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Luis Sanchez-Perez,
Bryan D Choi,
Elizabeth A Reap,
Elias J Sayour,
Pamela Norberg,
Robert J Schmittling,
Gerald E Archer, James E Herndon,
Duane A Mitchell,
Amy B Heimberger,
Darell D Bigner,
John H Sampson
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ABSTRACT: B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy.
Cancer Immunology and Immunotherapy 04/2013; · 3.70 Impact Factor
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Emil Lou,
Katherine B Peters,
Ashley L Sumrall,
Annick Desjardins,
David A Reardon,
Eric S Lipp, James E Herndon,
April Coan,
Leighann Bailey,
Scott Turner,
Henry S Friedman,
James J Vredenburgh
[show abstract]
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ABSTRACT: Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.
Cancer medicine. 04/2013; 2(2):185-95.
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Susan G Lakoski,
Carolyn E Barlow,
Graeme J Koelwyn,
Whitney E Hornsby,
Jesse Hernandez,
Laura F Defina,
Nina B Radford,
Samantha M Thomas, James E Herndon,
Jeffrey Peppercorn,
Pamela S Douglas,
Lee W Jones
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ABSTRACT: We examined cardiorespiratory fitness (CRF) levels in early stage breast cancer patients and determined whether CRF differs as a function of adjuvant therapy regimen. A total of 180 early breast cancer patients representing three treatment groups (surgery only, single-, and multi-modality adjuvant therapy) in the Cooper Center Longitudinal Study (CCLS) were studied. A non-cancer control group (n = 180) matched by sex, age, and date of the CCLS visit was included. All subjects underwent an incremental exercise tolerance test to symptom limitation to assess CRF (i.e., peak metabolic equivalents [METs] and time to exhaustion). The mean time from breast cancer diagnosis to exercise tolerance testing was 7.4 ± 6.2 years. In adjusted analyses, time to exhaustion and peak METs were incrementally impaired with the addition of surgery, single-, and multi-modality adjuvant therapy compared to those of matched controls (p = 0.006 and 0.028, respectively). CRF was lowest in the multi-modality group compared to all other groups (all p's < 0.05). Despite being 7 years post-diagnosis, asymptomatic early breast cancer survivors have marked reductions in CRF. Patients treated with multi-modal adjuvant therapy have the greatest impairment in CRF.
Breast Cancer Research and Treatment 03/2013; · 4.43 Impact Factor
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ABSTRACT: RATIONALE: Indeterminate pulmonary nodules are a common radiographic finding and require further evaluation because of the concern for lung cancer. OBJECTIVE: We developed an algorithm to assign patients to a low or high-risk category for lung cancer, based on a combination of serum biomarker levels and nodule size. METHODS: For the serum biomarker assay, we determined levels of carcinoembryonic antigen, alpha-1-antitrypsin and squamous cell carcinoma antigen. Serum data and nodule size from a training set of 509 patients with (n=298) and without (n=211) lung cancer were subjected to classification and regression tree and logistic regression analyses. Multiple models were developed and tested in an independent, blinded validation set for their ability to categorize patients with (n=203) or without (n=196) lung cancer as being low or high-risk for lung cancer. MEASUREMENTS AND MAIN RESULTS: In all models, a large percentage of individuals in the validation study with small nodules (< 1 cm) were assigned to the low-risk group, and a large percentage of individuals with large nodules (≥ 3 cm) were assigned to the high-risk group. In the validation study, the classification and regression tree algorithm had overall sensitivity, specificity, and positive and negative predictive values for determining lung cancer of 88%, 82%, 84%, 87%, respectively. The logistic regression model had overall sensitivity, specificity, and positive and negative predictive values of 80%, 89%, 89%, and 81%, respectively. CONCLUSION: Integration of biomarkers with lung nodule size has the potential to help guide the management of patients with indeterminate pulmonary nodules.
American Journal of Respiratory and Critical Care Medicine 01/2013; · 11.08 Impact Factor
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ABSTRACT: While curable at early stages, few treatment options exist for advanced melanoma. Currently, no consensus exists regarding the optimal surveillance strategy for patients after resection. The objectives of this study were to identify patterns of metastatic recurrence, to determine the influence of metastatic site on survival, and to identify high-risk periods for recurrence.
A retrospective review of the Duke Melanoma Database from 1970 to 2004 was conducted that focused on patients who were initially diagnosed without metastatic disease. The time to first recurrence was computed from the date of diagnosis, and the associated hazard function was examined to determine the peak risk period of recurrence. Metastatic sites were coded by the American Joint Committee on Cancer (AJCC) system including local skin, distant skin and nodes (M1a), lung (M1b), and other distant (M1c).
