284 results on '"Kelly WK"'
Search Results
2. Efficacy of peripheral androgen blockade in prostate cancer patients with biochemical failure after definitive local therapy: results of Cancer and Leukemia Group B (CALGB) 9782.
- Author
-
Monk JP, Halabi S, Picus J, Hussain A, Philips G, Kaplan E, Ahles T, Gu L, Vogelzang N, Kelly WK, Small EJ, Cancer and Leukemia Group B, Monk, J Paul, Halabi, Susan, Picus, Joel, Hussain, Arif, Philips, George, Kaplan, Ellen, Ahles, Tim, and Gu, Lin
- Abstract
Background: The treatment for prostate cancer patients with biochemical failure after local therapy remains controversial. Peripheral androgen blockade using a combination of a 5-alpha reductase inhibitor and an antiandrogen may allow control of the prostate-specific antigen (PSA). Because testosterone levels are not suppressed, this approach may be associated with less morbidity than conventional gonadal androgen suppression.Methods: All patients had undergone previous definitive local therapy and had evidence of a rising PSA >1ng/mL, with no evidence of recurrent disease. Patients received both finasteride, 5 mg orally per day, and flutamide, 250 mg orally 3× a day. Patients were followed for a PSA response and quality of life assessment.Results: Ninety-nine of 101 accrued patients were eligible. A ≥80% PSA decline was seen in 96 (96%) patients. The median time to PSA progression was 85 months. With a median follow-up of 10 years, the median survival time had not been reached, and the 5-year overall survival rate was 87%. Toxicity was mild, with 18 patients stopping for toxicity; 15 had diarrhea, 4 had gynecomastia, and 3 had transaminase elevation. Baseline Functional Assessment of Cancer Therapy Prostate Module and Treatment Outcome Index scores decreased by 5 points each at 6 months after enrollment.Conclusions: The use of the finasteride/flutamide combination is feasible, and results in PSA declines of ≥80% in 96% of patients with serologic progression after definitive local therapy. There were no unexpected toxicities, and the change in quality of life was mild. Further evaluation of this or a similar regimen in a controlled clinical trial is warranted. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
3. 99. Studies on the bioavailability of orally administered all-tarns-retinoic acid in cancer patients; its modulation by ketoconazole
- Author
-
Muindi, J, primary, Young, C, additional, Rigas, J, additional, Francis, P, additional, Kris, M, additional, Scher, H, additional, Kelly, WK, additional, and Warrell, R, additional
- Published
- 1992
- Full Text
- View/download PDF
4. A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006.
- Author
-
Picus J, Halabi S, Kelly WK, Vogelzang NJ, Whang YE, Kaplan EB, Stadler WM, Small EJ, Cancer and Leukemia Group B, Picus, Joel, Halabi, Susan, Kelly, W Kevin, Vogelzang, Nicholas J, Whang, Young E, Kaplan, Ellen B, Stadler, Walter M, and Small, Eric J
- Abstract
Background: The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.Methods: This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.Results: Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.Conclusions: The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
5. Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.
- Author
-
Morris MJ, Pandit-Taskar N, Carrasquillo J, Divgi CR, Slovin S, Kelly WK, Rathkopf D, Gignac GA, Solit D, Schwartz L, Stephenson RD, Hong C, Delacruz A, Curley T, Heller G, Jia X, O'Donoghue J, Larson S, Scher HI, and Morris, Michael J
- Published
- 2009
- Full Text
- View/download PDF
6. Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer.
- Author
-
Galsky MD, Eisenberger M, Moore-Cooper S, Kelly WK, Slovin SF, DeLaCruz A, Lee Y, Webb IJ, Scher HI, Galsky, Matthew D, Eisenberger, Mario, Moore-Cooper, Sandra, Kelly, W Kevin, Slovin, Susan F, DeLaCruz, Anthony, Lee, Yih, Webb, Iain J, and Scher, Howard I
- Published
- 2008
- Full Text
- View/download PDF
7. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
- Author
-
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, and Hussain M
- Published
- 2008
- Full Text
- View/download PDF
8. Histone deacetylase inhibitors: biology and mechanism of action.
- Author
-
Mehnert JM and Kelly WK
- Published
- 2007
- Full Text
- View/download PDF
9. Second-line chemotherapy for prostate cancer: patient characteristics and survival.
- Author
-
Beekman KW, Fleming MT, Scher HI, Slovin SF, Ishill NM, Heller G, and Kelly WK
- Published
- 2005
- Full Text
- View/download PDF
10. Preliminary assessment of magnetic resonance spectroscopic imaging in predicting treatment outcome in patients with prostate cancer at high risk for relapse.
- Author
-
Pucar D, Koutcher JA, Shah A, Dyke JP, Schwartz L, Thaler H, Kurhanewicz J, Scardino PT, Kelly WK, Hricak H, and Zakian KL
- Published
- 2004
- Full Text
- View/download PDF
11. Anti-epidermal growth factor receptor monoclonal antibody cetuximab plus doxorubicin in the treatment of metastatic castration-resistant prostate cancer.
- Author
-
Slovin SF, Kelly WK, Wilton A, Kattan M, Myskowski P, Mendelsohn J, and Scher HI
- Abstract
Purpose: An open-label, dose-escalating phase Ib/IIa trial was performed to establish a safety profile of ascending doses of cetuximab (IMC C225) in combination with doxorubicin administered weekly for 6 treatments in patients with metastatic castration-resistant prostate cancer. The secondary endpoint was to assess the efficacy of cetuximab in combination with doxorubicin as well as to determine the optimal biologic dose and the maximum tolerated dose. Patients and Methods: Patients in 8 groups received escalating doses of cetuximab 20-300 mg/m2 plus doxorubicin 15 or 20 mg/m2 given intravenously weekly for 6 consecutive weeks, followed by a 1-week observation period. A treatment response was defined as a > 50% decline in prostate-specific antigen (PSA) or regression of radiographically measurable disease. Results: Of the 36 treated patients, 25% had grade 2 neutropenia, 39% had leukopenia, and 44% had stomatitis at doxorubicin 20 mg/m2. Erythematous skin exanthema was seen in 38% of the patients. There was no significant regression of bone or soft tissue disease, but stable disease was observed in 20 (65%) of the 31 patients with bone disease and 14 (61%) of the 23 patients with lymph node disease. Declines in PSA were modest in the 36 patients, with 1 (2.7%) with an 80% decline from baseline, 2 (5.6%) with > 50% to < 80% declines, and 14 (39%) with progression. Median survival was approximately 18 months. Conclusion: In a heavily pretreated population of men with metastatic castration-resistant prostate cancer, this study of cetuximab/doxorubicin was associated with minimal PSA declines posttherapy, though median survival was longer compared to historical control groups. Further studies with cetuximab combined with more contemporary chemotherapy for castration-resistant prostate cancer might be warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
12. Trial design for metastatic castration-resistant prostate cancer.
- Author
-
Sonpavde G, Fleming MT, Hutson TE, Galsky MD, Scher HI, Halabi S, Tannock IF, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak DP, Kantoff P, Basch E, Kelly WK, Figg WD, and Small EJ
- Published
- 2008
13. From the guest editor.
- Author
-
Kelly WK
- Published
- 2008
- Full Text
- View/download PDF
14. Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data.
