Publications by authors named "James T Symanowski"

34 Publications

Pulmonary Carcinosarcoma: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

Clin Lung Cancer 2020 03 10;21(2):160-170. Epub 2019 Jul 10.

Department of Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Atrium Health, Charlotte, NC.

Introduction: Pulmonary carcinosarcoma (PC) is a rare malignant neoplasm composed of epithelial and mesenchymal components. It accounts for < 1% of thoracic cancers and is not fully understood. This study examined Surveillance, Epidemiology, and End Results (SEER) data to describe demographic and clinical characteristics of patients with PC and assessed survival outcomes by treatment modality and stage.

Patients And Methods: SEER data were reviewed to identify patients diagnosed with primary PC (1973-2012). Overall survival (OS) and disease-specific survival (DSS) were analyzed by univariate/multivariable Cox proportional hazards models and Kaplan-Meier methods.

Results: A total of 411 patients were included. Median age was 67 (range, 24-96) years. Disease stage at the time of initial diagnosis was known for 74.7% of the identified patients (307/411). Of these patients, 23.1% had localized disease. Survival was significantly better for patients with localized disease (OS: 31 vs. 6 months, P < .001; DSS: 54 vs. 8 months, P < .001). Additionally, patients who received surgery alone had significantly improved OS (20 months; P < .001) and DSS (32 months; P < .001) compared to patients who received combined surgery and radiotherapy (OS: 7 months; DSS: 8 months) or radiotherapy alone (OS: 4 months; DSS: 4 months).

Conclusion: Treatment with surgery alone resulted in superior survival outcomes compared to other treatment modality combinations, regardless of patient age and disease stage. Within the limitations of this study, providers may wish to consider these findings when devising patient treatment plans.
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http://dx.doi.org/10.1016/j.cllc.2019.07.001DOI Listing
March 2020

Frequency of unplanned surgery in patients with stage IV colorectal cancer receiving palliative chemotherapy with an intact primary: An analysis of SEER-Medicare.

J Surg Oncol 2019 Sep 18;120(3):407-414. Epub 2019 May 18.

Department of Surgery, Carolinas Medical Center, Levine Cancer Institute, Charlotte, North Carolina.

Background And Objectives: Stage IV colorectal cancer is often treated with palliative chemotherapy with the primary tumor in place. Low rates of unplanned surgical intervention (due to obstruction or perforation) have been reported. We examined a large national dataset to determine the rate of unplanned surgical intervention in these patients.

Methods: Surveillance Epidemiology and End Results-Medicare were queried for patients with metastatic colorectal cancer receiving chemotherapy (1998-2013). Patient who underwent planned surgery to the primary or metastasectomy were excluded. The primary outcome was the need for nonelective surgery. Time to surgery or death was measured. Conditional analyses were performed to determine the risk of surgical intervention at 6-month, 1-, and 2-year after diagnosis.

Results: The analytic cohort consisted of 4692 patients (median age = 75). At 24 months, 80% of the patients had died. The overall unplanned intervention rate was 12%. The probability of requiring unplanned surgery between 6 and 12 months was 8.1%; 12 and 24 months = 6.7%, and >24 months = 5.3%. Males, those with right-sided tumors, and older patients were less likely to require surgery.

Conclusions: Patients treated with palliative chemotherapy who are not resected upfront are unlikely to require unplanned surgery. Prophylactic surgery to reduce the risk of perforation or obstruction may not be necessary.
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http://dx.doi.org/10.1002/jso.25508DOI Listing
September 2019

Minimally Invasive Ivor Lewis Esophagectomy Without Patient Repositioning.

J Gastrointest Surg 2019 04 8;23(4):870-873. Epub 2019 Jan 8.

Department of Surgery, Division of Surgical Oncology, Carolinas Medical Center, Levine Cancer Institute, 1021 Morehead Medical Drive #6100, Charlotte, NC, 28204, USA.

Introduction: The standard technique for Ivor Lewis minimally invasive esophagectomy involves a two-stage approach necessitating repositioning mid-procedure.

Technique: We describe our technique for a one-stage hand-assisted minimally invasive esophagectomy that allows sequential access to the chest and abdomen within the same surgical field, eliminating the need for repositioning. The patient is positioned in a "corkscrew" configuration with the abdomen supine and the chest rotated to the left to allow access to the right chest. The abdomen and chest are prepped into a single operative field. This technique allows sequential access to the abdomen for gastric mobilization, chest for division of the esophagus, abdomen for construction of the gastric conduit, and chest for intrathoracic anastomosis.

Conclusion: This approach enables extracorporeal construction of the conduit, which helps ensure a clear distal margin on the specimen and facilitates conduit length by placing the stomach on stretch during stapling.
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http://dx.doi.org/10.1007/s11605-018-4063-8DOI Listing
April 2019

Higher Incidence of Hemorrhagic Cystitis Following Haploidentical Related Donor Transplantation Compared with Matched Related Donor Transplantation.

Biol Blood Marrow Transplant 2019 04 20;25(4):785-790. Epub 2018 Dec 20.

Department of Cancer Biostatistics, Levine Cancer Research, Atrium Health, Charlotte, North Carolina.

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.142DOI Listing
April 2019

Daratumumab, pomalidomide and dexamethasone combination therapy in daratumumab and/or pomalidomide refractory multiple myeloma.

Br J Haematol 2019 07 11;186(1):140-144. Epub 2018 Dec 11.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.

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http://dx.doi.org/10.1111/bjh.15716DOI Listing
July 2019

Peripheral Immunotype Correlates with Minimal Residual Disease Status and Is Modulated by Immunomodulatory Drugs in Multiple Myeloma.

