Publications by authors named "Deukwoo Kwon"

85 Publications

Surveillance Intensity in Intermediate Risk Nonmuscle Invasive Bladder Cancer: Revisiting the Optimal Timing and Frequency of Cystoscopy.

J Urol 2021 Feb 22:101097JU0000000000001689. Epub 2021 Feb 22.

Department of Urology, University of Miami Miller School of Medicine, Miami, Florida.

Purpose: To determine the optimal cystoscopic interval for intermediate-risk nonmuscle invasive bladder cancer (IR-NMIBC).

Materials And Methods: A retrospective analysis of IR-NMIBC patients (2010-2017) was performed and 3 hypothetical models of surveillance intensity applied: Model 1: high (3-months), Model 2: moderate (6-months) and Model 3: low-intensity (12-months) over a 2-year period and we compared timing of actual detection of recurrence and progression to proposed cystoscopy timing between each model. We calculated number of avoidable cystoscopies and associated costs.

Results: Of 107 patients with 37 months median follow-up, 66/107 (77.6%) developed recurrence and 12/107(14.1%) had progression. Relative to model 1, there were 33 (50%) delayed detection of recurrences in model 2 and 41 (62%) in model 3. There was 1.7 months mean delay in detection of recurrence for model 1 vs 3.2 and 7.6 months for model 2 and 3 (p<0.001 Model 1 vs 2; p<0.001 Model 2 vs 3). Relative to model 1, there were 8(67%) and 9(75%) delayed detection of progression events in model 2 and 3. There were no progression-related bladder cancer deaths or radical cystectomy due to delayed detection. Mean number of avoidable cystoscopies was higher in model 1 (2) vs model 2 (1) and 3 (0) respectively. Model 1 had the highest aggregate cost of surveillance ($46,262.52).

Conclusions: High-intensity (3-month) surveillance intervals provides faster detection of recurrences but with increased cost and more avoidable cystoscopies without clear oncologic benefit. Moderate intensity (6-month) intervals in IR-NMIBC allows timely detection without oncologic compromise and is less costly with fewer cystoscopies.
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http://dx.doi.org/10.1097/JU.0000000000001689DOI Listing
February 2021

Repeatability of CBCT Radiomic Features and Their Correlation to CT Radiomic Features for Prostate Cancer.

Med Phys 2021 Feb 18. Epub 2021 Feb 18.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: Radiomic features of Cone Beam CT (CBCT) images have potential as biomarkers to predict treatment response and prognosis for patients of prostate cancer. Previous studies of radiomic feature analysis for prostate cancer were assessed in a variety of imaging modalities, including MRI, PET, and CT, but usually limited to a pre-treatment setting. However, CBCT images may provide an opportunity to capture early morphological changes to the tumor during treatment that could lead to timely treatment adaptation. This work investigated the quality of CBCT-based radiomic features and their relationship to reconstruction methods applied to the CBCT projections and the preprocessing methods used in feature extraction. Moreover, CBCT features were correlated to planning CT (pCT) features to further assess the viability of CBCT radiomic features.

Methods: The quality of forty-two CBCT-based radiomic features were assessed according to their repeatability and reproducibility. Repeatability was quantified by correlating radiomic features between twenty CBCT scans that also had repeated scans within 15 minutes. Reproducibility was quantified by correlating radiomic features between the planning CT (pCT) and the first fraction CBCT for twenty patients. Concordance correlation coefficients (CCC) of radiomic features were used to estimate the repeatability and reproducibility of radiomic features. The same patient data set was assessed using different reconstruction methods applied to the CBCT projections. CBCT images were generated using eighteen reconstruction methods using iterative (iCBCT) and standard (sCBCT) reconstructions, three convolution filters, and five noise suppression filters. Eighteen preprocessing settings were also considered.

Results: Overall, CBCT radiomic features were more repeatable than reproducible. Five radiomic features are repeatable in >97% of the reconstruction and preprocessing methods, and come from the gray-level-size-zone-matrix (GLSZM), neighborhood-gray-level-difference-matrix (NGTDM), and gray-level-run-length-matrix (GLRLM) radiomic feature classes. These radiomic features were reproducible in >9.8% of the reconstruction and preprocessing methods. Noise suppression and convolution filter smoothing increased radiomic features repeatability, but decreased reproducibility. The top-repeatable iCBCT method (iCBCT-Sharp-VeryHigh) is more repeatable than the top-repeatable sCBCT method (sCBCT-Smooth) in 64% of the radiomic features.

Conclusion: Methods for reconstruction and preprocessing that improve CBCT radiomic feature repeatability often decrease reproducibility. The best approach may be to use methods that strike a balance repeatability and reproducibility such as iCBCT-Sharp-VeryLow-1-Lloyd-256 that has 17 repeatable and eight reproducible radiomic features. Previous radiomic studies that only used pCT radiomic features have generated prognostic models of prostate cancer outcome. Since our study indicate that CBCT radiomic features correlated well with a subset of pCT radiomic features, one may expect CBCT radiomics to also generate prognostic models for prostate cancer.
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http://dx.doi.org/10.1002/mp.14787DOI Listing
February 2021

Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.

Clin Cancer Res 2021 Jan 25. Epub 2021 Jan 25.

Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Purpose: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).

Patients And Methods: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).

Results: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34 cell phenotype at baseline, including decreased and expression, compared with nonresponders that exhibited a more proliferative CD34 phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.

Conclusions: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4054DOI Listing
January 2021

Heterogeneity in Genomic Risk Assessment from Tissue Based Prognostic Signatures Used in the Biopsy Setting and the Impact of Magnetic Resonance Imaging Targeted Biopsy.

J Urol 2020 Dec 24:101097JU0000000000001559. Epub 2020 Dec 24.

Department of Urology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida.

Purpose: Genomic prognostic signatures are used on prostate biopsy tissue for cancer risk assessment, but tumor heterogeneity and multifocality may be an issue. We evaluated the variability in genomic risk assessment from different biopsy cores within the prostate using 3 prognostic signatures (Decipher, CCP, GPS).

