Publications by authors named "Thomas K Lee"

54 Publications

Choriocapillaris Flow Deficit as a risk factor for progression of Age-Related Macular Degeneration.

Retina 2020 Sep 28. Epub 2020 Sep 28.

Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, California, United States.

Purpose: To evaluate the association between choriocapillaris (CC) flow deficits and structural OCT biomarkers, and the progression of intermediate AMD (iAMD) to complete retinal pigment epithelial and outer retinal atrophy (cRORA).

Methods: Retrospective analysis of consecutive patients with iAMD with a minimum follow-up of 12 months. Odds ratios of intraretinal hyperreflective foci (IRHF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDD), presence of drusen volume (DV) ≥ 0.03 mm within a central 3-mm circle, fellow eye with late stage of AMD, CC FD at baseline and months of follow-up were estimated from logistic regression.

Results: A total of 112 eyes with iAMD were included. Eyes which progressed were significantly more likely to show IRHF, hDC and DV ≥ 0.03 mm. The CC flow deficit was also significantly greater in eyes which developed cRORA. IRHF, hDC, DV ≥ 0.03 mm and higher CC flow deficit were significantly and independently associated with the development of cRORA.

Conclusions: CC flow deficit was significantly greater in iAMD eyes that progressed to cRORA, and remained an independent risk factor when structural OCT biomarkers were considered. CC flow deficit may be useful for enhancing risk stratification and prognostication of patients with iAMD.
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http://dx.doi.org/10.1097/IAE.0000000000002990DOI Listing
September 2020

Initial Evaluation of a Novel Modulated Radiofrequency-based Bladder Denervation Device.

Urology 2019 Dec 17;134:237-242. Epub 2019 Sep 17.

Department of Urology, University of California, Irvine, CA.

Objective: To determine if targeted and modulated radiofrequency ablation (RFA) of the urinary bladder using our novel ablation device (Denerblate) reduces bladder nerve density, potentially leading to a novel strategy for the management of overactive bladder.

Methods: Fifteen pigs were divided into 4 groups: control (n = 3), 1-week (n = 4), 4-week (n = 4) and 12-week (n = 4) survival times. Denerblate was deployed on the trigone area of the bladder. Three 240-second cycles of modulated RFA were applied with 30 seconds between cycles. At the end of each survival term, urinary bladders were harvested for histopathologic evaluation. Nerve count and density were manually calculated.

Results: All procedures were successfully completed, and all animals survived to the desired time points. Mean nerve density (nerves/mm) was highest in the control and 1-week survival group compared to the 4-week and 12-week groups, both of which demonstrated significant diminishment. Nerve density in the bladder neck at control, 1 week, 4 weeks, and 12 weeks were 1.8, 1.35, 0.87, and 0.12, respectively (P <.001). Nerve density in the bladder trigone area at control, 1 week, 4 weeks, and 12 weeks were 1.5, 0.98, 0.65, and 0.112, respectively (P <.001). Epithelial heat injury was observed in 14.3% at 1 week, 10.7% at 4 weeks, but completely resolved by 12 weeks.

Conclusion: In the porcine model, modulated RFA delivered by our novel device reduced nerve density in the bladder neck and trigone by 88.6% and 88.9% at 12 weeks without evidence of lasting epithelial injury.
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http://dx.doi.org/10.1016/j.urology.2019.08.046DOI Listing
December 2019

Laser Endoscopic X-Ray-Guided Intrarenal Tract: Comparison Among Renal Access Modalities in the Porcine Kidney.

J Endourol 2019 09 16;33(9):719-724. Epub 2019 Jul 16.

Department of Urology, University of California, Irvine, California.

Laser endoscopic X-ray-guided intrarenal tract (LEXIT) is a recently described holmium laser retrograde access technique for creating percutaneous access during a percutaneous nephrolithotomy. We compared bleeding, ease of access, and the time to achieve access for each of the following three modalities: LEXIT, retrograde Lawson puncture wire, and antegrade 18-gauge nephrostomy needle access in the porcine kidney. Eight pigs underwent an average of five nephrostomy accesses per kidney under simultaneous laparoscopic vision at 5 mm Hg insufflation pressure. Data collected included: access time (seconds), bleeding intensity (scale: 1 [no bleeding] - 10 [severe bleeding]), bleeding duration (seconds), accuracy of caliceal entry, and surgeon comfort with the technique (scale: 1 [very easy] - 10 [very difficult]). A total of 64 nephrostomy accesses were obtained. The speed of nephrostomy access with LEXIT was significantly faster than the nephrostomy needle and Lawson wire ( < 0.001). Bleeding intensity ( = 0.002) and severity ( = 0.001) were lower with the Lawson puncture wire, followed by LEXIT and then by the nephrostomy needle. LEXIT was rated as easier in acquiring access within the upper pole ( = 0.003) and interpolar calices ( < 0.001). Histopathology demonstrated no difference in parenchymal damage between LEXIT and nephrostomy needle ( = 0.18); however, LEXIT was associated with significantly increased peri-tract thermal injury, although within a narrow focus of 1.6 mm ( < 0.01). Among the three renal access techniques, LEXIT provided the fastest access times and greatest ease of access specifically for upper pole and interpolar calices. Also, bleeding with LEXIT was significantly less compared with the standard antegrade nephrostomy needle access. Histopathological analysis demonstrated that the holmium laser resulted in focal thermal tissue effects similar in range to the blunt tissue trauma caused by the 18-gauge nephrostomy needle.
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http://dx.doi.org/10.1089/end.2019.0234DOI Listing
September 2019

Expression and prognostic utility of PD-L1 in patients with squamous cell carcinoma of the bladder.

