Publications by authors named "Jodi K Maranchie"

51 Publications

A 25 year perspective on the evolution and advances in an understanding of the biology, evaluation and treatment of kidney cancer.

Urol Oncol 2021 Sep 4;39(9):548-560. Epub 2021 Jun 4.

Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.

The diagnosis, evaluation and management of patients with renal cell carcinoma has transformed in the 21st century. Utilizing biological discoveries and technological advances, the field has moved from blunt surgical and largely ineffective medical treatments, to nuanced and fine-tuned approaches based on biology, extent of disease and patient preferences. In this review we will summarize the last 25 years of progress in kidney cancer.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.038DOI Listing
September 2021

ACR Appropriateness Criteria® Post-Treatment Surveillance of Bladder Cancer: 2021 Update.

J Am Coll Radiol 2021 May;18(5S):S126-S138

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

Urothelial cancer is the second most common cancer, and cause of cancer death, related to the genitourinary tract. The goals of surveillance imaging after the treatment of urothelial cancer of the urinary bladder are to detect new or previously undetected urothelial tumors, to identify metastatic disease, and to evaluate for complications of therapy. For surveillance, patients can be stratified into one of three groups: 1) nonmuscle invasive bladder cancer with no symptoms or additional risk factors; 2) nonmuscle invasive bladder cancer with symptoms or additional risk factors; and 3) muscle invasive bladder cancer. This document is a review of the current literature for urothelial cancer and resulting recommendations for surveillance imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2021.02.011DOI Listing
May 2021

ACR Appropriateness Criteria® Recurrent Lower Urinary Tract Infections in Females.

J Am Coll Radiol 2020 Nov;17(11S):S487-S496

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

Urinary tract infections (UTIs) in women are common, with an overall lifetime risk over >50%. UTIs are considered recurrent when they follow complete clinical resolution of a previous UTI and are usually defined as at least three episodes of infection within the preceding 12 months. An uncomplicated UTI is classified as a UTI without structural or functional abnormalities of the urinary tract and without relevant comorbidities. Complicated UTIs are those occurring in patients with underlying structural or medical problems. In women with recurrent uncomplicated UTIs, cystoscopy and imaging are not routinely used. In women suspected of having a recurrent complicated UTI, cystoscopy and imaging should be considered. CT urography or MR urography are usually appropriate for the evaluation of recurrent complicated lower urinary tract infections or for women who are nonresponders to conventional therapy, develop frequent reinfections or relapses, or have known underlying risk factors. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.09.003DOI Listing
November 2020

Editorial Comment.

Authors:
Jodi K Maranchie

J Urol 2020 08 20;204(2):258. Epub 2020 May 20.

University of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1097/JU.0000000000001006.01DOI Listing
August 2020

ACR Appropriateness Criteria® Post-Treatment Surveillance of Bladder Cancer.

J Am Coll Radiol 2019 Nov;16(11S):S417-S427

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

Urothelial cancer is the second most common cancer, and cause of cancer death, related to the genitourinary tract. The goals of surveillance imaging after the treatment of urothelial cancer of the urinary bladder are to detect new or previously undetected urothelial tumors, to identify metastatic disease, and to evaluate for complications of therapy. For surveillance, patients can be stratified into one of three groups: (1) nonmuscle invasive bladder cancer with no symptoms or additional risk factors; (2) nonmuscle invasive bladder cancer with symptoms or additional risk factors; and (3) muscle invasive bladder cancer. This article is a review of the current literature for urothelial cancer and resulting recommendations for surveillance imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2019.05.026DOI Listing
November 2019

ACR Appropriateness Criteria® Penetrating Trauma-Lower Abdomen and Pelvis.