Biol Blood Marrow Transplant 2019 03 24;25(3):459-465. Epub 2018 Nov 24.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina. Electronic address:

Data indicate reversal of immune dysfunction with active treatment; however, the precise contribution of specific immune effector and immune suppressor components to achieve a minimal residual disease (MRD) state and immunomodulatory drug-mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in natural killer (NK), NK-T, and T cells, including maturation and activating/inhibitory repertoire associated with MRD versus MRD status after autologous stem cell transplantation (ASCT) and during lenalidomide-based maintenance therapy. Of the 46MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pretherapy and after cycles 1, 3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. Although the absolute number of NK cells was significantly lower in patients with MRD response, phenotypically NK cells in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRD group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRD versus MRD patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function, and acquisition of PD1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during the maintenance phase in MRD patients. Put together, these observations provide a distinctive signature for MRD and MRD groups. These data support exploration of immune profiling in prospective clinical trials according to MRD-defined responses to identify patients that may benefit from maintenance intensification/modification or maintenance withdrawal.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.015DOI Listing
March 2019

Acupuncture for Cancer Pain and Symptom Management in a Palliative Medicine Clinic.

Am J Hosp Palliat Care 2019 Apr 4;36(4):326-332. Epub 2018 Oct 4.

2 Section of Palliative Medicine, Department of Supportive Oncology, Atrium Health, Charlotte, NC, USA.

Objective:: Studies suggest acupuncture improves cancer-related symptoms; however, it is unclear whether patient characteristics predict pain response. This study determined acupuncture's effect on cancer-related pain and identified variables associated with pain response.

Methods:: A retrospective chart review included adult patients with cancer referred to palliative medicine and received acupuncture for pain management. Paired t tests compared differences in pain scores from pre- to postacupuncture. Clinically meaningful pain improvement was defined as ≥2-point reduction in pain score. Logistic regression was used to evaluate associations between patient characteristics and pain improvement.

Results:: One hundred seventy acupuncture treatments from 68 individual patients were studied. Significant reductions in mean pain scores were observed after the first treatment (-1.9 ± 1.8; P < .001) and across all treatments (-1.7 ± 1.9; P < .001). Multivariable analysis demonstrated clinically meaningful pain improvement with higher baseline pain scores (odds ratio [OR]: 1.79, 95% confidence interval [CI]: 1.44-2.22; P < .001) and stage III/IV disease (OR: 3.23, 95% CI: 1.11-9.40; P < .001). There were significant improvements in anxiety, depression, drowsiness, dyspnea, fatigue, nausea, and well-being after the first treatment and across all treatments ( P < .001).

Conclusions:: Acupuncture improved cancer-related pain and other symptoms. Those with higher baseline pain scores and advanced disease were more likely to achieve significant pain reduction. Improved depression and fatigue were closely related to pain reduction. Further studies are needed to confirm pain response variables, establish durability, and develop a personalized approach to acupuncture.
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http://dx.doi.org/10.1177/1049909118804464DOI Listing
April 2019

Effects of Reduction in Tumor Burden on Survival in Epithelioid Malignant Pleural Mesothelioma.

Mayo Clin Proc 2018 08 24;93(8):1026-1033. Epub 2018 May 24.

Department of Cancer Biostatistics, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, and University of South Carolina Arnold School of Public Health, Columbia, SC.

Objective: To understand the relationship between response and survival in malignant pleural mesothelioma (MPM).

Patients And Methods: The original clinical trial was conducted from April 1999 through March 2001. Patients with epithelioid MPM (n=305) were categorized using modified pleural Response Evaluation Criteria in Solid Tumors by whether they responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were estimated and hazard ratios for responders and nonresponders were estimated and compared using the log-rank test. Multivariable Cox proportional hazards models were used to adjust for baseline prognostic factors.

Results: Patients who responded to frontline therapy had a significantly longer OS (hazard ratio, 0.34; 95% CI, 0.24-0.49; median, 20.6 months; 95% CI, 15.3 months to not reached) than did those who did not respond (median, 9.4 months; 95% CI, 8.1-11.0 months) (P<.001). Similarly, responders had a significantly longer PFS (hazard ratio, 0.50; 95% CI, 0.39-0.64; median, 7.8 months; 95% CI, 6.5-8.5 months) than did nonresponders (median, 3.7 months; 95% CI, 2.9-4.3 months) (P<.001). These results were confirmed when adjusting for baseline prognostic factors. We also observed a survival benefit associated with disease stabilization in MPM.

Conclusion: Our findings indicate that reduction in tumor burden or disease stabilization determined using modified pleural Response Evaluation Criteria in Solid Tumors is strongly associated with OS and PFS in epithelioid MPM.
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http://dx.doi.org/10.1016/j.mayocp.2018.01.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077096PMC
August 2018

Validating the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer: data from TRUMPET.

Future Oncol 2018 Mar 8;14(6):527-536. Epub 2018 Feb 8.

Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37250, USA.

Aim: To validate the total illness burden index for prostate cancer (TIBI-CaP) in castration-resistant prostate cancer (CRPC) patients.

Patients & Methods: Baseline comorbidity scores collected using the TIBI-CaP were compared with the baseline patient-reported health-related quality of life using the SF-12v2 and FACT-P questionnaires in 302 patients enrolled in the Treatment Registry for Outcomes in CRPC Patients (TRUMPET).

Results: Baseline TIBI-CaP scores were negatively correlated with all baseline SF-12v2 domain/composite (p < 0.001) and FACT-P subscale/total (p < 0.020) scores. There was a significant decreasing linear trend in SF12v2 and FACT-P scores over the categories based on TIBI-CaP quartiles of comorbidity burden (from 'least' to 'severe').

Conclusion: The TIBI-CaP is a valid measure of comorbidity burden in patients with CRPC in the real world.
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http://dx.doi.org/10.2217/fon-2017-0438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941708PMC
March 2018

Quantitative assessment of neuropilin-2 as a simple and sensitive diagnostic assay for spitzoid melanocytic lesions.

Melanoma Res 2018 02;28(1):71-75

Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts.

