A multi-site phase I trial of Veliparib with standard radiation and temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM).

PURPOSE: A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma. METHODS: Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed. RESULTS: Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%). CONCLUSIONS: Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.

Aquaporin-4 Expression Patterns in Glioblastoma Pre-Chemoradiation and at Time of Suspected Progression.

There has been controversy about the presence and potential role of aquaporin-4 (AQP4) in glioblastoma (GBM). We analyzed tissue from 22 patients with newly-diagnosed GBM as well as matching tissue from 17 of these cases who underwent repeat resection for suspected recurrence and performed immunohistochemical analysis for AQP-4 expression. While some degree of AQP4 expression was detected in all 22 cases (39 samples), there was no clear relationship between staining pattern and disease status (active versus inactive GBM) between baseline and time of repeat biopsy. In addition, there was no clear relationship between AQP4 expression and degree of edema.

Correction to: White matter changes in primary central nervous system lymphoma patients treated with high-dose methotrexate with or without rituximab.

The following discrepancies and errors were found in the original publication.

White matter changes in primary central nervous system lymphoma patients treated with high-dose methotrexate with or without rituximab.

PURPOSE: White matter changes (WMCs) can develop following systemic chemotherapy in patients with primary central nervous system lymphomas (PCNSLs), but the frequency and extent of these changes is not well characterized. This single center retrospective semi-quantitative study was performed to determine the rate, timing and grade of WMC on MRI in adult patients with newly-diagnosed radiotherapy-naïve PCNSL undergoing treatment with high-dose methotrexate (HD-MTX) with or without the addition of rituximab (-R). METHODS: Serial MRI scans of consecutive adult PCNSL patients treated with HD-MTX ± R were assessed for WMC comparing the pre-treatment to post-treatment scans utilizing a 0-to-8-point severity scoring system. RESULTS: Forty-seven PCNSL patients treated with either HD-MTX-R (n = 34; median age 66, 50% male) or HD-MTX (n = 13; median age 53, 54% male) were included in the analysis. WMC were detected in 62% (95% CI 46-76%) overall, in 68% of the HD-MTX-R, and in 46% of the HD-MTX group. Among patients with WMC (n = 29), WMC were first detected at an average of 2.8 months from beginning of therapy in the HD-MTX-R versus at 10.7 months in the HD-MTX group. Average WMC non-zero scores when first detected following the start of treatment were 2.5 (± 1.1) in HD-MTX-R and 1.5 (± 0.6) in HD-MTX. CONCLUSIONS: Development of WMC in PCNSL patients treated with MTX and MTX-R is common. WMC changes appear to be more frequent, occur earlier and are more extensive in patients treated with HD-MTX-R compared to HD-MTX. Prospective studies are required to determine whether WMC correlate with survival or neurocognitive outcomes.

The consistency of neuropathological diagnoses in patients undergoing surgery for suspected recurrence of glioblastoma.

PURPOSE: Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor progression from pseudo-progression. As a result, surgery is commonly recommended to establish a final diagnosis. However, studies evaluating the pathologists' agreement on pathologic diagnoses in this setting have not been previously evaluated. METHODS: A hypothetical clinical history coupled with images of histological sections from 13 patients with glioblastoma who underwent diagnostic surgery for suspected early recurrence were sent to 101 pathologists from 50 NCI-designated Cancer Centers. Pathologists were asked to provide a final diagnosis (active tumor, treatment effect, or unable to classify) and to report on percent active tumor, treatment effect, and degree of cellularity and degree of mitotic activity. RESULTS: Forty-eight pathologists (48%) from 30 centers responded. In three cases > 75% of pathologists diagnosed active tumor. In two cases > 75% diagnosed treatment effect. However, in the remaining eight cases the disparity in diagnoses was striking (maximum agreement on final diagnosis ranged from 36 to 68%). Overall, only marginal agreement was observed in the overall assessment of disease status [kappa score 0.228 (95% CI 0.22-0.24)]. CONCLUSIONS: Confidence in any clinical diagnostic assay requires that very similar results are obtained from identical specimens evaluated by sophisticated clinicians and institutions. The findings of this study illustrate that the diagnostic agreement between different cases of repeat resection for suspected recurrent glioblastoma can be variable. This raises concerns as pathological diagnoses are critical in directing standard and experimental care in this setting.

Severe Treatment-Related Lymphopenia in Patients with Newly Diagnosed Rectal Cancer.

