Publications by authors named "Mark E Smolkin"

53 Publications

Specialty-Specific Readmission Risk Models Outperform General Models in Estimating Hepatopancreatobiliary Surgery Readmission Risk.

J Gastrointest Surg 2021 May 4. Epub 2021 May 4.

Department of Surgery, University of Virginia, Box 800709, Charlottesville, VA, 22908-0709, USA.

Background: Readmissions are costly and inconvenient for patients, and occur frequently in hepatopancreatobiliary (HPB) surgery practice. Readmission prediction tools exist, but most have not been designed or tested in the HPB patient population.

Methods: Pancreatectomy and hepatectomy operation-specific readmission models defined as subspecialty readmission risk assessments (SRRA) were developed using clinically relevant data from merged 2014-15 ACS NSQIP Participant Use Data Files and Procedure Targeted datasets. The two derived procedure-specific models were tested along with 6 other readmission models in institutional validation cohorts in patients who had pancreatectomy or hepatectomy, respectively, between 2013 and 2017. Models were compared using area under the receiver operating characteristic curves (AUC).

Results: A total of 16,884 patients (9169 pancreatectomy and 7715 hepatectomy) were included in the derivation models. A total of 665 patients (383 pancreatectomy and 282 hepatectomy) were included in the validation models. Specialty-specific readmission models outperformed general models. AUC characteristics of the derived pancreatectomy and hepatectomy SRRA (pancreatectomy AUC=0.66, hepatectomy AUC=0.74), modified Readmission After Pancreatectomy (AUC=0.76), and modified Readmission Risk Score for hepatectomy (AUC=0.78) outperformed general models for readmission risk: LOS/2 + ASA integer-based score (pancreatectomy AUC=0.58, hepatectomy AUC=0.66), LACE Index (pancreatectomy AUC=0.54, hepatectomy AUC=0.62), Unplanned Readmission Nomogram (pancreatectomy AUC=0.52, hepatectomy AUC=0.55), and institutional ARIA (pancreatectomy AUC=0.46, hepatectomy AUC=0.58).

Conclusion: HPB readmission risk models using 30-day subspecialty-specific data outperform general readmission risk tools. Hospitals and practices aiming to decrease readmissions in HPB surgery patient populations should use specialty-specific readmission reduction strategies.
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http://dx.doi.org/10.1007/s11605-021-05023-zDOI Listing
May 2021

Prediction of Prolonged Intensive Care Unit Length of Stay Following Cardiac Surgery.

Semin Thorac Cardiovasc Surg 2021 Mar 6. Epub 2021 Mar 6.

Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Intensive care unit (ICU) costs comprise a significant proportion of the total inpatient charges for cardiac surgery. No reliable method for predicting intensive care unit length of stay following cardiac surgery exists, making appropriate staffing and resource allocation challenging. We sought to develop a predictive model to anticipate prolonged ICU length of stay (LOS). All patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery with a Society of Thoracic Surgeons (STS) predicted risk score were evaluated from an institutional STS database. Models were developed using 2014-2017 data; validation used 2018-2019 data. Prolonged ICU LOS was defined as requiring ICU care for at least three days postoperatively. Predictive models were created using lasso regression and relative utility compared. A total of 3283 patients were included with 1669 (50.8%) undergoing isolated CABG. Overall, 32% of patients had prolonged ICU LOS. Patients with comorbid conditions including severe COPD (53% vs 29%, P < 0.001), recent pneumonia (46% vs 31%, P < 0.001), dialysis-dependent renal failure (57% vs 31%, P < 0.001) or reoperative status (41% vs 31%, P < 0.001) were more likely to experience prolonged ICU stays. A prediction model utilizing preoperative and intraoperative variables correctly predicted prolonged ICU stay 76% of the time. A preoperative variable-only model exhibited 74% prediction accuracy. Excellent prediction of prolonged ICU stay can be achieved using STS data. Moreover, there is limited loss of predictive ability when restricting models to preoperative variables. This novel model can be applied to aid patient counseling, resource allocation, and staff utilization.
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http://dx.doi.org/10.1053/j.semtcvs.2021.02.021DOI Listing
March 2021

Characterization and comparison of innate and adaptive immune responses at vaccine sites in melanoma vaccine clinical trials.

Cancer Immunol Immunother 2021 Jan 16. Epub 2021 Jan 16.

Department of Surgery, University of Virginia, P.O. Box 801329, Charlottesville, VA, 22908, USA.