Materials And Methods: Men in this study came from 2 prospective prostate cancer trials of patients undergoing multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy with genomic profiling of positive biopsy cores. We explored the relationship among tumor grade, magnetic resonance imaging risk and genomic risk for each signature. We evaluated the variability in genomic risk assessment between different biopsy cores and assessed how often magnetic resonance imaging targeted biopsy or the current standard of care (profiling the core with the highest grade) resulted in the highest genomic risk level.

Results: In all, 224 positive biopsy cores from 78 men with prostate cancer were profiled. For each signature, higher biopsy grade (p <0.001) and magnetic resonance imaging risk level (p <0.001) were associated with higher genomic scores. Genomic scores from different biopsy cores varied with risk categories changing by 21% to 62% depending on which core or signature was used. Magnetic resonance imaging targeted biopsy and profiling the core with the highest grade resulted in the highest genomic risk level in 72% to 84% and 75% to 87% of cases, respectively, depending on the signature used.

Conclusions: There is variation in genomic risk assessment from different biopsy cores regardless of the signature used. Magnetic resonance imaging directed biopsy or profiling the highest grade core resulted in the highest genomic risk level in most cases.
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http://dx.doi.org/10.1097/JU.0000000000001559DOI Listing
December 2020

Low-Fat, High-Fiber Diet Reduces Markers of Inflammation and Dysbiosis and Improves Quality of Life in Patients With Ulcerative Colitis.

Clin Gastroenterol Hepatol 2020 May 20. Epub 2020 May 20.

Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami-Leonard Miller School of Medicine, Miami, Florida. Electronic address:

Background & Aims: A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC.

Methods: We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or with mild disease (with a flare within the past 18 mo), from February 25, 2015, through September 11, 2018. Participants were assigned randomly to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%-40% of calories from fat) for the first 4-week period, followed by a 2-week washout period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients' homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s ribosomal RNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in the Short-Form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet.

Results: Participants' baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001). Serum amyloid A decreased significantly from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P = .02), but did not decrease significantly compared with iSAD (7.20 mg/L; iSAD vs LFD, P = .07). The serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P = .07). The relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P = .017), whereas the relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P = .015). The relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P = .04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09). The fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P = .43), but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD, P = .04; iSAD vs LFD, P = .08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD, P = .04; iSAD vs LFD, P = .02).

Conclusions: In a cross-over study of patients with UC in remission, we found that a catered LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions therefore might benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598.
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http://dx.doi.org/10.1016/j.cgh.2020.05.026DOI Listing
May 2020

Impact of radiotherapy duration on overall survival in squamous cell carcinoma of the anus.

J Gastrointest Oncol 2020 Apr;11(2):277-290

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine, Miami, FL, USA.

Background: Prolongation of radiotherapy (RT) in the treatment of numerous types of cancer has been shown to reduce overall survival (OS). Treatment delays are common in squamous cell carcinoma of the anus (SCCA) due to the toxicity of definitive chemoradiation (CRT). The effect of these delays on outcomes has not been well evaluated. This study investigated the effects of RT prolongation on OS in patients receiving CRT for SCCA.

Methods: The National Cancer Database was queried for adult patients diagnosed with SCCA and treated with CRT from 2004-2014. Cox proportional hazard regression models examined the effect of duration of RT, measured as fractions delivered per week, on OS. Negative binomial regression assessed the effects of demographic and prognostic factors on the duration of RT.

Results: A total of 8,948 patients were included in the analysis of factors impacting treatment duration, and 6,429 patients in the OS analysis. Multivariable analysis (MVA) showed female gender, non-private insurance, treatment at a low or intermediate volume facility, Charlson/Deyo score ≥2, and advanced disease were associated with longer RT duration. Treatment with IMRT, with single agent chemotherapy, at an academic center, and in later years were associated with shorter RT duration. A decrease in fractions delivered per week was independently associated with reduced OS with a cutoff of 4.72 fractions per week (about 2 missed fractions over a 30 fraction treatment) delineating the largest differences in OS.

Conclusions: Efforts should be made to avoid RT interruptions of any length in SCCA patients and to compensate for treatment breaks to reduce the total duration of RT.
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http://dx.doi.org/10.21037/jgo.2020.02.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212100PMC
April 2020

Predictive value of 0.35 T magnetic resonance imaging radiomic features in stereotactic ablative body radiotherapy of pancreatic cancer: A pilot study.

Med Phys 2020 Aug 16;47(8):3682-3690. Epub 2020 May 16.

Department of Radiation Oncology, University of Miami, Miami, FL, 33136, USA.

Purpose: The aim of this study was to evaluate the potential and feasibility of radiomic features extracted from low field strength (0.35 T) magnetic resonance images (MRIs) in predicting treatment response for patients with pancreatic cancer undergoing stereotactic body radiotherapy (SBRT).

Methods: Twenty patients with unresected, non-metastatic pancreatic ductal adenocarcinoma (PDAC) were enrolled, all of whom received neoadjuvant chemotherapy followed by five-fraction MR-guided SBRT with a radiation dose range of 33-50 Gy. For each patient, five daily setup scans were acquired from a hybrid 0.35 T MRI/radiotherapy unit. Tumor heterogeneity quantified with radiomic features extracted from the gross tumor volume (GTV) was averaged over the course of treatment. Random forest (RF) and adaptive least absolute shrinkage and selection operator (LASSO) classification models were constructed to identify radiomics features predictive of treatment response. Predictive capability of the top-performing features was then evaluated using the receiver operating characteristic area under curve (AUC) obtained using leave-one-out cross-validation.

Results: Half of the 20 patients showed response to treatment, defined by tumor regression on histopathology or tumor response on follow-up dynamic contrast-enhanced computed tomography (CT). The most predictive features selected by the RF method were GLCM energy and GLSZM gray-level variance. The RF-based model achieved an AUC = 0.81 with a 95% confidence interval of [0.594 to 1] The LASSO algorithm selected GLCM energy as the only predictive feature, achieving an AUC = 0.81 with 95% confidence interval of [0.596 to 1].