BACKGROUND: Although treatment-related lymphopenia (TRL) is common in many cancers no data exists in rectal cancer. METHODS: Serial lymphocyte counts were analyzed retrospectively in patients with newly diagnosed rectal cancer, serial blood counts, and complete records at Johns Hopkins Hospital. RESULTS: Fifty-seven patients with normal pretreatment lymphocyte counts were studied. Two months after beginning chemoradiation, 35% of these patients developed grade III-IV lymphopenia [median lymphocyte counts fell from 1590 to 490 cell/mm3 (p < 0.001)] which persisted throughout one year of observation. CONCLUSION: Severe and prolonged TRL is common in rectal cancer. Further studies are required to determine TRL's relationship to survival.

Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors.

BRAF V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with BRAF V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors.

Role of Temozolomide in the Treatment of Cancers Involving the Central Nervous System.

Temozolomide has been available to oncologists for over 30 years. During this time, it has become an integral part of standard therapy in patients with high-grade gliomas. Given its ability to traverse the blood-brain barrier, temozolomide has also been evaluated in other cancers that involve the central nervous system (CNS). We review its role in the management of patients with primary brain tumors, brain metastases, leptomeningeal carcinomatosis, and other selected CNS cancers. There is strong evidence that temozolomide is effective in patients with high-grade astrocytomas and oligodendrogliomas. Modest evidence supports its activity in primary CNS lymphomas and aggressive pituitary adenomas. Temozolomide, however, has minimal efficacy in a wide variety of systemic cancers. Given that concentrations of temozolomide in the CNS are only 20% of those in the blood, it is not surprising that it is generally inactive in patients with CNS metastases from solid tumors.

The effect of regadenoson on the integrity of the human blood-brain barrier, a pilot study.

Regadenoson is an FDA approved adenosine receptor agonist which increases blood-brain barrier (BBB) permeability in rodents. Regadenoson is used clinically for pharmacologic cardiac stress testing using SPECT or CT imaging agents that do not cross an intact BBB. This study was conducted to determine if standard doses of regadenoson transiently disrupt the human BBB allowing higher concentrations of systemically administered imaging agents to enter the brain. Patients without known intracranial disease undergoing clinically indicated pharmacologic cardiac stress tests were eligible for this study. They received regadenoson (0.4 mg) followed by brain imaging with either 99mTc-sestamibi for SPECT or visipaque for CT imaging. Pre- and post-regadenoson penetration of imaging agents into brain were quantified [SPECT: radioactive counts, CT: Hounsfield units (HU)] and compared using a matched-pairs t-test. Twelve patients (33% male, median 60 yo) were accrued: 7 SPECT and 5 CT. No significant differences were noted in pre- and post-regadenoson values using mean radionuclide counts (726 vs. 757) or HU (29 vs. 30). While animal studies have demonstrated that regadenoson transiently increases the permeability of the BBB to dextran and temozolomide, we were unable to document changes in the penetration of contrast agents in humans with intact BBB using the FDA approved doses of regadenoson for cardiac evaluation. Further studies are needed exploring alternate regadenoson dosing, schedules, and studies in patients with brain tumors; as transiently disrupting the BBB to improve drug entry into the brain is critical to improving the care of patients with CNS malignancies.

Serial changes in lymphocyte subsets in patients with newly diagnosed high grade astrocytomas treated with standard radiation and temozolomide.

The immune system plays a significant role in cancer prevention and outcome. In high grade astrocytomas (HGA), severe lymphopenia is associated with shortened survival due to tumor progression. This study was performed to quantify serial changes in lymphocyte subsets in HGA following standard radiation (RT) and temozolomide (TMZ). Adults (KPS >60, HIV negative) with newly diagnosed HGA scheduled to receive concurrent RT and TMZ and adjuvant TMZ were eligible. Blood was collected before beginning concurrent RT/TMZ and at weeks 6, 10, 18, and 26, and 3 months after completing adjuvant TMZ. Lymphocyte subsets were analyzed by flow cytometry. Twenty patients (70% glioblastoma, median age 53, 50% male, 80% Caucasian) who enrolled from January 2014 to August 2014 were followed until April 2016. Baseline dexamethasone dose was 0.5 mg/day and 15% had absolute lymphocyte counts (ALC) <1000 cells/mm3 before starting RT/TMZ. However, 75% developed lymphopenia with ALC <1000 cells/mm3 after completion of RT/TMZ. NK cells, B cells and all T lymphocytes subsets dropped significantly after concurrent RT/TMZ and remained depressed for the 48 weeks of observation. The CD4+/CD8+ ratio was not affected significantly during follow-up. Severe lymphopenia involving all subsets occurred early in treatment and remained present for nearly 1 year. To our knowledge, this is the first report of serial trends in lymphocyte subsets following standard RT and TMZ for HGA.