J Am Coll Radiol 2019 Nov;16(11S):S392-S398

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

Lower urinary tract injury is most commonly the result of blunt trauma but can also result from penetrating or iatrogenic trauma. Clinical findings in patients with a mechanism of penetrating trauma to the lower urinary tract include lacerations or puncture wounds of the pelvis, perineum, buttocks, or genitalia, as well as gross hematuria or inability to void. CT cystography or fluoroscopy retrograde cystography are usually the most appropriate initial imaging procedures in patients with a mechanism of penetrating trauma to the lower urinary tract. CT of the pelvis with intravenous contrast, pelvic radiography, fluoroscopic retrograde urethrography, and CT of the pelvis without intravenous contrast may be appropriate in some cases. Arteriography, radiographic intravenous urography, CT of the pelvis without and with intravenous contrast, ultrasound, MRI, and nuclear scintigraphy are usually not appropriate. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2019.05.023DOI Listing
November 2019

ACR Appropriateness Criteria® Lower Urinary Tract Symptoms-Suspicion of Benign Prostatic Hyperplasia.

J Am Coll Radiol 2019 Nov;16(11S):S378-S383

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

Lower urinary tract symptoms due to benign prostatic enlargement have a high prevalence in men over 50 years of age. Diagnosis is made with a combination of focused history and physician examination and validated symptom questionnaires. Urodynamic studies can help to differentiate storage from voiding abnormalities. Pelvic ultrasound may be indicated to assess bladder volume and wall thickness. Other imaging modalities, including prostate MRI, are usually not indicated in the initial workup and evaluation of uncomplicated lower urinary tract symptoms from an enlarged prostate. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2019.05.031DOI Listing
November 2019

E-cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer.

Prostate 2019 08 18;79(11):1226-1237. Epub 2019 Jun 18.

Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Background: We previously reported the presence of prostate-specific antigen (PSA) in the stromal compartment of benign prostatic hyperplasia (BPH). Since PSA is expressed exclusively by prostatic luminal epithelial cells, PSA in the BPH stroma suggests increased tissue permeability and the compromise of epithelial barrier integrity. E-cadherin, an important adherens junction component and tight junction regulator, is known to exhibit downregulation in BPH. These observations suggest that the prostate epithelial barrier is disrupted in BPH and E-cadherin downregulation may increase epithelial barrier permeability.

Methods: The ultra-structure of cellular junctions in BPH specimens was observed using transmission electron microscopy (TEM) and E-cadherin immunostaining analysis was performed on BPH and normal adjacent specimens from BPH patients. In vitro cell line studies using benign prostatic epithelial cell lines were performed to determine the impact of small interfering RNA knockdown of E-cadherin on transepithelial electrical resistance and diffusion of fluorescein isothiocyanate (FITC)-dextran in transwell assays.

Results: The number of kiss points in tight junctions was reduced in BPH epithelial cells as compared with the normal adjacent prostate. Immunostaining confirmed E-cadherin downregulation and revealed a discontinuous E-cadherin staining pattern in BPH specimens. E-cadherin knockdown increased monolayer permeability and disrupted tight junction formation without affecting cell density.

Conclusions: Our results indicate that tight junctions are compromised in BPH and loss of E-cadherin is potentially an important underlying mechanism, suggesting targeting E-cadherin loss could be a potential approach to prevent or treat BPH.
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http://dx.doi.org/10.1002/pros.23806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599563PMC
August 2019

ACR Appropriateness Criteria Acute Onset of Scrotal Pain-Without Trauma, Without Antecedent Mass.

J Am Coll Radiol 2019 May;16(5S):S38-S43

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

An acute scrotum is defined as testicular swelling with acute pain and can reflect multiple etiologies including epididymitis or epididymo-orchitis, torsion of the spermatic cord, or torsion of the testicular appendages. Quick and accurate diagnosis of acute scrotum and its etiology with imaging is necessary because a delayed diagnosis of torsion for as little as 6 hours can cause irreparable testicular damage. Ultrasound duplex Doppler of the scrotum is usually appropriate as the initial imaging for the acute onset of scrotal pain without trauma or antecedent mass in an adult or child. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2019.02.016DOI Listing
May 2019

Small cell bladder cancer: should we consider prophylactic cranial irradiation?

Int Braz J Urol 2019 Mar-Apr;45(2):299-305

Department of Urology, University of Pittsburgh, Pennsylvania, U.S.A.

Purpose: To describe the clinical characteristics, treatment patterns, and outcomes in patients with small cell bladder cancer at our institution, including those who received prophylactic cranial irradiation (PCI) for the prevention of intracranial recurrence.

Materials And Methods: Patients with small cell bladder cancer treated at a single institution between January 1990 and August 2015 were identified and analyzed retrospectively for demographics, tumor stage, treatment, and overall survival.

