Matthew I Milowsky

University of North Carolina at Chapel Hill, North Carolina, United States

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Publications (107)617.78 Total impact

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    ABSTRACT: Objective: To evaluate outcomes for men with high Gleason score and low prostate-specific antigen (PSA) prostate cancer. Low PSA levels among men with Gleason 8-10 prostate cancer may be owing to cellular dedifferentiation rather than low disease burden. We hypothesized that men with Gleason 8-10 prostate cancer and low PSA levels have increased risk for advanced disease and worse survival. Materials and methods: Men diagnosed from 2004 to 2007 with Gleason 8-10 prostate adenocarcinoma in the National Cancer Data Base were included. Patients were stratified by PSA levels at diagnosis: 0.1 to 3.9, 4.0 to 9.9, 10.0 to 19.9, and≥20.0ng/ml. Outcomes were clinical TNM category, pathologic stage (for prostatectomy patients), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards models were used. Results: A total of 37,283 patients were included. Men with PSA levels of<4.0ng/ml were more likely than those with PSA levels of 4 to 9.9ng/ml to present with clinical T3-4 disease (15% vs. 10%, P<0.001), nodal (4% vs. 2%, P<0.001) and distant (5% vs. 3%, P<0.001) metastasis. However, among patients treated with prostatectomy, lower PSA levels were not associated with increased likelihood of pathologic T3-4 disease or nodal metastasis. Six-year OS was 89.1% (PSA: 0.1-3.9ng/ml) vs. 91.0% (PSA: 4.0-9.9ng/ml) for prostatectomy (log-rank P<0.001), and 75.8% vs. 81.0% for radiotherapy (P<0.001). Multivariable analyses showed OS of patients with PSA levels of 0.1 to 3.9ng/ml to be similar to those with PSA levels of 10 to 19.9ng/ml. Conclusions: Patients with Gleason 8-10 cancer and PSA levels of<4.0ng/ml have more aggressive disease than those with PSA levels of 4 to 9.9ng/ml; these low PSA cancers behave more like those with PSA levels of 10 to 19.9ng/ml. Further study is needed to evaluate potential biological differences in these patients with low PSA-producing cancers.
    Urologic Oncology 11/2015; DOI:10.1016/j.urolonc.2015.09.014 · 2.77 Impact Factor

  • International journal of radiation oncology, biology, physics 11/2015; 93(3):S23. DOI:10.1016/j.ijrobp.2015.07.2206 · 4.26 Impact Factor
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    ABSTRACT: A 33-year-old male with a history of left testis Leydig cell tumor (LCT), 3-month status after left radical orchiectomy, presented with a rapidly enlarging (0.6 cm to 3.7 cm) right testicular mass. He underwent a right radical orchiectomy, sections interpreted as showing a similar Leydig cell-like oncocytic proliferation, with a differential diagnosis including metachronous bilateral LCT and metachronous bilateral testicular tumors associated with congenital adrenal hyperplasia (a.k.a. “testicular adrenal rest tumors” (TARTs) and “testicular tumors of the adrenogenital syndrome” (TTAGS)). Additional workup demonstrated a markedly elevated serum adrenocorticotropic hormone (ACTH) and elevated adrenal precursor steroid levels. He was diagnosed with congenital adrenal hyperplasia, 3 β -hydroxysteroid dehydrogenase deficiency (3BHSD) type, and started on treatment. Metachronous bilateral testicular masses in adults should prompt consideration of adult presentation of CAH. Since all untreated CAH patients are expected to have elevated serum ACTH, formal exclusion of CAH prior to surgical resection of a testicular Leydig-like proliferation could be accomplished by screening for elevated serum ACTH.
    09/2015; 2015:459318. DOI:10.1155/2015/459318
  • Tracy L Rose · Matthew I Milowsky ·