- Author
-
Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard JC, Logothetis CJ, Pignon JP, Michiels S, and Meta-analysis of Estramustine in Prostate Cancer (MECaP) Trialists' Collaborative Group
- Abstract
BACKGROUND: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer. METHODS: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used. FINDINGS: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275). INTERPRETATION: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
15. Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer
- Author
-
Massimo Imbriaco, P. Ouyang, Zuo-Feng Zhang, C. Ding, I. D. Horak, Howard I. Scher, Wm. Kevin Kelly, Maxine Sun, Steven M. Larson, Henry Yeung, Paul Sabbatini, M. Conolly, A. B. Kremer, Sabbatini, P, Larson, Sm, Kremer, A, Zhang, Zf, Sun, M, Yeung, H, Imbriaco, Massimo, Horak, I, Conolly, M, Ding, C, Ouyang, P, Kelly, Wk, and Scher, Hi
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,medicine.drug_class ,Bone Neoplasms ,Technetium Tc 99m Medronate ,law.invention ,Metastasis ,Prostate cancer ,chemistry.chemical_compound ,Randomized controlled trial ,law ,Prostate ,Prednisone ,Internal medicine ,medicine ,Humans ,Liarozole ,Radionuclide Imaging ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Performance status ,business.industry ,Prostatic Neoplasms ,Middle Aged ,Prostate-Specific Antigen ,medicine.disease ,Androgen ,Prognosis ,Survival Analysis ,medicine.anatomical_structure ,chemistry ,Androgens ,business ,Algorithms ,medicine.drug - Abstract
PURPOSE: To evaluate the prognostic significance of a bone scan index (BSI) based on the weighted proportion of tumor involvement in individual bones, in relation to other factors and to survival in patients with androgen-independent prostate cancer. PATIENTS AND METHODS: Baseline radionuclide bone scans were reviewed in 191 assessable patients with androgen-independent disease who were enrolled onto an open, randomized trial of liarozole versus prednisone. The extent of skeletal involvement was assessed by scoring each scan using the BSI and independently according to the number of metastatic lesions. The relationship of the scored bone involvement to other known prognostic factors was explored in single- and multiple-variable analyses. RESULTS: In single-variable analyses, the pretreatment factors found to be associated with survival were age (P = .0446), performance status (P = .0005), baseline prostate-specific antigen (P = .0001), hemoglobin (P = .0001), alkaline phosphatase (P = .0002), AST (P = .0021), lactate dehydrogenase (P = .0001), and treatment (P = .0098). The extent of osseous disease was significant using both the BSI (P = .0001) and the number of lesions present (P = .0001). In multiple-variable proportional hazards analyses, only BSI, age, hemoglobin, lactate dehydrogenase, and treatment arm were associated with survival. When the patient population was divided into three equal groups, with BSI values of < 1.4%, 1.4% to 5.1%, and > 5.1%, median survivals of 18.3, 15.5, and 8.1 months, respectively, were observed (P = .0079). CONCLUSION: The BSI quantifies the extent of skeletal involvement by tumor. It allows the identification of patients with distinct prognoses for stratification in clinical trials. Further study is needed to assess the utility of serial BSI determinations in monitoring treatment effects. The BSI may be particularly useful in the evaluation of agents for which prostate-specific antigen changes do not reflect clinical outcomes accurately.
16. Comparative mitochondrial genomics in Nematoda reveal astonishing variation in compositional biases and substitution rates indicative of multi-level selection.
- Author
-
Gendron EMS, Qing X, Sevigny JL, Li H, Liu Z, Blaxter M, Powers TO, Thomas WK, and Porazinska DL
- Subjects
- Animals, Base Composition, Evolution, Molecular, Codon genetics, Genome, Mitochondrial, Nematoda genetics, Selection, Genetic, Genomics methods, Phylogeny
- Abstract
Background: Nematodes are the most abundant and diverse metazoans on Earth, and are known to significantly affect ecosystem functioning. A better understanding of their biology and ecology, including potential adaptations to diverse habitats and lifestyles, is key to understanding their response to global change scenarios. Mitochondrial genomes offer high species level characterization, low cost of sequencing, and an ease of data handling that can provide insights into nematode evolutionary pressures., Results: Generally, nematode mitochondrial genomes exhibited similar structural characteristics (e.g., gene size and GC content), but displayed remarkable variability around these general patterns. Compositional strand biases showed strong codon position specific G skews and relationships with nematode life traits (especially parasitic feeding habits) equal to or greater than with predicted phylogeny. On average, nematode mitochondrial genomes showed low non-synonymous substitution rates, but also high clade specific deviations from these means. Despite the presence of significant mutational saturation, non-synonymous (dN) and synonymous (dS) substitution rates could still be significantly explained by feeding habit and/or habitat. Low ratios of dN:dS rates, particularly associated with the parasitic lifestyles, suggested the presence of strong purifying selection., Conclusions: Nematode mitochondrial genomes demonstrated a capacity to accumulate diversity in composition, structure, and content while still maintaining functional genes. Moreover, they demonstrated a capacity for rapid evolutionary change pointing to a potential interaction between multi-level selection pressures and rapid evolution. In conclusion, this study helps establish a background for our understanding of the potential evolutionary pressures shaping nematode mitochondrial genomes, while outlining likely routes of future inquiry., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
17. STEAP1 as a potential target for new therapies in prostate cancer.
- Author
-
Kelly WK
- Subjects
- Humans, Male, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Prostatic Neoplasms metabolism, Molecular Targeted Therapy
- Published
- 2024
18. The rates of septicemia in older adults with prostate cancer treated with abiraterone or enzalutamide: A population-based study.
- Author
-
Nikita N, Gandhi K, Keith SW, Sharma S, Kelly WK, and Lu-Yao G
- Subjects
- Humans, Male, Aged, Aged, 80 and over, United States epidemiology, Hospitalization statistics & numerical data, SEER Program, Prostatic Neoplasms drug therapy, Antineoplastic Agents therapeutic use, Antineoplastic Agents adverse effects, Incidence, Medicare, Phenylthiohydantoin therapeutic use, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin adverse effects, Nitriles therapeutic use, Benzamides therapeutic use, Sepsis epidemiology, Sepsis chemically induced, Androstenes therapeutic use, Androstenes adverse effects
- Abstract
Introduction: Prostate cancer (PCa) is the most common non-cutaneous tumor among American men. Androgen receptor signaling inhibitors such as abiraterone and enzalutamide have been approved for similar disease states among patients with advanced PCa. Existing data suggest using steroids is associated with an increased risk of infection. Because abiraterone is usually prescribed with prednisone, we sought to compare the risk of septicemia in patients using abiraterone vs. enzalutamide., Materials and Methods: We utilized the SEER-Medicare-linked data and used negative binomial regression models to compare the changes in the rates of septicemia-related hospitalizations six months pre- and post-abiraterone and enzalutamide initiation., Results: We found that the incidence of septicemia-related hospitalizations increased 2.77 fold within six months of initiating abiraterone (incidence rate ratio [IRR]: 2.77, 95% confidence interval [CI]: 2.17-3.53) 1.97 fold within six months of starting enzalutamide (IRR: 1.97, 95% CI: 1.43-2.72). However, the difference in the changes did not reach statistical significance (interaction IRR: 0.71, 95% CI: 0.48-1.06)., Discussion: The findings suggest that both abiraterone and enzalutamide are associated with an increased risk of septicemia-related hospitalizations. However, the difference in the increase of septicemia risk following the two treatments did not reach statistical significance. Further studies are warranted to understand the mechanisms at play., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
19. Prostein expression on circulating tumor cells as a prognostic marker in metastatic castration-resistant prostate cancer.