The strength and durability of systemic anti-tumor immune responses induced by cancer vaccines depends on adjuvants to support an immunogenic vaccine site microenvironment (VSME). Adjuvants include water-in-oil emulsions with incomplete Freund's adjuvant (IFA) and combinations of toll-like receptor (TLR) agonists, including a preparation containing TLR4 and TLR9 agonists with QS-21 (AS15). IFA-containing vaccines can promote immune cell accumulation at the VSME, whereas effects of AS15 are largely unexplored. Therefore, we assessed innate and adaptive immune cell accumulation and gene expression at the VSME after vaccination with AS15 and compared to effects with IFA. We hypothesized that AS15 would promote less accumulation of innate and adaptive immune cells at the VSME than IFA vaccines. In two clinical trials, patients with resected high-risk melanoma received either a multipeptide vaccine with IFA or a recombinant MAGE-A3 protein vaccine with AS15. Vaccine site biopsies were obtained after one or multiple vaccines. T cells accumulated early after vaccines with AS15, but this was not durable or of the same magnitude as vaccination in IFA. Vaccines with AS15 increased durable expression of DC- and T cell-related genes, as well as PD-L1 and IDO1, suggesting complex activation and regulation of innate and adaptive immune function with AS15. These changes were generally greater with vaccines containing IFA, but IFA induced reduction in myeloid suppressor cells markers. Evidence of tertiary lymphoid structure (TLS) formation was observed with both adjuvants. Our findings highlight adjuvant-dependent changes in immune features at the VSME that may impact systemic immune responses.
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http://dx.doi.org/10.1007/s00262-020-02844-wDOI Listing
January 2021

IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice.

Front Immunol 2020 16;11:1516. Epub 2020 Jul 16.

Bloodworks Northwest Research Institute, Seattle, WA, United States.

It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system.
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http://dx.doi.org/10.3389/fimmu.2020.01516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378678PMC
April 2021

MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma.

J Immunother Cancer 2020 05;8(1)

Department of Surgery/Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Background: Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides.

Methods: Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3) was determined by Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA-IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund's adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay.

Results: pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3 controlled outgrowth of a tumor xenograft. The pIRS2 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3-4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS2 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3 peptide in 2/12 patients (17%, 90% CI 3% to 44%).

Conclusion: This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3 and pIRS2, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses.

Trial Registration Number: NCT01846143.
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http://dx.doi.org/10.1136/jitc-2019-000262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228659PMC
May 2020

The impact of cirrhosis and MELD score on postoperative morbidity and mortality among patients selected for liver resection.

Am J Surg 2020 09 20;220(3):682-686. Epub 2020 Jan 20.

Surgical Outcomes Research Center, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.

Background: Independent associations between chronic liver disease, MELD, and postoperative outcomes among patients selected for liver resection have not been completely established. We hypothesized independent associations between MELD, cirrhosis, and postoperative mortality.

Methods: Patient-level data from the targeted hepatectomy module and ACS NSQIP PUF during 2014-2015 were merged. Multivariable regression models with interaction effect between MELD and liver texture (normal, congested/fatty, cirrhotic) tested the independent effects of covariates on mortality and morbidity.

Results: 3,530 patients were included, of whom 668 patients (19%) had cirrhosis. ACS NSQIP defined mortality (3.9%vs1.1%) and morbidity (23.5%vs15.8%) were higher in patients with cirrhosis (both p < 0.001). In multivariable models, cirrhosis (OR = 2.24; 95%CI:1.16-4.34, p = 0.016) and MELD (OR = 1.10; 95%CI:1.03-1.18, p = 0.007) were independently associated with mortality. MELD (OR = 1.04; 95%CI:1.002-1.08, p = 0.038) was associated with postoperative morbidity.

Conclusions: Higher MELD and presence of cirrhosis have an independent negative effect on mortality after liver resection. MELD could be used to estimate postoperative risk in patients with and without cirrhosis.
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http://dx.doi.org/10.1016/j.amjsurg.2020.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369232PMC
September 2020

A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund's adjuvant in melanoma patients.

J Immunother Cancer 2019 06 27;7(1):163. Epub 2019 Jun 27.

Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Pinn Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.

Background: Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8 T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses.

Patients And Methods: Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).

Results: Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.

Conclusions: LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.

Trial Registration: The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.
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http://dx.doi.org/10.1186/s40425-019-0625-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598303PMC
June 2019

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

J Neurol Neurosurg Psychiatry 2019 11 7;90(11):1251-1256. Epub 2019 Jun 7.

Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA.

Objective: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD.

Methods: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models.

Results: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (β=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (β=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (β=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (β=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (β=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (β=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (β=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls.

Conclusion: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.
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http://dx.doi.org/10.1136/jnnp-2019-320450DOI Listing
November 2019

Nonadherence to Biologic Therapies in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2018 08;24(9):2053-2061

Division of Gastroenterology & Hepatology, University of Virginia School of Medicine, Charlottesville, VA.

Background: Nonadherence to medications is common with patients with inflammatory bowel disease (IBD). The aim of this study was to assess adherence to biologic medications prescribed for IBD and to identify risk factors for biologic nonadherence.

Methods: This was a single center retrospective cohort study investigating IBD patient adherence to biologic therapies over a 2-year period from September 2014 to September 2016. Specialty pharmacy and infusion center records were obtained and a modified medication possession ratio was calculated. Patient characteristics associated with nonadherence in a univariate model were placed into a multivariate logistic regression to assess independent predictors of nonadherence.

Results: Three hundred sixty-five patients met inclusion criteria; 63 patients were on vedolizumab. Three hundred and one patients (82%) had Crohn's disease. The pooled 24-month adherence rate was 66%; adherence to individual biologic therapy included vedolizumab 83%, infliximab 70%, adalimumab 57%, and certolizumab pegol 50%. Facility-administered biologics were independently associated with higher adherence than self-administered biologics (OR 2.39, 95% CI 1.50 - 3.80). Additional risk factors for nonadherence included younger age (OR 1.22, 95% CI 1.01-1.47) and noncommercial insurance (OR 1.78, 95% CI 1.01 - 3.13).

Conclusions: This is the first study to assess adherence to vedolizumab in IBD patients, which was higher than 3 other commonly prescribed biologic medications. Self-administered injections were strongly associated with biologic nonadherence. Younger age and noncommercial insurance also were associated with biologic nonadherence. Modality of administration should be taken into account when selecting a biologic agent for treatment of IBD.
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http://dx.doi.org/10.1093/ibd/izy102DOI Listing
August 2018

Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease.

Neurology 2018 05 4;90(18):e1618-e1626. Epub 2018 Apr 4.

From the Departments of Neurology (M.J.B., S.A.S.) and Public Health Sciences (M.E.S.), University of Virginia; and Department of Radiology and Medical Imaging (J.C.B., T.J.D.), Division of Neuroradiology, University of Virginia Health System, Charlottesville.

Objective: Determining baseline predictors of future psychosis in Parkinson disease (PD) may identify those at risk for more rapidly progressive disease, i.e., a more malignant PD subtype.

Methods: This cohort study evaluated 423 patients with newly diagnosed PD collected as part of the Parkinson's Progression Markers Initiative. Psychotic symptoms were assessed with the Movement Disorders Society-Unified Parkinson Disease Rating Scale item 1.2, which assesses hallucinations and psychosis over the past week. At baseline, participants completed the Scales for Outcomes in Parkinson's Disease-Autonomic, the REM Sleep Behavior Disorder (RBD) Screening Questionnaire, and the Epworth Sleepiness Scale. Cholinergic nucleus 4 (Ch4) density was calculated for 228 participants with PD and 101 healthy controls.

Results: Multivariate logistic regression adjusted for age and sex found that greater autonomic symptoms ( = 0.002), RBD ( = 0.021), and excessive daytime sleepiness (EDS) ( = 0.003) at baseline were associated with increased risk of reporting psychotic symptoms on ≥2 occasions. Having 2 or 3 of these baseline symptoms was associated with lower Ch4 density ( = 0.007). In a logistic regression model adjusted for age and sex, higher Ch4 gray matter density was associated with lower risk of reporting psychotic symptoms on ≥2 occasions (odds ratio 0.96 [for an increase in density of 1 unit], = 0.03).

Conclusions: This study confirms that RBD, EDS, and greater autonomic symptom burden are associated with greater risk of future psychotic symptoms in PD. Reduced Ch4 density at baseline is associated with future psychotic symptoms and a greater burden of RBD, EDS, and autonomic symptoms.
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http://dx.doi.org/10.1212/WNL.0000000000005421DOI Listing
May 2018

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer.

J Immunother Cancer 2017 11 21;5(1):92. Epub 2017 Nov 21.

University of Virginia, Charlottesville, VA, 22908, USA.

Background: Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial.