Patterns of Radiation-Associated Lymphopenia in Children with Cancer.

Adults with cancer commonly develop severe lymphopenia two months following chemoradiation therapy, which is an independent predictor of survival. In this retrospective study of 53 children with central nervous system tumors and sarcomas, the frequency, severity, and duration of radiation-associated lymphopenia was similar to that seen in adults. Pretreatment lymphocyte counts were 1,000 cells/mm(3) or greater in all patients, with 66% experiencing grade III-IV lymphopenia two months after chemoradiation. Lymphocyte counts remained significantly lower than baseline 12 months later. Further studies are needed to determine if this is also associated with poorer survival, as seen in adults.

The role of temozolomide in the management of patients with newly diagnosed anaplastic astrocytoma: a comparison of survival in the era prior to and following the availability of temozolomide.

Adding temozolomide (TMZ) to radiation for patients with newly-diagnosed anaplastic astrocytomas (AAs) is common clinical practice despite the lack of prospective studies demonstrating a survival advantage. Two retrospective studies, each with methodologic limitations, provide conflicting advice regarding treatment. This single-institution retrospective study was conducted to determine survival trends in patients with AA. All patients ≥18 years with newly-diagnosed AA treated at Johns Hopkins from 1995 to 2012 were included. As we incorporated TMZ into high-grade glioma treatment regimens in 2004, patients were divided into pre-2004 and post-2004 groups for analysis. Clinical, radiographic, and pathologic data were collected. Median overall survival (OS) was calculated using Kaplan-Meier estimates. A total of 196 patients were identified; 74 pre-2004 and 122 post-2004; mean age 47 ± 15 years; 57 % male; 87 % white, 69 % surgical debulking. Mean RT dose 5676 + 746 cGy; duration of concurrent chemoradiation 5.8 ± 0.8 weeks; and mean adjuvant chemotherapy 4.3 + 2.8 cycles. Baseline prognostic factors did not differ between groups. Chemotherapy was administered to 12 % of patients pre-2004 (TMZ = 1, procarbazine, lomustine and vincristine = 2, carmustine wafer = 6) and 94 % post-2004 (TMZ in all, p < 0.001). Median OS was 32 months (95 % CI 23-43). Survival was longer in the post-2004 cohort (37 mo, 24-64) than pre-2004 (27 mo, 19-40; HR 0.75, 0.53-1.06, p = 0.11). Multivariate analysis controlling for age, Karnofsky performance status, and extent of resection revealed a 36 % reduced risk of death (HR 0.64, 0.44-0.91, p = 0.015) in patients treated post-2004. This retrospective review found survival in newly diagnosed patients with AA improved with the addition of temozolomide to standard radiation. Until prospective randomized phase III data are available, these data support the practice of incorporating TMZ in the management of newly-diagnosed AA.

The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain.

The blood-brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60-90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 µg/g, P < 0.05). A similar trend was noted in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders.

Caring for Patients with Newly Diagnosed High-Grade Gliomas.

Novel diagnostic and therapeutic information has had a major impact on the care of patients with high-grade gliomas. These advances and discoveries are highlighted using case-based discussions to focus attention on the important diagnostic and treatment decisions that commonly arise during the care of patients with newly diagnosed glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma.

Optimizing the Delivery of Antineoplastic Therapies to the Central Nervous System.

