Publications by authors named "Charles Guo"

102 Publications

Progression of Disease after BCG Therapy: Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy.

J Urol 2021 Jun 29:101097JU0000000000001943. Epub 2021 Jun 29.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Data from the pre-neoadjuvant chemotherapy (NAC) era suggests patients who progress on BCG to muscle-invasive bladder cancer (P-MIBC) exhibit worse outcomes compared to MIBC (D-MIBC). Herein, we investigate whether P-MIBC is an independent poor risk factor in the setting of contemporary NAC use.

Materials And Methods: A review of patients who underwent radical cystectomy (RC) for cT2-3 MIBC from 2005-2018 was performed. Patients were stratified into high-risk (lymphovascular invasion, variant histology, hydronephrosis, cT3b) vs. low-risk (no risk factors) and P-MIBC (≤pT1 treated with at least induction BCG who progressed to ≥cT2) vs. D-MIBC.

Results: Among 801 patients who underwent RC 20.3% had P-MIBC and 79.7% had D-MIBC. In low-risk patients treated without NAC, P-MIBC was associated with pathologic upstaging (64.9% vs. 42.7%, p=0.004) and worse overall (OS, p=0.006) and cancer-specific survival (CSS, p=0.001) compared to D-MIBC. P-MIBC status conferred uniformly poor survival outcomes to patients who did not receive NAC compared to D-MIBC without NAC (median OS 51.5 months [95% CI 40.0-81.0] vs. 85.1 months [95% CI 62.8-96.0], p=0.040; median CSS not reached, p=0.014). However, P-MIBC status did not remain a negative prognostic factor in the setting of NAC (median OS 90.5 months [95% CI 34.0-not estimable] vs. 87.8 months [95% CI 68.7-not estimable], p=0.606; median CSS not reached, p=0.448).

Conclusions: P-MIBC confers a poor prognosis when managed with RC alone. Treatment with NAC results in equivalent pathologic response and survival outcomes compared to D-MIBC. P-MIBC should be included in risk-stratified approaches to NAC selection.
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http://dx.doi.org/10.1097/JU.0000000000001943DOI Listing
June 2021

Patient Satisfaction With Heart Health Clinics in Fraser Health, Canada.

J Patient Exp 2021 20;8:2374373520981475. Epub 2021 Jan 20.

Fraser Health Authority, Royal Columbian Hospital, New Westminster, British Columbia, Canada.

The Fraser Health heart function clinics explored patient satisfaction using a survey with the goal of understanding and improving care and service delivery. Data were collected from 124 respondents at 3 ambulatory care sites in the region. Patient satisfaction scores were high, with an average score of 8.85 out of 10 and 95% of respondents rating the service higher than 6 out of 10. The results highlighted the importance of multidisciplinary teams, good communication, adequate information, and emphasis on how a patient is treated. The patient's understanding of the information provided and of their heart health treatment plan were identified as two areas that require greater awareness.
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http://dx.doi.org/10.1177/2374373520981475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205352PMC
January 2021

The Genitourinary Pathology Society Update on Classification of Variant Histologies, T1 Substaging, Molecular Taxonomy, and Immunotherapy and PD-L1 Testing Implications of Urothelial Cancers.

Adv Anat Pathol 2021 Jul;28(4):196-208

Department of Pathology, West German Cancer Center/University Hospital Essen, University of Duisburg-Essen, Duisburg.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.
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http://dx.doi.org/10.1097/PAP.0000000000000309DOI Listing
July 2021

The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia.

Adv Anat Pathol 2021 Jul;28(4):179-195

Medicine.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.
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http://dx.doi.org/10.1097/PAP.0000000000000308DOI Listing
July 2021

Urinary Large Cell Neuroendocrine Carcinoma: A Clinicopathologic Analysis of 22 Cases.

Am J Surg Pathol 2021 Jun 2. Epub 2021 Jun 2.

Departments of Pathology Radiology Medical Oncology, British Columbia Cancer Vancouver Centre Department of Urology, Vancouver General Hospital Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada Department of Pathology, MD Anderson Cancer Center, Houston, TX.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a rare disease. We present a relatively large retrospective cohort of urinary LCNEC, 20 from the urinary bladder, and 2 from the ureter, from a single institution. The patients included 16 men and 6 women with a median age of 74.5 years. Most LCNEC presented at an advanced stage with tumors invading the muscularis propria and beyond (21/22). Eight cases were pure LCNEC, while 14 cases were mixed with other histologic types, including conventional urothelial carcinoma (n=9), carcinoma in situ (n=7), small cell carcinoma (n=6), and urothelial carcinoma with glandular (n=3) features. Most LCNEC expressed neuroendocrine markers synaptophysin (22/22), chromogranin (13/16), CD56 (7/7), TTF1 (8/8), and INSM1 (2/3). They were negative for common urothelial markers including HMWCK (0/3), p40/p63 (0/6), CK20 (0/10), and had variable GATA3 staining (4/8). Ki-67 stained 25% to nearly 100% tumor cell nuclei. Patient survival was associated with cancer stage, and pure LCNEC showed worse survival than mixed LCNEC. Compared with small cell carcinoma at similar stages from a prior study, LCNEC had a worse prognosis only when patients developed metastatic disease. For organ-confined LCNEC, neoadjuvant chemotherapy followed by radical resection is the treatment option to achieve long-term survival.
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http://dx.doi.org/10.1097/PAS.0000000000001740DOI Listing
June 2021