    European Urology 09/2015; DOI:10.1016/j.eururo.2015.08.039 · 13.94 Impact Factor
  • Daniel J Crona · Matthew I Milowsky · Young E Whang ·
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    ABSTRACT: Reactivated androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC). Novel AR targeting drugs abiraterone and enzalutamide have improved survival of CRPC patients. However, resistance to these agents develops and patients ultimately succumb to CRPC. Potential mechanisms of resistance include the following: 1) Expression of AR splice variants such as the AR-V7 isoform which lacks the ligand-binding domain, 2) AR missense mutations in the ligand-binding domain, such as F876L and T877A, and 3) Mutation or overexpression of androgen biosynthetic enzymes or glucocorticoid receptor. Several novel agents may overcome resistance mechanisms. Galeterone acts through multiple mechanisms that include degradation of AR protein and is being evaluated in CRPC patients positive for AR-V7. EPI-001 and related compounds inhibit AR splice variants by targeting the N-terminal transactivation domain of AR. Promising therapies and novel biomarkers, such as AR-V7, may lead to improved outcomes for CRPC patients. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
    Clinical Pharmacology &#38 Therapeutics 09/2015; DOI:10.1002/cpt.256 · 7.90 Impact Factor
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    ABSTRACT: Neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). Many patients are referred to an academic medical center (AMC) for cystectomy but receive NAC in the community setting. This study examines if administration of NAC in the community is associated with differences in type of NAC received, pathologic response rate (pT0), and time to cystectomy as compared to NAC administered at an AMC. We performed a retrospective study of patients with MIBC (cT2a-T4-Nx-M0) referred to a single AMC between 1/2012 and 1/2014 who received NAC. We analyzed chemotherapy received, time to cystectomy, pT0, and survival in patients who received NAC in our AMC compared to those treated in the community. In all, 47 patients were analyzed. A similar total dose of cisplatin (median: 280mg/m(2) for both groups, P = 0.82) and pT0 rate (25% vs. 29%, P = 0.72) were seen in patients treated in our AMC and the community. However, administration of NAC in the community was associated with a prolonged time to cystectomy compared with that in our AMC (median number of days 162 vs. 128, P<0.01). This remained significant after adjusting for stage, comorbidity status, and distance to the AMC (P = 0.02). Disease-free survival and overall survival did not differ. Patients with MIBC treated with NAC in the community as compared to an AMC received similar chemotherapy and achieved comparable pT0 rates, indicating effective implementation of NAC in the community. However, NAC in the community was associated with longer time to cystectomy, suggesting a delay in the transition of care between settings. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 06/2015; 33(9). DOI:10.1016/j.urolonc.2015.05.028 · 2.77 Impact Factor
  • Tracy L Rose · Matthew I Milowsky ·
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    ABSTRACT: The number of cases of muscle-invasive bladder cancer is increasing along with the age of the population. Management of muscle-invasive bladder cancer in the elderly is complex, requiring a multidisciplinary team approach and a comprehensive assessment of each individual patient. A geriatric assessment should be used to inform treatment decisions in elderly patients with bladder cancer. There is increasing evidence to support aggressive therapy in appropriate elderly patients, including radical cystectomy and neoadjuvant chemotherapy. Adjuvant chemotherapy also has a role in patients with high-risk disease after cystectomy. A bladder preservation approach with trimodality therapy is a well tolerated and effective alternative to cystectomy in appropriately selected patients. Treatment decisions should not be based on chronologic age alone and advanced age should not preclude aggressive or curative therapy. The recent molecular characterization of bladder cancer and several recent immunotherapy trials provide hope of a more targeted approach to treatment of bladder, potentially improving both effectiveness and tolerability of treatment regimens in the elderly.
    Current opinion in urology 06/2015; 25(5). DOI:10.1097/MOU.0000000000000190 · 2.33 Impact Factor
  • Arjun V Balar · Matthew I Milowsky ·

    Urologic Clinics of North America 05/2015; 42(2):xiii. DOI:10.1016/j.ucl.2015.03.001 · 1.20 Impact Factor
  • Arjun V. Balar · Matthew I. Milowsky ·

    Urologic Clinics of North America 05/2015; 42(2). DOI:10.1016/S0094-0143(15)00016-6 · 1.20 Impact Factor
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    ABSTRACT: Mitoxantrone was approved for use in metastatic castrate-resistant prostate cancer (mCRPC) based on pain palliation without observed survival benefit in a small phase III trial in 1996. To re-evaluate for possible survival benefits in a larger contemporary sample and to demonstrate analytic uses of the newly available Project Data Sphere online resource, we used data from control arms of completed clinical trials to compare survival and toxicity among patients with postdocetaxel mCRPC treated with mitoxantrone and prednisone. Control arm data from two phase III randomized control trials, SUN 1120 and TROPIC, were used to examine the efficacy of mitoxantrone plus prednisone (n = 305) versus prednisone alone (n = 257) among patients with postdocetaxel mCRPC. Propensity score matching was used to balance patient characteristics between the separate trials, conditioned on age and key prognostic variables of survival. The primary outcome was overall survival. Secondary endpoints evaluated safety. Median survival was similar among patients receiving mitoxantrone plus prednisone versus prednisone alone (385 days vs. 336 days; deceleration factor = 0.04; 95% confidence interval: -0.12 to 0.22). Prevalence of several any-grade toxicity, including fatigue, back pain, and peripheral neuropathy, was increased among patients who received mitoxantrone. There was no significant survival benefit for mitoxantrone plus prednisone over prednisone alone among men with mCRPC after docetaxel therapy. This finding is consistent with prior studies showing no survival advantage with mitoxantrone in the predocetaxel setting. Furthermore, our data suggest that mitoxantrone may be associated with increased toxicity compared with prednisone alone. ©AlphaMed Press.
    The Oncologist 04/2015; 20(5). DOI:10.1634/theoncologist.2014-0432 · 4.87 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e383. DOI:10.1016/j.juro.2015.02.663 · 4.47 Impact Factor
  • Arjun V. Balar · Matthew I. Milowsky ·