Methods: A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, -A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8 T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays.

Results: Twelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8 T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series.

Conclusions: Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination.

Trial Registration: ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://clinicaltrials.gov/show/NCT01532960.
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http://dx.doi.org/10.1186/s40425-017-0295-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697108PMC
November 2017

Characteristics, correlates, and assessment of psychosis in Parkinson disease without dementia.

Parkinsonism Relat Disord 2017 Oct 15;43:56-60. Epub 2017 Jul 15.

Department of Neurology, University of Virginia, Charlottesville, VA, USA. Electronic address:

Introduction: Considering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia.

Methods: 101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied.

Results: Of the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis.

Conclusion: This study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.
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http://dx.doi.org/10.1016/j.parkreldis.2017.07.011DOI Listing
October 2017

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome.

Oncoimmunology 2016;5(11):e1235107. Epub 2016 Sep 20.

Department of Surgery, University of Virginia School of Medicine , Charlottesville, VA, USA.

Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8, CD45, CD4, CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.
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http://dx.doi.org/10.1080/2162402X.2016.1235107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139635PMC
September 2016

More than Just the Number of Brain Metastases: Evaluating the Impact of Brain Metastasis Location and Relative Volume on Overall Survival After Stereotactic Radiosurgery.

World Neurosurg 2017 Mar 2;99:111-117. Epub 2016 Dec 2.

Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia, USA; Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA.

Objective: Most evidence describing outcomes of patients with brain metastases is based on number of brain metastases, rather than location or volume. We evaluated the impact of tumor location and relative volume on overall survival (OS) among a large cohort of patients treated with stereotactic radiosurgery.

Methods: Clinical, radiographic, and dosimetric data were collected on patients treated with first (if multiple) stereotactic radiosurgery for brain metastases. Multivariate analyses were performed to investigate the impact of brain metastasis relative location and volume on OS after stereotactic radiosurgery.

Results: Analysis included 300 patients with 817 tumors (116 patients with single brain metastasis). The most common tumor locations were supratentorial (75% of tumors), cerebellar (19%), and brainstem (5%). Median tumor volume was 0.4 mL (range, 0.003-65.0 mL). Tumor-specific factors associated with inferior OS included brainstem location versus both supratentorial and cerebellum locations for particular assumed values of cube root tumor volume (P < 0.001 for each) and increasing total supratentorial tumor volume (P = 0.004). Patients with supratentorial tumors and cerebellar tumors demonstrated similar OS, and cube root total tumor volume within the cerebellum and brainstem did not predict for OS.

Conclusions: The presence of brainstem metastases and cumulative supratentorial tumor volume are adverse features that result in inferior survival. These results can be used to inform patient prognosis and future clinical trial design.
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http://dx.doi.org/10.1016/j.wneu.2016.11.119DOI Listing
March 2017

Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases.

Cancer Immunol Immunother 2016 10 13;65(10):1201-12. Epub 2016 Aug 13.

Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.

Introduction: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases.

Patients And Methods: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression.

Results And Conclusions: Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.
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http://dx.doi.org/10.1007/s00262-016-1880-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037037PMC
October 2016

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

Cancer Immunol Immunother 2016 10 13;65(10):1189-99. Epub 2016 Aug 13.

Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.

Introduction: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.

Patients And Methods: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression.

Results: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures.

Conclusion: The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.
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http://dx.doi.org/10.1007/s00262-016-1881-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037033PMC
October 2016

Orbital Metastases from Breast Cancer: Retrospective Analysis at an Academic Cancer Center.

Breast J 2016 Jul 3;22(4):447-50. Epub 2016 May 3.

Department of Hematology-Oncology, University of Virginia, Charlottesville, Virginia.

Orbital metastases from breast cancer (BC) are rare, but often debilitating. BC accounts for nearly half of metastases to the orbit. Orbital metastases may be discovered years after the initial diagnosis of BC, and are rare at initial presentation. A search of the institutional data base at an academic cancer center identified BC patients who developed or presented with orbital metastases from 2000 to 2013. Baseline characteristics, treatment modalities, survival and treatment responses were collected from the electronic medical record. There were 20 patients identified with orbital metastases (0.7% of all BC cases). The median age at diagnosis of BC was 49 years; 80% had estrogen positive disease. The interval between the initial diagnosis of BC and the presentation of orbital metastases was 8.5 years (0-19 years). Orbital disease was the initial presentation of BC in two cases. Three patients developed bilateral orbital metastases and seven had accompanying brain metastases. The most common presentation was decreased vision (55%), followed by diplopia (25%). The median survival after orbital metastases was 24 months. Thirteen patients (65%) received local radiation therapy. Of those radiated, 90% reported improvement of orbital symptoms. Other treatments included intraocular bevacizumab, surgery, and systemic therapy. Orbital metastases tend to occur in estrogen receptor positive disease and are often found years after BC onset. Orbital metastases may be associated with the development of brain metastases. Radiotherapy is the preferred local therapy and had high symptom control in this cohort. Oncologists should be aware of the signs of orbital metastases and the treatment options.
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http://dx.doi.org/10.1111/tbj.12604DOI Listing
July 2016