There is a significant need for the development of diagnostic tools that can precisely distinguish Spitz nevi and spitzoid melanomas. Here, we report the development of a PCR-based quantitative diagnostic assay for spitzoid melanocytic lesions utilizing the expression ratio of neuropilin-2 and melan-A genes in primary tumor specimens. We find that the expression ratio of neuropilin-2/melan-A is significantly increased in spitzoid melanomas compared with Spitz nevi. The diagnostic potential of this quantitative assay was validated in two independent sets of patient samples as demonstrated in a receiver operating characteristic curve analysis showing an area under the curve value of 91.8%. Furthermore, the assay was found to quantitatively distinguish the clinical nature of atypical spitzoid melanocytic lesions that were diagnostically undetermined using histopathologic criteria alone. Our data indicate that this quantitative assay may be used as a tool in determining the diagnostic classification of histologically challenging spitzoid tumors.
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http://dx.doi.org/10.1097/CMR.0000000000000416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805139PMC
February 2018

Single-Fraction Stereotactic Radiosurgery (SRS) Alone Versus Surgical Resection and SRS for Large Brain Metastases: A Multi-institutional Analysis.

Int J Radiat Oncol Biol Phys 2017 10 11;99(2):459-467. Epub 2017 Apr 11.

Southeast Radiation Oncology Group, Levine Cancer Institute, Charlotte, North Carolina.

Purpose: Stereotactic radiosurgery (SRS) dose is limited by brain metastasis (BM) size. The study goal was to retrospectively determine whether there is a benefit for intracranial outcomes and overall survival (OS) for gross total resection with single-fraction SRS versus SRS alone for patients with large BMs.

Methods And Materials: A large BM was defined as ≥4 cm (2 cm in diameter) prior to the study. We reviewed the records of consecutive patients treated with single-fraction SRS alone or surgery with preoperative or postoperative SRS between 2005 and 2013 from 2 institutions.

Results: Overall, 213 patients with 223 treated large BMs were included; 66 BMs (30%) were treated with SRS alone and 157 (70%) with surgery and SRS (63 preoperatively and 94 postoperatively). The groups (SRS vs surgery and SRS) were well balanced except regarding lesion volume (median, 5.9 cm vs 9.6 cm; P<.001), median number of BMs (1.5 vs 1, P=.002), median SRS dose (18 Gy vs 15 Gy, P<.001), and prior whole-brain radiation therapy (33% vs 5%, P<.001). The local recurrence (LR) rate was significantly lower with surgery and SRS (1-year LR rate, 36.7% vs 20.5%; P=.007). There was no difference in radiation necrosis (RN) by resection status, but there was a significantly increased RN rate with postoperative SRS versus with preoperative SRS and with SRS alone (1-year RN rate, 22.6% vs 5% and 12.3%, respectively; P<.001). OS was significantly higher with surgery and SRS (2-year OS rate, 38.9% vs 19.8%; P=.01). Both multivariate adjusted analyses and propensity score-matched analyses demonstrated similar results.

Conclusions: In this retrospective study, gross total resection with SRS was associated with significantly reduced LR compared with SRS alone for patients with large BMs. Postoperative SRS was associated with the highest rate of RN. Surgical resection with SRS may improve outcomes in patients with a limited number of large BMs compared with SRS alone. Further studies are warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2017.04.006DOI Listing
October 2017

Investigation of a gene signature to predict response to immunomodulatory derivatives for patients with multiple myeloma: an exploratory, retrospective study using microarray datasets from prospective clinical trials.

Lancet Haematol 2017 Sep;4(9):e443-e451

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC, USA. Electronic address:

Background: Immunomodulatory derivatives (IMiDs), along with proteasome inhibitors, are key components of treatment regimens for multiple myeloma. Nonetheless, outcomes vary among treated individuals. Drug-specific gene-expression profile (GEP) signatures that aid the prediction of favourable and unfavourable outcomes can provide patients with the most effective therapy for their individual disease. We aimed to develop and validate a gene expression signature to suggest which patients would benefit most from IMiD-based therapies.

Methods: For this exploratory retrospective study, we selected a cohort of patients with newly diagnosed or relapsed or refractory multiple myeloma who were treated in clinical trials with IMiD-containing regimens. Cohorts were eligible if they had publicly available GEP data from patients' bone marrow plasma cells, with long-term follow-up and clinicopathological data. In the development stage of the model, we identified 176 IMiD response genes that were differentially expressed before and after IMiD exposure using pharmacogenomic GEP data from patients who had bone marrow samples taken before and 48 h after a test dose exposure with thalidomide (n=42), lenalidomide (n=18), or pomalidomide (n=18). 14 of these genes had p values less than 0·05 for associations with progression-free survival in patients who received thalidomide in induction and maintenance therapy in the Total Therapy (TT) 2 trial (ie, the training cohort). We combined the 14 genes to create a continuous IMiD-14 score and an optimal cutoff. The subgroup with an IMiD-14 score higher than the cutoff was deemed to be IMiD-resistant. We obtained validation cohorts from four studies of IMiD combination regimens: the TT3a trial (thalidomide in induction and maintenance), the TT3b trial (thalidomide in induction and lenalidomide in maintenance), the TT6 trial (thalidomide in induction and lenalidomide in maintenance), and the vincristine, doxorubicin, and dexamethasone (VAD) group of the HOVON65/GMMG-HD4 trial (thalidomide in maintenance). The primary endpoint was to show the prognostic value of the IMiD-14 gene signature for progression-free survival.