Expression Analysis of Same-Patient Metachronous and Synchronous Upper Tract and Bladder Urothelial Carcinoma.

J Urol 2021 Apr 21:101097JU0000000000001788. Epub 2021 Apr 21.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: We compared upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) in same-patient metachronous UTUC and synchronous UTUC and BUC using next-generation sequencing.

Materials And Methods: Consecutive untreated same-patient samples of UTUC and BUC were macrodissected from unstained formalin-fixed, paraffin-embedded slides after quality control. Samples were divided into 4 groups: 1) UTUC-metachronous BUC, 2) BUC-metachronous UTUC, 3) synchronous UTUC-BUC, 4) UTUC without BUC. Exclusions were inadequate clinical data or histological tumor purity <30%. Whole transcriptome RNA sequencing was performed. After quality assessment, gene expression clusters using unsupervised hierarchical consensus clustering and correlation with pertinent clinicopathologic variables, a prior RNASeq dataset and other published data were performed.

Results: RNAseq was performed on 95 samples (UTUC=61, BUC=34) from 40 untreated patients. Unsupervised consensus clustering segregated the tumors into 2 clusters that were enriched with BASE47 basal-like or luminal-like gene expression. Almost two-thirds (61.9%) of Group 2 tumors were basal-like, while the majority of Groups 1, 3, 4 (80.6%, 70.0% and 69.6%, respectively) were luminal-like (p=0.017). Further analyses revealed that the differences in basal-like and luminal-like gene expression were associated with differential fibroblast and immune cell gene expression signatures. In all, 87.5% of metachronous tumors maintained subtype membership.

Conclusions: Gene expression analysis of same-patient metachronous UTUC-BUC suggests that the majority of mUTUC developing after BUC appear more basal-like, while synchronous and initial UTUC tumors appear luminal-like. Metachronous tumors largely maintain molecular subtype membership of the initial tumor regardless of chronologic development or anatomic origin.
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http://dx.doi.org/10.1097/JU.0000000000001788DOI Listing
April 2021

Pathogenesis and Diagnosis of Genitourinary Cancer.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, 6565 Fannin St, Houston, TX 77030, USA.

Genitourinary (GU) cancers are among the most common malignant diseases in men [...].
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http://dx.doi.org/10.3390/cancers13020347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832837PMC
January 2021

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.

Nat Med 2020 12 12;26(12):1845-1851. Epub 2020 Oct 12.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.
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http://dx.doi.org/10.1038/s41591-020-1086-yDOI Listing
December 2020

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2021 05 15;39(5):295.e1-295.e8. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
May 2021

Secondary tumors of the bladder: A survival outcome study.

Ann Diagn Pathol 2020 Oct 14;48:151593. Epub 2020 Aug 14.

University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

The urinary bladder may be involved by a variety of secondary tumors that originate from other organs. Bladder secondary tumors are rare and may be mistaken as bladder primary tumors because of their overlapping morphologic features. To avoid the diagnostic pitfalls, we analyzed the clinicopathologic features of bladder secondary tumors in a large cohort of patients. Our patient cohort consisted of 45 females and 38 males with a mean age of 58.7 ± 15.4 years (range 10-87 years). The tumors involved the bladder via direct extension from adjacent organs (n = 42) and distant metastasis (n = 41). In females, the majority of secondary tumors originated from the gynecologic tract (n = 25), and other common origins included the colon/rectum (n = 5) and breast (n = 4). In males, the most common origin was the prostate (n = 18), followed by the colon/rectum (n = 4) and kidney (n = 3). 75.9% of the secondary tumors were adenocarcinoma (n = 63), and other common tumor types included sarcoma (n = 6), squamous cell carcinoma (n = 5), melanoma (n = 4), and neuroendocrine carcinoma (n = 3). 67.5% of patients (n = 56) died of the disease with a median overall survival of 23 months from the time of secondary involvement of the bladder. Patients with secondary tumors via direct extension had a median survival time of 20 months, which was not significantly different from that for patients with secondary involvement via distant metastasis (24 months) (p = 0.83). Median survival in cases with prostate primary was 20 months as compared to 23 months for all other tumor types (p = 0.68). The majority of secondary tumors are composed of adenocarcinoma, which highlights the importance of differentiating primary from secondary involvement in bladder adenocarcinoma. Regardless of the origin, bladder secondary tumors are associated with a poor prognosis.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151593DOI Listing
October 2020

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2021 04;145(4):461-493

Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Maclean).