Prognostic value of albumin in patients with head and neck cancer.

Laryngoscope 2016 07 10;126(7):1567-71. Epub 2016 Feb 10.

Department of Otolaryngology-Head and Neck Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A.

Objectives/hypothesis: Albumin is an indicator of nutritional status and has been investigated as a predictor of cancer survival and perioperative outcomes. This study investigated the prognostic value of preoperative serum albumin in surgical patients with head and neck cancer (HNC).

Study Design: Retrospective cohort study.

Methods: A chart review was performed of patients who underwent HNC resection over a 6-year period at a single institution. Statistical analyses including Cox proportional hazards models, Pearson's correlation, and logistic regression were used to identify relationships between preoperative serum albumin and postoperative outcomes. Albumin was analyzed as a continuous variable.

Results: A total of 604 patients were studied representing all cancer types. There was no association between albumin and pneumonia, flap complications, or length of stay. Albumin was found to have statistically significant inverse associations with overall survival (OS) (hazard ratio [HR] = 0.685, P < .001) and postoperative wound infection (HR = 0.455, P = .001). In multivariate analysis of OS, albumin did not achieve significance as an independent predictor (HR = 0.78, P = .064), whereas hemoglobin, age, and cancer stage remained significant. In a subgroup of 280 patients with upper aerodigestive squamous cell carcinoma (SCCA), albumin maintained significance in multivariate analysis of OS (HR = 0.74, P = .046). When controlling for preoperative radiotherapy, salvage surgery, and cancer stage in multivariate analysis, albumin was a significant predictor of wound infection (OR = 0.55, P = .018).

Conclusions: In patients with HNC, lower preoperative serum albumin is associated with an increased rate of wound infection and poorer OS. The effect on OS is most pronounced in patients with upper aerodigestive SCCA.

Level Of Evidence: 2b Laryngoscope, 126:1567-1571, 2016.
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http://dx.doi.org/10.1002/lary.25877DOI Listing
July 2016

A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites.

Cancer Immunol Immunother 2016 Jan 18;65(1):25-36. Epub 2015 Nov 18.

Division of Hematology-Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.

Introduction: Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m. but not i.d. or s.c. This study tests hypotheses that the i.d./s.c. route is safe and will increase CD4(+) and CD8(+) T cell responses to MAGE-A3.

Patients And Methods: Twenty-five patients with resected stage IIB-IV MAGE-A3(+) melanoma were randomized to immunization with recMAGE-A3 combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) either i.m. (group A, n = 13) or i.d./s.c. (group B, n = 12). Adverse events were recorded. Ab responses to MAGE-A3 were measured by ELISA. T cell responses to overlapping MAGE-A3 peptides were assessed in PBMC and a sentinel immunized node (SIN) after 1 in vitro stimulation with recMAGE-A3, by IFN-γ ELISPOT assay and by flow cytometry for multifunctional (TNF-α/IFN-γ) responses.

Results: Both routes of immunization were well tolerated without treatment-related grade 3 adverse events. All patients had durable Ab responses. For all 25 patients, the T cell response rate by ELISPOT assay was 30 % in SIN (7/23) but only 4 % (1/25) in PBMC. By flow cytometry, multifunctional CD8(+) T cell responses were identified in one patient in each group; multifunctional CD4(+) T cell response rates for groups A and B, respectively, were 31 and 64 % in SIN and 31 and 50 % in PBMC.

Conclusion: The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4(+) T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration.
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http://dx.doi.org/10.1007/s00262-015-1770-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010424PMC
January 2016

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials' experience.

Cancer Immunol Immunother 2015 Dec 21;64(12):1531-9. Epub 2015 Sep 21.

Department of Surgery, University of Virginia, PO Box 800709, Charlottesville, VA, 22908, USA.