- Author
-
Zhang Z, Luo R, Kelly WK, Chen J, Donahue S, Ip K, Handley NR, Tester WJ, Tsang ML, Kim FJ, Myers R, Lu-Yao G, Gu J, Lin J, Li B, Wang C, and Yang H
- Subjects
- Humans, Male, Prognosis, Aged, Middle Aged, Aged, 80 and over, Prostate-Specific Antigen blood, Follow-Up Studies, Neoplasm Metastasis, Neoplastic Cells, Circulating metabolism, Neoplastic Cells, Circulating pathology, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant blood, Prostatic Neoplasms, Castration-Resistant mortality, Prostatic Neoplasms, Castration-Resistant metabolism, Biomarkers, Tumor metabolism, Biomarkers, Tumor blood
- Abstract
Background: Identification of emerging molecular biomarkers on circulating tumor cells (CTCs) represents an attractive feature of liquid biopsy that facilitates precision and tailored medicine in the management of metastatic castration-resistant prostate cancer (mCRPC). Prostein is an androgen-regulated transmembrane protein with high prostate specificity. Prostein-positive circulating tumor cell (CTC) was recently suggested to have diagnostic potential; however, no study has been conducted to evaluate its prognostic value in mCRPC., Methods: CTCs from mCRPC patients were enumerated using the CellSearch System. Prostein-positive CTCs were identified by immunostaining results. The relationships between prostein expression on CTCs and PSA response rate, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (PFS), and overall survival (OS) were tested by Fisher's exact test or evaluated using Kaplan-Meier and multivariate Cox analyses., Results: Prostein-positive CTCs were identified in 31 of 87 baseline samples from mCRPC patients and 16 of 51 samples collected at the first follow-up visit. PSA response rates were significantly lower in baseline prostein-positive patients (0%, 0/31) than in prostein-negative patients (19.6%, 11/56) (p = 0.007). The 31 prostein-positive patients had significantly shorter PSA-PFS (p < 0.001), radiographic PFS (p < 0.001), and OS (p = 0.018), compared to the 56 prostein-negative patients at baseline. The association with PSA-PFS maintained its significance (p = 0.028) in multivariate analyses. Analyzing prostein expression at the first follow-up as well as the conversion of prostein expression from baseline to follow-up samples not only confirmed the association with PSA-PFS, but also demonstrated prognostic significance with OS., Conclusion: Our study provides the first evidence to support the potential of prostein expression on CTCs to serve as a novel prognostic marker in mCRPC patients. Future large-scale prospective studies are needed to validate our findings., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF
20. Hepatocellular carcinoma presenting as an extrahepatic mass: A case report and review of literature.
- Author
-
Wu WK, Patel K, Padmanabhan C, and Idrees K
- Abstract
Background: Hepatocellular carcinoma (HCC) is a primary liver tumor generally diagnosed based on radiographic findings. Metastatic disease is typically associated with increased tumor diameter, multifocality, and vascular invasion. We report a case of a patient who presented with extrahepatic HCC metastasis to a portocaval lymph node with occult hepatic primary on computed tomography (CT). We review the literature for cases of extrahepatic HCC presentation without known hepatic lesions and discuss strategies to differentiate between metastatic and ectopic HCC., Case Summary: A 67-year-old male with remotely treated hepatis C was referred for evaluation of an enlarging portocaval, mixed cystic-solid mass. Serial CT evaluations demonstrated steatosis, but no cirrhosis or liver lesions. Endoscopic ultrasound demonstrated a normal-appearing pancreas, biliary tree, and liver. Fine needle aspiration yielded atypical cells. The differential diagnosis included duodenal or pancreatic cyst, lymphoproliferative cyst, stromal or mesenchymal lesions, nodal involvement from gastrointestinal or hematologic malignancy, or duodenal gastro-intestinal stromal tumor. After review by a multidisciplinary tumor board, the patient underwent open surgical resection of a 5.2 cm × 5.5 cm retroperitoneal mass with pathology consistent with moderately-differentiated HCC. Magnetic resonance imaging (MRI) subsequently demonstrated a 1.2 cm segment VIII hepatic lesion with late arterial enhancement, fatty sparing, and intrinsic T1 hyperintensity. Alpha fetoprotein was 23.3 ng/mL. The patient was diagnosed with HCC with portocaval nodal involvement. Review: We surveyed the literature for HCC presenting as extrahepatic masses without history of concurrent or prior intrahepatic HCC. We identified 18 cases of extrahepatic HCC ultimately found to represent metastatic lesions, and 30 cases of extrahepatic HCC found to be primary, ectopic HCC., Conclusion: Hepatocellular carcinoma can seldomly present with extrahepatic metastasis in the setting of occult primary. In patients with risk factors for HCC and lesions suspicious for metastatic disease, MRI may be integral to identifying small hepatic lesions and differentiating from ectopic HCC. Tumor markers may also have utility in establishing the diagnosis., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
21. Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).
- Author
-
Patel JN, Jiang C, Owzar K, Hertz DL, Wang J, Mulkey FA, Kelly WK, Halabi S, Furukawa Y, Lassiter C, Dorsey SG, Friedman PN, Small EJ, Carducci MA, Kelley MJ, Nakamura Y, Kubo M, Ratain MJ, Morris MJ, and McLeod HL
- Subjects
- Male, Humans, Bevacizumab adverse effects, Gastrointestinal Hemorrhage chemically induced, Gastrointestinal Hemorrhage genetics, Risk Factors, Pharmacogenetics, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics
- Abstract
The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10
-8 ) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
22. TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing.
- Author
-
Loeb S, Keith SW, Cheng HH, Leader AE, Gross L, Sanchez Nolasco T, Byrne N, Hartman R, Brown LH, Pieczonka CM, Gomella LG, Kelly WK, Lallas CD, Handley N, Mille PJ, Mark JR, Brown GA, Chopra S, McClellan A, Wise DR, Hollifield L, and Giri VN
- Subjects
- Humans, Male, Genetic Testing, Germ Cells, Health Knowledge, Attitudes, Practice, Genetic Counseling methods, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, Prostatic Neoplasms therapy
- Abstract
Purpose: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services., Methods: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at baseline, after pretest education/counseling, and after GT result disclosure. The primary end point was noninferiority in reducing decisional conflict between webtool and GC using the validated Decisional Conflict Scale. Mixed-effects regression modeling was used to compare decisional conflict between groups. Participants opting for GT received a 51-gene panel, with results delivered to participants and their providers., Results: The analytic data set includes primary outcome data from 315 participants (GC [n = 162] and webtool [n = 153]). Mean difference in decisional conflict score changes between groups was -0.04 (one-sided 95% CI, -∞ to 2.54; P = .01), suggesting the patient-driven webtool was noninferior to GC. Overall, 145 (89.5%) GC and 120 (78.4%) in the webtool arm underwent GT, with pathogenic variants in 15.8% (8.7% in PCA genes). Satisfaction did not differ significantly between arms; knowledge of cancer genetics was higher but attitudes toward GT were less favorable in the webtool arm., Conclusion: The results of the TARGET study support the use of patient-driven digital webtools for expanding access to pretest genetic education for PCA GT. Further studies to optimize patient experience and evaluate them in diverse patient populations are warranted.