Conclusion: The findings of this study suggest that radiomic features extracted during MR-guided SBRT may contain predictive information about response of PDAC patients to treatment. Using the images acquired during treatment of PDAC patients supports continued expansion of radiomic analysis based on low field strength MR images and may hold the potential for providing timely indications of response to treatment.
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http://dx.doi.org/10.1002/mp.14200DOI Listing
August 2020

Vaccination against Nonmutated Neoantigens Induced in Recurrent and Future Tumors.

Cancer Immunol Res 2020 07 15;8(7):856-868. Epub 2020 Apr 15.

Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.

Vaccination of patients against neoantigens expressed in concurrent tumors, recurrent tumors, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Human CD8 T cells stimulated with TAP dendritic cells elicited a polyclonal T-cell response that recognized tumor cells with experimentally reduced TAP expression. Vaccination against TAP downregulation-induced antigens overcomes the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a simpler vaccination strategy that will be applicable to most patients with cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339786PMC
July 2020

Cancer mortality among US blacks: Variability between African Americans, Afro-Caribbeans, and Africans.

Cancer Epidemiol 2020 06 30;66:101709. Epub 2020 Mar 30.

Surveillance and Health Services Research, American Cancer Society, United States. Electronic address:

Introduction: Aggregation of all Black populations in US cancer mortality profiles masks remarkable heterogeneity by place of birth. Comparing U.S-born African Americans with African and Afro-Caribbean immigrants may highlight specific cancer prevention and control needs and clarify global cancer epidemiology. Such a comparison has yet to be undertaken on a population basis.

Methods: Using 2012-2017 vital statistics data from California, Florida, Minnesota and New York, age-standardized cancer mortality rates were computed for distinct Black populations. Comparisons were made to the majority White population using mortality rate ratios (MRR) obtained from negative binomial regression.

Results: Of the 83,460 cancer deaths analyzed among Blacks, nearly 20 % were immigrants. African males and females had the lowest all-sites-combined cancer mortality rates (121 and 99 per 100,000, respectively), African Americans had the highest (232 and 163), while Afro-Caribbean were in between (140 and 106 respectively). The average Black:White MRR was significant for prostate (2.11), endometrial (2.05), stomach (2.02), multiple myeloma (1.87), premenopausal breast (1.66), liver (1.58) and cervical (1.56) cancers, (P < 0.05).

Conclusion: While, in aggregate, Blacks in the US have high cancer mortality rates, race itself is not the primary determinant of these disparities. Black immigrant populations show lower cancer mortality than both African Americans and Whites, especially for cancers where environmental factors feature more predominantly: lung, colorectal and breast. Even for cancers with high mortality among all African-descent groups, this study suggests a complex interplay between genetic and environmental factors. Endometrial cancer was unique; mortality rates were similarly high for all three analyzed Black groups.
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http://dx.doi.org/10.1016/j.canep.2020.101709DOI Listing
June 2020

Phase I Trial of MRI-Guided Prostate Cancer Lattice Extreme Ablative Dose (LEAD) Boost Radiation Therapy.

Int J Radiat Oncol Biol Phys 2020 06 19;107(2):305-315. Epub 2020 Feb 19.

Departments of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.

Purpose: A phase I clinical trial was designed to test the feasibility and toxicity of administering high-dose spatially fractionated radiation therapy to magnetic resonance imaging (MRI)-defined prostate tumor volumes, in addition to standard treatment.

Methods And Materials: We enrolled 25 men with favorable to high-risk prostate cancer and 1 to 3 suspicious multiparametric MRI (mpMRI) gross tumor volumes (GTVs). The mpMRI-GTVs were treated on day 1 with 12 to 14 Gy via dose cylinders using a lattice extreme ablative dose technique. The entire prostate, along with the proximal seminal vesicles, was then treated to 76 Gy at 2 Gy/fraction. For some high-risk patients, the distal seminal vesicles and pelvic lymph nodes received 56 Gy at 1.47 Gy/fraction concurrently in 38 fractions. The total dose to the lattice extreme ablative dose cylinder volume(s) was 88 to 90 Gy (112-123 Gy in 2.0 Gy equivalents, assuming an α-to-β ratio of 3).

Results: Dosimetric parameters were satisfactorily met. Median follow-up was 66 months. There were no grade 3 acute/subacute genitourinary or gastrointestinal adverse events. Maximum late genitourinary toxicity was grade 1 in 15 (60%), grade 2 in 4 (16%), and grade 4 in 1 (4%; sepsis after a posttreatment transurethral resection). Maximum late gastrointestinal toxicity was grade 1 in 11 (44%) and grade 2 in 4 (16%). Two patients experienced biochemical failure.

Conclusions: External beam radiation therapy delivered with an upfront spatially fractionated, stereotactic high-dose mpMRI-GTV boost is feasible and was not associated with any unexpected events. The technique is now part of a follow-up phase II randomized trial.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424349PMC
June 2020

Liver cancer: A leading cause of cancer death in the United States and the role of the 1945-1965 birth cohort by ethnicity.

JHEP Rep 2019 Sep 17;1(3):162-169. Epub 2019 Jun 17.

Sylvester Comprehensive Cancer Center, University of Miami School of Medicine.

Liver cancer is highly fatal and the most rapidly increasing cancer in the US, where chronic hepatitis C (HCV) infection is the leading etiology. HCV is particularly prevalent among the 1945-1965 birth cohort, the so-called "baby boomers". Focusing on this cohort-etiology link, we aim to characterize liver cancer patterns for 15 unique US populations: White, African American, Mexican Immigrant, Mexican American, Cuban and Chinese, among others.

Methods: Individual-level mortality data from 2012-2016 from the health departments of 3 large states - California, Florida, New York - were pooled to compute liver cancer mortality rates for each racial/ethnic group and for 2 birth cohorts of interest: "1945-1965 cohort" and "older cohort".