Findings: In the training cohort, progression-free survival was significantly shorter in the 83 patients with IMiD-14 high scores than in the 92 patients with IMiD-14 low scores; 3 year progression-free survival was 52% (95% CI 42-64) for the IMiD-14 high group versus 85% (78-92) for the IMiD-14 low group, with a hazard ratio (HR) of 2·51 (95% CI 1·72-3·66; p<0·0001). These findings were supported by the results in the validation cohorts, TT3a (115 patients with IMiD-14 high vs 160 patients with IMiD-14 low; 3 year progression-free survival 63% [95% CI 55-73] vs 87% [82-92]; HR 1·54 [1·11-2·15], p=0·010), TT3b (77 patients with IMiD-14 high vs 89 patients with IMiD-14 low; 62% [52-74] vs 80% [72-89]; HR 2·07 [1·28-3·34], p=0·0024), TT6 (20 patients with IMiD-14 high vs 36 patients with IMiD-14 low; 39% [22-68] vs 74% [61-90]; HR 2·40 [1·09-5·30], p=0·026), and the VAD group of HOVON65/GMMG-HD4 (65 patients with IMiD-14 high vs 77 patients with IMiD-14 low; 16% [9-28] vs 54% [44-67]; HR 2·29 [1·52-3·45], p<0·0001).

Interpretation: Our results suggest that the IMiD-14 model has prognostic value in patients with multiple myeloma who are treated with IMiDs. Some genes in the model could provide novel targets for IMiD resistance and therapeutic intervention. The IMiD-14 model warrants evaluation in prospective studies.

Funding: Conquer Cancer Foundation ASCO Young Investigator Award and the Carolinas Myeloma Research Fund.
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http://dx.doi.org/10.1016/S2352-3026(17)30143-6DOI Listing
September 2017

External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases.

Int J Radiat Oncol Biol Phys 2017 07 14;98(3):632-638. Epub 2017 Mar 14.

Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina; Southeast Radiation Oncology Group, Charlotte, North Carolina.

Background: A scoring system using pretreatment factors was recently published for predicting the risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm, with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population.

Methods: We reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence.

Results: The low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53).

Conclusion: The 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2017.03.012DOI Listing
July 2017

Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis.

J Neurooncol 2017 02 20;131(3):611-618. Epub 2016 Dec 20.

Southeast Radiation Oncology Group, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, USA.

Pre-operative stereotactic radiosurgery (pre-SRS) has been shown as a viable treatment option for resectable brain metastases (BM). The aim of this study is to compare oncologic outcomes and toxicities for pre-SRS and post-operative WBRT (post-WBRT) for resectable BM. We reviewed records of consecutive patients who underwent resection of BM and either pre-SRS or post-WBRT between 2005 and 2013 at two institutions. Overall survival (OS) was calculated using the Kaplan-Meier method. Cumulative incidence was used for intracranial outcomes. Multivariate analysis (MVA) was performed using the Cox and Fine and Gray models, respectively. Overall, 102 patients underwent surgical resection of BM; 66 patients with 71 lesions received pre-SRS while 36 patients with 42 cavities received post-WBRT. Baseline characteristics were similar except for the pre-SRS cohort having more single lesions (65.2% vs. 38.9%, p = 0.001) and smaller median lesion volume (8.3 cc vs. 15.3 cc, p = 0.006). 1-year OS was similar between cohorts (58% vs. 56%, respectively) (p = 0.43). Intracranial outcomes were also similar (2-year outcomes, pre-SRS vs. post-WBRT): local recurrence: 24.5% vs. 25% (p = 0.81), distant brain failure (DBF): 53.2% vs. 45% (p = 0.66), and leptomeningeal disease (LMD) recurrence: 3.5% vs. 9.0% (p = 0.66). On MVA, radiation cohort was not independently associated with OS or any intracranial outcome. Crude rates of symptomatic radiation necrosis were 5.6 and 0%, respectively. OS and intracranial outcomes were similar for patients treated with pre-SRS or post-WBRT for resected BM. Pre-SRS is a viable alternative to post-WBRT for resected BM. Further confirmatory studies with neuro-cognitive outcomes comparing these two treatment paradigms are needed.
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http://dx.doi.org/10.1007/s11060-016-2334-3DOI Listing
February 2017

Treatment registry for outcomes in patients with castration-resistant prostate cancer (TRUMPET): a methodology for real-world evidence and research.

Future Oncol 2016 Dec 16;12(23):2689-2699. Epub 2016 Aug 16.

Astellas Pharma, Inc., Northbrook, IL, USA.

Aim: This study seeks to improve the understanding of treatment patterns and associated health-related quality of life (HRQoL), clinical outcomes and healthcare utilization in US patients with castration-resistant prostate cancer (CRPC).

Patients & Methods: Treatment Registry for Outcomes in CRPC Patients (TRUMPET) is a US-based, prospective, observational multicenter registry (NCT02380274) involving patients with CRPC and their caregivers. Patients initiating their first active treatment course will be enrolled from urology and medical oncology practices, with data captured up to 4 years.

Results: Information on prescribing patterns, HRQoL, clinical outcomes and healthcare utilization will be collected.

Conclusion: TRUMPET will enable scientific understanding of disease management in terms of HRQoL, clinical outcomes and healthcare utilization in clinical practice for patients with CRPC.
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http://dx.doi.org/10.2217/fon-2016-0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116579PMC
December 2016

Margin re-excision and local recurrence in invasive breast cancer: A cost analysis using a decision tree model.

J Surg Oncol 2015 Sep 16;112(4):443-8. Epub 2015 Sep 16.

Division of Surgical Oncology, Department of Surgery, Levine Cancer Institute, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, North Carolina.

Background: SSO-ASTRO recently published guidelines defining adequate margins in breast conservation therapy (BCT) as no tumor on ink based on studies demonstrating little difference in local recurrence (LR) with wider margins. We hypothesize that not routinely re-excising close margins results in decreased costs without compromising care.

Methods: A decision tree model was developed for the management of margins after BCT for invasive cancer. Patients were compared among three margin status groups: positive, close (≤2 mm) and negative (>2 mm). Ten publications provided re-excision rates (RER) and LR rates. The model assumed 140,000 BCT/year. Sensitivity analyses determined the most cost-effective strategy. Surgical costs were estimated using 2013 Medicare reimbursement rates.