Urol Oncol 2019 07 23;37(7):478-484. Epub 2019 Mar 23.

Department of Urology, University of California Irvine, Orange, CA. Electronic address:

Objectives: Checkpoint inhibitors are approved for the treatment of urothelial bladder cancer. However, there have been no reports on the prognostic value of programmed-death receptor ligand 1 (PD-L1) expression in squamous cell carcinoma (SCC) of the bladder. We assessed the relationship between PD-L1 expression, clinicopathological features, and oncologic outcomes in bladder SCC.

Methods And Materials: Immunohistochemistry of PD-L1 was performed on 151 radical cystectomy specimens with pure SCC treated in Mansoura, Egypt from 1997 to 2004.

Results: Median patient age was 52 years (range: 36-74 years) and median length of follow up was 63 months (range: 1-100 months). Schistosomiasis was present in 81% of the specimens and 93% had muscle-invasive disease on pathologic staging. PD-L1 expression was negative in 50 (33%) of the specimens. Negative PD-L1 expression was associated with higher pathologic tumor stage (P = 0.04), higher grade lesions (P = 0.01), and the presence of lymphovascular invasion (P < 0.01). Kaplan-Meier analyses showed that negative PD-L1 expression is associated with worse recurrence-free (P = 0.01) and worse cancer-specific survival (P = 0.01). Multivariable Cox regression analyses showed negative PD-L1 expression was an independent predictor of disease recurrence (hazards ratio 2.05, 95% confidence interval 1.06-3.96, P = 0.03) and cancer-specific mortality (hazards ratio 2.89, 95% confidence interval 1.22-6.82, P = 0.02).

Conclusions: Negative PD-L1 expression is associated with higher pathologic tumor stage, higher grade lesions, presence of lymphovascular invasion, and worse oncologic outcomes after radical cystectomy for SCC. These findings support the need for the inclusion of patients with bladder SCC into immunotherapy clinical trials.
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http://dx.doi.org/10.1016/j.urolonc.2019.02.017DOI Listing
July 2019

Carving out another slice of the pie: Exceptional response to single agent imatinib in an asian female never-smoker with advanced NSCLC with a de-novo PDGFR-α N848 K mutation.

Lung Cancer 2018 10 31;124:86-89. Epub 2018 Jul 31.

Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, CA 92868, USA; Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA 92868, USA. Electronic address:

Non-small cell lung cancer (NSCLC) has emerged as a paradigm for clinical application of precision medicine as optimal therapy is commonly chosen based on genomic biomarkers identified in a patient's tumor sample. Recurrent driver alterations are well described, however, a need to continually identify rare variants remains clinically relevant. We identified an incident case of advanced NSCLC with a PDGFR-α N848 K activation loop mutation with no other concurrent oncogenic drivers. Amino acid sequence alignment confirmed homology to the imatinib-sensitive KIT N822 K activation loop mutation observed in GIST. The patient achieved a 2-year response to single agent imatinib that is ongoing. While PDGFR-α N848 K is rare among public sequencing databases our cases strongly suggests functional relevance and highlights the importance of studying rare variants in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2018.07.043DOI Listing
October 2018

Spectrum of Cribriform Proliferations of the Prostate: From Benign to Malignant.

Arch Pathol Lab Med 2018 08;142(8):938-946

From the Department of Pathology and Urology, University of California Irvine, Orange (Dr Lee); and the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weil Cornell Medical College, Houston, Texas (Dr Ro).

Context: - The presence of cribriform glands/ducts in the prostate can pose a diagnostic challenge. Cribriform glands/ducts include a spectrum of lesions, from benign to malignant, with vastly different clinical, prognostic, and treatment implications.

Objective: - To highlight the diagnostic features of several entities with a common theme of cribriform architecture. We emphasize the importance of distinguishing among benign entities such as cribriform changes and premalignant to malignant entities such as high-grade prostatic intraepithelial neoplasia, atypical intraductal cribriform proliferation, intraductal carcinoma of the prostate, and invasive adenocarcinoma (acinar and ductal types). The diagnostic criteria, differential diagnosis, and clinical implications of these cribriform lesions are discussed.

Data Sources: - Literature review of pertinent publications in PubMed up to calendar year 2017. Photomicrographs obtained from cases at the University of California at Irvine and authors' collections.

Conclusions: - Although relatively uncommon compared with small acinar lesions (microacinar carcinoma and small gland carcinoma mimickers), large cribriform lesions are increasingly recognized and have become clinically and pathologically important. The spectrum of cribriform lesions includes benign, premalignant, and malignant lesions, and differentiating them can often be subtle and difficult. Intraductal carcinoma of the prostate in particular is independently associated with worse prognosis, and its presence in isolation should prompt definitive treatment. Patients with atypical intraductal cribriform proliferation, intraductal carcinoma of the prostate, or even focal cribriform pattern of invasive adenocarcinoma in biopsies would not be ideal candidates for active surveillance because of the high risk of adverse pathologic findings associated with these entities.
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http://dx.doi.org/10.5858/arpa.2018-0005-RADOI Listing
August 2018

Diagnosis of paraganglioma as a pancreatic mass: A case report.

