Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. METHODS AND RESULTS: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. CONCLUSION: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy.

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial.

BACKGROUND: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM. METHODS: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events. DISCUSSION: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development. TRIAL REGISTRATION: ISRCTN: 11460478. CLINICALTRIALS: Gov: NCT05629702.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers.

BACKGROUND: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). METHODS: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. RESULTS: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. CONCLUSION: GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.

Differences in clinical outcomes based on molecular markers in glioblastoma patients treated with concurrent tumor-treating fields and chemoradiation: exploratory analysis of the SPARE trial.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite enormous research efforts, GBM remains a deadly disease. The standard-of-care treatment for patients with newly diagnosed with GBM as per the National Cancer Comprehensive Cancer Network (NCCN) is maximal safe surgical resection followed by concurrent chemoradiation and maintenance temozolomide (TMZ) with adjuvant tumor treating fields (TTF). TTF is a non-pharmacological intervention that delivers low-intensity, intermediate frequency alternating electric fields that arrests cell proliferation by disrupting the mitotic spindle. TTF have been shown in a large clinical trial to improve patient outcomes when added to radiation and chemotherapy. The SPARE trail (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields) evaluated adding TTF concomitantly to radiation and chemotherapy. METHODS: This study is an exploratory analysis of the SPARE trial looking at the prognostic significance of common GBM molecular alterations, namely MGMT, EGFR, TP53, PTEN and telomerase reverse transcriptase (TERT), in this cohort of patients treated with concomitant TTF with radiation and chemotherapy. RESULTS: As expected, MGMT promoter methylation was associated with improved overall survival (OS) and progression-free survival (PFS) in this cohort. In addition, TERT promoter mutation was associated with improved OS and PFS in this cohort as well. CONCLUSIONS: Leveraging the molecular characterization of GBM alongside advancing treatments such as chemoradiation with TTF presents a new opportunity to improve precision oncology and outcomes for GBM patients.

Sequential Treatment with Temozolomide Plus Naturally Derived AT101 as an Alternative Therapeutic Strategy: Insights into Chemoresistance Mechanisms of Surviving Glioblastoma Cells.

Glioblastoma (GBM) is a poorly treatable disease due to the fast development of tumor recurrences and high resistance to chemo- and radiotherapy. To overcome the highly adaptive behavior of GBMs, especially multimodal therapeutic approaches also including natural adjuvants have been investigated. However, despite increased efficiency, some GBM cells are still able to survive these advanced treatment regimens. Given this, the present study evaluates representative chemoresistance mechanisms of surviving human GBM primary cells in a complex in vitro co-culture model upon sequential application of temozolomide (TMZ) combined with AT101, the R(-) enantiomer of the naturally occurring cottonseed-derived gossypol. Treatment with TMZ+AT101/AT101, although highly efficient, yielded a predominance of phosphatidylserine-positive GBM cells over time. Analysis of the intracellular effects revealed phosphorylation of AKT, mTOR, and GSK3ß, resulting in the induction of various pro-tumorigenic genes in surviving GBM cells. A Torin2-mediated mTOR inhibition combined with TMZ+AT101/AT101 partly counteracted the observed TMZ+AT101/AT101-associated effects. Interestingly, treatment with TMZ+AT101/AT101 concomitantly changed the amount and composition of extracellular vesicles released from surviving GBM cells. Taken together, our analyses revealed that even when chemotherapeutic agents with different effector mechanisms are combined, a variety of chemoresistance mechanisms of surviving GBM cells must be taken into account.

Study on the activation of cell death mechanisms: in search of new therapeutic targets in glioblastoma multiforme.

Malignant primary brain tumors remain among the most difficult cancers to treat, in particular, Glioblastoma Multiforme (GBM) is the deadliest brain tumor. The standard therapies currently used are not efficient enough in improving patients' survival and quality of life. Cisplatin (CDDP), a platinum-based drug, has shown efficacy against different solid neoplasms, but it is also associated to different forms of off-target toxicity. To overcome the limitation in the use of CDDP in the treatment of GBM patients, fourth generation platinum compounds are been synthesized, one of them is the Pt(IV)Ac-POA, a prodrug with a medium-chain fatty acid as axial ligand, which acts as a histone 3 deacetylase inhibitor. Moreover, recently, the antioxidant effects of medicinal mushrooms have been shown to induce a lowering of the toxicity of chemotherapy drugs, inducing greater therapeutic efficiency, thus the combined therapy of chemotherapy and micotherapy could be helpful in the treatment of GBM reducing the adverse effects of the former thanks to phytotherapy's antioxidant, anti-inflammatory, immunomodulatory and antitumoral activities. Here, through immunoblotting, ultrastructural and immunofluorescence analysis, we evaluated the contribution in the activation of different cell death pathway of Micotherapy U-Care, a medicinal blend supplement, used together with platinum-based compounds on human glioblastoma U251 cells.

Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study.

Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression. MATERIALS AND METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion. RESULTS: Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 15.2 months (1.7-23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26-6.95 cm). One infratentorial progression was noted. CONCLUSIONS: We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy.