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
April 2021

Assessment of Luminal and Basal Phenotypes in Bladder Cancer.

Sci Rep 2020 06 16;10(1):9743. Epub 2020 Jun 16.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy. We analyzed the mRNA expressions of signature luminal and basal genes in bladder cancer tumor samples from publicly available and MD Anderson Cancer Center cohorts. We developed a quantitative classifier referred to as basal to luminal transition (BLT) score which identified the molecular subtypes of bladder cancer with 80-94% sensitivity and 83-93% specificity. In order to facilitate molecular subtyping of bladder cancer in primary care centers, we analyzed the protein expressions of signature luminal (GATA3) and basal (KRT5/6) markers by immunohistochemistry, which identified molecular subtypes in over 80% of the cases. In conclusion, we provide a tool for assessment of molecular subtypes of bladder cancer in routine clinical practice.
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http://dx.doi.org/10.1038/s41598-020-66747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298008PMC
June 2020

Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer.

iScience 2020 Jun 27;23(6):101201. Epub 2020 May 27.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with The Cancer Genome Atlas cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation signature 3 associated with loss of BRCA1/2 function. SCCs were characterized by downregulation of luminal and basal markers and were referred to as double-negative. Transcriptome analyses indicated that SCCs displayed lineage plasticity driven by a urothelial-to-neural phenotypic switch with a dysregulated epithelial-to-mesenchymal transition network. SCCs were depleted of immune cells, and expressed high levels of the immune checkpoint receptor, adenosine receptor A2A (ADORA2A), which is a potent inhibitor of immune infiltration. Our observations have important implications for the prognostication and development of more effective therapies for this lethal bladder cancer variant.
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http://dx.doi.org/10.1016/j.isci.2020.101201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286965PMC
June 2020

Bladder Cancer Involving Smooth Muscle of Indeterminate Type or Muscularis Mucosae in Transurethral Biopsy Specimens.

Am J Clin Pathol 2020 07;154(2):208-214

Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Objectives: Bladder cancers invading the muscularis mucosae (MM) are treated differently from those invading the muscularis propria (MP). However, it may be difficult to determine the type of smooth muscle in transurethral resection (TUR) or biopsy specimens. We aimed to investigate the clinicopathologic features of bladder cancers involving smooth muscle of indeterminate type (SMIT) in TUR specimens in comparison with those invading the MM.

Methods: We identified 103 patients with bladder cancer involving SMIT (n = 27) or the MM (n = 76) in TUR specimens. All patients underwent subsequent restaging TUR or cystectomy.

Results: Bladder cancer with SMIT invasion showed a significantly higher rate of MP invasion in the subsequent specimens than those invading the MM (52% vs 29%). Lack of MP in the TUR specimens had a significantly higher risk of MP invasion in the subsequent specimens than those with the MP (61% vs 40%). The overall survival time for patients with SMIT invasion was significantly shorter than those with MM invasion.

Conclusions: Bladder cancers with SMIT invasion in TUR specimens show more frequent cancer upstaging in the subsequent specimens and a poorer clinical outcome than those invading the MM, which highlights the importance of a cancer restaging procedure for these patients.
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http://dx.doi.org/10.1093/ajcp/aqaa030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768762PMC
July 2020

Perivascular Epithelioid Cell Tumor of the Urinary Bladder: A Systematic Review.

Int J Surg Pathol 2020 Jun 22;28(4):393-400. Epub 2019 Dec 22.

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Perivascular epithelioid cell tumor (PEComa) of the urinary bladder is a rare neoplasm showing distinct melanocytic and smooth muscle differentiation. We aimed to review the clinicopathologic features of bladder PEComa using all the available cases in the literature, along with 2 new cases from our database. The patients included 15 females and 15 males with a mean age of 39.2 ± 15.3 years. Painless hematuria was the most common clinical presentation. The tumors were usually well circumscribed with a mean tumor size of 4.4 ± 2.7 cm. Bladder PEComas demonstrated nests, trabeculae, or sheets of epithelioid cells with intermixed spindled cells and numerous thin-walled vessels. Immunohistochemical studies showed that the tumors were positive for HMB45 (27/27), cathepsin (4/4), SMA (20/22), and caldesmon (3/3) and were negative for pan cytokeratin (0/18) and EMA (0/4). Molecular studies revealed that PEComa was associated with the (n = 3) and (n = 1) gene rearrangements. Treatment included partial cystectomy (n = 18), transurethral resection (n = 8), and radical cystectomy (n = 4). Twenty patients had no evidence of disease during a mean follow-up time of 19.4 ± 17.2 months. Two patients had recurrence, and 1 patient died of metastatic disease. In conclusion, bladder PEComas demonstrate distinct morphologic and immunohistochemical features. Although most tumors follow a benign course, a small subset may develop metastasis and cause death.
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http://dx.doi.org/10.1177/1066896919895810DOI Listing
June 2020