Diagn Cytopathol 2018 Sep 7;46(9):804-806. Epub 2018 Jun 7.

Department of Pathology and Laboratory Medicine, University of California, Irvine, California.

Paragangliomas are rare neoplasms that arise from the chromaffin cells of the autonomic nervous system. Although paragangliomas can occur anywhere paraganglia are present, they tend to occur in the head, neck, and retroperitoneum. Rarely, paragangliomas can occur in the peripancreatic area and present as a pancreatic mass, creating a diagnostic challenge for the clinician, radiologist, and pathologist. Here, we present a case of a 70-year-old woman with history of breast carcinoma who presented with chronic constipation, early satiety, and an abdominal mass. Her first abdominal CT described a 3.6 cm × 5 cm × 4.5 cm cystic and solid mass involving the pancreatic tail that was suspicious for a pancreatic neoplasm. A subsequent abdominal CT described a 5.9 cm multilobulated solid and cystic lesion close to the pancreatic tail. Endoscopic ultrasound-guided fine-needle aspirate of the mass demonstrated scant to moderate cellularity of a heterogeneous population of atypical cells, some with epithelioid morphology and others appearing neuroendocrine-like. By morphology and immunohistochemical stains, an extra-adrenal paraganglioma or pheochromocytoma was considered as a possible diagnosis. The surgical resection specimen confirmed the diagnosis of paraganglioma. This case demonstrates the importance of awareness of paragangliomas in the differential diagnosis of a fine-needle aspiration of a pancreatic mass to avoid erroneous diagnosis.
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http://dx.doi.org/10.1002/dc.23974DOI Listing
September 2018

Multi-institutional Evaluation of Upper Urinary Tract Biopsy Using Backloaded Cup Biopsy Forceps, a Nitinol Basket, and Standard Cup Biopsy Forceps.

Urology 2018 Jul 6;117:89-94. Epub 2018 Apr 6.

Department of Urology, University of California, Irvine (UCI) Medical Center, Orange, CA.

Objective: To compare the performance of 3 contemporary ureteroscopic biopsy devices for the histopathologic diagnosis of upper tract urothelial carcinoma (UTUC).

Methods: We retrospectively reviewed 145 patients who underwent 182 urothelial biopsies using 2.4F backloaded cup biopsy forceps, a nitinol basket, or 3F standard cup biopsy forceps at 3 tertiary academic centers between 2011 and 2016. Experienced genitourinary pathologists provided an assessment of each specimen without knowledge of the device used for biopsy. For patients who underwent nephroureterectomy without neoadjuvant chemotherapy within 3 months of biopsy-proven UTUC diagnosis, the biopsy grade was compared with both the grade and stage of the surgical specimen.

Results: Biopsy utilization varied among the 3 institutions (P <.0001). Significant variabilities in specimen size (P = .001), the presence of intact urothelium (P = .008), and crush artifact (P = .028) were found among the biopsy devices. The quality of specimens from backloaded cup forceps was rated similarly to the nitinol basket (P >.05) and was favored over standard cup forceps specimens. Grade concordance was not affected by specimen size (P >.05), morphology (P >.1), or location (P >.5). No difference existed among the devices in the rate of acquiring a grade concordant biopsy; however, the backloaded cup forceps provided concordant biopsies that could be distinguished as low- and high-grade (P = .02).

Conclusion: The backloaded cup forceps and nitinol basket obtained a higher quality urothelial specimen compared with standard cup forceps. Ureteroscopic biopsy device selection did not significantly impact the accuracy of the histologic diagnosis of UTUC.
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http://dx.doi.org/10.1016/j.urology.2018.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214198PMC
July 2018

Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.

Prostate 2018 02 22;78(3):233-238. Epub 2017 Nov 22.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown.

Methods: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer.

Results: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells.

Conclusion: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.
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http://dx.doi.org/10.1002/pros.23462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774625PMC
February 2018

Diffusion-weighted imaging in hemorrhagic abdominal and pelvic lesions: restricted diffusion can mimic malignancy.

Abdom Radiol (NY) 2018 07;43(7):1772-1784

Radiology, UCSF School of Medicine, 513 Parnassus Ave, Med Sci, San Francisco, CA, 94143, USA.

Diffusion-weighted imaging (DWI) is an increasingly utilized sequence in the assessment of abdominal and pelvic lesions. Benign lesions containing hemorrhagic products, with conglomerates of tightly packed blood cells or fibers, can have restricted water diffusion on DWI and apparent diffusion coefficient maps. Such lesions can have restricted diffusion erroneously attributed to malignancy. This review illustrates benign hemorrhagic lesions displaying restricted diffusion, with histopathologic correlation in relevant cases.
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http://dx.doi.org/10.1007/s00261-017-1366-2DOI Listing
July 2018

Collision and composite tumors; radiologic and pathologic correlation.

Abdom Radiol (NY) 2017 12;42(12):2909-2926

Department of Radiological Sciences, Irvine School of Medicine, University of California, 101 The City Drive South, Suite #1105, Orange, CA, 92868, USA.