Background: The impacts of patient age and gender on immune response (IR) and clinical outcome after cancer vaccines are not known. We hypothesized younger and female patients would have higher IR rates and better survival.

Methods: Patients with resected stage IIB-IV melanoma in three clinical trials (Mel43, Mel44, Mel48) were vaccinated with 12 melanoma-associated peptides restricted by class I MHC. The cumulative incidence rate of CD8(+) T cell responses (direct interferon-gamma ELIspot assay) by week 7 was compared by age and gender. Overall survival (OS) and disease-free survival (DFS) landmark analyses were compared by Kaplan-Meier estimates and in multivariate analyses.

Results: T cell responses were evaluated in 327 patients and detected in 50 % of males and 48 % of females, with no difference in IR by gender or menopausal status. Males had trends toward longer DFS (p = 0.12) and OS (p = 0.09). Cumulative incidence of IR was higher in patients <64 years of age versus older patients (p = 0.03). OS and DFS were similar by age group (p > 0.50). In multivariate modeling, younger age was associated with better IR (OR 0.40, p value 0.003), without an impact of age or gender on clinical outcomes.

Conclusion: These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age 64 years.
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http://dx.doi.org/10.1007/s00262-015-1758-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644444PMC
December 2015

The Risk Factors of Readmission in Postoperative Gynecologic Oncology Patients at a Single Institution.

Int J Gynecol Cancer 2015 Nov;25(9):1697-703

*Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Medical Center; †University of Virginia Medical School; and ‡Translational Research and Applied Statistics, University of Virginia, Charlottesville, VA.

Introduction: Hospital readmission rates are an important measure of quality care and have recently been tied to reimbursement. This study seeks to identify the risk factors for postoperative readmission in patients treated by a gynecologic oncology service.

Methods: A 7-year retrospective review (2007-2013) of all patients operated on by the University of Virginia gynecologic oncology service who were readmitted within 30 days of discharge was performed. Abstracted data included demographics, dates of surgery, operative details, cancer history, and relevant medical history. The readmitted patients (n = 166) were compared with randomly selected controls (n = 168) from the same service in a matching time frame and analyzed using univariate and multivariate models.

Results: In the study period, 2993 operations were performed. One hundred sixty-six unique patients (5.5%) were readmitted within 30 days of discharge from their operative procedure. On multivariate analysis, the factors that were associated with a higher risk of readmission were a history of psychiatric disease, postoperative complication, type of insurance, surgical modality, and lysis of adhesions at the time of surgery. The most common readmission diagnoses were infection (44%), nausea/vomiting (28%), thrombosis (6%), bowel leak (4%), and bleeding (4%).

Conclusions: Postoperative readmissions are a common problem and are increasingly important as a measure of quality. Although patients were generally admitted for infections or gastrointestinal complaints, we also found that individual factors such as mental health and socioeconomic status also contributed. Our data suggest that we can preoperatively identify high-risk individuals for whom extra resources can be directed postoperatively to avoid unnecessary readmissions.
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http://dx.doi.org/10.1097/IGC.0000000000000535DOI Listing
November 2015

Impact of blood transfusions on patients with head and neck cancer undergoing free tissue transfer.

Laryngoscope 2015 Jan 14;125(1):86-91. Epub 2014 Aug 14.

Department of Otolaryngology-Head and Neck Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A.

Objectives/hypothesis: To determine whether blood transfusions are associated with adverse outcomes in patients with head and neck cancer (HNC) undergoing microvascular free tissue transfer.

Study Design: Retrospective cohort study.

Methods: The records of all patients who underwent free flaps for reconstruction after HNC resection from July 2007 through February 2013 at a single institution were reviewed. Rates of overall survival (OS), recurrence free survival (RFS), and postoperative wound infection were determined. Statistical analyses included Cox proportional hazards models and chi-square tests.

Results: Of 167 patients, 90 received 0 to 2 units of blood and 77 received ≥ 3. After controlling for age, preoperative hemoglobin, preoperative albumin, cancer stage, and adverse pathologic features, transfusion of ≥ 3 (versus 0 to 2) units was associated with poorer OS (P = 0.0006; hazard ratio [HR] = 2.96) and RFS (P = 0.003; HR = 2.35). The rates of wound infection in patients who received 0, 1, 2, or ≥ 3 units were 13.3%, 21.2%, 33.3%, and 31.2%, respectively. There was a statistically significant difference in wound infection rates between those patients receiving 0 to 1 versus ≥ 2 units (P = 0.04).