Results: Re-excising close margins was significantly more costly than the alternative, $233.1 million versus $214.3 million, per year in the United States. Total surgical cost was most sensitive to re-excision of close margins-increasing the RER from 0% to 100% resulted in an $18.8 million cost difference.

Conclusions: The strategy of re-excising close margins resulted in a predicted cost of $18.8 million per year. This does not include hospital costs, the cost of surgical complications after re-excision, and underestimates the potential savings by using Medicare reimbursement rates.
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http://dx.doi.org/10.1002/jso.23990DOI Listing
September 2015

BCNU wafer placement with temozolomide (TMZ) in the immediate postoperative period after tumor resection followed by radiation therapy with TMZ in patients with newly diagnosed high grade glioma: final results of a prospective, multi-institutional, phase II trial.

J Neurooncol 2015 Jun 7;123(2):259-66. Epub 2015 May 7.

Southeast Radiation Oncology Group, Department of Radiation Oncology, Levine Cancer Institute at Carolinas Medical Center, 1021 Morehead Medical Drive, Charlotte, NC, 28204, USA,

Temozolomide (TMZ) and BCNU have demonstrated anti-glioma synergism in preclinical models. We report final data from a prospective, multi-institutional study of BCNU wafers and early TMZ followed by radiation therapy with TMZ in patients with newly diagnosed malignant glioma. 65 patients were consented in 4 institutions, and 46 patients (43 GBM, 3 AA) were eligible for analysis. After resection and BCNU wafer placement, TMZ began on day four postoperatively. Radiation and TMZ (RT/TMZ) were then administered, followed by monthly TMZ at 200 mg/m2 for the first 26 patients, which was reduced to 150 mg/m2 for the remaining 20 patients. Non-hematologic toxicities were minimal. Nine of 27 patients (33 %) who received 200 mg/m2 TMZ, but only 1 of 20 (5 %) who received 150 mg/m2, experienced grade 3/4 thrombocytopenia. Median progression free survival (PFS) and overall survival (OS) period was 8.5 and 18 months, respectively. The 1-year OS rate was 76 %, which is a significant improvement compared with the historical control 1-year OS rate of 59 % (p = 0.023). However, there was no difference in 1-year OS compared with standard RT/TMZ (p = 0.12) or BCNU wafer followed by RT/TMZ (p = 0.87) in post hoc analyses. Early post-operative TMZ can be safely administered with BCNU wafers following resection of malignant glioma at the 150 mg/m2 dose level. Although there was an OS benefit compared to historical control, there was no indication of benefit for BCNU wafers and early TMZ in addition to standard RT/TMZ or early TMZ in addition to regimens of BCNU wafers followed by RT/TMZ.
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http://dx.doi.org/10.1007/s11060-015-1793-2DOI Listing
June 2015

Breast cancer detection in axillary sentinel lymph nodes: the impact of the method of pathologic examination.

Hum Pathol 2014 Dec 2;45(12):2497-501. Epub 2014 Oct 2.

Division of Surgical Oncology, Department of Surgery, Levine Cancer Institute, Carolinas Medical Center, Carolinas HealthCare System, Charlotte, NC 28204. Electronic address:

At Carolinas Medical Center, before 2008, axillary sentinel lymph nodes (SLNs) from breast cancer patients were evaluated with a single hematoxylin and eosin-stained slide. In 2008, the protocol changed to include a limited step sectioning at 500 μm. In this study, we compared the intraoperative and permanent section pathologic findings for SLN biopsies from 2006 to 2007 to those from 2009 to 2010. We hypothesized that evaluating 2 slides would increase the detection of micrometastases and isolated tumor cells (ITCs) on permanent sections and correspondingly decrease the sensitivity of intraoperative touch preparation cytology (IOTPC). From 2006 to 2007, 140 (23.5%) of 597 of SLN permanent sections contained tumor cells: 92 macrometastases (65.7%), 36 micrometastases (25.7%), and 12 ITCs 0.2 mm or less (8.6%). The sensitivity of IOTPC for 2006 to 2007 was 51.4% for any tumor cells and 71.7% for macrometastases. From 2009 to 2010, 160 (21.9%) of 730 SLN permanent sections were positive for any tumor cells: 76 macrometastases (47.5%), 55 micrometastases (34.4%), and 29 ITCs (18.1%). The sensitivity of IOTPC for 2009 to 2010 was 39.4% for any tumor cells and 76.3% for macrometastases. With limited step sectioning, we observed an approximately 10% increase in the detection of both micrometastases and ITCs in SLN. The increased detection of ITCs on permanent sections reached statistical significance (P = .018). However, under current clinical guidelines, patients with limited SLN involvement may not be required to undergo completion axillary lymph node dissection. The ability to detect SLN tumor deposits less than 2 mm must be balanced with the clinical utility of doing so.
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http://dx.doi.org/10.1016/j.humpath.2014.09.004DOI Listing
December 2014

Systematic review of response rates of sarcomatoid malignant pleural mesotheliomas in clinical trials.

Lung Cancer 2014 Nov 1;86(2):133-6. Epub 2014 Sep 1.

Department of Internal Medicine, Division of Pulmonary Medicine, Mayo Clinic, Rochester, MN, United States.

Rationale: Malignant pleural mesothelioma is an almost universally fatal malignancy primarily related to asbestos exposure. Based on the differences in immunologic markers and gene expression between histologic subtypes of mesothelioma, and our clinical impression that response rates vary by histology, we decided to examine the reported response rates of mesothelioma subtypes.

Objectives: Our objective was to compare the response rates of sarcomatoid mesotheliomas to the overall response rates in published clinical trials.

Methods: We searched PubMed for "mesothelioma" with the clinical trials filter selected. We included articles published between January 1, 2000 and March 20, 2014 in which subjects received first or second line systemic therapy for malignant pleural mesothelioma. Studies investigating multi-modality therapy including surgery were excluded. Response rates [including 95% confidence intervals (95% CI)] were estimated for the entire patient cohort and then separately for subjects with sarcomatoid tumors.