Results: Liver cancer is a major cause of cancer death among all US male groups and the leading cause in Mexican American men. Over 50% of the age-adjusted liver cancer mortality of White, African American, Mexican American, and Puerto Rican males came from the 1945-1965 birth cohort. In contrast, foreign-born male and all female populations had higher liver cancer mortality originating from the older cohort. Internationally, US White male baby boomers had a 49% higher liver cancer mortality rate than their counterparts in Europe (mortality rate ratio 1.49; 95% CI 1.43-1.56).

Conclusions: Populations burdened disproportionately by liver cancer in the 1945-1965 cohort include US-born males who were all present in the US during the 1960s-1990s when significant HCV transmission took place; these individuals will benefit most from HCV screening and treatment. For the others, including all women, Asian subgroups, and especially burgeoning Hispanic immigrant populations, comprehensive liver cancer prevention efforts will require detailed study of the distribution of etiologies.

Lay Summary: Liver cancer, a major cause of cancer death among US males, is increasing. The causes of liver cancer are varied, including hepatitis C, hepatitis B, alcohol-related liver disease, and non-alcoholic fatty liver disease. Racial/ethnic groups are impacted differently, but the highest rates are seen among US-born men born between 1945-1965, the so-called "baby boomers", whether White, Black, or Hispanic, likely linked to the known high prevalence of hepatitis C infection among this cohort.
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http://dx.doi.org/10.1016/j.jhepr.2019.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001577PMC
September 2019

Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer.

Mol Cancer Res 2020 04 16;18(4):623-631. Epub 2020 Jan 16.

Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis . Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance. IMPLICATIONS: These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127944PMC
April 2020

Reply by Authors.

J Urol 2020 03 19;203(3):511. Epub 2019 Dec 19.

Department of Urology, University of Miami Miller School of Medicine, Miami, Florida.

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http://dx.doi.org/10.1097/JU.0000000000000593.02DOI Listing
March 2020

The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma.

Oncogene 2020 03 5;39(10):2103-2117. Epub 2019 Dec 5.

Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.

Rational new strategies are needed to treat tumors resistant to kinase inhibitors. Mechanistic studies of resistance provide fertile ground for development of new approaches. Cancer drug addiction is a paradoxical resistance phenomenon, well-described in MEK-ERK-driven solid tumors, in which drug-target overexpression promotes resistance but a toxic overdose of signaling if the inhibitor is withdrawn. This can permit prolonged control of tumors through intermittent dosing. We and others showed previously that cancer drug addiction arises also in the hematologic malignancy ALK-positive anaplastic large-cell lymphoma (ALCL) resistant to ALK-specific tyrosine kinase inhibitors (TKIs). This is driven by the overexpression of the fusion kinase NPM1-ALK, but the mechanism by which ALK overactivity drives toxicity upon TKI withdrawal remained obscure. Here we reveal the mechanism of ALK-TKI addiction in ALCL. We interrogated the well-described mechanism of MEK/ERK pathway inhibitor addiction in solid tumors and found it does not apply to ALCL. Instead, phosphoproteomics and confirmatory functional studies revealed that the STAT1 overactivation is the key mechanism of ALK-TKI addiction in ALCL. The withdrawal of TKI from addicted tumors in vitro and in vivo leads to overwhelming phospho-STAT1 activation, turning on its tumor-suppressive gene-expression program and turning off STAT3's oncogenic program. Moreover, a novel NPM1-ALK-positive ALCL PDX model showed a significant survival benefit from intermittent compared with continuous TKI dosing. In sum, we reveal for the first time the mechanism of cancer drug addiction in ALK-positive ALCL and the benefit of scheduled intermittent dosing in high-risk patient-derived tumors in vivo.
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http://dx.doi.org/10.1038/s41388-019-1136-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060126PMC
March 2020

Long-term opioid use in curative-intent radiotherapy: One-Year outcomes in head/neck cancer patients.

Head Neck 2020 04 30;42(4):608-624. Epub 2019 Nov 30.

Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, Florida.

Background: No study has determined the incidence of long-term opioid use, or risk factors for long-term use, ≥1 year after radiotherapy.

Methods: Medical records of 276 head/neck cancer patients were retrospectively assessed for persistent opioid use 1-year after curative-intent radiotherapy. Numerous potential risk factors were assessed and the physicians' documented reasons for continued use were qualitatively categorized as suspected opioid use disorder (OUD) or as medically indicated for control of ongoing pain.

Results: Of note, 20 of 276 patients continued using opioids long-term. High maximum opioid dose and the use of opioids and/or psychotropics/non-opioid analgesics at the radiation oncology intake visit were associated with this outcome. Three patients continued due to suspected OUD and 17 due to medical indications.

Conclusion: Of note, 7.2% of patients developed long-term opioid use, which was associated with high maximum opioid dose and early initiation of opioids and/or psychotropics/non-opioid analgesics. Physicians cited medical indications as the primary reason for continued use.
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http://dx.doi.org/10.1002/hed.26034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703799PMC
April 2020

Association of the prognostic model iSEND with PD-1/L1 monotherapy outcome in non-small-cell lung cancer.

Br J Cancer 2020 02 25;122(3):340-347. Epub 2019 Nov 25.

University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA.

Background: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR).

Methods: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events.

Results: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort.

Conclusion: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.
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http://dx.doi.org/10.1038/s41416-019-0643-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000664PMC
February 2020

Prostatic Ductal Adenocarcinoma Controlled for Cancer Grade and Tumor Volume Does Not Have an Independent Effect on Adverse Radical Prostatectomy Outcomes Compared to Usual Acinar Prostatic Adenocarcinoma.

Urology 2020 Mar 9;137:108-114. Epub 2019 Nov 9.

Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL; Department of Urology, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL. Electronic address:

Objective: To study if prostatic ductal adenocarcinoma (PDA) controlled by Grade Group (GG), PSA, and tumor volume (TV) is an independent predictor of adverse radical prostatectomy (RP) outcomes.

Materials: One-hundred and twenty-eight PDA and 1141 acinar continuous RPs were studied. Each tumor nodule (TN) was individually graded, staged, and its TV measured. Univariate analysis (UVA) identified features associated with lymph node metastasis (LN+), extraprostatic extension (EPE), positive surgical margins (SM+), and seminal vesicle invasion (SV+). We then assessed PDA effect on RP outcomes in a multivariate analysis (MVA).