- Published
- 2024
- Full Text
- View/download PDF
23. Perioperative Characteristics and Outcomes of Fontan Versus Non-Fontan Patients Undergoing Combined Heart-Liver Transplantation: A Retrospective Cohort Study.
- Author
-
Wu WK, Siegrist KK, Ziogas IA, Mishra KL, Matsuoka LK, Menachem JN, Izzy M, Shingina A, Do NL, Bacchetta M, Shah AS, and Alexopoulos SP
- Subjects
- Adult, Humans, Retrospective Studies, Liver surgery, Liver Transplantation, Fontan Procedure, Heart Transplantation, Heart Defects, Congenital surgery
- Abstract
Objectives: Combined heart-liver transplantation (CHLT) is becoming increasingly frequent as a maturing population of patients with Fontan-palliated congenital heart disease develop advanced liver fibrosis or cirrhosis. The authors present their experience with CHLT for congenital and noncongenital indications, and identify characteristics associated with poor outcomes that may guide intervention in high-risk patients., Design: This was a single-center retrospective cohort study., Setting: This study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee., Participants: The study included 16 consecutive adult recipients of CHLT at the authors' institution between April 2017 and February 2022., Interventions: Eleven patients underwent transplantation for Fontan indications, and 5 were transplanted for non-Fontan indications., Measurements and Main Results: Compared with non-Fontan patients, Fontan recipients had longer cardiopulmonary bypass duration (199 v 119 minutes, p =m0.002), operative times (786 v 599 minutes, p = 0.01), and larger blood product transfusions (15.4 v 6.3 L, p = 0.18). Six of 16 patients required extracorporeal membrane oxygenation (ECMO), of whom 4 were Fontan patients who subsequently died. Patients who required ECMO had lower 5-hour lactate clearance (0.0 v 3.5 mmol/L, p = 0.001), higher number of vasoactive infusions, lower pulmonary artery pulsatility indices (0.58 v 1.77, p = 0.03), and higher peak inspiratory pressures (28.0 v 18.5 mmHg, p = 0.01) after liver reperfusion., Conclusions: Combined heart-liver transplantation in patients with Fontan-associated end-organ disease is particularly challenging and associated with higher recipient morbidity compared with non-Fontan-related CHLT. Early hemodynamic intervention for signs of ventricular dysfunction may improve outcomes in this growing high-risk population., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2024
- Full Text
- View/download PDF
24. Prognostic and predictive analyses of circulating plasma biomarkers in men with metastatic castration resistant prostate cancer treated with docetaxel/prednisone with or without bevacizumab.
- Author
-
Nixon AB, Liu Y, Yang Q, Luo B, Starr MD, Brady JC, Kelly WK, Beltran H, Morris MJ, George DJ, Armstrong AJ, and Halabi S
- Abstract
Background: CALGB 90401 (Alliance) was a phase III trial of 1050 patients with metastatic castration-resistant prostate cancer (mCRPC) comparing docetaxel, prednisone, bevacizumab (DP+B) versus DP alone. While this trial did not show an improvement in overall survival (OS), there were improved intermediate outcomes suggesting that subsets of men may derive benefit from this combination. The purpose of this analysis was to identify prognostic and predictive biomarkers associated with OS and progression-free survival (PFS) benefit from DP+B., Methods: Baseline EDTA plasma samples from 650 consenting patients were analyzed for 24 biomarkers. The proportional hazards model was utilized to test for the prognostic and predictive importance of the biomarkers for OS. The statistically significant biomarkers of OS were further investigated for prognostic and predictive importance for other secondary outcomes., Results: 15 markers [ICAM-1, VEGF-R3, TIMP-1, TSP-2, Ang-2, Her-3, Osteopontin (OPN), PlGF, VCAM-1, HGF, VEGF, Chromogranin A, IL-6, VEGF-R1, BMP-9] were prognostic of OS, while 9 markers (ICAM-1, VEGF-R3, Her-3, TIMP-1, Ang-2, OPN, PlGF, HGF, and VEGF) were also prognostic of PFS. All markers were statistically significant in univariate analyses after adjustment for multiplicity (FDR < 0.1). In multivariable analyses of OS adjusting for risk score, seven markers had FDR < 0.1, including ICAM-1, VEGF-R3, TIMP-1, Ang-2, VEGF, TSP-2 and HGF. In unadjusted analysis, OPN was predictive of PFS improvement with DP+B, in both univariate and multivariable analysis. However, none of the biomarkers tested were predictive of clinical outcomes after adjusting for multiple comparisons., Conclusions: Multiple biomarkers were identified in CALGB 90401 as prognostic of clinical outcomes but not predictive of OS. While OPN may have promise as a potential biomarker for anti-angiogenic therapies, further mechanistic and clinical studies are needed to determine the underlying biology and potential clinical application., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF
25. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.
- Author
-
Kelly WK, Danila DC, Lin CC, Lee JL, Matsubara N, Ward PJ, Armstrong AJ, Pook D, Kim M, Dorff TB, Fischer S, Lin YC, Horvath LG, Sumey C, Yang Z, Jurida G, Smith KM, Connarn JN, Penny HL, Stieglmaier J, and Appleman LJ
- Subjects
- Male, Humans, Immunotherapy, Treatment Outcome, Antigens, Neoplasm, Oxidoreductases therapeutic use, Prostate-Specific Antigen therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development., Significance: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
26. Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer.