Measurements And Main Results: We reviewed 544 publications of which 41 trials met our inclusion criteria. Eleven of these trials did not include patients with sarcomatoid mesothelioma (27% of eligible studies). The remaining 30 publications included 1475 subjects, 1011 with epithelioid tumors (68.5%), 203 with biphasic tumors (13.8%), 137 with sarcomatoid tumors (9.3%) and 124 with unknown subtypes (8.4%). In total, there were 323 responses (21.9%, complete and partial responses, 95% CI: 16.3, 28.8) to systemic therapy across all histological subtypes. In patients with sarcomatoid tumors (n=137) 19 responses were observed. This accounted for 5.9% of all responses and yields a 13.9% (95% CI: 8.6, 21.6) response rate for patients with sarcomatoid tumors. Multiple biases likely affected this systematic review.

Conclusion: Response rates for different histological subtypes of malignant pleural mesothelioma are infrequently reported. Partial and complete responses to systemic therapies appear to be less common among patients with sarcomatoid tumors.
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http://dx.doi.org/10.1016/j.lungcan.2014.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254081PMC
November 2014

A retrospective analysis of the clinical performance of human papillomavirus testing using SurePath sample collection.

J Am Soc Cytopathol 2014 May - Jun;3(3):165-169. Epub 2014 Feb 23.

Department of Pathology, Carolinas Pathology Group, Carolinas HealthCare System, 1000 Blythe Boulevard, Charlotte, North Carolina.

Introduction: We present a retrospective analysis of our high-risk human papillomavirus (hr-HPV) test performance using SurePath samples, and we compare these results to published results from Kaiser Permanente of Northern California, where hr-HPV testing was performed using collection in standard transport medium.

Methods And Materials: We retrospectively identified histopathologic cases of cervical intraepithelial neoplasia (CIN) 2+ from 2010 through 2012, as well as all hr-HPV results performed from SurePath samples in these women. Testing for hr-HPV in our laboratory consisted of either Hybrid-Capture 2 or Cervista. These results were used to calculate false negative rates for CIN 2+, CIN 3+, and carcinoma, for both test methods, and these rates are compared with those published by Kaiser Permanente of Northern California.

Results: The false negative rate for hr-HPV testing from SurePath samples (combined Hybrid-Capture 2 and Cervista) at the histopathologic level of CIN2+ was 7.9% (95% confidence interval: 5.9-10.2). This is compared with the false negative rates from collection in standard transport medium reported by Kaiser Permanente of Northern California for CIN 2+ of 20.4% (95% confidence interval: 18.9-22.0). Similar calculations for CIN 3+ and carcinoma are presented, along with comparison to the Kaiser Permanente of Northern California results. With regard to false negative hr-HPV results, for all levels of histopathologic abnormality, our hr-HPV testing from SurePath samples showed either significantly better performance (for CIN 2+ regardless of method, CIN 3+ using Cervista), or equivalent performance (for CIN 3+ using Hybrid-Capture 2 and carcinoma regardless of method).

Conclusions: Our retrospective analysis demonstrates that hr-HPV testing from SurePath samples meets the proposed sensitivity of ≥90% in cases of biopsy proven CIN 2+.
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http://dx.doi.org/10.1016/j.jasc.2014.02.002DOI Listing
February 2014

PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer.

J Clin Oncol 2013 Dec 14;31(35):4400-6. Epub 2013 Oct 14.

R. Wendel Naumann and James T. Symanowski, Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC; Robert L. Coleman, MD Anderson Cancer Center, University of Texas, Houston; Michael G. Teneriello, Texas Oncology, Austin, TX; Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Edward A. Sausville, Greenebaum Cancer Center, University of Maryland, Baltimore, MD; Elzbieta Kutarska, Centrum Onkologii Ziemi Lubelskiej, Lubland; Elzbieta Nowara, Instytut im. Marii Skłodowskiej-Curie, Gliwice, Poland; Sharad A. Ghamande, Georgia Health Sciences University, Augusta, GA; Nashat Y. Gabrail, Gabrail Cancer Center, Canton, OH; Stephen E. DePasquale, Chattanooga's Program in Women's Oncology, Chattanooga, TN; Lucy Gilbert, McGill University Health Centre, Montreal, Quebec, Canada; Robert H. Gersh, Cancer Care Northwest, Spokane, WA; Wael A. Harb, Horizon Oncology Research, Lafayette; Chandra D. Lovejoy, Christopher P. Leamon, David E. Morgenstern, and Richard A. Messmann, Endocyte, West Lafayette, IN; Panagiotis A. Konstantinopoulos, Beth Israel Deaconess Medical Center; and Richard T. Penson, Dana-Farber Cancer Center, Massachusetts General Hospital, Boston, MA.

Purpose: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.

Patients And Methods: Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups.

Results: The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806).

Conclusion: Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
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http://dx.doi.org/10.1200/JCO.2013.49.7685DOI Listing
December 2013

Comparison of complex permittivities of isotonic colloids containing single-wall carbon nanotubes of varying chirality.

Bioelectromagnetics 2012 Feb 18;33(2):134-46. Epub 2011 Jul 18.

Nevada Cancer Institute, Las Vegas, Nevada.