Results: In 127 cases PDA was present in 1 TN and no TN was pure PDA. One-hundred and twenty-three cases had PDA in TNs with highest grade, stage, and TV. Patients with PDA were older (65 vs 63 years, P < 0.001), had higher GG (P < 0.001), and LN+ (6.3% vs 2.7%, P = 0.049). Controlling these variables by GG eliminated statistical significance. Overall, there were 3249 separate TNs (129 PDA and 3120 acinar). In UVA, PDA predicted EPE (92/124 vs 517/3045), SV+ (28/1129 vs 116/3,120), and SM+ (51/129 vs 296/3120), all P < 0.001. In MVA, PDA lost its effect on EPE (OR = 0.88, P = 0.64), SM+ (OR = 0.86, P = 0.5), and SV+ (OR = 0.99, P = 0.98).

Conclusion: Controlled for grade and TV, PDA was not an independent predictor of adverse RP outcomes, but former 2 were. Hence, higher GG and TV associated with PDA TNs may be predictive of adverse RP outcomes rather than PDA by itself. These conclusions may be used in preoperative risk stratification and definitive therapy planning when PDA is identified on needle biopsy.
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http://dx.doi.org/10.1016/j.urology.2019.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682250PMC
March 2020

Use and Validation of the AUA/SUO Risk Grouping for Nonmuscle Invasive Bladder Cancer in a Contemporary Cohort.

J Urol 2020 03 14;203(3):505-511. Epub 2019 Oct 14.

Department of Urology, University of Miami Miller School of Medicine, Miami, Florida.

Purpose: We applied nonmuscle invasive bladder cancer AUA (American Urological Association)/SUO (Society of Urologic Oncology) guidelines for risk stratification and analyzed predictors of recurrence and progression.

Materials And Methods: We retrospectively reviewed the records of 398 patients with nonmuscle invasive bladder cancer treated between 2001 and 2017. Descriptive statistics were used to compare AUA/SUO risk groups. Predictors of recurrence and progression were determined by multivariable regression. Kaplan-Meier analysis was done, a Cox proportional hazards regression model was created and time dependent AUCs were calculated to determine progression-free and recurrence-free survival by risk group.

Results: Median followup was 37 months (95% CI 35-42). Of the patients 92% underwent bacillus Calmette-Guérin induction and 46% received at least 1 course of maintenance treatment. Of the patients 11.5% were at low, 32.5% were at intermediate and 55.8% were at high risk. In patients at low, intermediate and high risk the 5-year progression-free survival rate was 93%, 74% and 54%, and the 5-year recurrence-free survival rate was 43%, 33% and 23%, respectively. Kaplan-Meier analysis was done to stratify high grade Ta 3 cm or less tumor recurrence-free and progression-free survival in the intermediate vs the high risk group. Relative to low risk, classification as intermediate and as high risk was an independent predictor of progression (HR 9.7, 95% CI 2.23-42.0, p <0.01, and HR 36, 95% CI 8.16-159, p <0.001, respectively). Recurrence was more likely in patients at high risk than in those at low risk (HR 2.03, 95% CI 1.11-3.71, p=0.022). For recurrence and progression the 1-year AUC was 0.60 (95% CI 0.546-0.656) and 0.68 (95% CI 0.622-0.732), respectively.

Conclusions: The AUA/SUO nonmuscle invasive bladder cancer risk classification system appropriately stratifies patients based on the likelihood of recurrence and progression. It should be used at diagnosis to counsel patients and guide therapy.
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http://dx.doi.org/10.1097/JU.0000000000000593DOI Listing
March 2020

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.

Cancer 2019 Oct 28;125(20):3603-3614. Epub 2019 Jun 28.

Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Background: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response.

Methods: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features.

Results: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10.

Conclusions: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab.
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http://dx.doi.org/10.1002/cncr.32339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592647PMC
October 2019

Complications of Intrathecal Chemotherapy in Adults: Single-Institution Experience in 109 Consecutive Patients.

J Oncol 2019 2;2019:4047617. Epub 2019 May 2.

Sylvester Comprehensive Cancer Center, USA.

Acute lymphoblastic leukemia and other aggressive lymphoid malignancies like Burkitt leukemia/lymphoma have high incidence of central nervous system (CNS) involvement. Various solid tumors, most notably breast cancer, can also metastasize into the CNS as a late stage complication causing devastating effects. Intrathecal (IT) chemotherapy consisting of methotrexate, cytarabine, or the two in combination is frequently used for the prophylaxis and treatment of CNS metastasis. Because of the high toxicity of these chemotherapeutic agents, however, their side effect profiles are potentially catastrophic. The incidence of neurotoxicity secondary to IT chemotherapy is well defined in the pediatric literature but is poorly reported in adults. Here, we investigated the incidence of neurologic and nonneurologic side effects secondary to IT chemotherapy in 109 consecutive adult patients over a two-year time period at hospitals associated with our institution. Of 355 IT chemotherapy treatments received by these patients, 11 (3.10%) resulted in paresthesias or paralysis, which we defined as significant neurologic events in our analysis. We also examined minor events that arose after IT chemotherapy, including back pain, headache, fever, vomiting, and asthenia. At least one of these occurred after 30.70% of IT chemotherapy doses. Clinicians involved in the care of patients receiving IT chemotherapy should be aware of these findings and consider treatment options lower rate of neurotoxicity such as high-dose systemic methotrexate.
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http://dx.doi.org/10.1155/2019/4047617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521528PMC
May 2019

Optimal radiation dosing in concurrent neoadjuvant chemoradiation for resectable esophageal cancer: a meta-analysis.

J Gastrointest Oncol 2019 Jun;10(3):391-399

Department of Radiation Oncology, University of Miami, Miami, FL, USA.

Background: This is the first meta-analysis to study optimal radiation dose in the setting of concurrent neoadjuvant chemoradiotherapy (cnCRT) for esophageal cancer (EC). We sought to compare outcomes between high dose radiotherapy (HDRT) [>48.85 Gy biologically effective dose (BED)] group and low dose radiotherapy (LDRT) (≤48.85 Gy BED) for patients with EC receiving cnCRT.