- Author
-
Santasusagna S, Zhu S, Jawalagatti V, Carceles-Cordon M, Ertel A, Garcia-Longarte S, Song WM, Fujiwara N, Li P, Mendizabal I, Petrylak DP, Kelly WK, Reddy EP, Wang L, Schiewer MJ, Lujambio A, Karnes J, Knudsen KE, Cordon-Cardo C, Dong H, Huang H, Carracedo A, Hoshida Y, Rodriguez-Bravo V, and Domingo-Domenech J
- Subjects
- Male, Humans, Transcription Factors, Androgen Antagonists pharmacology, Androgen Antagonists therapeutic use, Immune Evasion, Receptors, Androgen genetics, Castration, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies., Significance: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
27. Targeting the αVβ3/NgR2 pathway in neuroendocrine prostate cancer.
- Author
-
Testa A, Quaglia F, Naranjo NM, Verrillo CE, Shields CD, Lin S, Pickles MW, Hamza DF, Von Schalscha T, Cheresh DA, Leiby B, Liu Q, Ding J, Kelly WK, Hooper DC, Corey E, Plow EF, Altieri DC, and Languino LR
- Subjects
- Male, Humans, Androgen Antagonists, Signal Transduction, Antibodies, Monoclonal, Integrins, Integrin alphaVbeta3 genetics, Integrin alphaVbeta3 metabolism, Cell Line, Tumor, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism
- Abstract
Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients' plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as "adhesion competent". Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer., Competing Interests: Declaration of Competing Interest FQ is an employee/contractor at Janssen Pharmaceutical. EC is a consultant of Dotquant and received funding under institutional SRA from Janssen Research, Bayer Pharmaceuticals, Forma Therapeutics, Foghorn, Kronos Bios, Genentech, Astra Zeneca, and MacroGenics. No potential conflict of interest was reported by the other authors., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2023
- Full Text
- View/download PDF
28. Reply: Xenogeneic cross-circulation of ex vivo human livers or liver xenotransplantation?
- Author
-
Wu WK, Alexopoulos SP, and Bacchetta M
- Subjects
- Humans, Transplantation, Heterologous, Graft Rejection, Liver surgery, Liver Transplantation
- Published
- 2023
- Full Text
- View/download PDF
29. Racial disparities in new-onset diabetes mellitus in prostate cancer patients on androgen deprivation therapy: a retrospective analysis of TriNetX data.
- Author
-
Gomaa S, Kelly WK, Mitchell E, Storozynsky E, Zeigler-Johnson C, Juon HS, and Wen KY
- Subjects
- Male, Humans, Retrospective Studies, Androgen Antagonists adverse effects, Androgens, Prostatic Neoplasms drug therapy, Prostatic Neoplasms epidemiology, Prostatic Neoplasms complications, Diabetes Mellitus epidemiology
- Abstract
Background: Prostate cancer (PCa) is the most common cancer in men in the US and androgen deprivation therapy (ADT) is the most frequently used systemic therapy for PCa. Data suggest that ADT is associated with an increased risk of new-onset diabetes mellitus (NODM) and cardiovascular complications. As the incidence and mortality of PCa are highest among the African American (AA) population, it is important to evaluate the difference in the incidence of NODM and ischemic heart disease (IHD) between AA men compared to Caucasian men., Methods: This is a retrospective cohort study utilizing the TriNetX database to assess NODM and IHD risk, risk difference, and risk ratio (RR) after recent ADT initiation in an AA cohort and a Caucasian cohort of patients with PCa. Propensity score matching (PSM) was performed by age, BMI, and confounding comorbidities., Results: After matching, the cohort included 1159 AA patients and 843 Caucasian patients with NODM after ADT initiation. The IHD cohort included 1269 AA patients and 1248 Caucasian patients. The risk of incidence of NODM is higher among AA men at 11.6% risk compared to Caucasian men at 7.4%. The risk difference is 4.1% (95% CI = 3.4, 4.9) p = 0.000. The RR is 1.56 (95% CI = 1.43, 1.70). In contrast, risk difference and risk ratio of IHD was not significant between AA and Caucasian groups., Conclusion: ADT exposure increases the risk of NODM in men with PCa, especially among AA men compared with Caucasian men. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome and diabetes. Targeted close monitoring of AA men on ADT would be critical to prevent and treat metabolic complications with potential of reducing disparities in PCa morbidity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
30. Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers.
- Author
-
Wu WK, Ukita R, Patel YJ, Cortelli M, Trinh VQ, Ziogas IA, Francois SA, Mentz M, Cardwell NL, Talackine JR, Grogan WM, Stokes JW, Lee YA, Kim J, Alexopoulos SP, and Bacchetta M
- Subjects
- Humans, Swine, Animals, Bile, Perfusion methods, Organ Preservation methods, Liver pathology, Liver Transplantation methods
- Abstract
Background and Aims: The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation., Approach and Results: Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% ( p = 0.16). Lactate clearance increased from -0.4 ± 15.5% to 31.4 ± 19.0% ( p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained., Conclusions: Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
- Full Text
- View/download PDF
31. Large animal preclinical investigation into the optimal extracorporeal life support configuration for pulmonary hypertension and right ventricular failure.
- Author
-
Ukita R, Stokes JW, Wu WK, Patel YJ, Talackine JR, Cardwell N, Benson C, Lefevre RJ, Eagle S, Demarest C, Simonds E, Tipograf Y, Cortelli M, Skoog DJ, Cook K, Rosenzweig EB, and Bacchetta M
- Subjects
- Animals, Sheep, Heart Ventricles, Heart Atria, Hemodynamics, Extracorporeal Membrane Oxygenation, Hypertension, Pulmonary therapy, Heart Failure
- Abstract
Introduction: Right ventricular failure (RVF) is a major cause of mortality in pulmonary hypertension (PH). Mechanical circulatory support holds promise for patients with medically refractory PH, but there are no clinical devices for long-term right ventricular (RV) support. Investigations into optimal device parameters and circuit configurations for PH-induced RVF (PH-RVF) are needed., Methods: Eleven sheep underwent previously published chronic PH model. We then evaluated a low-profile, ventricular assist device (VAD)-quality pump combined with a novel low-resistance membrane oxygenator (Pulmonary Assist Device, PAD) under one of four central cannulation strategies: right atrium-to-left atrium (RA-LA, N = 3), RA-to-pulmonary artery (RA-PA, N=3), pumpless pulmonary artery-to-left atrium (PA-LA, N = 2), and RA-to-ascending aorta (RA-Ao, N = 3). Acute-on-chronic RVF (AoC RVF) was induced, and mechanical support was provided for up to 6 hours at blood flow rates of 1 to 3 liter/min. Circuit parameters, physiologic, hemodynamic, and echocardiography data were collected., Results: The RA-LA configuration achieved blood flow of 3 liter/min. Meanwhile, RA-PA and RA-Ao faced challenges maintaining 3 liter/min of flow due to higher circuit afterload. Pumpless PA-LA was flow-limited due to anatomical limitations inherent to this animal model. RA-LA and RA-Ao demonstrated serial RV unloading with increasing circuit flow, while RA-PA did not. RA-LA also improved left ventricular (LV) and septal geometry by echocardiographic assessment and had the lowest inotropic dependence., Conclusion: RA-LA and RA-Ao configurations unload the RV, while RA-LA also lowers pump speed and inotropic requirements, and improves LV mechanics. RA-PA provide inferior support for PH-RVF, while an alternate animal model is needed to evaluate PA-LA., Competing Interests: Disclosure statement Drs. David Skoog, Keith Cook, and Mathew Bacchetta are partners in Advanced Respiratory Technologies, LLC. Pumps used in the study were donated to us by CardioDyme Inc., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