Conclusions: Patients who receive ≥ 3 units of blood after free tissue transfer for HNC had a significantly increased risk of death after controlling for age, preoperative hemoglobin and albumin, cancer stage, and adverse pathologic features. Increased transfusions are also associated with higher wound infection rates. The increased tendency to transfuse free flap patients in order to maintain a threshold hematocrit may have a detrimental impact on survival and wound infections and should be revisited.
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http://dx.doi.org/10.1002/lary.24847DOI Listing
January 2015

Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.

Ann Surg Oncol 2014 Nov 20;21(12):3978-84. Epub 2014 May 20.

Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, Charlottesville, VA, USA,

Background: Multipeptide vaccines for melanoma may cause inflammatory adverse events (IAE). We hypothesize that IAE are associated with a higher rate of immune response (IR) to vaccination and improved clinical outcomes.

Methods: Adult patients with resected, high-risk (stage IIB to IV) melanoma were vaccinated with a combination of 12 class I major histocompatibility complex (MHC)-restricted melanoma epitopes, and IAE were recorded. A separate category for hypopigmentation (vitiligo) was also assessed. CD8(+) T cell IR was assessed by direct interferon gamma ELISpot analysis. Overall survival and disease-free survival were analyzed by Cox proportional hazard modeling.

Results: Out of 332 patients, 57 developed IAE, the majority of which were dermatologic (minimum Common Terminology Criteria for Adverse Events [CTCAE] grade 3). Most nondermatologic IAE were CTCAE grade 1 and 2. Vitiligo developed in 23 patients (7 %). A total of 174 patients (53 %) developed a CD8(+) response. Presence of IAE was significantly associated with development of IR (70 vs. 49 %, p = 0.005) and with disease-free survival (hazard ratio 0.54, p = 0.043). There were no significant associations relating vitiligo or IR alone with clinical outcomes.

Conclusions: IAE are associated with a higher rate of CD8(+) T cell response after vaccination therapy for high-risk melanoma. Our findings suggest either that antitumor activity induced by class I MHC-restricted peptide vaccines may depend on immunologic effects beyond simple expansion of CD8(+) T cells or that the intrinsic inflammatory response of patients contributes to clinical outcome in melanoma.
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http://dx.doi.org/10.1245/s10434-014-3794-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192070PMC
November 2014

Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine.

Cancer Immunol Immunother 2014 Aug 23;63(8):779-86. Epub 2014 Apr 23.

Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, PO Box 800679, Charlottesville, VA, 22908-0679, USA,

Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4(+) and CD8(+) T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-γ ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4(+) T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE-A3281-295 (49 %) and tyrosinase386-406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8(+) T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4(+) and CD8(+) T cell responses against melanoma antigens. CD4(+) T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8(+) T cell responses suggests epitope spreading and systemic activity mediated at the tumor site.
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http://dx.doi.org/10.1007/s00262-014-1551-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174310PMC
August 2014

Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide.

Cancer Immunol Immunother 2013 Jul 9;62(7):1149-59. Epub 2013 May 9.

Division of Surgical Oncology, Department of Surgery, University of Virginia, Charlottesville, VA, USA.

We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund's adjuvant (IFA) alone, or a melanoma vaccine in IFA. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA. Lymphocytes isolated from replicate vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naïve and greater proportions of effector memory CD8(+) T cells (TCD8). The vast majority of TCD8 within the VSME were activated (CD69(+)), with a concentration of antigen-specific (tetramer(pos)) cells in the VSME, particularly in vaccine sites with peptide (group 2). CXCR3(+) lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. TCD8 expression of retention integrins αEβ7 and α1β1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). TCD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-γ production in response to peptide stimulation and few tetramer(pos) cells producing IFN-γ. These data suggest that vaccine-induced selective retention and dysfunction of antigen-specific TCD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide vaccines administered in IFA.
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http://dx.doi.org/10.1007/s00262-013-1435-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813823PMC
July 2013

Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47).

Clin Cancer Res 2013 Jul 25;19(13):3611-20. Epub 2013 Apr 25.

University of Virginia, Charlottesville, VA 22908, USA.

Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma.

Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood.

Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAF(WT) tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67(+)) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4(+)FoxP3(+) cells.

Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAF(wt) melanoma. Mixed effects on immunologic function also support combination with immune therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700572PMC
July 2013

A substance use decision aid for medically at-risk adolescents: results of a randomized controlled trial for cancer-surviving adolescents.