What Is the Significance of Variant Histology in Urothelial Carcinoma?

Eur Urol Focus 2020 07 15;6(4):653-663. Epub 2019 Sep 15.

Division of Surgery, Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Context: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions.

Objective: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma.

Evidence Acquisition: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy".

Evidence Synthesis: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive.

Conclusions: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment.

Patient Summary: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.
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http://dx.doi.org/10.1016/j.euf.2019.09.003DOI Listing
July 2020

Using Grade of Recurrent Tumor to Guide Further Therapy While on Bacillus Calmette-Guerin: Low-grade Recurrences Are not Benign.

Eur Urol Oncol 2019 05 10;2(3):286-293. Epub 2018 Sep 10.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Tumors that recur after bacillus Calmette-Guerin (BCG) therapy are considered to be of very high risk, and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood.

Objective: To characterize the pattern of bladder cancer progression and cancer-specific survival (CSS) in patients with recurrences dichotomized by low grade (LG) versus high grade (HG) after intravesical BCG treatment, and to assess the safety of continued bladder-sparing therapy in these patients.

Design, Setting, And Participants: We performed an Institutional Review Board-approved review of our bladder cancer database. Overall, 146 non-muscle-invasive bladder cancer (NMIBC) patients were found to have NMIBC recurrence while on BCG therapy; this recurrence was LG in 38 and HG in 108. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity, and concurrent carcinoma in situ were also evaluated. The primary endpoint was progression-free survival (PFS), with progression defined as the development of muscle-invasive bladder cancer (MIBC)/distant metastasis. In addition, recurrence-free survival (RFS), HG RFS, cystectomy-free survival (CFS), and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two sided, and p<0.05 was considered statistically significant.

Intervention: Further intravesical therapy versus salvage RC.

Results And Limitations: Overall, estimated 5-yr PFS was 72.4% (95% confidence interval [CI] 60.4-81.3%). As dichotomized by grade of recurrent tumor, PFS was greater for patients with LG recurrences (85.6%, 95% CI 60.8-95.2%) than for those with HG recurrence (67.9%, 95% CI 54.1-78.4%; p=0.010). Furthermore, patients whose initial recurrence on BCG therapy was LG had improved subsequent RFS (median 62 vs 34mo, p=0.007), HG RFS (median 112 vs 36mo, p<0.001), and CFS (estimated 5-yr CFS 80.8% vs 49.8%, p<0.001) compared with those who had HG initial recurrence. On univariate and multivariate analyses, grade of tumor recurrence after BCG was an independent predictor of time to progression to MIBC/distant metastasis (hazard ratio 3.60, 95% CI 1.18-10.94, p=0.024).

Conclusions: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/metastatic urothelial carcinoma. While, patients with LG recurrences have less than half the progression events compared with those with HG recurrences, their estimated 5-yr progression rate is still 14.4%. Hence all patients should be carefully counseled on bladder-sparing therapy. This also has implications for clinical trial design.

Patient Summary: If bladder cancer recurs after bacillus Calmette-Guerin treatment, there are many factors that determine the further clinical outcome. Although low-grade recurrent tumors confer a less aggressive course, disease progression can still occur, and hence continued vigilance is important.
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http://dx.doi.org/10.1016/j.euo.2018.08.013DOI Listing
May 2019

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer.

Cell Rep 2019 05;27(6):1781-1793.e4

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.04.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546434PMC
May 2019

The 58th Annual Symposium of the Houston Society of Clinical Pathologists.

Arch Pathol Lab Med 2019 05;143(5):548-549

From the Department of Pathology, University of Texas MD Anderson Cancer Center, Houston (Dr Guo); and the Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Weill Medical College of Cornell University, Houston, Texas (Dr Ro).

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http://dx.doi.org/10.5858/arpa.2018-0236-EDDOI Listing
May 2019

Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis.