32. Standard: Human intestinal cancer organoids.
- Author
-
Lin H, Wang Y, Cheng C, Qian Y, Hao J, Zhang Z, Sheng W, Song L, Deng CX, Zhao B, Cao J, Wang L, Wang L, Liang L, Chen WK, Yu C, Sun Z, Yang Y, Wang C, Zhang Y, Li Q, Li K, Ma A, Zhao T, Chen YG, and Hua G
- Abstract
Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. "Human intestinal cancer organoids" is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
33. Bispecific PSMA antibodies and CAR-T in metastatic castration-resistant prostate cancer.
- Author
-
Zarrabi KK, Narayan V, Mille PJ, Zibelman MR, Miron B, Bashir B, and Kelly WK
- Abstract
Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, 'on-target, off-tumor' immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)
- Published
- 2023
- Full Text
- View/download PDF
34. Standard: Human intestinal organoids.
- Author
-
Wang Y, Lin H, Zhao L, Hong F, Hao J, Zhang Z, Sheng W, Song L, Deng CX, Zhao B, Cao J, Wang L, Wang L, Liang L, Chen WK, Yu C, Sun Z, Yang Y, Wang C, Zhang Y, Li Q, Li K, Ma A, Zhao T, Hua G, and Chen YG
- Abstract
Organoids have attracted great interest for disease modelling, drug discovery and development, and tissue growth and homeostasis investigations. However, lack of standards for quality control has become a prominent obstacle to limit their translation into clinic and other applications. "Human intestinal organoids" is the first guideline on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods, inspection rules for human intestinal organoids, which is applicable to quality control during the process of manufacturing and testing of human intestinal organoids. It was originally released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of human intestinal organoids for applications., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
35. Enhancing bladder cancer care through the multidisciplinary clinic approach.
- Author
-
Mark JR, Gomella LG, Lallas CD, Smentkowski KE, Calvaresi A, Handley N, Den RB, Mille P, Tester WJ, Hoffman-Censits J, Dicker AP, Klonicke E, Halpern E, McCue P, Kelly WK, and Trabulsi EJ
- Subjects
- Humans, Cystectomy methods, Neoadjuvant Therapy, Retrospective Studies, United States epidemiology, Urinary Bladder, Delivery of Health Care, Urinary Bladder Neoplasms surgery
- Abstract
Introduction: To report the impact of our 25-year multidisciplinary care delivery model experience on patients with muscle invasive bladder cancer treated at our National Cancer Institute (NCI)-designated Sidney Kimmel Cancer Center at Jefferson University. To our knowledge, our multidisciplinary genitourinary cancer clinic (MDC) is the longest continuously operating center of its kind at an NCI Cancer Center in the United States., Materials and Methods: We selected a recent group of patients with cT2-4 N0-1 M0 bladder cancer seen in the Sidney Kimmel Cancer Center Genitourinary Oncology MDC from January 2016 to September 2019. These patients were identified retrospectively. SEER-18 (Surveillance, Epidemiology, and End Results) database, November 2019 submission was queried to obtain patients with similarly staged disease diagnosed between 2015 and 2017. Completion rates of radical cystectomy, use of neoadjuvant therapies, and survival outcomes were compared between the two cohorts., Results: Ninety-one patients from the MDC form this time period were identified; 65.9% underwent radical cystectomy and 71.8% received neoadjuvant therapy in the form of chemotherapy, immune checkpoint inhibition or a combination of the two - higher than reported national trends for neoadjuvant therapies. Progression of disease was seen in 24.2% of patients. A total of 8675 patients met inclusion criteria in the SEER database. Rates of radical cystectomy were significantly higher in MCD patients when compared to SEER derived data (65.9% vs. 37.7%, p =< 0.001). MCD patients had significantly better cancer-specific survival (mean 20.4 vs. 18.3 months p = 0.028, median survival not reached)., Conclusion: Our long term experience caring for patients with genitourinary malignancies such as bladder cancer in a uniform multidisciplinary team results in a high utilization of neoadjuvant therapies. When compared to a contemporary SEER-derived cohort, multidisciplinary patients were more likely to undergo radical cystectomy and had longer cancer-specific survival.
- Published
- 2023
36. External Validation of a Prognostic Model of Overall Survival in Men With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.
- Author
-
Halabi S, Yang Q, Roy A, Luo B, Araujo JC, Logothetis C, Sternberg CN, Armstrong AJ, Carducci MA, Chi KN, de Bono JS, Petrylak DP, Fizazi K, Higano CS, Morris MJ, Rathkopf DE, Saad F, Ryan CJ, Small EJ, and Kelly WK
- Subjects
- Male, Humans, Prognosis, Docetaxel therapeutic use, Proportional Hazards Models, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Treatment Outcome, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Purpose: We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model., Methods: Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high)., Results: The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001)., Conclusion: This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.
- Published
- 2023
- Full Text
- View/download PDF
37. Neuroendocrine gene subsets are uniquely dysregulated in prostate adenocarcinoma.
- Author
-
Naranjo NM, Kennedy A, Testa A, Verrillo CE, Altieri AD, Kean R, Hooper DC, Yu J, Zhao J, Abinader O, Pickles MW, Hawkins A, Kelly WK, Mitra R, and Languino LR
- Subjects
- Humans, Male, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Synaptophysin metabolism, Synaptophysin genetics, Extracellular Vesicles metabolism, Extracellular Vesicles genetics, Gene Expression Profiling methods, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Adenocarcinoma genetics, Adenocarcinoma pathology, Adenocarcinoma metabolism
- Abstract
Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.
- Published
- 2024
- Full Text
- View/download PDF
38. T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer.
- Author
-
Palecki J, Bhasin A, Bernstein A, Mille PJ, Tester WJ, Kelly WK, and Zarrabi KK
- Subjects
- Humans, Male, Antigens, Neoplasm immunology, Animals, Antibodies, Bispecific therapeutic use, Antibodies, Bispecific pharmacology, Antibodies, Bispecific immunology, Prostatic Neoplasms immunology, Prostatic Neoplasms therapy, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, T-Lymphocytes immunology, Immunotherapy methods
- Abstract
Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor activity, but challenges related to drug delivery, immunogenicity, and treatment-associated adverse effects limited their success. The ongoing development of novel BiTE constructs continues to address these barriers and to yield promising results in terms of efficacy and safety. This review will highlight some of most recent developments of BiTE therapies for patients with advanced prostate cancer and the evolving data surrounding BiTE constructs undergoing clinical evaluation.
- Published
- 2024
- Full Text
- View/download PDF
39. Review of Cardiovascular Risk of Androgen Deprivation Therapy and the Influence of Race in Men with Prostate Cancer.
- Author
-
Fradin J, Kim FJ, Lu-Yao GL, Storozynsky E, and Kelly WK
- Abstract
Androgen deprivation therapy is the cornerstone of prostate cancer therapy. Recent studies have revealed an association between androgen deprivation therapy and cardiovascular adverse effects such as myocardial infarction and stroke. This review summarizes the available research on the cardiovascular risk of men using androgen deprivation therapy. We also discuss racial disparities surrounding both prostate cancer and cardiovascular disease, emphasizing the importance of biological/molecular and socioeconomic factors in assessing baseline risk in patients beginning androgen ablation. Based on the literature, we provide recommendations for monitoring patients who are at high risk for a cardiovascular adverse event while being treated on androgen deprivation therapy. This review aims to present the current research on androgen deprivation therapy and cardiovascular toxicity with an emphasis on racial disparities and provides a framework for clinicians to decrease the cardiovascular morbidity in men that are being treated with hormone therapy.