Methods: Medline, Embase, and Cochrane databases were searched independently by two members of our team on August 07, 2017. Articles were screened using Covidence. Study quality was assessed via CONSORT. Eligible studies had to be randomized controlled trials (RCT) comparing cnCRT . surgery alone in full-text English. Those with induction or sequential chemoradiotherapy were excluded. We captured data points including radiation dose, hazard ratios (HRs) for overall survival (OS), and treatment-related mortality (TRM). We analyzed HRs for OS and risk ratio (RR) for TRM and corresponding 95% confidence interval (CI) as the summary statistic. We used both fixed- and random-effects models in the presence of heterogeneity. The primary outcome was OS; secondary endpoint was treatment related mortality (TRM). We compared outcomes by HDRT . LDRT. To minimize chemotherapy heterogeneity, we performed a pre-planned analysis excluding the CROSS trial.

Results: The eleven included studies contained a total of 1,697 patients. Eight hundred forty-eight were randomized into the cnCRT. Of these 848 patients, 287 received HDRT and 561 received LDRT. HR for OS was not statistically different between LDRT (HR 0.67; 95% CI, 0.55-0.8) and HDRT (HR 0.68; 95% CI, 0.45-0.91). Excluding the CROSS trial, there was still no difference in outcomes between LDRT and HDRT. TRM was similar between LDRT and HDRT.

Conclusions: With no difference in OS or TRM between LDRT and HDRT, 48.85 Gy BED cnCRT may be a sufficient radiation dose for cnCRT for patients with EC fit for surgery.
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http://dx.doi.org/10.21037/jgo.2019.01.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534709PMC
June 2019

Validation of dominant and secondary sequence utilization in PI-RADS v2 for classifying prostatic lesions.

Can J Urol 2019 06;26(3):9763-9768

Department of Urology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Introduction: To assess the secondary sequence rule in The Prostate Imaging Reporting Data System (PI-RADS) version 2 by comparing the detection of Grade group 1+ (GG1+) and 2+ (GG2+) cancers in PI-RADS 3, an upgraded PI-RADS 4, and true (non-upgraded) PI-RADS 4 targets.

Materials And Methods: We analyzed a total of 589 lesions scored as PI-RADS 3 or 4 obtained from 434 men who underwent mpMRI-US fusion biopsy from September 2015 to November 2017 for evaluation of GG1+ and GG2+ prostate cancer. PI-RADS 4 lesions were differentiated into those that were 'upgraded' to PI-RADS 4 based on the secondary sequence and those that were 'true' PI-RADS 4 based on the dominant sequence.

Results: The odds of detecting a GG2+ cancer was significantly higher for an upgraded 4 (peripheral zone (PZ): OR 5.06, 95%CI 2.04-12.54, p < 0.001, transitional zone (TZ): OR 3.08, 95%CI 1.04-9.08, p = 0.042) and true 4 (PZ: OR 5.82, 95%CI 3.10-10.94, p < 0.0001, TZ: OR 2.43, 95%CI 1.14-5.18, p = 0.022) lesions compared to PI-RADS 3 lesions. Additionally, we found no difference in the odds of detecting a GG2+ prostate cancer between a true PI-RADS 4 (OR 1.15, 95%CI 0.49-2.71 p = 0.746) and upgraded 4 (referent) in the PZ. Similar non-significance was noted between true 4 (OR 0.79, 95%CI 0.26-2.38 p = 0.674) and upgraded 4 lesions in the TZ for detection of GG2+ cancers.

Conclusions: Upgraded PI-RADS 4 and true 4 targets have a higher odds of detecting GG1+ and GG2+ compared to PI-RADS 3 in the PZ and TZ. Our findings validate the revised scoring system for PI-RADS.
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June 2019

Androgen Suppression Therapy Is Associated with Lower Recurrence of Non-muscle-invasive Bladder Cancer.

Eur Urol Focus 2019 May 15. Epub 2019 May 15.

Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Background: The challenge of managing non-muscle-invasive bladder cancer (NMIBC) is its high recurrence rate. Clinical investigations have begun to explore the role of androgen suppression as an adjunct to bladder cancer (BC) treatment.

Objective: To examine the effect of androgen suppression therapy (AST) on recurrence and progression rate of risk-stratified NMIBC.

Design, Setting, And Participants: Male patients with NMIBC were identified retrospectively from a US institutional database between 2001 and 2017. AST included 5α-reductase inhibitor, gonadotropin-releasing hormone agonist, and antiandrogen. Patients who were exposed to AST prior to documented recurrence/progression were included in the treatment arm. BC was risk stratified to investigate the differential response to AST.

Outcome Measurements And Statistical Analysis: Hazard ratios (HRs) for NMIBC recurrence and progression were estimated using Cox proportional hazards multivariate regression models with stepwise method. Recurrence-free survival (RFS) and progression-free survival (PFS) were compared between groups with and without AST.

Results And Limitations: We identified a total of 274 males with a median follow-up period of 3.1 yr (interquartile range [IQR] 1.5-5.2). Thirty-six patients were exposed to AST with a median duration of 1.7 yr (IQR 0.7-2.6). AST was associated with a lower risk of recurrence (HR 0.53, 95% confidence interval 0.30-0.88) as well as improved RFS (p =  0.014). However, no significant reduction of progression or improvement of PFS (p =  0.23) was found with AST. After risk stratification, all five patients who progressed in the AST cohort had high-risk disease on initial transurethral resection (TUR), whereas no patients with low/intermediate-risk disease progressed on AST. Limitations of the study include nonstandardized initiation of AST in relation to initial TUR, lack of androgen level quantification, and small sample size in the treatment arm.

Conclusions: In this retrospective, single-institution study, AST was associated with a lower risk of recurrence in NMIBC. No significant association between AST and progression was found. Further investigation is warranted to define the role of AST as an adjunctive therapy for NMIBC.