The terms composite and collision tumors have been used interchangeably throughout radiological literature. Both composite and collision tumors involve two morphologically and immunohistochemically distinct neoplasms coexisting within a single organ. However, collision tumors lack the histological cellular intermingling seen in composite tumors. Composite tumors often arise from a common driver mutation that induces a divergent histology from a common neoplastic source while collision tumors may arise from coincidental neoplastic change. The purpose of this review is to provide an overview of abdominal composite and collision tumors by discussing hallmark radiographic and pathological presentations of rare hepatic, renal, and adrenal case studies. A better understanding of the presentation of each lesion is imperative for proper recognition, diagnosis, and management of these unique tumor presentations.
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http://dx.doi.org/10.1007/s00261-017-1200-xDOI Listing
December 2017

Dual occurrence of ALK G1202R solvent front mutation and small cell lung cancer transformation as resistance mechanisms to second generation ALK inhibitors without prior exposure to crizotinib. Pitfall of solely relying on liquid re-biopsy?

Lung Cancer 2017 04 9;106:110-114. Epub 2017 Feb 9.

Department of Medicine, Division of Hematology-Oncology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib. The patient's central nervous system (CNS) metastases responded to lorlatinib together with clearance of ALK G1202R mutation by repeat ctDNA assay. However, the patient developed a new large pericardial effusion. Resected pericardium from the pericardial window revealed SCLC transformation with positive immunostaining for synaptophysin, chromogranin, and ALK (D5F3 antibody). Comprehensive genomic profiling (CGP) of the tumor infiltrating pericardium revealed the retainment of an ALK rearrangement with emergence of an inactivating Rb1 mutation (C706Y) and loss of exons 1-11 in p53 that was not detected in the original tumor tissue at diagnosis. The patient was subsequently treated with carboplatin/etoposide and alectinib, but had rapid clinical deterioration and died. The patient never received crizotinib. This case illustrates that multiple/compound resistance mechanisms to ALK inhibitors can occur and provide supporting information that loss of p53 and Rb1 are important in SCLC transformation. If clinically feasible, tissue-based re-biopsy allowing histological examination and CGP remains the gold standard to assess resistance mechanism(s) and to direct subsequent rational clinical care.
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http://dx.doi.org/10.1016/j.lungcan.2017.02.005DOI Listing
April 2017

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers.

Oncologist 2017 02 13;22(2):152-157. Epub 2017 Feb 13.

The Angeles Clinic and Research Institute, Los Angeles, California, USA

Background: Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios.

Materials And Methods: We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities.

Results: A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination.

Conclusions: Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. 2017;22:152-157 Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.
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http://dx.doi.org/10.1634/theoncologist.2015-0511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330711PMC
February 2017

Deep pelvic endometriosis: a radiologist's guide to key imaging features with clinical and histopathologic review.

Abdom Radiol (NY) 2016 12;41(12):2380-2400

Department of Radiology, University of California Irvine School of Medicine, 1001 Health Sciences Road, Irvine, CA, 92617, USA.

While endometriosis typically affects the ovaries, deep infiltrating endometriosis can affect the gastrointestinal tract, urinary tract, and deep pelvis, awareness of which is important for radiologists. Symptoms are nonspecific and can range from chronic abdominal and deep pelvic pain to nausea, vomiting, diarrhea, constipation, hematuria, and rectal bleeding. Ultrasound and computed tomography may show nonspecific soft-tissue density masses causing bowel obstruction and hydronephrosis. This constellation of presenting symptoms and imaging evidence is easily mistaken for other pathologies including infectious gastroenteritis, diverticulitis, appendicitis, and malignancy, which may lead to unnecessary surgery or mismanagement. With this, deep pelvic endometriosis should be considered in the differential diagnosis in a female patient of reproductive age who presents with such atypical symptoms, and further work up with magnetic resonance imaging is imperative for accurate diagnosis, treatment selection, and preoperative planning.
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http://dx.doi.org/10.1007/s00261-016-0956-8DOI Listing
December 2016

Precise Characterization and 3-Dimensional Reconstruction of the Autonomic Nerve Distribution of the Human Ureter.

J Urol 2017 03 14;197(3 Pt 1):723-729. Epub 2016 Sep 14.

Department of Urology, University of California-Irvine, Orange, California. Electronic address:

Purpose: We sought to characterize and 3-dimensionally reconstruct the distribution of the autonomic innervation of the human ureter.

Materials And Methods: Three male and 3 female pairs of ureters were evaluated at 2 mm serial transverse sections along the entire length of the ureter. The location of nerve tissue was immunohistochemically identified using the neuronal marker, S100 protein. ImageJ software was used to calculate nerve count and density in the adventitia and smooth muscle. Blender® graphics software was used to create a 3-dimensional reconstruction of autonomic nerve distribution.