Cell Rep 2019 02;26(8):2241-2256.e4

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

We used whole-organ mapping to study the locoregional molecular changes in a human bladder containing multifocal cancer. Widespread DNA methylation changes were identified in the entire mucosa, representing the initial field effect. The field effect was associated with subclonal low-allele frequency mutations and a small number of DNA copy alterations. A founder mutation in the RNA splicing gene, ACIN1, was identified in normal mucosa and expanded clonally with an additional 21 mutations in progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and foci of carcinoma were almost identical, confirming their clonal origins. The pathways affected by the DNA copy alterations and mutations, including the Kras pathway, were preceded by the field changes in DNA methylation, suggesting that they reinforced mechanisms that had already been initiated by methylation. The results demonstrate that DNA methylation can serve as the initiator of bladder carcinogenesis.
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http://dx.doi.org/10.1016/j.celrep.2019.01.095DOI Listing
February 2019

Outcomes of nonmetastatic micropapillary variant upper tract urothelial carcinoma.

Urol Oncol 2019 06 16;37(6):354.e19-354.e26. Epub 2019 Feb 16.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Purpose: Micropapillary variant upper tract urothelial cancer (MP-UTUC) is a rare malignancy with little known regarding its clinical course and/or optimal treatment. In this case series, we describe patient characteristics, surgical treatment, oncologic outcomes, and response to perioperative chemotherapy.

Materials And Methods: We conducted a review to identify patients with MP-UTUC treated at our center between January 1994 and October 2017. Clinicopathologic data was obtained. Descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards, and nearest neighbor matching were used to examine the cohort.

Results: Eighteen, (4.3%) of 416 patients were found to have MP-UTUC at our institution over a 23-year period. The majority of patients had ≥pT3 disease at the time of extirpative surgery (13/18, 72%) and one was identified as MP-UTUC prior to surgery. Seven patients received neoadjuvant chemotherapy and six patients received adjuvant chemotherapy. Median overall, cancer specific, and recurrence free survival were 3.29, 3.29, and 1.69 years, respectively for MP-UTUC. There was no survival difference between conventional UTUC and MP-UTUC when matched for age, stage, grade, lymphovascular invasion, and margins (HR 1.18, P = 0.567). No MP-UTUC patients receiving neoadjuvant and adjuvant chemotherapy had apparent pathologic down staging, and of those receiving adjuvant chemotherapy two-thirds died of disease within 2 years.

Conclusions: MP-UTUC is a rare, and in most cases aggressive malignancy that commonly presents as locally advanced disease. In this case series, MP-UTUC does not appear to respond to perioperative chemotherapy as neoadjuvant and adjuvant chemotherapy did not result in apparent pathologic down staging and the majority of those receiving adjuvant chemotherapy died from MP-UTUC.
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http://dx.doi.org/10.1016/j.urolonc.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511295PMC
June 2019

Bladder Cancer in the Genomic Era.

Arch Pathol Lab Med 2019 06 23;143(6):695-704. Epub 2019 Jan 23.

From the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Bladder cancer is a heterogeneous disease that exhibits a wide spectrum of clinical and pathologic features. The classification of bladder cancer has been traditionally based on morphologic assessment with the aid of immunohistochemistry. However, recent genomic studies have revealed that distinct alterations of DNA and RNA in bladder cancer may underlie its diverse clinicopathologic features, leading to a novel molecular classification of this common human cancer.

Objective.—: To update recent developments in genomic characterization of bladder cancer, which may shed insights on the molecular mechanisms underlying the origin of bladder cancer, dual-track oncogenic pathways, intrinsic molecular subtyping, and development of histologic variants.

Data Sources.—: Peer-reviewed literature retrieved from PubMed search and authors' own research.

Conclusions.—: Bladder cancer is likely to arise from different uroprogenitor cells through papillary/luminal and nonpapillary/basal tracks. The intrinsic molecular subtypes of bladder cancer referred to as and exhibit distinct expression signatures, clinicopathologic features, and sensitivities to standard chemotherapy. Genomic characterization of bladder cancer provides new insights to understanding the biological nature of this complex disease, which may lead to more effective treatment.
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http://dx.doi.org/10.5858/arpa.2018-0329-RADOI Listing
June 2019

Prognostic Implication of the United States Food and Drug Administration-defined BCG-unresponsive Disease.