Results: Of 44 patients diagnosed with small cell bladder cancer, 11 (25%) had metastatic disease at the time of presentation. Treatment included systemic chemotherapy (70%), radical surgery (59%), and local radiation (39%). Six patients (14%) received PCI. Median overall survival was 10 months (IQR 4 - 41). Patients with extensive disease had worse overall survival than those with organ confined disease (8 months vs. 36 months, respectively, p = 0.04). Among those who received PCI, 33% achieved 5 - year survival.

Conclusion: Outcomes for patients with small cell bladder cancer remain poor. Further research is indicated to determine if PCI increases overall survival in small call bladder cancer patients, especially those with extensive disease who respond to chemotherapy.
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http://dx.doi.org/10.1590/S1677-5538.IBJU.2018.0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541124PMC
July 2019

ACR Appropriateness Criteria Pretreatment Staging of Muscle-Invasive Bladder Cancer.

J Am Coll Radiol 2018 May;15(5S):S150-S159

Specialty Chair, University of Alabama at Birmingham, Birmingham, Alabama.

Muscle-invasive bladder cancer (MIBC) has a tendency toward urothelial multifocality and is at risk for local and distant spread, most commonly to the lymph nodes, bone, lung, liver, and peritoneum. Pretreatment staging of MIBC should include imaging of the urothelial upper tract for synchronous lesions; imaging of the chest, abdomen, and pelvis for metastases; and MRI pelvis for local staging. CT abdomen and pelvis without and with contrast (CT urogram) is recommended to assess the urothelium and abdominopelvic organs. Pelvic MRI can improve local bladder staging accuracy. Chest imaging is also recommended with chest radiograph usually being adequate. FDG-PET/CT may be appropriate to identify nodal and metastatic disease. Chest CT may be useful in high-risk patients and those with findings on chest radiograph. Nonurogram CT and MRI of the abdomen and pelvis are usually not appropriate, and neither is radiographic intravenous urography, Tc-99m whole body bone scan, nor bladder ultrasound for pretreatment staging of MIBC. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2018.03.020DOI Listing
May 2018

The comparative effectiveness of quadratus lumborum blocks and paravertebral blocks in radical cystectomy patients.

Can J Urol 2018 04;25(2):9255-9261.

School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: Multimodal analgesia is an effective way to control pain and limit opioid use after surgery. The quadratus lumborum block and paravertebral block are two regional anesthesia techniques that leverage multimodal analgesia to improve postoperative pain control. We sought to compare the efficacy of these blocks for pain management following radical cystectomy.

Materials And Methods: We performed a retrospective review of radical cystectomy patients who received bilateral continuous paravertebral blocks (n = 125) or bilateral single shot quadratus lumborum blocks (n = 50) between 2014-2016. The primary outcome was postoperative opiate consumption on day 0. Secondary outcomes included self-reported pain scores and hospital length of stay.

Results: Quadratus lumborum block patients had similar opioid use on postoperative day 0 compared with paravertebral block patients (29 mg versus 30 mg, p = 0.90). Pain scores on postoperative day 0 were similar between quadratus lumborum block and paravertebral block groups (4.0 versus 3.8, p = 0.72); however, the paravertebral block group had lower pain scores on days 1-3 compared with the quadratus lumborum block group (all p < 0.05). Hospital length of stay was similar between groups (6.6 days versus 6.2 days, p = 0.41).

Conclusions: There were no differences in opioid consumption among patients receiving bilateral single shot quadratus lumborum blocks and bilateral continuous paravertebral blocks after radical cystectomy. These data suggest that the quadratus lumborum block is a viable alternative for delivering multimodal analgesia in cystectomy patients.
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April 2018

Small Renal Masses in Close Proximity to the Collecting System and Renal Sinus Are Enriched for Malignancy and High Fuhrman Grade and Should Be Considered for Early Intervention.

Clin Genitourin Cancer 2018 08 5;16(4):e729-e733. Epub 2018 Feb 5.

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Introduction: Recent reports show a correlation between renal tumor radiographic characteristics and pathologic features. We hypothesize that a more central location within the relatively hypoxic renal medulla might confer a more aggressive tumor phenotype. To test this, radiographic tumor characteristics were compared with tumor grade and histology.