Results: Within the adventitia nerve density was highest in the mid and distal ureter (females 2.87 and 2.71 nerves per mm, and males 1.68 and 1.69 nerves per mm) relative to the proximal ureter (females and males 1.94 and 1.22 nerves per mm, respectively, p >0.0005). Females had significantly higher nerve density throughout the adventitia, especially in the distal ureter (2.87 vs 1.68 nerves per mm, p <0.0005). In smooth muscle the nerve density progressively increased from the proximal to the distal ureter (p >0.0005). Smooth muscle nerve density was similar in the 2 genders (p = 0.928). However, in females nerve density was significantly higher in the first 2 cm of the distal ureter relative to the second 2 cm (3.6 vs 1.5 nerves per mm, p <0.001) but not in males (3.0 vs 2.1 nerves per mm, p = 0.126).

Conclusions: Nerve density was highly concentrated at the distal ureter in the adventitia and smooth muscle of the male and female human ureters. The female ureter had greater nerve density in the adventitia, and in smooth muscle nerves were significantly concentrated at the ureteral orifice and the ureteral tunnel.
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http://dx.doi.org/10.1016/j.juro.2016.08.118DOI Listing
March 2017

Single-shot thoracic epidural: an aid to earlier discharge for pediatric laparoscopic cholecystectomy.

Paediatr Anaesth 2016 Sep;26(9):945-6

CWRU/University Hospitals, Rainbow Babies and Children's, Cleveland, OH, USA.

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http://dx.doi.org/10.1111/pan.12960DOI Listing
September 2016

BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy.

Cancer Discov 2016 06 5;6(6):594-600. Epub 2016 Apr 5.

Foundation Medicine, Inc., Cambridge, Massachusetts.

Unlabelled: Neuroendocrine tumors comprise a heterogeneous group of malignancies with a broad spectrum of clinical behavior. Poorly differentiated tumors follow an aggressive course with limited treatment options, and new approaches are needed. Oncogenic BRAF V600E (BRAF(V600E)) substitutions are observed primarily in melanoma, colon cancer, and non-small cell lung cancer, but have been identified in multiple tumor types. Here, we describe the first reported recurrent BRAF(V600E) mutations in advanced high-grade colorectal neuroendocrine tumors and identify a BRAF alteration frequency of 9% in 108 cases. Among these BRAF alterations, 80% were BRAF(V600E) Dramatic response to BRAF-MEK combination therapy occurred in two cases of metastatic high-grade rectal neuroendocrine carcinoma refractory to standard therapy. Urinary BRAF(V600E) circulating tumor DNA monitoring paralleled disease response. Our series represents the largest study of genomic profiling in colorectal neuroendocrine tumors and provides strong evidence that BRAF(V600E) is an oncogenic driver responsive to BRAF-MEK combination therapy in this molecular subset.

Significance: BRAF(V600E) is an established oncogenic driver, but significant disparities in response exist among tumor types. Two patients with treatment-refractory high-grade colorectal neuroendocrine tumors harboring BRAF(V600E) exhibited rapid and durable response to combined BRAF-MEK inhibition, providing the first clinical evidence of efficacy in this aggressive tumor type. Cancer Discov; 6(6); 594-600. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.
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http://dx.doi.org/10.1158/2159-8290.CD-15-1192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008024PMC
June 2016

Prediagnostic Obesity and Physical Inactivity Are Associated with Shorter Telomere Length in Prostate Stromal Cells.

Cancer Prev Res (Phila) 2015 Aug 19;8(8):737-42. Epub 2015 May 19.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

Obesity and inactivity have been associated with advanced-stage prostate cancer, and poor prostate cancer outcomes, though the underlying mechanism(s) is unknown. To determine whether telomere shortening, which has been associated with lethal prostate cancer, may be a potential underlying mechanism, we prospectively evaluated the association between measures of adiposity, physical activity, and telomere length in 596 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays, we measured telomere length in cancer and benign cells using a telomere-specific FISH assay. Adiposity and activity were assessed via questionnaire within 2 years of diagnosis. Adjusting for age, pathologic stage, and grade, the median and SD of the per cell telomere signals were determined for each man for stromal cells and cancer cells by adiposity and activity categories. Overweight/obese men (54%) were similar to normal weight men on most factors, but had higher Gleason sum and lower activity levels. Overweight/obese men had 7.4% shorter telomeres in stromal cells than normal weight men (P = 0.06). The least active men had shorter telomeres in stromal cells than more active men (Ptrend = 0.002). Men who were overweight/obese and the least active had the shortest telomeres in stromal cells (20.7% shorter; P = 0.0005) compared with normal weight men who were the most active. Cancer cell telomere length and telomere length variability did not differ by measures of adiposity or activity. Telomere shortening in prostate cells may be one mechanism through which lifestyle influences prostate cancer risk and outcomes.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526348PMC
August 2015

Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death.

Cancer Discov 2013 Oct 18;3(10):1130-41. Epub 2013 Jun 18.

1Department of Pathology; 2James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine; 3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; 4Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; Departments of 5Nutrition and 6Epidemiology, Harvard School of Public Health; and 7Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 8Department of Pathology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.

Unlabelled: Current prognostic indicators are imperfect predictors of outcome in men with clinically localized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal (CAS) cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies.

Significance: In this prospective study, the combination of more variable telomere length among cancer cells and shorter telomere length in CAS cells was strongly associated with progression to metastasis and prostate cancer death, pointing to the translational potential for prognostication and risk stratifi cation for individualized therapeutic and surveillance strategies.
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http://dx.doi.org/10.1158/2159-8290.CD-13-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797255PMC
October 2013

Partial nephrectomy for a large renal lymphatic malformation in a child presenting with hypertension.