The application of bio-compatible, conductive nanoparticles in combination with radiofrequency (RF) irradiation to raise tissue temperatures between 40 and 60 °C for hyperthermia and ablation spurred interest in the complex permittivities of isotonic nanoparticle-based colloids. Nanoparticles with large aspect ratios and high permittivities increase the bulk permittivity of the colloid and RF losses at the macroscopic scale. The complex permittivities of isotonic colloids with and without single-wall carbon nanotubes (SWCNTs) containing either metallic, semiconducting, or mixed chiralities were measured from 20 MHz to 1 GHz at room temperature. The colloids were made with one of three different isotonic solvents: phosphate buffered saline (PBS), and Dulbecco's modified eagle medium (DMEM) with and without 0.5% weight/volume bovine serum albumin to simulate cytosol and blood, respectively. The concentration of elemental carbon from the SWCNTs in the colloids ranged from 16 to 17 mM. The permittivities were corrected for electrode polarization effects by fitting the data to the Cole-Cole relaxation model with a constant phase angle element. The presence of SWCNTs increased both the real and imaginary components of the permittivities of the colloids. For all three solvents, the direct current (DC) components of the real and imaginary permittivities were greatest for the colloids containing the mixed chirality SWCNTs, followed by the colloids with semiconducting SWCNTs, and then metallic SWCNTs.
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http://dx.doi.org/10.1002/bem.20689DOI Listing
February 2012

Comparison of circulating MicroRNA 141 to circulating tumor cells, lactate dehydrogenase, and prostate-specific antigen for determining treatment response in patients with metastatic prostate cancer.

Clin Genitourin Cancer 2011 Sep 1;9(1):39-45. Epub 2011 Jul 1.

Department of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, 89135, USA.

Our aim was to determine the utility of circulating micro RNA miR-141 as a potential biomarker of therapeutic response in prostate cancer (CaP) patients. We compared the values of miR-141 in plasma of 21 CaP patients to the levels of prostate specific antigen (PSA), circulating tumor cells (CTC) and lactate dehydrogenase (LDH). Data suggest a strong correlation of miR-141 values and clinical course. For prostate cancer (CaP), the measurement of prostate-specific antigen (PSA) and radiographic studies do not adequately predict response to therapy and survival, and, therefore, new relevant biomarkers are needed. We and other researchers have shown that longitudinal measurements of PSA, circulating tumor cells (CTC), and lactate dehydrogenase (LDH) may aid in predicting response to therapy. Results of recent studies have determined that circulating microRNA (miRNA) miR-141 is detected in plasma of patients with CaP. We, therefore, compared the temporal changes of miR-141 with the levels of CTC, LDH, and PSA in 21 patients with CaP, and longitudinally examined these markers alone or in combinations to determine the utility of miR-141 in the predicting a patient's clinical course and response to therapy. Levels of miR-141 in plasma of 21 patients with CaP were measured by using quantitative reverse transcription-polymerase chain reaction. A total of 35 intervals were assessed. Directional changes (increasing or decreasing) in PSA, CTC, and miR-141 had sensitivity in predicting clinical outcome (progression vs. nonprogressing) of 78.9%. Logistic regression modeling of the probability of clinical progression demonstrates that miR-141 levels predicted clinical outcomes with an odds ratio of at least 8.3. miR-141 also had the highest correlation with temporal changes of PSA with a correlation of R = 0.77 (P < .001). In this retrospective study, miR-141 demonstrated a similar ability to predict clinical progression when compared with other clinically validated biomarkers. Furthermore, miR-141 demonstrated high correlation with changes of the other biomarkers.
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http://dx.doi.org/10.1016/j.clgc.2011.05.008DOI Listing
September 2011

Circulating tumor cells as a predictive biomarker in patients with hormone-sensitive prostate cancer.

Clin Genitourin Cancer 2011 Sep 25;9(1):31-8. Epub 2011 Jun 25.

Department of Clinical Oncology, Nevada Cancer Institute, Las Vegas, 89135, USA.

Unlabelled: Little information exists regarding the utility circulating tumor cell (CTC) enumeration in hormone sensitive prostate cancer. We enumerated CTC in 33 consecutive patients undergoing androgren deprivation therapy (ADT) at our institution. Multivariate analysis revealed baseline CTC as the only independent predictor of progression to CRPC. These data suggest that baseline CTC may identify those unlikely to benefit from ADT.

Introduction: Circulating tumor cell (CTC) enumeration by using the Cellsearch platform has established prognostic and predictive value in patients with metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding the clinical utility of CTC enumeration in metastatic hormone-sensitive prostate cancer (mHSPC). The goal of this study was to prospectively determine the relative clinical utility of CTCs in mHSPC.

Patients And Methods: We analyzed serial CTC in conjunction with other classic biomarkers in 33 consecutive patients treated at the Nevada Cancer Institute with HSPC initiating androgen deprivation therapy and correlated these patients with prognostic prostate-specific antigen (PSA) endpoints and onset of CRPC.

Results: Initial CTC correlated positively with lactate dehydrogenase and alkaline phosphatase, and were unrelated to PSA and testosterone. In univariate analysis, baseline CTC, alkaline phosphatase, lactate dehydrogenase, testosterone, and follow-up CTC were individual predictors of progression to CRPC. In a multivariate Cox regression, only baseline CTC retained independent predictive value. Threshold analysis revealed the cutpoint that optimized specificity and sensitivity of the test to be 3 cells per 7.5 mL whole blood. Baseline CTC also correlated well with PSA nadir benchmarks.

Conclusions: Initial CTC values predict the duration and magnitude of response to hormonal therapy. CTC enumeration may identify patients at risk of progression to CRPC before initiation of androgen deprivation therapy.
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http://dx.doi.org/10.1016/j.clgc.2011.04.001DOI Listing
September 2011

A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer.

Cancer Prev Res (Phila) 2011 Mar;4(3):375-83

Division of Cancer Prevention, National Cancer Institute, National Institute of Health, Bethesda, MD 20892-7346, USA.