    Urologic Clinics of North America 03/2015; 42(2). DOI:10.1016/j.ucl.2015.02.004 · 1.20 Impact Factor
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    ABSTRACT: BACKGROUND Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting.METHODS Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC.RESULTSIn total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48).CONCLUSIONS Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice. Cancer 2015. © 2015 American Cancer Society.
    Cancer 03/2015; 121(15). DOI:10.1002/cncr.29387 · 4.89 Impact Factor
  • A.V. Balar · M.D. Galsky · A.O. Siefker-Radtke · S.T. Tagawa · M.I. Milowsky ·
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    ABSTRACT: Urothelial cancer is a chemotherapy-sensitive pan-urothelial disease that arises from both the upper and lower urinary tract. Due to its rarity, the principles for management of upper tract urothelial cancer are derived from evidence gathered in bladder cancer trials. To date, no definitive evidence has differentiated upper tract from lower tract cancer and both are managed similarly. Epidemiologic observations, tissue-based genetic studies, and recent subset analyses from randomized trials suggest potential differences between upper tract and bladder cancers which will need to be validated in prospective trials. This chapter will review the current role for perioperative chemotherapy in high-grade upper tract urothelial cancer as well as the use of chemotherapy in advanced disease. © Springer Science+Business Media New York 2015. All rights reserved.
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    ABSTRACT: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Most of the patients were men (75%) and over half of the patients were aged ⩾65years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. NCT00790426. Copyright © 2014 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 12/2014; 50(18):3145-52. DOI:10.1016/j.ejca.2014.10.013 · 5.42 Impact Factor
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    ABSTRACT: Salvage systemic therapy for advanced urothelial carcinoma has substantial unmet needs. Small phase II trials have been conducted with varying eligibility criteria, which render cross-trials comparisons difficult. Moreover, accrual to trials is hampered by comorbidities, elderly age and poor performance status. Therefore, improvements in clinical trial design may facilitate further advances. This commentary summarizes recent data regarding prognostic factors, which allow us to recommend inclusive, yet rational, eligibility criteria and stratification factors to enhance accrual and improve interpretability of data from phase II trials: 1) allowing either prior perioperative platinum-based chemotherapy within 1 year or prior platinum-based chemotherapy for metastatic disease, 2) allowing ≤2 prior lines of therapy, 3) allow patients regardless of quality of response to prior therapy, 4) allow all sites of primary urothelial malignancy, and 5) a preplanned analysis of outcomes controlled for baseline prognostic factors.
    Clinical Genitourinary Cancer 12/2014; 12(6). DOI:10.1016/j.clgc.2014.03.016 · 2.32 Impact Factor
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    ABSTRACT: Background Outcomes with concurrent chemoradiation for penile squamous cell carcinoma (PSCC) are unclear and only anecdotal reports have been published. We performed a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and methods Individual patient level data were obtained from 5 institutions for outcomes with concurrent chemoradiation for PSCC. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic impact of candidate factors on progression-free survival (PFS) and overall survival (OS). Results A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was ≤3 in 9 patients (36%) and stage 4 in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients and the median (range) of external beam radiotherapy administered was 4900 cGy (1800-7000). The median OS was 6.9 months (95% CI: 5, 14) and the median PFS was 5.1 months (95% CI: 2.5, 7.0). When excluding patients with M1 disease, the remaining patients (N=21) had a median OS and PFS of 10.0 months (95% CI: 5, 14) and 6.0 months (95% CI: 2.0, 7.0), respectively. Baseline neutrophil by lymphocyte ratio (NLR) was significantly associated with survival and visceral metastasis showed a trend for association with OS. Conclusions Concurrent chemoradiation demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted.
    Clinical Genitourinary Cancer 12/2014; 12(6). DOI:10.1016/j.clgc.2014.03.009 · 2.32 Impact Factor
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    Angela B Smith · Matthew I Milowsky ·

