fusion partners result in different diseases with distinct prognostic and therapeutic implications.
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http://dx.doi.org/10.1016/j.humpath.2019.08.006DOI Listing
November 2019

Prognostic significance of laterality in renal cell carcinoma: A population-based study from the surveillance, epidemiology, and end results (SEER) database.

Cancer Med 2019 Sep 12;8(12):5629-5637. Epub 2019 Aug 12.

Department of Urology and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Various prognostic characteristics have been established in the renal cell carcinoma (RCC). However, the impact of tumor laterality is unknown. The objective of the current study was to explore the predictive and prognostic impact of tumor laterality of RCC after surgery.

Methods: This investigation was a population-based retrospective cohort study of patients with RCC from the surveillance, epidemiology, and end results (SEER) database in the USA. All patients received surgical treatment between January 2010 and December 2014. Cancer-specific survival (CSS) measured from the time of surgery.

Results: This study identified 41 138 surgically treated RCC patients: Of these patients, 50.6% had right-sided RCC, 59.5% were younger than 65 years of age, 63.8% were male, and 81.0% were Caucasian. The stage distribution was 67.0% (I), 9.5% (II), 17.1% (III), and 6.4% (IV). Patients with right-sided RCC were more likely to have favorable clinicopathological features compared with patients with left-sided RCC. In adjusted analyses, patients with right-sided RCC showed significantly better CSS than those with left-sided RCC within different subgroups including tumor size ≥10 cm (P = .004), age <65 years (P = .002), male gender (P = .001), Caucasian race (P = .001), clear cell carcinoma type (P = .024), and radical nephrectomy (P = 0.008). Moreover, in the subgroup of tumor size ≥10 cm, right-sided cancer was an independent predictor of CSS (P = .022).

Conclusion: Right-sided RCC is associated with more early-stage, low-grade disease and shows better CSS than left-sided RCC. Moreover, laterality remained as an independent prognostic factor for cancer-specific survival in subgroup of tumor size ≥10 cm RCC.
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http://dx.doi.org/10.1002/cam4.2484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745836PMC
September 2019

Impact of biopsy perineural invasion on the outcomes of patients who underwent radical prostatectomy: a systematic review and meta-analysis.

Scand J Urol 2019 Oct 10;53(5):287-294. Epub 2019 Aug 10.

Department of Urology and Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.

To investigate the association between biopsy perineural invasion (PNI) and oncological outcomes of prostate cancer (PCa) after radical prostatectomy (RP). A systematic literature search was performed using PubMed, EMBASE and Web of Science up to December 2018 to identify the eligible studies that included localized PCa patients who underwent biopsy and subsequently RP as well as follow-up information. Meta-analyses were conducted using available hazard ratios (HRs) of biopsy PNI from both univariate and multivariate analyses. Eighteen studies including 14,855 patients with treatment follow-up information were included in the current systematic review. The rate of biopsy PNI varied between 7.0% and 33.0%. Seven out of the 18 studies that demonstrated biopsy PNI were associated with adverse pathologic features. Thirteen out of the 18 studies showed biopsy PNI correlated significantly with higher rates of biochemical recurrence (BCR)/cancer progression status or worse prognostic outcomes. With pooled data based on four studies with available univariate analysis results and four studies with multivariate analysis, statistically significant associations were found between biopsy PNI and BCR with univariate analysis (HR = 2.05; 95% CI = 1.57-2.68;  < 0.001) and with multivariate analysis (HR = 1.57; 95% CI = 1.28-1.93;  < 0.001). Evidence from the included observational studies indicated that biopsy PNI was not only correlated with adverse pathologic characteristics but also with worse BCR prognosis of local PCa after RP. The status of biopsy PNI could serve as a promising risk-stratification factor to help the decision-making process, considering active surveillance (AS) or further treatment for PCa patients.
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http://dx.doi.org/10.1080/21681805.2019.1643913DOI Listing
October 2019

Correction to: MicroRNA-30d promotes angiogenesis and tumor growth via MYPT1/c-JUN/VEGFA pathway and predicts aggressive outcome in prostate cancer.

Mol Cancer 2019 Aug 6;18(1):122. Epub 2019 Aug 6.

Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China.

After publication of the article [1], the author reported that this article contained some errors.
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http://dx.doi.org/10.1186/s12943-019-1051-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683342PMC
August 2019

Offsetting Expression Profiles of Prognostic Markers in Prostate Tumor vs. Its Microenvironment.

Front Oncol 2019 26;9:539. Epub 2019 Jun 26.

Department of Pathology and Urology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Diagnosis of the presence of tumors and subsequent prognosis based on tumor microenvironment becomes more clinically practical because tumor-adjacent tissues are easy to collect and they are more genetically homogeneous. The purpose of this study was to identify new prognostic markers in prostate stroma that are near the tumor. We have demonstrated the prognostic features of FGFR1, FRS2, S6K1, LDHB, MYPT1, and P-LDHA in prostate tumors using tissue microarrays (TMAs) which consist of 241 patient samples from Massachusetts General Hospital (MGH). In this study, we investigated these six markers in the tumor microenvironment using an Aperio Imagescope system in the same TMAs. The joint prognostic power of markers was further evaluated and classified using a new algorithm named Weighted Dichotomizing. The classifier was verified via rigorous 10-fold cross validation. Statistical analysis of the protein expression indicated that in tumor-adjacent stroma FGFR1 and MYPT1 were significantly correlated with patient outcomes and LDHB showed the outcome-association tendency. More interestingly, these correlations were completely opposite regarding tumor tissue as previously reported. The results suggest that prognostic testing should utilize either tumor-enriched tissue or stroma with distinct signature profiles rather than using mixture of both tissue types. The new classifier based on stroma tissue has potential value in the clinical management of prostate cancer patients.
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http://dx.doi.org/10.3389/fonc.2019.00539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611437PMC
June 2019

Assessment of 5-year overall survival in bladder cancer patients with incidental prostate cancer identified at radical cystoprostatectomy.

Int Urol Nephrol 2019 Sep 10;51(9):1527-1535. Epub 2019 Jun 10.

Department of Urology and Pathology, Massachusetts General Hospital, Harvard Medical School, Warren Building 225, 55 Fruit Street, Boston, MA, 02114, USA.

Objective: To investigate the oncological impact of incidental prostate cancer (iPCa) found during radical cystoprostatectomy (RCP) on overall survival (OS) prognosis of urothelial carcinoma of the bladder (BCa).

Patients And Methods: A total of 122 RCP cases resected between 2002 and 2012 at our center were included for study. Survival of BCa patient was compared using the Kaplan-Meier method and the log-rank test. Cox proportional hazards regression models were used to analyze the impact of iPCa on the 5-year overall mortality of BCa patients after RCP.

Results: Among the 122 BCa cases that underwent RCP, 38 cases (31.1%) had iPCa, in which, 17 cases (44.7%) were identified as clinically significant iPCa (csPCa). BCa patients with iPCa were older (71 vs 64 years, p = 0.004) and had higher preoperative PSA level (3.1 ng/mL vs 1.4 ng/mL, p = 0.017) when compared to those without iPCa. Cases with iPCa showed a more favorable 5-year OS than cases without iPCa, although this difference did not reach statistical significance (p = 0.219). When excluding the higher risk cases with Gleason score (GS) ≥ 4 + 3 and/or preoperative PSA > 10 ng/mL, BCa patients with iPCa showed a significantly longer OS than cases without iPCa on univariate analysis (p = 0.044), but not on multivariate analysis (p = 0.125).

Conclusion: Our results demonstrated that the frequent findings of low-risk iPCa in BCa patients could indicate the potential possibility of shared pathogenesis pathways between iPCa and BCa. Future study with a larger cohort is warranted to validate this result.
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http://dx.doi.org/10.1007/s11255-019-02181-7DOI Listing
September 2019

Oncolytic Herpes Simplex Virus and PI3K Inhibitor BKM120 Synergize to Promote Killing of Prostate Cancer Stem-like Cells.

Mol Ther Oncolytics 2019 Jun 29;13:58-66. Epub 2019 Mar 29.

Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence, and they are important therapeutic targets. We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium, and we characterized stem-like properties of clonogenicity and tumorigenicity. The efficacy of two different oncolytic herpes simplex viruses (oHSVs) (G47Δ and MG18L) in PCSCs was tested alone and in combination with radiation; chemotherapy; and inhibitors of phosphoinositide 3-kinase (PI3K), Wnt, and NOTCH ; and, G47Δ was tested with the PI3K inhibitor BKM120 in a PCSC-derived tumor model . PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing , while the combination was synergistic. oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, the combination of intra-tumoral G47Δ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals, and it exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. oHSV synergizes with BKM120 in killing PCSCs , and the combination markedly inhibits tumor growth, even inducing regression .
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http://dx.doi.org/10.1016/j.omto.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468160PMC
June 2019

The clinicopathological characteristics and prognostic value of squamous differentiation in patients with bladder urothelial carcinoma: a meta-analysis.

World J Urol 2020 Feb 22;38(2):323-333. Epub 2019 Apr 22.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Urothelial carcinoma with squamous differentiation (UCSD) is the most common histologic variant in bladder cancer (BCa). Previously, some studies have linked the presence of UCSD with the risk of worse survival outcomes in BCa patients. However, such association is still controversial. In this study, we performed a meta-analysis to clarify the clinicopathological characteristics and to further investigate the prognostic value of UCSD in BCa.

Methods: A systematic literature search was performed in electronic databases including PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang Data until October 2018. Subgroup analyses were performed according to different treatments and study outcomes.

Results: Total of 13,284 patients were enrolled in 19 studies which were included in this meta-analysis. The percentage of female patients with UCSD was significantly higher than those with pure urothelial carcinoma. UCSD was correlated with tumor stage T3/T4, tumor grade 3, positive surgical margin, and lymph node involvement. Moreover, the recurrence rate was higher in patients with UCSD after surgery. UCSD was associated with poorer disease-free survival (DFS). No significant difference of cancer-specific survival (CSS) or overall survival (OS) was found on multivariable analysis between the two groups.

Conclusions: Our study demonstrated that UCSD in BCa was associated not only with unfavorable clinicopathological features, but also with high risk of recurrence and poorer prognosis for DFS. However, UCSD is not independently significant for CSS and OS. Well-designed randomized study with larger sample size is warranted to verify the findings and to further explore the role of UCSD in BCa.
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http://dx.doi.org/10.1007/s00345-019-02771-1DOI Listing
February 2020

A genome-wide association study implicates in lymphangioleiomyomatosis pathogenesis.

Eur Respir J 2019 06 27;53(6). Epub 2019 Jun 27.

Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

Introduction: Lymphangioleiomyomatosis (LAM) occurs either associated with tuberous sclerosis complex (TSC) or as sporadic disease (S-LAM). Risk factors for development of S-LAM are unknown. We hypothesised that DNA sequence variants outside of / might be associated with susceptibility for S-LAM and performed a genome-wide association study (GWAS).

Methods: Genotyped and imputed data on 5 426 936 single nucleotide polymorphisms (SNPs) in 426 S-LAM subjects were compared, using conditional logistic regression, with similar data from 852 females from COPDGene in a matched case-control design. For replication studies, genotypes for 196 non-Hispanic White female S-LAM subjects were compared with three different sets of controls. RNA sequencing and immunohistochemistry analyses were also performed.

Results: Two noncoding genotyped SNPs met genome-wide significance: rs4544201 and rs2006950 (p=4.2×10 and 6.1×10, respectively), which are in the same 35 kb linkage disequilibrium block on chromosome 15q26.2. This association was replicated in an independent cohort. (nuclear receptor subfamily 2 group F member 2), a nuclear receptor and transcription factor, was the only nearby protein-coding gene. expression was higher by RNA sequencing in one abdominal LAM tumour and four kidney angiomyolipomas, a LAM-related tumour, compared with all cancers from The Cancer Genome Atlas. Immunohistochemistry showed strong nuclear expression in both LAM and angiomyolipoma tumours.

Conclusions: SNPs on chromosome 15q26.2 are associated with S-LAM, and chromatin and expression data suggest that this association may occur through effects on expression, which potentially plays an important role in S-LAM development.
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http://dx.doi.org/10.1183/13993003.00329-2019DOI Listing
June 2019