J Pediatr Surg 2012 Jan;47(1):e23-6

Department of Urology, Stony Brook University Medical Center, Stony Brook, NY 11794, USA.

A 9-year-old girl had hypertension (systolic blood pressure of 125 mm Hg) noted at an annual well child visit. An ultrasound study demonstrated a large right renal cystic mass. A partial nephrectomy was performed. The surgical specimen was 9.7 × 9.4 × 6.4 cm and weighed 413.2 g. The tumor stained diffusely positive for smooth muscle actin and focally positive for factor VIII. Final histologic diagnosis was primary intrarenal lymphatic malformation. The case is unusual because of the presentation, size of the mass, as well as the therapeutic approach of partial nephrectomy.
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http://dx.doi.org/10.1016/j.jpedsurg.2011.10.003DOI Listing
January 2012

Identification of Gleason pattern 5 on prostatic needle core biopsy: frequency of underdiagnosis and relation to morphology.

Am J Surg Pathol 2011 Nov;35(11):1706-11

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

The presence of a Gleason pattern 5 prostatic adenocarcinoma is associated with a worse outcome. This study assesses the accuracy of grading a tumor as having Gleason pattern 5 and the potential factors contributing to its undergrading. From the consultation service of one of the authors, we identified 59 consecutive needle biopsy cases comprising 138 parts that, upon review, were graded as having Gleason pattern 5. All cases were reported as the final diagnosis by the outside pathologist. They were sent for a second opinion at the behest of clinicians or patients and not because the pathologist was seeking a second opinion. Considering the highest Gleason score in a given multicore specimen as the overall Gleason score, Gleason pattern 5 was missed in 34 of 59 (57.6%) cases by the outside pathologist. Compared with the outside pathologist's diagnosis, the Gleason score rendered at the second opinion was increased in 101 of 138 (73.2%) parts, was decreased in 5 of 138 (3.6%) parts, and remained unchanged in 32 of 138 (23.2%) parts. Gleason pattern 5 was not identified by the initiating pathologist in 67 of 138 (48.6%) of the evaluated parts. The architectural patterns of pattern 5 were as follows: single cells (n=104, 75.3%); solid sheets (n=69, 50%); cords (n=62, 44.9%); and comedonecrosis (n=3, 2.2%). Pattern 5 was missed more frequently when it was not the primary pattern. The most common Gleason pattern 5 architectural type was single cells and the least common was comedonecrosis. None of the architectural patterns appeared to be more correctly identified than the others; however, the most accurate grading was when the primary pattern was 5 and was composed mostly of solid sheets. Owing to the important prognostic and therapeutic implications of Gleason pattern 5, pathologists must be attuned to its varied patterns and to the fact that it may often represent a secondary or tertiary component of the carcinoma.
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http://dx.doi.org/10.1097/PAS.0b013e318228571dDOI Listing
November 2011

Pediatric venous thromboembolism in relation to adults.

J Vasc Surg 2012 Jun 23;55(6):1785-93. Epub 2011 Sep 23.

Division of Vascular Surgery, Stony Brook University Medical Center, Stony Brook, NY 11794, USA.

Objective: This review was performed to analyze the current knowledge and controversies in the pathophysiology, diagnosis, treatment, and outcomes of pediatric venous thromboembolism (VTE) compared with adults.

Methods: Searches of the MEDLINE database and manual searches of the references of selected articles were performed to select reports for their relevance and quality of information on the similarities and differences in pathophysiology, diagnosis, and treatment of VTE in children and adults.

Results: Symptomatic VTE incidence is reported at a rate of 0.07 in every 10,000 children, which is significantly lower than the rate in adults. Pulmonary emboli in adolescents are rarely fatal, unlike in adults. VTE recurrence is also much lower in children. Young age has been shown to be protective of VTE, whereas central venous catheters are very important in pediatric venous thrombosis. The incidence of postthrombotic syndrome varies from 20% to 65%, with mild symptoms in most children. Cerebral and visceral vein thrombosis may lead to severe morbidity and death. Some factors of thrombophilia have a significant effect in the pediatric population; however, its overall significance is controversial. Most data on VTE treatment are extrapolated from studies in adults. Children with acute VTE should be treated with anticoagulation therapy. Treatment duration depends on the nature of the thrombosis and previous VTE events.

Conclusions: There is a paucity of prospective randomized studies with data determining not only the effect of VTE but also the treatment options in children. Thrombophilia is a risk factor for pediatric VTE, but its significance has not been thoroughly investigated. Guidelines specific to children for antithrombotic therapy, prophylaxis, and optimal duration need re-evaluation and support by strong evidence.
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http://dx.doi.org/10.1016/j.jvs.2011.07.047DOI Listing
June 2012

High-grade papillary urothelial carcinoma of the urinary tract: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center.

Hum Pathol 2012 Jan 4;43(1):115-20. Epub 2011 Aug 4.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231, USA.