Materials And Methods: We retrospectively reviewed renal masses <4 cm in diameter that underwent resection between 2008 and 2013. Tumor location was recorded using standard R.E.N.A.L. Nephrometry Score. Multivariate logistic regression was performed to compare independent anatomic features with incidence of malignancy and high nuclear grade.

Results: A total of 334 renal tumors had information available for analysis. Univariate analysis showed that increasing endophycity and proximity to the collecting system (<4 mm) were predictors of malignancy and high-grade features. In multivariate analysis, proximity to the collecting system <4 mm remained the as the only anatomical variable predictive of malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.06-12.05; P = .04) and high nuclear grade (OR, 2.81; 95% CI, 1.44-5.51; P = .003).

Conclusion: Malignancy and high tumor grade occur with much greater frequency when tumors are located deep in the kidney, in close proximity to the collecting system and renal sinus. Ninety-six percent of small renal masses in this region were cancers and nearly half were Fuhrman Grade 3 or 4, suggesting that these small centrally located tumors should be targeted for early intervention.
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http://dx.doi.org/10.1016/j.clgc.2018.01.017DOI Listing
August 2018

Systemic therapy following metastasectomy for renal cell carcinoma: Using insights from other clinical settings to address unanswered questions.

Urol Oncol 2018 01 20;36(1):17-22. Epub 2017 Jul 20.

Department of Urology, University of Pittsburgh, Pittsburgh, PA.

Surgical resection for metastatic renal cell carcinoma (RCC) was first described several decades ago, but the appropriate role for surgery in coordinated multidisciplinary care has not been well-defined. The explosive development of new therapies for advanced RCC over the past 10 years has improved the outlook for patients, and there is now renewed interest in surgical metastasectomy for selected patients with metastatic RCC, moving away from the conventional dichotomy between surgery for local disease and systemic therapy for metastatic disease. Patients rendered disease-free after metastasectomy are at high risk of recurrence, but to date no postoperative medical treatment has been shown to be beneficial. Ongoing studies and relevant data will be reviewed to frame the multidisciplinary approach to patients with oligometastatic RCC and to outline future challenges and opportunities for advancing their care.
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http://dx.doi.org/10.1016/j.urolonc.2017.06.005DOI Listing
January 2018

Basic/Translational Science Survey Section: Kidney Cancer.

Authors:
Jodi K Maranchie

Urol Oncol 2017 04 15;35(4):158-159. Epub 2017 Feb 15.

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http://dx.doi.org/10.1016/j.urolonc.2017.01.010DOI Listing
April 2017

Basic/Translational Science Survey Section: Kidney Cancer.

Authors:
Jodi K Maranchie

Urol Oncol 2017 04 15;35(4):157. Epub 2017 Feb 15.

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http://dx.doi.org/10.1016/j.urolonc.2017.01.008DOI Listing
April 2017

Basic/Translational Science Survey Section: Kidney Cancer.

Authors:
Jodi K Maranchie

Urol Oncol 2017 04 15;35(4):156. Epub 2017 Feb 15.

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http://dx.doi.org/10.1016/j.urolonc.2017.01.007DOI Listing
April 2017

Computed Tomography Loopogram: A Novel Technique for Upper Tract Evaluation After Radical Cystectomy.

Clin Genitourin Cancer 2016 08 27;14(4):e427-30. Epub 2016 May 27.

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA.

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http://dx.doi.org/10.1016/j.clgc.2016.02.010DOI Listing
August 2016

Total Psoas Area Predicts Complications following Radical Cystectomy.

Adv Urol 2015 21;2015:901851. Epub 2015 Dec 21.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.