Patient Summary: Non-muscle-invasive bladder cancer is a highly recurrent disease that often requires patients to undergo repeated surgical treatments. This single-institution report suggests that medical suppression of androgen may be a potential preventive therapy to reduce recurrence in certain patients.
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http://dx.doi.org/10.1016/j.euf.2019.04.021DOI Listing
May 2019

Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.

Lancet Oncol 2019 06 8;20(6):837-848. Epub 2019 May 8.

Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miami, FL, USA.

Background: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.

Methods: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.

Findings: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1-19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6-79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1-90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.

Interpretation: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.

Funding: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
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http://dx.doi.org/10.1016/S1470-2045(19)30153-6DOI Listing
June 2019

Methods to account for uncertainties in exposure assessment in studies of environmental exposures.

Environ Health 2019 04 8;18(1):31. Epub 2019 Apr 8.

Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, 2nd floor, Box 0560, San Francisco, CA, 94143, USA.

Background: Accurate exposure estimation in environmental epidemiological studies is crucial for health risk assessment. Failure to account for uncertainties in exposure estimation could lead to biased results in exposure-response analyses. Assessment of the effects of uncertainties in exposure estimation on risk estimates received a lot of attention in radiation epidemiology and in several studies of diet and air pollution. The objective of this narrative review is to examine the commonly used statistical approaches to account for exposure estimation errors in risk analyses and to suggest how each could be applied in environmental epidemiological studies.

Main Text: We review two main error types in estimating exposures in epidemiological studies: shared and unshared errors and their subtypes. We describe the four main statistical approaches to adjust for exposure estimation uncertainties (regression calibration, simulation-extrapolation, Monte Carlo maximum likelihood and Bayesian model averaging) along with examples to give readers better understanding of their advantages and limitations. We also explain the advantages of using a 2-dimensional Monte-Carlo (2DMC) simulation method to quantify the effect of uncertainties in exposure estimates using full-likelihood methods. For exposures that are estimated independently between subjects and are more likely to introduce unshared errors, regression calibration and SIMEX methods are able to adequately account for exposure uncertainties in risk analyses. When an uncalibrated measuring device is used or estimation parameters with uncertain mean values are applied to a group of people, shared errors could potentially be large. In this case, Monte Carlo maximum likelihood and Bayesian model averaging methods based on estimates of exposure from the 2DMC simulations would work well. The majority of reviewed studies show relatively moderate changes (within 100%) in risk estimates after accounting for uncertainties in exposure estimates, except for the two studies which doubled/tripled naïve estimates.

Conclusions: In this paper, we demonstrate various statistical methods to account for uncertain exposure estimates in risk analyses. The differences in the results of various adjustment methods could be due to various error structures in datasets and whether or not a proper statistical method was applied. Epidemiological studies of environmental exposures should include exposure-response analyses accounting for uncertainties in exposure estimates.
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http://dx.doi.org/10.1186/s12940-019-0468-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454753PMC
April 2019

Classification of suspicious lesions on prostate multiparametric MRI using machine learning.

J Med Imaging (Bellingham) 2018 Jul 6;5(3):034502. Epub 2018 Sep 6.

University of Miami Miller School of Medicine, Department of Radiation Oncology, Miami, Florida, United States.

We present a radiomics-based approach developed for the SPIE-AAPM-NCI PROSTATEx challenge. The task was to classify clinically significant prostate cancer in multiparametric (mp) MRI. Data consisted of a "training dataset" (330 suspected lesions from 204 patients) and a "test dataset" (208 lesions/140 patients). All studies included T2-weighted (T2-W), proton density-weighted, dynamic contrast enhanced, and diffusion-weighted imaging. Analysis of the images was performed using the MIM imaging platform (MIM Software, Cleveland, Ohio). Prostate and peripheral zone contours were manually outlined on the T2-W images. A workflow for rigid fusion of the aforementioned images to T2-W was created in MIM. The suspicious lesion was outlined using the high b-value image. Intensity and texture features were extracted on four imaging modalities and characterized using nine histogram descriptors: 10%, 25%, 50%, 75%, 90%, mean, standard deviation, kurtosis, and skewness (216 features). Three classification methods were used: classification and regression trees (CART), random forests, and adaptive least absolute shrinkage and selection operator (LASSO). In the held out by the organizers test dataset, the areas under the curve (AUCs) were: 0.82 (random forests), 0.76 (CART), and 0.76 (adaptive LASSO). AUC of 0.82 was the fourth-highest score of 71 entries (32 teams) and the highest for feature-based methods.
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http://dx.doi.org/10.1117/1.JMI.5.3.034502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126494PMC
July 2018

Dosimetric comparison of circular Eye Physics and Collaborative Ocular Melanoma Study plaques to treat uveal melanoma.

Brachytherapy 2019 May - Jun;18(3):404-410. Epub 2019 Feb 20.

Department of Radiation Oncology, University of Miami/Jackson Memorial Hospital, Miami, FL. Electronic address:

Purpose: We sought to formally compare Collaborative Ocular Melanoma Study (COMS) and similar-shaped (circular) eye physics (EP) plaques dosimetrically by examining both tumor coverage and critical structure doses.

Methods And Materials: The plans of patients with uveal melanoma treated consecutively with eye plaque brachytherapy at a single institution from January 2016 to December 2017 were reviewed. Both a COMS plan and an EP plan using plaques of the same shape were generated for each patient using the Isoaid Plaque Simulator software such that >90% of the tumor + 2 mm margin received 85 Gy over 72 hours from iodine-125 sources. Dose statistics were recorded and analyzed using standard statistical methods.

Results: Plans from a total of 62 patients were analyzed. The mean tumor volume was 0.46 cm (range: 0.02-2.02), and tumors were located on average 5.89 mm (range: 0-15.0) from the macula and 6.25 mm (range: 0-16.0) from the optic disc. All plans met the treatment planning criteria for tumor coverage and were optimized to reduce dose to the adjacent organs at risk. There were no significant differences in the mean doses to the fovea (mean difference [MD] = -0.87 Gy; 95% confidence interval [CI]: -4.90 to 3.16; p = 0.80), macula (MD = -1.02 Gy; 95% CI: -4.15 to 2.11; p = 0.65), or optic disc (MD = 1.07 Gy; 95% CI: -0.77 to 2.91; p = 0.34) between the COMS and circular EP plaques.