Despite significant advances in the treatment of systemic cancers, progress in the treatment of primary brain tumors has been quite modest. In addition, an increasing proportion of patients with systemic cancers are presenting with brain-only metastases. These observations highlight the critical role that the blood-brain barrier plays in preventing antineoplastic therapies from reaching the central nervous system in therapeutic concentrations. This review describes the anatomy of the blood-brain barrier and currently available methods to quantify the entry of therapeutic compounds into the brain. It also summarizes data from a variety of approaches designed to improve drug delivery to the central nervous system. These include: 1) directly placing drugs inside the blood-brain barrier (polymeric implants, convection-enhanced delivery, and intraventricular administration), 2) modifying systemic chemotherapy (by using high-dose methotrexate and intra-arterial drug administration), 3) temporary disruption of the blood-brain barrier (via use of intra-arterial mannitol, focused ultrasound, or pharmacologic agents), and 4) designing drugs that can pass through the blood-brain barrier. Given that lymphocytes readily traverse the blood-brain barrier, immunotherapy represents a novel approach to cancer therapy that is of particular interest to practitioners in the field of neuro-oncology. The efficacy of vaccines and immune checkpoint inhibitors is currently being actively investigated in patients with primary and metastatic brain tumors, as well as leptomeningeal carcinomatosis. The challenge of delivering effective antineoplastic therapies to the central nervous system remains a primary obstacle to improving outcomes in patients with primary and metastatic brain tumors.

Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors.

BACKGROUND: The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. MATERIALS AND METHODS: Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non-small cell lung cancer (N=47). RESULTS: Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13-2.87; resected pancreas: HR, 2.2; 95% CI, 1.17-4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53-5.42; and lung: HR, 1.7; 95% CI, 0.8-3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54-2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. CONCLUSIONS: Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors.

A prospective multicenter study of venous thromboembolism in patients with newly-diagnosed high-grade glioma: hazard rate and risk factors.

Venous thromboembolism (VTE) is a common complication in patients with high-grade gliomas. The purpose of this prospective multicenter study was to determine the hazard rate of first symptomatic VTE in newly-diagnosed glioma patients and identify clinical and laboratory risk factors. On enrollment, demographic and clinical information were recorded and a comprehensive coagulation evaluation was performed. Patients were followed until death. The study end point was objectively-documented symptomatic VTE. One hundred seven patients were enrolled with a median age of 57 years (range 29-85) between June 2005 and April 2008. Ninety-one (85 %) had glioblastoma multiforme (GBM). During an average survival of 17.7 months, 26 patients (24 %) (95 % CI 17-34 %) developed VTE (hazard rate 0.15 per person-year) and 94 patients (88 %) died. Median time to VTE was 14.2 weeks post-operation (range 3-126). Patients with an initial tumor biopsy were 3.0 fold more likely to suffer VTE (p = 0.02). Patients with an elevated factor VIII activity (>147 %) were 2.1-fold more likely to develop VTE. ABO blood group, D dimer and thrombin generation were not associated with VTE. No fatal VTE occurred. VTE is a common complication in patients with newly-diagnosed high grade gliomas, particularly in the first six months after diagnosis. Patients with an initial tumor biopsy and elevated factor VIII levels are at increased risk. However, VTE was not judged to be primarily responsible for any patient deaths. Therefore, outpatient primary VTE prophylaxis remains investigational until more effective primary prophylaxis strategies and therapies for glioma are identified.

Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas.

Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed ≥80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days × 6 weeks) in conjunction with iniparib (i.v. 2 days/week) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 years; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19 mg/kg/week (rash/hypersensitivity). At 17.2 mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2 mg/kg/week. Dose escalation stopped at 16 mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was ≤5% of the corresponding iniparib concentration. Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2 mg/kg/week with mTMZ and 16 mg/kg/week with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing.

Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas.

Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm(3) underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm(3)). After 6 weeks of RT/TMZ, TLC fell 69 % (p < 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 10(7) lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm(3) was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/reinfusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG.

The Role of Glucose Modulation and Dietary Supplementation in Patients With Central Nervous System Tumors.

OPINION STATEMENT: Central nervous system gliomas are the most common primary brain tumor, and these are most often high-grade gliomas. Standard therapy includes a combination of surgery, radiation, and chemotherapy which provides a modest increase in survival, but virtually, no patients are cured, the overall prognosis remains poor, and new therapies are desperately needed. Tumor metabolism is a well-recognized but understudied therapeutic approach to treating cancers. Dietary and nondietary modulation of glucose homeostasis and the incorporation of dietary supplements and other natural substances are potentially important interventions to affect cancer cell growth, palliate symptoms, reduce treatment-associated side effects, and improve the quality and quantity of life in patients with cancer. These approaches are highly desired by patients. However, they can be financially burdensome, associated with toxicities, and have, on occasion, reduced the efficacy of proven therapies and negatively impacted patient outcomes. The lack of rigorous scientific data evaluating almost all diet and supplement-based therapies currently limits their incorporation into standard oncologic practice. Rigorous studies are needed to document and improve these potentially useful approaches in patients with brain and other malignancies.