About one half of all bladder neoplasms are noninvasive, and in those, the histologic grade is a crucial prognosticator. Few single-center studies have assessed the recurrence, progression, and cancer-related mortality rates of noninvasive high-grade papillary urothelial carcinomas. With this aim, we evaluated the clinicopathologic and outcome features of 85 patients with high-grade papillary urothelial carcinoma. Median age was 68 years, and 80.5% were men. Tumor size ranged from 0.3 to 13.0 cm (median, 1.6 cm). Recurrence was found in 36.5% of the patients, whereas tumor progression, defined as invasion of lamina propria or beyond, was identified in 40% of all cases. When present, lesion reappearance involved mostly 1 to 2 episodes. Metastasis appeared in 20% of the patients, and 15% died of disseminated bladder cancer. All cancer-related deaths occurred in the group of patients with progression, whereas patients with recurrence showed similar outcomes to those with no recurrence. For patients with tumor progression, clinical stage was significantly associated with outcome (P = .002). As for prognosis, tumor size was strongly associated with progression (P < .01). In conclusion, recurrence, progression, and cancer-specific mortality rates were 36.5%, 40%, and 15%, respectively. All the patients who died of cancer had a history of tumor progression. Patients with recurrences showed similar outcomes to those with no recurrence. Tumor size was strongly associated with tumor progression and cancer-specific survival, whereas clinical stage was significantly associated with outcome in the progression group. In light of the high recurrence and progression rates of high-grade papillary urothelial carcinoma, strict clinical surveillance aimed to detect early recurrent lesions, especially in patients with larger tumors, is warranted.
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http://dx.doi.org/10.1016/j.humpath.2011.04.013DOI Listing
January 2012

Papillary urothelial neoplasm of low malignant potential of the urinary bladder: clinicopathologic and outcome analysis from a single academic center.

Hum Pathol 2011 Nov;42(11):1799-803

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231, USA.

Few long-term single-center studies have addressed the outcome of patients with papillary urothelial neoplasms of low malignant potential. Our study evaluates the behavior of these tumors occurring as primary urinary bladder lesions. For this purpose, 34 primary in-house cases diagnosed and treated between 1998 and 2008 were identified from our medical records. Upon review, 3 cases were upgraded to noninvasive low-grade urothelial carcinomas and excluded from further evaluation. During follow-up (range, 3-108 months; mean, 42 months), 13 patients developed recurrences; and 9 patients progressed to a noninvasive higher grade lesion (8 to low-grade and 1 to high-grade urothelial carcinomas). None of our patients developed stage progression (>pTa) or died of bladder cancer. Size of the primary tumor was associated with the risk of recurrence (P = .043), whereas the number of episodes of recurrence was associated with the likelihood of grade progression (P = .034). In conclusion, recurrences were observed in 42% of all our patients, with a grade progression rate of 29%. None of our patients developed invasive carcinoma or died as a consequence of their disease. Considering the low but definitive risk of recurrence and grade progression, appropriate clinical follow-up of patients with primary papillary urothelial neoplasm of low malignant potential is warranted.
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http://dx.doi.org/10.1016/j.humpath.2011.03.006DOI Listing
November 2011

An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.

Cancer Res 2011 Jun 21;71(11):3812-21. Epub 2011 Apr 21.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

Like many carcinomas, urothelial carcinoma (UroCa) is associated with chronic injury. A better understanding of this association could inform improved strategies for preventing and treating this disease. We investigated the expression, regulation, and function of the transcriptional regulator SRY-related high-mobility group box 9 (Sox9) in urothelial development, injury repair, and cancer. In mouse bladders, Sox9 levels were high during periods of prenatal urothelial development and diminished with maturation after birth. In adult urothelial cells, Sox9 was quiescent but was rapidly induced by a variety of injuries, including exposure to the carcinogen cyclophosphamide, culture with hydrogen peroxide, and osmotic stress. Activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was required for Sox9 induction in urothelial injury and resulted from activation of the epidermal growth factor receptor (Egfr) by several Egfr ligands that were dramatically induced by injury. In UroCa cell lines, SOX9 expression was constitutively upregulated and could be suppressed by EGFR or ERK1/2 blockade. Gene knockdown showed a role for SOX9 in cell migration and invasion. Accordingly, SOX9 protein levels were preferentially induced in invasive human UroCa tissue samples (n = 84) compared with noninvasive cancers (n = 56) or benign adjacent urothelium (n = 49). These results identify a novel, potentially oncogenic signaling axis linking urothelial injury to UroCa. Inhibiting this axis is feasible through a variety of pharmacologic approaches and may have clinical utility.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-3072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107391PMC
June 2011

A novel approach reveals temporal patterns of synaptogenesis between the isolated growth cones of Lymnaea neurons.

Eur J Neurosci 2010 Nov 12;32(9):1442-51. Epub 2010 Oct 12.

Faculty of Medicine, Department of Cell Biology and Anatomy, and the Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.

