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Purpose 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? Methods 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. Results 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]. Conclusions 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.

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.

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31 %) subjects had recurrent WHO grade III gliomas and 164 (69 %) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60 months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95 %, 0.77–1; p  = 0.048) and FACIT-F (HR 0.82; CI 95 %, 0.68–0.99; p  = 0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95 %, 0.68–0.9; p  = 0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.

We conducted a phase I clinical trial of the combination of SCH 66336 with temozolomide administered on the standard 5-day dosing schedule. The primary objective was to determine the maximum tolerated dose and dose limiting toxicity (DLT) of twice daily SCH 66336 when administered with temozolomide to adults with malignant glioma previously treated with radiation therapy. Patients were enrolled to two strata: stratum A, patients not on enzyme-inducing antiepileptic drugs (EIAEDs); stratum B, patients receiving EIAEDs. Temozolomide was administered at a dose of 150 mg/m 2 daily for five days for the first 28-day cycle and escalated to 200 mg/m 2 , during subsequent cycles. SCH 66336 was administered twice daily on a continuous daily dosing schedule. The starting dose of SCH 66336 was 75 mg twice daily for stratum A and 125 mg twice daily for stratum B. Cohorts of 3–6 patients were treated per dose level until DLT was observed. Thirty six patients were enrolled on study, including 21 patients on stratum A and 15 on stratum B. All DLTs were grade 3 events and included hepatic, gastrointestinal, renal, thrombotic and constitutional events. No grade 4 or 5 toxicities were observed. The phase II dose of SCH 66336 when combined with temozolomide is 150 mg twice daily for patients not on EIAEDs and 175 mg twice daily for patients on EIAEDs.

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/m2 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. Forty‐one patients with unresectable glioblastomas were treated with an upfront regimen of 5‐day temozolomide and bevacizumab for four cycles prior to radiation. This combination resulted in partial response or stable disease in all but one patient and had acceptable tolerability.

Despite historical advancements toward gender equal policies, perceptions and attitudesregarding gender have the ability to impact the recruitment, retention, and promotion of gender minorities in the United States military. This quantitative study analyzed survey results from 493 military veterans regarding the perceptions and attitudes of gender equal statements, and sought to answer three research questions: 1) What factors predict perceptions and attitudes of gender equality in the United States military? 2) Do perceptions and attitudes of gender equality differ between different military branches? 3) Do demographic factors impact perceptions and attitudes of gender equality in the military? Chapter one of this dissertation introduces this study and its purpose, while chapter two discusses the historical background, literature review, and social theories that guided this study. Chapter three states the methodology of the study and outlines the design and limitations of this research. Chapter four presents the results of the study, which were obtained from descriptive statistics and analysis of a multiple regression, ANOVA, T-tests, and chi-squared tests. Results from the study concluded that gender, combat arms, generation, and military branch were significant variables in this research. Finally, chapter five summarizes findings, discusses follow up research, and acknowledges how this research and its results have contributed to the fields of conflict resolution and organizational behavior.

A clinical trial in patients with glioblastoma shows increased immune and anti-tumour responses to dendritic cell vaccination after pre-conditioning the site of vaccination with tetanus toxoid (Td); similar results are also seen in mice in part due to the actions of the chemokine CCL3, and the findings may represent new ways to improve the efficacy of anti-cancer vaccines. A novel anti-tumour immunotherapy strategy John Sampson and colleagues report on a small clinical trial in glioblastoma patients that shows that the immune and anti-tumour response to dendritic cell vaccination is increased by pre-conditioning the site of vaccination with tetanus/diptheria toxoid (Td). Experiments in mice showed similar effects and demonstrated that pre-conditioning with Td enhanced migration of dendritic cells to the tumours, at least in part due to the action of the cytokine CCL3. Although the clinical trial reported is small, these findings may pave the way for new ways of improving the efficacy of anti-cancer vaccines. After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses 1 . As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers 2 , 3 , 4 including glioblastoma 5 , 6 , 7 , the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs 8 or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain 9 , 10 , 11 , 12 , providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 week rest. Irinotecan was administered intravenously every other week. Each agent was alternatively escalated among cohorts of 3–6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m 2 of irinotecan. DLT were primarily hematologic and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematologic DLT included grade 3 mucositis ( n  = 1) and grade 3 dehydration ( n  = 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiographic response. The combination of sunitinib and irinotecan was associated with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors ( n  = 8) and those with grade II or III tumors ( n  = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, ( P  = 0.025 and P  = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

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.