Of 11,615 patients initially diagnosed without metastatic disease, 4616 (40%) had at least one recurrence. Overall the risk of initial recurrence peaked at 12 months. The risk of initial recurrence at the local skin, distant skin, and nodes peaked at 8 months, and the risk at lung and other distant sites peaked at 24 months. Patients with a cutaneous or nodal recurrence had improved survival compared to other recurrence types.
The risk of developing recurrent melanoma peaked at one year, and the site of first recurrence had a significant impact on survival. Defining the timing and expected patterns of recurrence will be important in creating an optimized surveillance strategy for this patient population.
PLoS ONE 01/2013; 8(3):e57665. · 4.09 Impact Factor
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Luis A Sanchez-Perez,
Bryan D Choi,
Gary E Archer,
Xiuyu Cui,
Catherine Flores,
Laura A Johnson,
Robert J Schmittling,
David Snyder, James E Herndon,
Darell D Bigner,
Duane A Mitchell,
John H Sampson
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ABSTRACT: Temozolomide (TMZ) is an alkylating agent shown to prolong survival in patients with high grade glioma and is routinely used to treat melanoma brain metastases. A prominent side effect of TMZ is induction of profound lymphopenia, which some suggest may be incompatible with immunotherapy. Conversely, it has been proposed that recovery from chemotherapy-induced lymphopenia may actually be exploited to potentiate T-cell responses. Here, we report the first demonstration of TMZ as an immune host-conditioning regimen in an experimental model of brain tumor and examine its impact on antitumor efficacy of a well-characterized peptide vaccine. Our results show that high-dose, myeloablative (MA) TMZ resulted in markedly reduced CD4(+), CD8(+) T-cell and CD4(+)Foxp3(+) TReg counts. Adoptive transfer of naïve CD8(+) T cells and vaccination in this setting led to an approximately 70-fold expansion of antigen-specific CD8(+) T cells over controls. Ex vivo analysis of effector functions revealed significantly enhanced levels of pro-inflammatory cytokine secretion from mice receiving MA TMZ when compared to those treated with a lower lymphodepletive, non-myeloablative (NMA) dose. Importantly, MA TMZ, but not NMA TMZ was uniquely associated with an elevation of endogenous IL-2 serum levels, which we also show was required for optimal T-cell expansion. Accordingly, in a murine model of established intracerebral tumor, vaccination-induced immunity in the setting of MA TMZ-but not lymphodepletive, NMA TMZ-led to significantly prolonged survival. Overall, these results may be used to leverage the side-effects of a clinically-approved chemotherapy and should be considered in future study design of immune-based treatments for brain tumors.
PLoS ONE 01/2013; 8(3):e59082. · 4.09 Impact Factor
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Journal of Neurosurgery 10/2012; · 2.96 Impact Factor
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ABSTRACT: Objectives: Metastatic melanoma (MM) is a leading cause of years of life lost due to malignancy. This study aimed to identify the average years of life lost (AYLL) in MM patients. Methods: MM patients were identified from a prospectively maintained database, and a linear model predicting AYLL was developed. Results: Between 1970 and 1999, 4,774 patients diagnosed with MM died. The AYLL was 23.2 years. AYLL remained stable across three decades. Conclusions: AYLL for MM is greater than 20 years, and has not improved. This burden underscores the need for continued research and access to funding for this disease.
Cancer Investigation 09/2012; 30(9):637-41. · 1.85 Impact Factor
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Lee W Jones,
Kerry S Courneya,
John R Mackey,
Hyman B Muss,
Edith N Pituskin,
Jessica M Scott,
Whitney E Hornsby,
April D Coan, James E Herndon,
Pamela S Douglas,
Mark Haykowsky
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ABSTRACT: To evaluate cardiopulmonary function (as measured by peak oxygen consumption [VO(2peak)]) across the breast cancer continuum and its prognostic significance in women with metastatic disease.
Patients with breast cancer representing four cross-sectional cohorts--that is, (1) before, (2) during, and (3) after adjuvant therapy for nonmetastatic disease, and (4) during therapy in metastatic disease--were studied. A cardiopulmonary exercise test (CPET) with expired gas analysis was used to assess VO(2peak). A Cox proportional hazards model was used to estimate the risk of death according to VO(2peak) category (< 15.4 v ≥ 15.4 mL · kg(-1) · min(-1)) with adjustment for clinical factors.