Cancer Nurs 2013 Sep-Oct;36(5):355-67

School of Nursing, University of Virginia, Charlottesville, VA 22908, USA.

Background: Adolescent survivors of childhood cancer engage in risky behaviors.

Objective: This study tested a decision aid for cancer-surviving adolescents aimed at difficult decisions related to engaging in substance use behaviors.

Methods: This randomized controlled trial recruited 243 teen survivors at 3 cancer centers. The cognitive-behavioral skills program focused on decision making and substance use within the context of past treatment. Effects at 6 and 12 months were examined for decision making, risk motivation, and substance use behaviors using linear regression models.

Results: The majority of the teen cancer survivors (90%) rated the program as positive. There was an intermediate effect at 6 months for change in risk motivation for low riskers, but this effect was not sustained at 12 months. For quality decision making, there was no significant effect between treatment groups for either time point.

Conclusions: The overall program effects were modest. Once teen survivors are in the program and learn what quality decision making is, their written reports indicated adjustment in their perception of their decision-making ability; thus, a more diagnostic baseline decision-making measure and a more intensive intervention are needed in the last 6 months. With 2 of 3 teen participants dealing with cognitive difficulties, the data suggest that this type of intervention will continue to be challenging, especially when 90% of their household members and 56% of their close friends model substance use.

Implications For Practice: This effectiveness trial using late-effects clinics provides recommendations for further program development for medically at-risk adolescents, particularly ones with cognitive difficulties.
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http://dx.doi.org/10.1097/NCC.0b013e31827910baDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758306PMC
August 2014

Predictors of Retention and BMI Loss or Stabilization in Obese Youth Enrolled in a Weight Loss Intervention.

Obes Res Clin Pract 2012 28;6(4):e330-e339. Epub 2011 Sep 28.

Division of Cardiology, University of Virginia School of Medicine, Charlottesville, VA, USA ; Department of Pediatrics, University of Virginia School of Medicine, PO Box 800386, Charlottesville, VA, 22908, USA.

OBJECTIVE: To evaluate predictors for intervention dropout and successful reduction of metabolic syndrome risk factors among obese children enrolled in a short-term, clinic-based weight-loss intervention. DESIGN, SETTING, SUBJECTS: Retrospective database review of 1080 children 8 months-17 y.o. seen a a pediatric obesity clinic. INTERVENTIONS: Behavior modification counseling to induce change in dietary and exercise choices. MAIN OUTCOME MEASURES: 1). Pre-/post-intervention change in body mass index (BMI), waist circumference, blood pressure, glucose, insulin, and cholesterol (LDL, HDL, & total). 2) Predictors of successful decrease in BMI and clinic drop-out. ANALYSIS: Paired t-tests for pre-/post-intervention comparisons. Linear regression to assess predictors of success and predictors of drop-out, with adjustment for age, gender, race, insurance status, and service area. RESULTS: Among children evaluated, adolescent females were most likely to achieve successful decrease in BMI, insulin level, and LDL cholesterol post-intervention. Nearly 40% of children dropped out early in the intervention. Predictors of drop out included age <6y, public insurance status, follow-up scheduled during summer months, and residence in a tertiary service area. CONCLUSIONS: Clinic-based weight loss interventions can lead to successful improvements in BMI and other metabolic parameters in pediatric populations and may be more likely among adolescent females than in younger children or males. Drop-out is common, particularly among younger children, children with public insurance and children scheduled for follow-up in the summer. Identification of these drop-out predictors in individual patients may help in targeting children likely to succeed in short-term, clinic-based, weight-loss interventions.
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http://dx.doi.org/10.1016/j.orcp.2011.08.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501750PMC
September 2011

Infrared thermography of cutaneous melanoma metastases.

J Surg Res 2013 Jun 27;182(1):e9-e14. Epub 2012 Sep 27.

Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908-0709, USA.

Background: Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions.

Materials And Methods: Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0-5, >5-15, >15-30, and >30 mm. Images were scored on a scale from -1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored.

Results: IR imaging was able to determine the malignancy of small (0-5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions >5-15 mm, sensitivity was 58% and specificity 98%. For lesions >15-30 mm, sensitivity was 95% and specificity 100%, and for lesions >30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%-100% across all strata, and the negative predictive value was 95% for >15-30 mm lesions and 80% for >30 mm lesions.

Conclusions: Malignant lesions >15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies.
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http://dx.doi.org/10.1016/j.jss.2012.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426199PMC
June 2013