Eur Urol 2019 01 6;75(1):8-10. Epub 2018 Oct 6.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

The category "BCG-unresponsive disease", formulated by experts at the request of the United States Food and Drug Administration, denotes a group of patients with recurrent non-muscle-invasive bladder cancer for whom continued BCG treatment is unlikely to provide benefit. Although quickly adopted for trial design, many of the nuances within the definition lack validation. In this study, we evaluated the prognostic value of BCG unresponsive designation (i.e. recurrence after induction plus at least 1 maintenance course of BCG) by comparing the oncologic outcomes of these patients with those recurring after induction BCG alone. We confirm that appropriately defined, BCG-unresponsive patients are more likely to require salvage radical cystectomy (54.5% vs 17.9%, p=0.002). Moreover, those opting for second-line bladder-sparing therapies are less likely to remain free of tumor recurrence (23% vs 69.2%, p=0.003). On multivariate analysis, BCG-unresponsive disease independently predicts inferior high-grade recurrence-free survival (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 2.27-16.67; p<0.001) and cystectomy-free survival (HR: 3.85, 95% CI: 1.49-10.0; p=0.006). Our data confirm the prognostic implication of the BCG unresponsive definition i.e. recurrence of high grade disease after induction and one course of maintenance BCG, and support its use in counseling and risk stratification of patients with tumor recurrence after BCG. Patient summary: Patients who have BCG-unresponsive disease, that is, high-grade non-muscle-invasive bladder cancer recurring after BCG induction and maintenance, have a low likelihood to respond to further BCG treatment and should consider radical cystectomy or clinical trial enrollment.
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http://dx.doi.org/10.1016/j.eururo.2018.09.028DOI Listing
January 2019

Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases.

Hum Pathol 2018 09 12;79:57-65. Epub 2018 May 12.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address:

Small cell carcinoma (SmCC) of the bladder is a rare disease. We retrospectively studied a large series of bladder SmCC from a single institution. The patients included 69 men and 12 women with a mean age of 68 years. Most bladder SmCCs were presented at advanced stage, with tumors invading the muscularis propria and beyond (n = 77). SmCC was pure in 27 cases and mixed with other histologic types in 54 cases, including urothelial carcinoma (UC) (n = 32), UC in situ (n = 26), glandular (n = 14), micropapillary (n = 4), sarcomatoid (n = 4), squamous (n = 3), and plasmacytoid (n = 1) features. Most SmCCs expressed neuroendocrine markers synaptophysin (41/56), chromogranin (26/55), and CD56 (39/41); however, they did not express UC luminal markers CK20 (0/17), GATA3 (1/30), and uroplakin II (1/22). Some SmCCs showed focal expression of CK5/6 (9/25), a marker for the basal molecular subtype. Furthermore, expression of the retinoblastoma 1 (RB1) gene protein was lost in most of the bladder SmCCs (2/23). The patients' survival was significantly associated with cancer stage but did not show a significant difference between mixed and pure SmCCs. Compared with conventional UC at similar stages, SmCC had a worse prognosis only when patients developed metastatic diseases. In conclusion, bladder SmCC is an aggressive disease that is frequently present at an advanced stage. A fraction of SmCCs show a basal molecular subtype, which may underlie its good response to chemotherapy. Inactivation of the RB1 gene may be implicated in the oncogenesis of bladder SmCC.
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http://dx.doi.org/10.1016/j.humpath.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133751PMC
September 2018

Contribution of bladder cancer pathology assessment in planning clinical trials.

Urol Oncol 2018 Feb 1. Epub 2018 Feb 1.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Bladder cancer is a heterogeneous disease that demonstrates a wide spectrum of histologic features. The modern classification of bladder cancer is largely based on pathologic analysis, which assesses tumor grade, stage, type, size, and other features that are essential for understanding the biological behavior of bladder cancer. Bladder cancers with similar histologic features are likely to show comparable responses to a new therapeutic agent in clinical trial. Furthermore, pathologic analysis also evaluates the quality of tissue samples in clinical trial to ensure the integrity of various molecular tests. In spite of the emerging role of genomic and molecular studies, pathology remains the cornerstone in the diagnosis, prognosis, and treatment of bladder cancer. Herein, the pathologic considerations for bladder cancer clinical trial planning are reviewed.
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http://dx.doi.org/10.1016/j.urolonc.2018.01.001DOI Listing
February 2018

High-grade neuroendocrine carcinoma of the urachus-report of 3 cases.

Hum Pathol 2017 09 18;67:126-133. Epub 2017 Aug 18.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Most urachal malignancies are composed of pure adenocarcinoma with mucin production. Urachal neuroendocrine carcinoma (NEC) is extremely rare, with only a few cases reported in the literature. Here we report 3 cases of urachal NEC, the largest series of this rare disease from a single institution. The patients were young, with a mean age of 27 years (range, 23-34). The urachal tumors showed 2 distinct components: high-grade NEC and enteric-type adenocarcinoma. The urachal NECs were composed of small cell carcinoma (n=2) or large cell NEC (n=1). The subsequent resection specimens showed that all the tumors were at advanced Sheldon stages. All 3 patients developed metastases, which were composed of NEC exclusively. Two patients died from disease in 10 and 31 months, respectively, and the third patient was alive with widespread metastases at 21 months. Our findings suggest that urachal NEC is an aggressive variant with an overwhelming growth advantage over conventional adenocarcinoma. The presence of high-grade NEC in the urachus is associated with poor prognosis.
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http://dx.doi.org/10.1016/j.humpath.2017.08.003DOI Listing
September 2017

Immunoaffinity based methods are superior to kits for purification of prostate derived extracellular vesicles from plasma samples.