- Published
- 2023
- Full Text
- View/download PDF
40. Pulmonary artery banding in sheep: a novel large animal model for congestive hepatopathy.
- Author
-
Ukita R, Wu WK, Liang J, Talackine JR, Patel YJ, Francois SA, Cardwell NL, Flynn CR, Shingina A, Washington MK, Trinh VQ, Bacchetta M, and Alexopoulos SP
- Subjects
- Animals, Humans, Fibrosis, Liver Cirrhosis pathology, Models, Animal, Pulmonary Artery, Sheep, Disease Models, Animal, Heart Failure, Vascular Diseases
- Abstract
Congestive hepatopathy is becoming increasingly recognized among Fontan-palliated patients. Elevated central venous pressure is thought to drive the pathologic progression, characterized by sinusoidal dilatation, congestion, and fibrosis. A clinically relevant large animal model for congestive hepatopathy would provide a valuable platform for researching novel biomarkers, treatment, and prevention. Here, we report on a titratable, sheep pulmonary artery banding model for this disease application. Pulmonary artery banding was achieved by progressively inflating the implanted pulmonary artery cuff. Right ventricular catheter was implanted to draw venous blood samples and measure pressure. The pulmonary artery cuff pressure served as a surrogate for the intensity of pulmonary artery banding and was measured weekly. After about 9 wk, animals were euthanized, and the liver was harvested for histopathological assessment. Nine animal subjects received pulmonary artery banding for 64 ± 8 days. Four of the nine subjects exhibited moderate to severe liver injury, and three of those four exhibited bridging fibrosis. Increasing pulmonary artery cuff pressure significantly correlated with declining mixed venous oxygen saturation ( P = 3.29 × 10
-5 ), and higher congestive hepatic fibrosis score ( P = 0.0238), suggesting that pulmonary artery banding strategy can be titrated to achieve right-sided congestion and liver fibrosis. Blood analyses demonstrated an increase in plasma bile acids, aspartate aminotransferase, and γ-glutamyltransferase among subjects with moderate to severe injury, further corroborating liver tissue findings. Our large animal pulmonary artery banding model recapitulates congestive hepatopathy and provides a basis to bridge the current gaps in scientific and clinical understanding about the disease. NEW & NOTEWORTHY We present here a large animal platform for congestive hepatopathy, a disease growing in clinical prevalence due to the increasing number of Fontan-palliated patients. Further data are needed to develop a better clinical management strategy for this poorly characterized patient population. Previous reports of animal models to study this disease have mostly been in small animals with limited fidelity. We show that congestive hepatopathy can be replicated in a chronic, progressive pulmonary artery banding model in sheep. We also show that the banding strategy can be controlled to titrate the level of liver injury. To date, we do not know of any other large animal model that can achieve this level of control over disease phenotype and clinical relevance.- Published
- 2023
- Full Text
- View/download PDF
41. PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer.
- Author
-
Gordon N, Gallagher PT, Neupane NP, Mandigo AC, McCann JK, Dylgjeri E, Vasilevskaya I, McNair C, Paller CJ, Kelly WK, Knudsen KE, Shafi AA, and Schiewer MJ
- Abstract
Prostate cancer (PCa) is the second leading cause of cancer death for men in the United States. While organ-confined disease has reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the CRPC population as a whole. The administration of ascorbate, more commonly known as ascorbic acid or Vitamin C, has proved lethal to and highly selective for a variety of cancer cell types. There are several mechanisms currently under investigation to explain how ascorbate exerts anti-cancer effects. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly(ADP-ribose) polymerase (PARP) inhibitors, by inhibiting DNA damage repair, would augment the toxicity of ascorbate., Results: Two distinct CRPC models were found to be sensitive to physiologically relevant doses of ascorbate. Moreover, additional studies indicate that ascorbate inhibits CRPC growth in vitro via multiple mechanisms including disruption of cellular energy dynamics and accumulation of DNA damage. Combination studies were performed in CRPC models with ascorbate in conjunction with escalating doses of three different PARP inhibitors (niraparib, olaparib, and talazoparib). The addition of ascorbate augmented the toxicity of all three PARP inhibitors and proved synergistic with olaparib in both CRPC models. Finally, the combination of olaparib and ascorbate was tested in vivo in both castrated and non-castrated models. In both cohorts, the combination treatment significantly delayed tumor growth compared to monotherapy or untreated control., Conclusions: These data indicate that pharmacological ascorbate is an effective monotherapy at physiological concentrations and kills CRPC cells. Ascorbate-induced tumor cell death was associated with disruption of cellular energy dynamics and accumulation of DNA damage. The addition of PARP inhibition increased the extent of DNA damage and proved effective at slowing CRPC growth both in vitro and in vivo . These findings nominate ascorbate and PARPi as a novel therapeutic regimen that has the potential to improve CRPC patient outcomes.
- Published
- 2023
- Full Text
- View/download PDF
42. Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer.
- Author
-
Simão DC, Zarrabi KK, Mendes JL, Luz R, Garcia JA, Kelly WK, and Barata PC
- Abstract
Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors' immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research.
- Published
- 2023
- Full Text
- View/download PDF
43. Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer.
- Author
-
Dhital B, Santasusagna S, Kirthika P, Xu M, Li P, Carceles-Cordon M, Soni RK, Li Z, Hendrickson RC, Schiewer MJ, Kelly WK, Sternberg CN, Luo J, Lujambio A, Cordon-Cardo C, Alvarez-Fernandez M, Malumbres M, Huang H, Ertel A, Domingo-Domenech J, and Rodriguez-Bravo V
- Subjects
- Male, Humans, Receptors, Androgen genetics, Receptors, Androgen metabolism, Chromosomal Instability, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins therapeutic use, Protein Serine-Threonine Kinases genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
44. Predictors of consenting to participate in a clinical trial among urban cancer patients.
- Author
-
McIntire RK, Keith SW, Nowlan T, Butt S, Cambareri K, Callaghan J, Halstead T, Chandrasekar T, Kelly WK, and Leader AE
- Subjects
- Humans, Logistic Models, Linear Models, Residence Characteristics, Neoplasms epidemiology, Neoplasms therapy
- Abstract
Background: Patient participation in clinical trials is influenced by demographic and other individual level characteristics. However, there is less research on the role of geography and neighborhood-level factors on clinical trial participation. This study identifies the demographic, clinical, geographic, and neighborhood predictors of consenting to a clinical trial among cancer patients at a large, urban, NCI-designated cancer center in the Mid-Atlantic region., Methods: We used demographic and clinical data from patients diagnosed with cancer between 2015 and 2017. We geocoded patient addresses and calculated driving distance to the cancer center. Additionally, we linked patient data to neighborhood-level educational attainment, social capital and cancer prevalence. Finally, we used generalized linear mixed-effects conditional logistic regression to identify individual and neighborhood-level predictors of consenting to a clinical trial., Results: Patients with higher odds of consenting to trials were: Non-Hispanic White, aged 50-69, diagnosed with breast, GI, head/neck, hematologic, or certain solid tumor cancers, those with cancers at regional stage, never/former tobacco users, and those with the highest neighborhood social capital index. Patients who lived further from the cancer center had higher odds of consenting to a trial. With every 1-km increase in residential distance, there was a 4% increase in the odds that patients would consent to a trial. Neither of the additional neighborhood-level variables predicted consenting to a clinical trial., Conclusions: This study identifies important demographic, patient-level, and geographic factors associated with consenting to cancer clinical trials, and lays the groundwork for future research exploring the role of neighborhood-level factors in clinical trial participation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
45. Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer.