All brain functions, ranging from motor behaviour to cognition, depend on precise developmental patterns of synapse formation between the growth cones of both pre- and postsynaptic neurons. While the molecular evidence for the presence of 'pre-assembled' elements of synaptic machinery prior to physical contact is beginning to emerge, the precise timing of functional synaptogenesis between the growth cones has not yet been defined. Moreover, it is unclear whether an initial assembly of various synaptic molecules located at the extrasomal regions (e.g. growth cones) can indeed result in fully mature and consolidated synapses in the absence of somata signalling. Such evidence is difficult to obtain both in vivo and in vitro because the extrasomal sites are often challenging, if not impossible, to access for electrophysiological analysis. Here we demonstrate a novel approach to precisely define various steps underlying synapse formation between the isolated growth cones of individually identifiable pre- and postsynaptic neurons from the mollusc Lymnaea stagnalis. We show for the first time that isolated growth cones transformed into 'growth balls' have an innate propensity to develop specific and multiple synapses within minutes of physical contact. We also demonstrate that a prior 'synaptic history' primes the presynaptic growth ball to form synapses quicker with subsequent partners. This is the first demonstration that isolated Lymnaea growth cones have the necessary machinery to form functional synapses.
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http://dx.doi.org/10.1111/j.1460-9568.2010.07428.xDOI Listing
November 2010

Effect of docosahexaenoic acid supplementation on the macular function of patients with Best vitelliform macular dystrophy: randomized clinical trial.

Can J Ophthalmol 2010 Oct;45(5):514-9

Department of Ophthalmology, University of Alberta, Edmonton, Alta.

Objective: Best disease is a slowly progressive macular dystrophy that typically has an onset in early childhood. Multiple lines of evidence suggest that dietary docosahexaenoic acid (DHA) protects against the development of macular degeneration. Our trial tested the effect of an oral supplement of DHA on visual function in patients with Best disease.

Design: Double-masked, randomized, placebo-controlled, crossover clinical trial.

Participants: Eight patients with Best disease.

Methods: Patients were given either an oral supplement of DHA (20 mg/kg daily) or placebo. Primary outcome measures were the multifocal electroretinogram (mfERG) and electro-oculogram (EOG). Plasma DHA was tracked along with visual acuity (Early Treatment Diabetic Retinopathy Study chart), VF-14 scores, and Humphrey visual fields.

Results: All 8 patients had increased plasma DHA levels (2-3 fold) during periods of DHA supplementation compared with periods without supplementation. Differences in visual acuity, VF-14 scores, and EOG Arden ratios during periods with and without DHA supplementation were all statistically insignificant. A positive correlation was found between the plasma concentration of DHA and mfERG amplitudes, but amplitude changes during the treatment periods were not significant. A carryover effect of DHA supplementation was a confounding error.

Conclusions: Our pilot trial of DHA supplementation in 8 patients with Best disease did not demonstrate an improvement in macular function. An expanded trial would be needed to examine the full effects of DHA supplementation on visual function in Best disease.
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http://dx.doi.org/10.3129/i10-028DOI Listing
October 2010

Low-grade papillary urothelial carcinoma of the urinary bladder: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center.

Arch Pathol Lab Med 2010 Aug;134(8):1160-3

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Context: Few large cohort studies have addressed outcome in patients with noninvasive low-grade papillary urothelial carcinoma (LG-UrCa) following implementation of the 2004 World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification.

Objective: To evaluate our cohort of LG-UrCa cases classified according to 2004 WHO/ISUP to reassess outcome and interobserver agreement.

Design: Files were searched for all patients diagnosed with LG-UrCa between 1998 and 2008. All sections were reevaluated for accuracy of classification.

Results: A total of 112 cases initially diagnosed as LG-UrCa were identified. Of those, 8 of 55 cases (15%) initially diagnosed by nonurologic pathologists were reclassified as high-grade papillary urothelial carcinoma and were excluded. The mean length of follow-up was 40.1 months (range, 2-113 months). Tumor recurrence was encountered in 56 of 104 patients (53.8%), including 37 (35.6%) with LG-UrCa or lower-grade tumors and 19 (18.3%) with high-grade papillary urothelial carcinoma. Of the 19 patients demonstrating grade progression, 7 (37%) also developed stage progression (invasive carcinoma, n = 5; metastatic carcinoma, n = 2). Seven patients eventually underwent radical cystectomy. None of the 104 patients died of bladder cancer. The mean number of recurrence episodes was 3.11. The mean durations of time to first recurrence and time to grade progression were 13.9 months and 25.1 months, respectively. The mean size of initial tumors was 1.73 cm. There was no significant correlation between tumor size, patient age, sex, or smoking history and the likelihood for recurrence or grade progression. A significantly higher rate of recurrence was seen in patients with multiple tumors at initial diagnosis (P = .04).

Conclusions: A tendency to underdiagnose high-grade papillary urothelial carcinoma continues to exist. More than half (53.8%) of patients with LG-UrCa developed recurrence, with an 18.3% incidence of grade progression and a 6.7% incidence of stage progression. Patients with multiple initial tumors had significantly higher risk of developing recurrence.
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http://dx.doi.org/10.1043/2009-0403-OA.1DOI Listing
August 2010

Conventional prostatic adenocarcinoma arising in a multilocular prostatic cystadenoma.

Pathol Int 2010 May;60(5):413-6

Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21231, USA.

Multilocular prostatic cystadenoma is a rare benign neoplasm located between the bladder and the rectum. These are prostatic tissue and have been shown to harbor high-grade intraepithelial neoplasia and likely susceptible to the same disease processes seen in the prostate gland. We report the first case of conventional prostatic adenocarcinoma involving a multilocular cystadenoma. Distinction from cystadenocarcinoma is also made.
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http://dx.doi.org/10.1111/j.1440-1827.2010.02536.xDOI Listing
May 2010