Prostate 2017 May 1;77(13):1335-1343. Epub 2017 Aug 1.

Translational Prostate Cancer Research Laboratory, Lawson Health Research Institute, London, Ontario.

Background: The ability to isolate extracellular vesicles (EVs) such as exosomes or microparticles is an important method that is currently not standardized. While commercially available kits offer purification of EVs from biofluids, such purified EV samples will also contain non-EV entities such as soluble protein and nucleic acids that could confound subsequent experimentation. Ideally, only EVs would be isolated and no soluble protein would be present in the final EV preparation.

Methods: We compared commercially available EV isolation kits with immunoaffinity purification techniques and evaluated our final EV preparations using atomic force microscopy (AFM) and nanoscale flow cytometry (NFC). AFM is the only modality capable of detecting distinguishing soluble protein from EVs which is important for downstream proteomics approaches. NFC is the only technique capable of quantitating the proportion of target EVs to non-target EVs in the final EV preparation.

Results: To determine enrichment of prostate derived EVs relative to non-target MPs, anti-PSMA (Prostate Specific Membrane Antigen) antibodies were used in NFC. Antibody-based immunoaffinity purification generated the highest quality of prostate derived EV preparations due to the lack of protein and RNA present in the samples. All kits produced poor purity EV preparations that failed to deplete the sample of plasma protein.

Conclusions: While attractive due to their ease of use, EV purification kits do not provide substantial improvements in isolation of EVs from biofluids such as plasma. Immunoaffinity approaches are more efficient and economical and will also eliminate a significant portion of plasma proteins which is necessary for downstream approaches.
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http://dx.doi.org/10.1002/pros.23393DOI Listing
May 2017

Salvage prostatectomy for post-radiation adenocarcinoma with treatment effect: Pathological and oncological outcomes.

Can Urol Assoc J 2017 Jul 11;11(7):E277-E284. Epub 2017 Jul 11.

Department of Urology; University of Texas MD Anderson Cancer Centre, Houston, TX, United States.

Introduction: Prostate biopsies following localized radiation therapy for prostate cancer often demonstrate residual prostatic carcinoma with treatment effect (CTE). The final oncological outcome of prostatic CTE is currently uncertain. We studied the pathological and oncological outcomes for a large cohort of patients who had CTE on post-radiation therapy biopsy and subsequently underwent salvage radical prostatectomy (SRP).

Methods: A single-centre retrospective review of all SRPs performed from 1995-2014 was performed. Cases were selected for this analysis if they had had a post-radiation "for-cause" biopsy. Biopsy results were compared to final pathology results following SRP. Pathological and clinical outcomes were compared by extent of treatment effect seen on the post-radiation biopsy.

Results: A total of 70 patients who had salvage prostatectomy at MD Anderson Cancer Centre from 2007-2015 met study criteria. CTE was found on biopsy in the absence of other adenocarcinoma in 16 patients. Among them, one (7%) patient had no evidence of carcinoma at the time of salvage prostatectomy, four (27%) had CTE, three (20%) had adenocarcinoma with minimal or partial treatment effect (PTE), and seven (47%) had adenocarcinoma with no treatment effect (NTE). For those with CTE on biopsy, 69% had biochemical recurrence at a median time of 0.4 years (interquartile range [IQR] 0.22-1.52) vs. 52% for all patients (median 0.44 years, IQR 0.11-1.70) and 47% for those with no treatment effect (median 0.62 years, IQR 0.05-1.90). Metastasis developed after salvage prostatectomy in 11.8% of the whole cohort (8/68, median time to metastasis was 3.03 years, IQR 2.45-4.47), 26.7% of patients with CTE (median 3.2 years, IQR 1.96-4.44), and 6.7% of patients with NTE (median 2.45 years, IQR 0.98-2.86). Median recurrence-free survival was 2.78 years (95% confidence interval [CI] 0.84-5.43) for all patients, 0.51 years (95% CI 0.22-2.35) for those with CTE, and 4.95 years (95% CI 0.95-7.08) for those with NTE; the difference was not significant (p=0.13). On multivariate analysis, pre-SRP biopsy Gleason grade <7 (hazard ratio [HR] 0.38; 95% CI 0.14-1.02) and number of biopsy cores positive for carcinoma (HR 1.11; 95% CI 1.00-1.22) were significant for prediction of cancer recurrence.