- Author
-
Quinn Z, Leiby B, Sonpavde G, Choudhury AD, Sweeney C, Einstein D, Szmulewitz R, Sartor O, Knudsen K, Yang ES, and Kelly WK
- Subjects
- Male, Humans, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant radiotherapy, Antineoplastic Agents therapeutic use, Radium adverse effects, Neutropenia chemically induced
- Abstract
Purpose: To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations., Patients and Methods: Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability <20% was defined as MTD. Secondary endpoints included PSA change and progression-free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples., Results: Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders., Conclusions: Combining niraparib with Radium-223 in patients with mCRPC was safe; however, further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents., (©2022 American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
46. Neuroendocrine transformation of prostate adenocarcinoma with corpora cavernosa metastases.
- Author
-
Foss H, Ragam R, Kelly WK, and Gomella LG
- Subjects
- Male, Humans, Middle Aged, Penis, Prostate pathology, Prostatic Neoplasms pathology
- Abstract
We report the case of a 61-year-old male with metastatic prostate cancer who presented with urinary retention secondary to subdermal penile and corpora cavernosa metastases with neuroendocrine transformation of his metastatic hormone sensitive prostate cancer. We highlight the presentation, diagnosis, and management of this rare condition.
- Published
- 2022
47. The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer.
- Author
-
Quaglia F, Krishn SR, Sossey-Alaoui K, Rana PS, Pluskota E, Park PH, Shields CD, Lin S, McCue P, Kossenkov AV, Wang Y, Goodrich DW, Ku SY, Beltran H, Kelly WK, Corey E, Klose M, Bandtlow C, Liu Q, Altieri DC, Plow EF, and Languino LR
- Subjects
- Animals, Humans, Male, Mice, Androgen Antagonists, Cell Line, Tumor, Integrins, Carcinoma, Neuroendocrine pathology, Prostatic Neoplasms pathology, Nogo Receptor 2 metabolism
- Abstract
Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
48. Substantial Gleason reclassification in Black men with national comprehensive cancer network low-risk prostate cancer - A propensity score analysis.
- Author
-
Awasthi S, Mahal BA, Park JY, Creed JH, Williams VL, Elkenawi A, Meadows SO, Pow-Sang JM, Lu-Yao G, Kelly WK, Lang DY, Zgibor J, Rebbeck TR, and Yamoah K
- Subjects
- Black People, Humans, Male, Neoplasm Grading, Propensity Score, Prostate-Specific Antigen, Prostatectomy, Retrospective Studies, Prostatic Neoplasms ethnology, Prostatic Neoplasms pathology
- Abstract
Background: Emerging evidence suggests that a subset of Black men with National Comprehensive Cancer Network (NCCN) low-risk prostate cancer (PCa) may harbor high volume and genomically aggressive disease. However, limited, and ambiguous research exist to evaluate the risk of extreme Gleason reclassification in Black men with low-risk PCa., Methods: This retrospective cohort study included 45,674 low-risk PCa patients who underwent prostatectomy and were not on active surveillance, from National Cancer Database (NCDB). A propensity score matched-pair design was employed, and the final cohort was limited to 1:1 matched 12,340 patients. Gleason score reclassification was used as primary endpoint. As such, any migration to pathologic Gleason score ≥7(3 + 4) was identified as overall, whereas migration to ≥7(4 + 3) was defined as extreme reclassification. A conditional Poisson regression model was used to estimate the risk of reclassification. Whereas spline model was used to estimate the impact of increasing time to treatment as a non-linear function on Gleason reclassification between race group., Results: Upon matching there were no differences in the baseline characteristics between race groups. In a matched cohort, higher proportion of low-risk Black men (6.6%) reported extreme reclassification to pathologic Gleason score than White men (5.0%), p < 0.001. In a conditional Poisson regression model adjusted for time to treatment, the risk of overall (RR = 1.09, 95% CI, 1.05-1.13, p < 0.001) and extreme (RR = 1.30, 95% CI, 1.12-1.50, p = 0.004) reclassification was significantly higher in Black men as compared to their White counterpart. In spline model, the probability of Gleason reclassification in Black men was elevated with increasing time to treatment, especially after 180 days (53% vs. 43% between Black and White men)., Conclusion: Risk of Gleason score reclassification is disparately elevated in Black men with low-risk PCa. Furthermore, time to treatment can non-linearly impact Gleason reclassification in Black men., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
49. Accrual-Monitoring Practices for Various Disease Trials among AACI Member Cancer Centers.
- Author
-
Elliott ZT, Goldberg Z, Philips R, Johnson JM, Kasner MT, Kelly WK, Osipowicz S, Dampman R, and Curry JM
- Abstract
Progress in the management of rare diseases, including rare cancers, is dependent upon clinical trials; however, as many as 32% of rare-disease trials go uncompleted or unpublished due to insufficient accrual. Monitoring practices may differ between institutions. We sought to survey the regulatory standards for various trial types among major U.S. cancer centers. A 10-question survey was designed using Qualtrics assessment software. The survey was sent via email to an internal server of member institutions of the Association of American Cancer Institutes (AACI). Of 103 AACI centers, 31% completed the survey ( n = 32). Respondents differed in their definitions of a rare disease, minimum expectations for rare tumor studies, and frequency of accrual monitoring by their institutional Protocol Review and Monitoring Committee. Seventy-three percent of respondents did not close trials based on low accrual. Strategies to optimize accrual included investigator incentives for high accrual and penalties for low accrual in 37% and 13% of respondents, respectively.
- Published
- 2022
- Full Text
- View/download PDF
50. A scoping review protocol to elucidate outcomes following abiraterone versus enzalutamide for prostate cancer.
- Author
-
Shah YB, Shaver AL, Kelly WK, and Lu-Yao G
- Subjects
- Abiraterone Acetate, Androstenes adverse effects, Benzamides, Humans, Male, Nitriles therapeutic use, Phenylthiohydantoin adverse effects, Review Literature as Topic, Treatment Outcome, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Introduction: Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making., Method and Analysis: The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation., Ethics and Dissemination: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.