A total of 248 women (age, 55 ± 8 years) completed a CPET. Mean VO(2peak) was 17.8 ± a standard deviation of 4.3 mL · kg(-1) · min(-1), the equivalent of 27% ± 17% below age-matched healthy sedentary women. For the entire cohort, 32% had a VO(2peak) less than 15.4 mL · kg(-1) · min(-1)--the VO(2peak) required for functional independence. VO(2peak) was significantly different across breast cancer cohorts for relative (mL · kg(-1) · min(-1)) and absolute (L · min(-1)) VO(2peak) (P = .017 and P < .001, respectively); VO(2peak) was lowest in women with metastatic disease. In patients with metastatic disease (n = 52), compared with patients achieving a VO(2peak) ≤ 1.09 L · min(-1), the adjusted hazard ratio for death was 0.32 (95% CI, 0.16 to 0.67, P = .002) for a VO(2peak) more than 1.09 L · min(-1).
Patients with breast cancer have marked impairment in VO(2peak) across the entire survivorship continuum. VO(2peak) may be an independent predictor of survival in metastatic disease.
Journal of Clinical Oncology 05/2012; 30(20):2530-7. · 18.37 Impact Factor
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Emil Lou,
Ashley L Sumrall,
Scott Turner,
Katherine B Peters,
Annick Desjardins,
James J Vredenburgh,
Roger E McLendon, James E Herndon,
Frances McSherry,
Julie Norfleet,
Henry S Friedman,
David A Reardon
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ABSTRACT: Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.
Journal of Neuro-Oncology 04/2012; 109(1):63-70. · 3.21 Impact Factor
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ABSTRACT: This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy
in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum
of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200mg/m2/day on days 1–5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The
primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall
survival (OS), safety, and tumor O6-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response.
Median PFS and median OS were 3.1 and 13.8months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most
of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal
AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure.
Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14
vs. 5months) or OS (21 vs. 15months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination
appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs
further evaluation in subsequent trials.
Journal of Neuro-Oncology 04/2012; 95(3):393-400. · 3.21 Impact Factor
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David A Reardon,
James J Vredenburgh,
Annick Desjardins,
Katherine B Peters,
Sith Sathornsumetee,
Stevie Threatt,
John H Sampson, James E Herndon,
April Coan,
Frances McSherry,
Jeremy N Rich,
Roger E McLendon,
Steven Zhang,
Henry S Friedman
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ABSTRACT: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.
Journal of Neuro-Oncology 03/2012; 108(3):499-506. · 3.21 Impact Factor
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David A Reardon, James E Herndon,
Katherine Peters,
Annick Desjardins,
April Coan,
Emil Lou,
Ashley Sumrall,
Scott Turner,
Sith Sathornsumetee,
Jeremy N Rich,
Susan Boulton,
Eric S Lipp,
Henry S Friedman,
James J Vredenburgh
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ABSTRACT: Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (n = 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3; P = 0.51) and 10.3 months (95% CI: 2.5, 14.4; P = 0.91) for patients who initiated non-bevacizumab containing therapy (n = 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation.
Journal of Neuro-Oncology 03/2012; 107(1):213-21. · 3.21 Impact Factor
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David A Reardon,
Annick Desjardins,
Katherine B Peters,
Sridharan Gururangan,
John H Sampson,
Roger E McLendon, James E Herndon,
Anuradha Bulusu,
Stevie Threatt,
Allan H Friedman,
James J Vredenburgh,
Henry S Friedman
[show abstract]
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ABSTRACT: We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).
Journal of Neuro-Oncology 03/2012; 107(1):155-64. · 3.21 Impact Factor
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David A Reardon,
Annick Desjardins,
James J Vredenburgh, James E Herndon,
April Coan,
Sridharan Gururangan,
Katherine B Peters,
Roger McLendon,
Sith Sathornsumetee,
Jeremy N Rich,
Eric S Lipp,
Dorothea Janney,
Henry S Friedman
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ABSTRACT: We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma.
A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate.
Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%).
Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity. Cancer 2012. © 2012 American Cancer Society.
Cancer 02/2012; 118(19):4759-67. · 4.77 Impact Factor
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ABSTRACT: Melanoma of the female genitalia has poor overall prognosis.
To examine prognostic factors influencing survival, the Duke Melanoma and Tumor Registry Databases were queried for patients who had received their clinical care at Duke University Medical Center, with a diagnosis of melanoma of the female genitalia, including vulva, vagina, and cervix, between 1970 and 2009. From this group, any available histopathologic specimens were procured for further review.
Eighty-five patients were identified. The median follow-up time was 8.8 years with 60% of the patients experiencing melanoma-related mortality at last follow-up. Survival rates at 1, 5, and 10 years were 85%, 51%, and 30%, respectively. The available histopathologic specimens from 36 cases were reviewed by a dermatopathologist (M.A.S.). Fifteen of 36 cases were notable for the presence of atypical melanocytic hyperplasia adjacent to the primary melanoma. Breslow depth, lymph node status, systemic therapy, and surgery were also examined for differences in survival distributions using the log-rank test. In general, survival was inversely correlated with Breslow depth, extent of nodal involvement, and provision of systemic therapy. A higher survival rate was observed among those who received wide local excision. Log-rank test demonstrated that survival between different decades of diagnosis was not significantly different.