Conclusions: Patients undergoing salvage prostatectomy for CTE or PTE demonstrated in a for-cause biopsy after radiation therapy had pathological evidence of viable, untreated cancer in more than 50% of cases and were at significant risk of adverse pathological features. Patients with CTE may therefore benefit from salvage radical prostatectomy. Our study is limited by its retrospective nature and sample size. More studies are required to further validate our findings and assess the benefit of SRP in this population.
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http://dx.doi.org/10.5489/cuaj.4304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519386PMC
July 2017

Impact of High-risk Features and Effect of Neoadjuvant Chemotherapy in Urothelial Cancer Patients with Invasion into the Lamina Propria on Transurethral Resection in the Absence of Deep Muscle Invasion.

Eur Urol Focus 2017 12 13;3(6):577-583. Epub 2017 Jul 13.

Departments of Urology at the University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) that invades into the lamina propria is frequently understaged and is associated with a risk of lymph node metastasis and death.

Objective: To identify high-risk features (HRFs) for NMIBC that may identify patients with poorer prognosis who may benefit from neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC).

Design, Setting, And Participants: We performed a single-center retrospective review of patients who underwent RC for NMIBC with invasion into the lamina propria between 1995 and 2013. HRFs included hydronephrosis, abnormal examination under anesthesia, lymphovascular invasion, or variant histology.

Outcome Measurements And Statistical Analysis: Pathology at RC, and overall (OS) and disease-specific (DSS) survival were evaluated and analyzed by Fisher's exact test, Student t test, Cox proportional hazards regression analysis, and the Kaplan-Meier method.

Results And Limitations: We identified 336 patients with a median follow-up of 130 mo. Of these, 159 (47%) had no HRF, 140 (41.5%) had one HRF, and 37 (11%) had ≥2 HRFs. At RC, patients with ≥2 HRFs had a significantly higher rate of pathologic T stage upstaging and lymph node metastasis (p<0.05). Median OS was 139 mo for those with no HRF, 127 mo for those with one HRF, and 56 mo for those with ≥2 HRF (p=0.0057). HRFs are also associated with a decreased DSS (p=0.0009). Patients with ≥2 HRFs (11/37) who received NAC showed improved OS (21% vs 55% 5-yr OS, p=0.0353) and trended toward an improvement in DSS (25% vs 56% 5-yr OS, p=0.0716) compared with RC alone.

Conclusions: The presence of ≥2 HRFs in NMIBC invading the lamina propria is associated with worse pathology at RC and a significant decrease in OS and DSS. NAC appears to provide benefit for these patients. Limitations include retrospective design and limited sample size.

Patient Summary: The presence of high-risk features in urothelial cancer with invasion into the lamina propria has a worse prognosis that may be mitigated by neoadjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.euf.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767145PMC
December 2017

Frequency and Prognostic Value of PTEN Loss in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy.

J Urol 2017 12 12;198(6):1269-1277. Epub 2017 Jul 12.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: To our knowledge the frequency and prognostic significance of PTEN protein expression in upper tract urothelial carcinoma have not yet been investigated in large studies. We analyzed PTEN protein status and its association with disease recurrence and survival outcomes in a large, multi-institutional upper tract urothelial carcinoma cohort.

Materials And Methods: We retrospectively analyzed the records of 611 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy between 1991 and 2008 at a total of 7 institutions. Median followup was 23 months. Tissue microarrays and immunohistochemical PTEN staining (monoclonal antibody) were performed. Univariable and multivariable Cox regression models were created to address the association of PTEN protein expression with disease recurrence, and cancer specific and overall mortality.

Results: PTEN staining was absent in 45 cases (7.4%). Patients with PTEN loss had significantly advanced pathological tumor stage and grade (p <0.001), and higher rates of lymph node metastasis (p <0.01) and lymphovascular invasion (p <0.001) compared to patients with PTEN expression. PTEN loss was associated with disease recurrence, and cancer specific and overall mortality on univariable Cox regression analyses. However, on multivariable Cox regression analyses adjusted for the effect of standard clinicopathological features PTEN loss was only associated with overall mortality (HR 1.69, 95% CI 1.09-2.61, p = 0.02).

Conclusions: In patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma loss of PTEN protein expression is rare but associated with features of biologically aggressive disease such as higher grade and stage as well as lymph node metastasis. Loss of PTEN expression was associated with overall mortality. PTEN loss seemed to promote worse outcomes in this relatively small group of patients.
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http://dx.doi.org/10.1016/j.juro.2017.06.096DOI Listing
December 2017
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