    Journal of Clinical Oncology 11/2014; 32(36). DOI:10.1200/JCO.2014.58.3195 · 18.43 Impact Factor
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    ABSTRACT: Background The complete remission (CR) rate with salvage systemic therapy for urothelial carcinoma (UC) is unclear and its value as an intermediate endpoint and association with survival are unknown. Materials and methods Data from Phase II trials of salvage chemotherapy and/or biologic agents were pooled. Data regarding response, overall survival (OS), progression-free survival (PFS), time from prior chemotherapy (TFPC), hemoglobin (Hb), performance status (PS) and liver metastasis (LM) status were collected. Cox proportional hazards regression was used to evaluate the association of CR and other prognostic factors with outcomes. Results 789 of 818 patients enrolled in 12 phase II trials were evaluable. CR and partial response (PR) were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% CI) OS for those with a CR was 21.5 (14.2-34.3) months, compared with 6.7 (6.0-7.0) months in those without a CR (p<0.001). Median (95% CI) PFS for those with a CR was 15.7 (8.2-27.1) months, compared with 2.6 (2.4-2.8) months for those without a CR (p<0.001). Prior cisplatin and TFPC ≥3 months were associated with CR (p<0.05). The presence of poor prognostic factors and suboptimal response to prior therapy did not preclude CR. Conclusions CR occurs in 1.8% of patients receiving salvage therapy for advanced UC, and is strongly associated with durable OS and PFS. CR warrants validation as an intermediate endpoint and may help select agents for further investigation and tumors for molecular interrogation.
    Clinical Genitourinary Cancer 10/2014; 13(2). DOI:10.1016/j.clgc.2014.09.004 · 2.32 Impact Factor
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    ABSTRACT: Microsystem-based technologies are providing new opportunities in the area of in vitro diagnostics due to their ability to provide process automation enabling point-of-care operation. As an example, microsystems used for the isolation and analysis of circulating tumor cells (CTCs) from complex, heterogeneous samples in an automated fashion with improved recoveries and selectivity are providing new opportunities for this important biomarker. Unfortunately, many of the existing microfluidic systems lack the throughput capabilities and/or are too expensive to manufacture to warrant their widespread use in clinical testing scenarios. Here, we describe a disposable, all-polymer, microfluidic system for the high-throughput (HT) isolation of CTCs directly from whole blood inputs. The device employs an array of high aspect ratio (HAR), parallel, sinusoidal microchannels (25 × 150 μm; W × D; AR = 6.0) with walls covalently decorated with anti-EpCAM antibodies to provide affinity-based isolation of CTCs. Channel width, which is similar to an average CTC diameter (10–20 μm), plays a critical role in maximizing the probability of cell/wall interactions and allows for achieving high CTC recovery. The extended channel depth allows for increased throughput at the optimized flow velocity (2 mm/s in a microchannel); maximizes cell recovery, and prevents clogging of the microfluidic channels during blood processing. Fluidic addressing of the microchannel array with a minimal device footprint is provided by large cross-sectional area feed and exit channels poised orthogonal to the network of the sinusoidal capillary channels (so-called Z-geometry). Computational modeling was used to confirm uniform addressing of the channels in the isolation bed. Devices with various numbers of parallel microchannels ranging from 50 to 320 have been successfully constructed. Cyclic olefin copolymer (COC) was chosen as the substrate material due to its superior properties during UV-activation of the HAR microchannels surfaces prior to antibody attachment. Operation of the HT-CTC device has been validated by isolation of CTCs directly from blood secured from patients with metastatic prostate cancer. High CTC sample purities (low number of contaminating white blood cells) allowed for direct lysis and molecular profiling of isolated CTCs.
    Microsystem Technologies 10/2014; 20(10-11). DOI:10.1007/s00542-013-1941-6 · 0.88 Impact Factor

Publication Stats

3k Citations
617.78 Total Impact Points


  • 2012-2015
    • University of North Carolina at Chapel Hill
      • • Lineberger Comprehensive Cancer Center
      • • Department of Medicine
      North Carolina, United States
  • 2004-2013
    • Cornell University
      • Department of Medicine
      Итак, New York, United States
  • 2002-2013
    • Memorial Sloan-Kettering Cancer Center
      • • Epidemiology & Biostatistics Group
      • • Department of Medicine
      • • Genitourinary Oncology Service
      • • Department of Surgery
      New York, New York, United States
  • 2009
    • New York Presbyterian Hospital
      • Department of Pain Medicine
      New York City, New York, United States
  • 2001-2009
    • Weill Cornell Medical College
      • • Department of Medicine
      • • Division of Hematology/Medical Oncology
      New York City, New York, United States