Because of its small sample size, this study may be underpowered.
Despite new treatments developed and attempted, there is no evidence that survival has improved over the past 40 years. In summary, patients with thinner melanomas amenable to surgical resection had a better prognosis than those with more extensive, metastatic disease at presentation.
Journal of the American Academy of Dermatology 01/2012; 67(4):598-605. · 3.99 Impact Factor
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John H Sampson,
Robert J Schmittling,
Gary E Archer,
Kendra L Congdon,
Smita K Nair,
Elizabeth A Reap,
Annick Desjardins,
Allan H Friedman,
Henry S Friedman, James E Herndon,
April Coan,
Roger E McLendon,
David A Reardon,
James J Vredenburgh,
Darell D Bigner,
Duane A Mitchell
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ABSTRACT: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.
To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.
A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).
Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.
ClinicalTrials.gov NCT00626015.
PLoS ONE 01/2012; 7(2):e31046. · 4.09 Impact Factor
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ABSTRACT: Spiritual care is an important part of healthcare, especially when facing the crisis of advanced cancer. Do oncology inpatients receive spiritual care consistent with their needs? When inconsistent, are there deleterious effects on patient outcomes?
Patients with advanced cancer (N = 150) were surveyed during their inpatient stay at a southeastern medical center using validated instruments documenting spirituality, quality of life, mood, and satisfaction with care. Relationships between the receipt of less spiritual care than desired and patient outcomes were examined.
Almost all patients had spiritual needs (91%) and the majority desired and received spiritual care from their healthcare providers (67%; 68%), religious community (78%; 73%), and hospital chaplain (45%; 36%). However, a significant subset received less spiritual care than desired from their healthcare providers (17%), religious community (11%), and chaplain (40%); in absolute terms, the number who received less care than desired from one or more sources was substantial (42 of 150). Attention to spiritual care would improve satisfaction with care while hospitalized for 35% of patients. Patients who received less spiritual care than desired reported more depressive symptoms [adjusted β (SE) = 1.2 (0.47), p = 0.013] and less meaning and peace [adjusted β (SE) = -2.37 (1.15), p = 0.042].
A substantial minority of patients did not receive the spiritual care they desired while hospitalized. When spiritual needs are not met, patients are at risk of depression and reduced sense of spiritual meaning and peace. Spiritual care should be matched to cancer patients' needs.
Supportive Care in Cancer 11/2011; 20(10):2269-76. · 2.09 Impact Factor
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Lee W Jones,
Whitney E Hornsby,
Amy Goetzinger,
Lindsay M Forbes,
Emily L Sherrard,
Morten Quist,
Amy T Lane,
Miranda West,
Neil D Eves,
Margaret Gradison,
April Coan, James E Herndon,
Amy P Abernethy
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ABSTRACT: To investigate the prognostic importance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer (NSCLC).
Using a prospective design, 118 consecutive participants with histologically confirmed metastatic (inoperable) NSCLC and Eastern Cooperative Oncology group (ECOG) 0-3 completed a six-minute walk test to assess functional capacity and questionnaire that assessed self-reported exercise behavior. Cox proportional models were used to estimate the risk of all-cause mortality according to six-minute walk distance (6MWD) (<358.5m, 358.5-450 m, ≥450 m) and exercise behavior (MET-hrswk(-1)) categories with adjustment for important covariates.
Median follow-up was 26.6 months; 77 deaths were reported during this period. Functional capacity was an independent predictor of survival (P(trend)=0.003) and added incremental prognostic value beyond that provided by PS plus other traditional markers of prognosis (P(trend)=0.025). Compared with patients achieving a 6MWD <358.5m, the adjusted hazard ratio (HR) for all-cause mortality was 0.61 (95% CI, 0.34-1.07) for a 6MWD of 358.5-450 m, and 0.48 (95% CI, 0.24-0.93) for a 6MWD >450 m. In unadjusted analysis, there was a borderline significant effect of exercise behavior on survival (p=0.052). Median survival was 12.89 months (95% CI, 9.11-21.05 months) for those reporting <9MET-hrswk(-1) compared with 25.63 months (95% CI, 11.28 to ∞ months) for those reporting ≥9MET-hrswk(-1).
Functional capacity is a strong independent predictor of survival in advanced NSCLC that adds to the prediction of survival beyond traditional risk factors. This parameter may improve risk stratification and prognostication in NSCLC.
Lung cancer (Amsterdam, Netherlands) 11/2011; 76(2):248-52. · 3.14 Impact Factor
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Journal of Neurosurgery 11/2011; 116(2):346-8; discussion 348. · 2.96 Impact Factor