Purpose. To determine whether total psoas area (TPA), a simple estimate of muscle mass, is associated with complications after radical cystectomy. Materials and Methods. Patients who underwent radical cystectomy at our institution from 2011 to 2012 were retrospectively identified. Total psoas area was measured on preoperative CT scans and normalized for patient height. Multivariable logistic regression was used to determine whether TPA was a predictor of 90-day postoperative complications. Overall survival was compared between TPA quartiles. Results. 135 patients were identified for analysis. Median follow-up was 24 months (IQR: 6-37 months). Overall 90-day complication rate was 56% (75/135). TPA was significantly lower for patients who experienced any complication (7.8 cm(2)/m(2) versus 8.8 cm(2)/m(2), P = 0.023) and an infectious complication (7.0 cm(2)/m(2) versus 8.7 cm(2)/m(2), P = 0.032) than those who did not. On multivariable analysis, TPA (adjusted OR 0.70 (95% CI 0.56-0.89), P = 0.003) and Charlson comorbidity index (adjusted OR 1.34 (95% CI 1.01-1.79), P = 0.045) were independently associated with 90-day complications. TPA was not a predictor of overall survival. Conclusions. Low TPA is associated with infectious complications and is an independent predictor of experiencing a postoperative complication following radical cystectomy.
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http://dx.doi.org/10.1155/2015/901851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698521PMC
January 2016

The Role of Interferon in the Management of BCG Refractory Nonmuscle Invasive Bladder Cancer.

Adv Urol 2015 13;2015:656918. Epub 2015 Oct 13.

Department of Urology, University of Pittsburgh Medical Center, 3471 5th Avenue, Suite 700 Kaufmann Building, Pittsburgh, PA 15213, USA.

Background. Thirty to forty percent of patients with high grade nonmuscle invasive bladder cancer (NMIBC) fail to respond to intravesical therapy with bacillus Calmette-Guerin (BCG). Interferon-α2B plus BCG has been shown to be effective in a subset of patients with NMIBC BCG refractory disease. Here we present a contemporary series on the effectiveness and safety of intravesical BCG plus interferon-α2B therapy in patients with BCG refractory NMIBC. Methods. From January of 2005 to April of 2014 we retrospectively found 44 patients who underwent induction with combination IFN/BCG for the management of BCG refractory NMIBC. A chart review was performed to assess initial pathological stage/grade, pathological stage/grade at the time of induction, time to IFN/BCG failure, pathological stage/grade at failure, postfailure therapy, and current disease state. Results. Of the 44 patients who met criteria for the analysis. High risk disease was found in 88.6% of patients at induction. The 12-month and 24-month recurrence-free survival were 38.6% and 18.2%, respectively. 25 (56.8%) ultimately had disease recurrence. Radical cystectomy was performed in 16 (36.4%) patients. Conclusion. Combination BCG plus interferon-α2B remains a reasonably safe alternative treatment for select patients with BCG refractory disease prior to proceeding to radical cystectomy.
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http://dx.doi.org/10.1155/2015/656918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621325PMC
November 2015

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

N Engl J Med 2016 Jan 4;374(2):135-45. Epub 2015 Nov 4.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775252PMC
January 2016

Fibronectin Matrix Formation is a Prerequisite for Colonization of Kidney Tumor Cells in Fibrin.

J Cancer 2015 1;6(2):98-104. Epub 2015 Jan 1.

1. Department of Urology, University of Pittsburgh School of Medicine, Shadyside Medical Center, 5200 Centre Avenue, Pittsburgh, PA15232, USA. ; 2. Prostate and Urological Cancers Program, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA. ; 3. Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Ringstr.52, D-66421 Homburg/Saar, Germany.

Fibrin plays an important role in lung metastasis. Here we show that fibrin promotes colony formation in primary kidney tumor cells from patients with kidney metastasis. In addition, we found that inhibition of fibrin formation with the thrombin inhibitor hirudin in nude mice in vivo significantly reduced the metastatic outgrowth of kidney tumor cells. Colony formation was significantly more efficient in tumor cells embedded in fibrin compared to matrigel and this effect correlates with the capacity of tumor cells to assemble a fibronectin matrix and generate stress fibers. Interestingly, stress fiber formation in fibrin was a specific function of metastatic kidney tumor cells while non-metastatic cells remained round. Inhibition of stress fiber formation with the Rho kinase inhibitor Y-27632, in turn, reduced fibronectin matrix assembly and colony formation in fibrin suggesting that spreading is a critical mechanism for the outgrowth of metastatic kidney tumor cells. Overall, our results indicate that adhesive interactions with fibrin play an important role for the progression of renal cell carcinoma and that inhibiting these interactions could be a promising strategy for treatment and prevention of kidney cancer metastasis.
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http://dx.doi.org/10.7150/jca.10496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280391PMC
January 2015

Expression of Ror2 mediates invasive phenotypes in renal cell carcinoma.