A panel of biomarkers may improve predictive performance over individual markers. Although many biomarker panels have been described for ovarian cancer, few studies used prediagnostic samples to assess the potential of the panels for early detection. We conducted a multisite systematic evaluation of biomarker panels using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial. Using a nested case-control design, levels of 28 biomarkers were measured laboratory-blinded in 118 serum samples obtained before cancer diagnosis and 951 serum samples from matched controls. Five predictive models, each containing 6 to 8 biomarkers, were evaluated according to a predetermined analysis plan. Three sequential analyses were conducted: blinded validation of previously established models (step 1); simultaneous split-sample discovery and validation of models (step 2); and exploratory discovery of new models (step 3). Sensitivity, specificity, sensitivity at 98% specificity, and AUC were computed for the models and CA125 alone among 67 cases diagnosed within one year of blood draw and 476 matched controls. In step 1, one model showed comparable performance to CA125, with sensitivity, specificity, and AUC at 69.2%, 96.6%, and 0.892, respectively. Remaining models had poorer performance than CA125 alone. In step 2, we observed a similar pattern. In step 3, a model derived from all 28 markers failed to show improvement over CA125. Thus, biomarker panels discovered in diagnostic samples may not validate in prediagnostic samples; utilizing prediagnostic samples for discovery may be helpful in developing validated early detection panels.
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http://dx.doi.org/10.1158/1940-6207.CAPR-10-0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057372PMC
March 2011

Increases in quantitative D-dimer levels correlate with progressive disease better than circulating tumor cell counts in patients with refractory prostate cancer.

Am J Clin Pathol 2010 Dec;134(6):964-9

Dept of Pathology, Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV 89135, USA.

Changes in quantitative D-dimer levels, circulating tumor cell (CTC) counts, and prostate-specific antigen (PSA) levels were measured in 28 patients with refractory castration-resistant prostate cancer to assess their concordance during the course of therapy and their relationship with risk of progressive disease. A significant correlation was identified between changes in PSA and both CTC counts and D-dimer levels (r = 0.67 and 0.58, respectively; P < .001). In addition, there was a significant correlation between changes in CTC count and D-dimer level (r = 0.62; P < .001). A significantly stronger concordance between these biomarkers was noted for increasing values (sensitivity, 72%-77.8%) compared with decreasing values (specificity, 43.8%-71.4%). Notably, increases in PSA and D-dimer levels, not CTC counts, were associated with increased risks for progressive disease (P < .024). Increases in quantitative D-dimer levels correlate with progressive disease better than CTC counts in patients with refractory prostate cancer.
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http://dx.doi.org/10.1309/AJCPH92SXYLIKKTSDOI Listing
December 2010

Quantitative analysis of cytokine-induced vascular toxicity and vascular leak in the mouse brain.

J Immunol Methods 2009 Sep 5;349(1-2):45-55. Epub 2009 Aug 5.

Section of Melanoma, Renal Cancer and Immunotherapy, Nevada Cancer Institute, Las Vegas, NV 89135, United States of America.

A storm of inflammatory cytokines is released during treatment with pro-inflammatory cytokines, such as interleukin-2 (IL-2), closely approximating changes initially observed during sepsis. These signals induce profound changes in neurologic function and cognition. Little is known about the mechanisms involved. We evaluated a number of experimental methods to quantify changes in brain blood vessel integrity in a well-characterized IL-2 treatment mouse model. Measurement of wet versus dry weight and direct measurement of small molecule accumulation (e.g. [(3)H]-H(2)O, sodium fluorescein) were not sensitive or reliable enough to detect small changes in mouse brain vascular permeability. Estimation of brain water content using proton density magnetic resonance imaging (MRI) measurements using a 7T mouse MRI system was sensitive to 1-2% changes in brain water content, but was difficult to reproduce in replicate experiments. Successful techniques included use of immunohistochemistry using specific endothelial markers to identify vasodilation in carefully matched regions of brain parenchyma and dynamic contrast enhanced (DCE) MRI. Both techniques indicated that IL-2 treatment induced vasodilation of the brain blood vessels. DCE MRI further showed a 2-fold increase in the brain blood vessel permeability to gadolinium in IL-2 treated mice compared to controls. Both immunohistochemistry and DCE MRI data suggested that IL-2 induced toxicity in the brain results from vasodilation of the brain blood vessels and increased microvascular permeability, resulting in perivascular edema. These experimental techniques provide us with the tools to further characterize the mechanism responsible for cytokine-induced neuropsychiatric toxicity.
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http://dx.doi.org/10.1016/j.jim.2009.07.014DOI Listing
September 2009

Circulating tumor cells in patients with castration-resistant prostate cancer baseline values and correlation with prognostic factors.

Cancer Epidemiol Biomarkers Prev 2009 Jun;18(6):1904-13

Department of Clinical Oncology, Nevada Cancer Institute, One Breakthrough Way, Las Vegas, Nevada 89135, USA.

Purpose: Circulating tumor cells (CTC) have been recently accepted by the Food and Drug Administration of the United States as a prognostic tool in advanced prostate cancer. However, a number of questions remain about the use of the test. The optimal clinical cut-off has never been determined. Also, the predictive value of CTCs in the setting of low-burden advanced prostate cancer has not been evaluated. Herein we describe our experience with the CellSearch method of CTC enumeration.

Experimental Design: CTCs enumerated from 100 patients with castration-resistant prostate cancer were correlated with clinicopathologic characteristics and conventional biomarkers, such as prostate-specific antigen and lactate dehydrogenase. Patients received ongoing medical oncologic follow-up for up to 26 months, and overall survival status was documented.

Results: Forty-nine of the patients (49%) were alive at the end of the study. CTC counts correlate well with overall survival (P < 0.001) but are also tightly interrelated to other biomarkers. Threshold analysis identified 4 CTC/7.5 cc (compared with the approved value of 5) as an optimal cut-off value with respect to correlation with survival outcomes as well as predictive of metastatic disease. Univariate analysis confirmed a tight interrelationship between cut-off CTC values and biomarkers. Multivariate analysis with bootstrap sampling validation identified lactate dehydrogenase (P = 0.002) and CTCs (P = 0.001) as independently prognostically significant.

Conclusions: Baseline CTC values provide important prognostic information and specific prediction of metastatic disease. Their presence correlates with classic biomarkers.
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http://dx.doi.org/10.1158/1055-9965.EPI-08-1173DOI Listing
June 2009