Conclusions: Overall, neither the COMS plaques nor the circular EP plaques provided consistently superior dosimetry for the treatment of uveal melanoma. The choice of plaque may be based on other considerations such as cost and surgeon preference.
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http://dx.doi.org/10.1016/j.brachy.2019.01.005DOI Listing
December 2019

Impact of Performance Status and Comorbidity on Palliative Radiation Treatment Tolerance and End-Of-Life Decision-Making.

Adv Radiat Oncol 2019 Jan-Mar;4(1):127-133. Epub 2018 Sep 14.

Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.

Purpose: Previous studies have indicated a relationship between functional status and comorbidity on overall survival when treating patients with bone and brain metastases. However, the degree to which these findings have been integrated into modern-day practice remains unknown. This study examines the impact of performance measures, including Karnofsky Performance Status (KPS) and comorbidity, on palliative radiation therapy treatment tolerance and fractionation schedule. The relationship between a shorter fractionation schedule (SFx) and pending mortality is examined.

Methods And Materials: This study included patients who were treated with palliative intent to the brain or bone between January 1, 2016 and June 30, 2016. Demographic and medical characteristics collected included KPS score (stratified as good [90-100], fair [70-80], and poor (≤60]), socioeconomic status, comorbidity (binary measure using the Adult Comorbidity Evaluation-27 scale), site of metastatic disease, and treatment facility. Univariable analyses were performed using the Cox proportional hazards regression model to assess the impact of the variables on the prescribed number of fractions (binary measure, ≥10 [long fractionation schedule], and <10 [SFx]), and major treatment interruptions (MTIs; defined as missing ≥3 radiation therapy treatment days or ending treatment prematurely).

Results: A total of 145 patients were eligible for study inclusion, including 95 patients who were treated for bony metastatic disease and 50 patients for brain metastases. High comorbidity ( = .029) and both fair ( = .051) and poor ( = .065) functional status were associated with more frequent MTIs. However, high comorbidity and low KPS score were not associated with shorter treatment plans. In addition, patients with an earlier time to death were not more likely to receive an SFx ( = .871).

Conclusions: Low KPS and elevated comorbidity scores predict for a poorer prognosis and more frequent MTIs; however, there was no indication that physicians incorporated this information in the fractionation scheduling.
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http://dx.doi.org/10.1016/j.adro.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349604PMC
September 2018

Nutrition and Swallowing Therapy in Head and Neck Cancer: Utilization of Care and Preventative Efficacy.

Nutr Cancer 2018 Nov-Dec;70(8):1290-1298. Epub 2019 Jan 11.

b Department of Radiation Oncology, Sylvester Comprehensive Cancer Center , University of Miami , Miami , Florida , USA.

Purpose: To examine the impact of ethnicity, Spanish language preference, socioeconomic status, and treatment setting on utilization of supportive services before radiotherapy (RT) among head and neck cancer patients and to determine whether a lack of these services is associated with an increased rate of adverse events.

Methods And Materials: Demographic, staging, and treatment details were retrospectively collected for patients treated at a safety-net hospital (n = 56) or adjacent private academic hospital (n = 183) from January 1, 2014, to June 30, 2016. Supportive care services evaluated were limited to speech/swallowing therapy and nutrition therapy. Adverse events and performance measures examined included weight loss during RT, gastric tube placement, emergency department visits, hospital admissions, and missed RT days.

Results: On multivariable analysis, patients receiving treatment at the safety-net hospital were less likely to receive speech/swallowing services. Receiving speech/swallowing therapy before treatment was associated with less weight loss during treatment, and in conjunction with nutrition therapy, was associated with fewer missed RT days.

Conclusion: Safety-net hospital treatment was associated with a lack of utilization of pre-RT speech/swallowing therapy which in turn was associated with increased weight loss. Interventions aimed at improving utilization of these services would improve treatment tolerance and patient outcomes.
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http://dx.doi.org/10.1080/01635581.2018.1557220DOI Listing
September 2019

Demographic disparities in delay of definitive chemoradiation for anal squamous cell carcinoma: a nationwide analysis.

J Gastrointest Oncol 2018 Dec;9(6):1109-1126

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine, Miami, USA.

Background: Prolonged time to treatment initiation (TTI) for patients with curable anal cancer may reduce tumor control. This study investigated demographic disparities in TTI for patients receiving definitive chemoradiation (CRT) for anal squamous cell carcinoma (A-SCC).

Methods: Adult patients with A-SCC diagnosed from 2004 to 2014 and treated with definitive CRT were identified in the National Cancer Database (NCDB). TTI was defined as days from diagnosis to start of CRT. A negative binomial regression model estimated predicted TTI (pTTI) values. Cox proportional hazards model evaluated the impact of TTI on overall survival (OS).

Results: Overall, 12,546 patients were included with 9% Non-Hispanic Black patients and 4% Hispanic patients. Multivariable analysis (MVA) showed that pTTI varied significantly by race/ethnicity with Non-Hispanic Black patients having a pTTI of 50 38 days for Non-Hispanic White patients [relative risk (RR), 1.21; 95% confidence interval (CI), 1.17-1.25]. For Hispanic patients, pTTI was 48 days, significantly longer than that of Non-Hispanic White patients (RR, 1.19; 95% CI, 1.14-1.24). Gender, insurance status, education level, urban category, distance to reporting facility, treatment facility type, intensity-modulated radiation therapy (IMRT)/proton use, T/N classification, and comorbidity status were all also associated with significant variation in TTI. TTI was not independently associated with changes in OS on MVA [hazard ratio (HR), 0.999; 95% CI, 0.997-1.002].

Conclusions: Non-Hispanic Black and Hispanic patients have longer delays in starting definitive CRT for A-SCC. While TTI was not associated with OS, future analyses should explore the impact of TTI on local control, metastases, and patient-reported outcomes.
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http://dx.doi.org/10.21037/jgo.2018.08.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286932PMC
December 2018