PLoS One 2014 26;9(12):e116101. Epub 2014 Dec 26.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America; Departments of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America.

Ror2 is a Wnt ligand receptor that is overexpressed in a variety of tumors including clear cell renal cell carcinoma (ccRCC). Here we demonstrate that expression of wild type Ror2 results in increased tumorigenic properties in in vitro cell culture and in vivo xenograft models. In addition, Ror2 expression produced positive changes in both cell migration and invasion, which were dependent on matrix metalloprotease 2 (MMP2) activity. Mutations in key regions of the kinase domain of Ror2 resulted in the abrogation of increased tumor growth, cell migration, and cell invasion observed with expression of wild-type Ror2. Finally, we examined Ror2 expression as a prognostic biomarker for ccRCC utilizing the TCGA ccRCC dataset. High expression of Ror2 showed a significant correlation with higher clinical stage, nuclear grade, and tumor stage. Furthermore, high expression of Ror2 in ccRCC patients correlated with significant lower overall survival, cancer specific survival, and recurrence free survival. Together, these findings suggest that Ror2 plays a central role in influencing the ccRCC phenotype, and can be considered as a negative prognostic biomarker and potential therapeutic target in this cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116101PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277431PMC
November 2015

Genomic investigation of etiologic heterogeneity: methodologic challenges.

BMC Med Res Methodol 2014 Dec 22;14:138. Epub 2014 Dec 22.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles.

Methods: We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types.

Results: The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery.

Conclusions: Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology.
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http://dx.doi.org/10.1186/1471-2288-14-138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292824PMC
December 2014

Relocation of CLIC1 promotes tumor cell invasion and colonization of fibrin.

Mol Cancer Res 2015 Feb 9;13(2):273-80. Epub 2014 Sep 9.

Department of Urology, University of Pittsburgh School of Medicine, Shadyside Medical Center, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Homburg, Saarland, Germany.

Unlabelled: Chloride intracellular channel 1 (CLIC1) has been shown to be upregulated in various malignancies but its exact function remains unclear. Here, it is revealed that CLIC1 is critical for the stability of invadopodia in endothelial and tumor cells embedded in a 3-dimensional (3D) matrix of fibrin. Invadopodia stability was associated with the capacity of CLIC1 to induce stress fiber and fibronectin matrix formation following its β3 integrin (ITGB3)-mediated recruitment into invadopodia. This pathway, in turn, was relevant for fibrin colonization as well as slug (SNAI2) expression and correlated with a significant role of CLIC1 in metastasis in vivo. Mechanistically, a reduction of myosin light chain kinase (MYLK) in CLIC1-depleted as well as β3 integrin-depleted cells suggests an important role of CLIC1 for integrin-mediated actomyosin dynamics in cells embedded in fibrin. Overall, these results indicate that CLIC1 is an important contributor to tumor invasion, metastasis, and angiogenesis.

Implications: This study uncovers an important new function of CLIC1 in the regulation of cell-extracellular matrix interactions and ability of tumor cells to metastasize to distant organs.
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http://dx.doi.org/10.1158/1541-7786.MCR-14-0249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336816PMC
February 2015

Epigenetic factors affect tumor initiation, progression and recurrence.

Authors:
Jodi K Maranchie

J Urol 2014 Nov 15;192(5):1318-9. Epub 2014 Aug 15.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1016/j.juro.2014.08.051DOI Listing
November 2014

NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2α.

Cancer Res 2014 Jul 22;74(13):3501-3511. Epub 2014 Apr 22.

University of Pittsburgh, Department of Urology and University of Pittsburgh Cancer Institute.

Most sporadically occurring renal tumors include a functional loss of the tumor suppressor von Hippel Lindau (VHL). Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor-2α (HIF2α), a master transcriptional regulator of genes that drive diverse processes, including angiogenesis, proliferation, and anaerobic metabolism. In determining the critical functions for HIF2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here, we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation, and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-2979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079760PMC
July 2014
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