BACKGROUND: Inherent resistance to radio/chemotherapy is one of the major reasons for early recurrence, treatment failure, and dismal prognosis of glioblastoma. Thus, the identification of resistance driving regulators as prognostic and/or predictive markers as well as potential vulnerabilities for combined modality treatment approaches is of pivotal importance. METHODS: We performed an integrative analysis of treatment resistance and DNA damage response regulator expression in a panel of human glioblastoma cell lines. mRNA expression levels of 38 DNA damage response regulators were analyzed by qRT-PCR. Inherent resistance to radiotherapy (single-shot and fractionated mode) and/or temozolomide treatment was assessed by clonogenic survival assays. Resistance scores were extracted by dimensionality reduction and subjected to correlation analyses with the mRNA expression data. Top-hit candidates with positive correlation coefficients were validated by pharmacological inhibition in clonogenic survival assays and DNA repair analyses via residual γH2AX/53BP1-foci staining. RESULTS: Inherent resistance to single-shot and similarly also to fractionated radiotherapy showed strong positive correlations with mRNA expression levels of known vulnerabilities of GBM, including PARP1, NBN, and BLM, as well as ATR and LIG4-two so far underestimated targets. Inhibition of ATR by AZD-6738 resulted in robust and dose-dependent radiosensitization of glioblastoma cells, whereas LIG4 inhibition by L189 had no noticeable impact. Resistance against temozolomide showed strong positive correlation with mRNA expression levels of MGMT as to be expected. Interestingly, it also correlated with mRNA expression levels of ATM, suggesting a potential role of ATM in the context of temozolomide resistance in glioblastoma cells. ATM inhibition exhibited slight sensitization effects towards temozolomide treatment in MGMT low expressing glioblastoma cells, thus encouraging further characterization. CONCLUSIONS: Here, we describe a systematic approach integrating clonogenic survival data with mRNA expression data of DNA damage response regulators in human glioblastoma cell lines to identify markers of inherent therapy resistance and potential vulnerabilities for targeted sensitization. Our results provide proof-of-concept for the feasibility of this approach, including its limitations. We consider this strategy to be adaptable to other cancer entities as well as other molecular data qualities, and its upscaling potential in terms of model systems and observational data levels deserves further investigation.

Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial.

Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma.

Beneficial Effects of Oral Nutritional Supplements on Body Composition and Biochemical Parameters in Women with Breast Cancer Undergoing Postoperative Chemotherapy: A Propensity Score Matching Analysis.

Aim: Recently, more attention has been paid to the role of nutritional intervention in preventing the side effects of chemotherapy in oncology patients. Therefore, the aim of the present study was to analyze the effects of oral nutritional supplements on the body composition and biochemical parameters in women with breast cancer receiving postoperative adjuvant chemotherapy. Patients and Methods: The study involved women diagnosed with breast cancer who underwent surgical treatment and were qualified for chemotherapy (doxorubicin and cyclophosphamide). Women were divided into two groups, depending on whether oral nutritional supplements were used during chemotherapy. Anthropometric and biochemical parameters were analyzed twice in all patients: before and after six weeks of chemotherapy. Propensity score (PS) matching was performed to select patients balanced in terms of age, BMI, and clinicopathological features of the tumor. Statistical comparisons were conducted in a propensity-matched cohort of patients. Results: The value of BMI was maintained constant in the supplemented women older than 56 years after six weeks of chemotherapy. Regardless of age in the supplemented women, a significant increase in muscle mass, fat free mass (FFM), and fat free mass index (FFMI) was demonstrated. An increase in fat mass (FM) including visceral fat was observed only in the non-supplemented control. Regardless of age or initial FM, supplemented women exhibited a constant level of albumin. Moreover, in the supplemented women with normal initial FM, the stable values of triglycerides and HDL cholesterol were maintained after six weeks of chemotherapy. Conclusion: The present study demonstrated that oral nutritional supplements could improve body composition and prevent hypoalbuminemia and lipid abnormalities in women with breast cancer undergoing chemotherapy.

Clinical study of apatinib plus temozolomide for the treatment of recurrent high-grade gliomas.

OBJECTIVES: Recurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma. PATIENTS AND METHODS: Eighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m2/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions. RESULTS: From the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%). CONCLUSION: Apatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.

Antioxidant responses related to temozolomide resistance in glioblastoma.

Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.

Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT.

BACKGROUND: There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). METHODS: We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. RESULTS: Median age of patients was 38 years (range 18-76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II-IV and III-IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. CONCLUSIONS: Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

INTRAVITREAL MELPHALAN FOR TREATMENT OF VITREOUS SEEDING FROM CHOROIDAL MELANOMA.

PURPOSE: To report treatment of vitreous seeding of choroidal melanoma with monthly injections of intravitreal melphalan. METHODS: Case report. RESULTS: A 70-year-old white woman noted floaters in her left eye, and further examination revealed visual acuity of 20/30 in both eyes. Funduscopically, there was a mushroom-shaped choroidal melanoma in her left eye, measuring 9 mm in basal dimension and 4.8 mm in thickness. Notably, there was apical retinal invasion of melanoma with mild vitreous hemorrhage, without vitreous seeding. The tumor was treated with iodine-125 plaque radiotherapy using an apex dose of 70 Gy over 99 hours, designed to include the retinal invasion. The melanoma demonstrated complete regression into a nearly flat scar of 1 mm and remained stable over 4 years. Five years after radiotherapy, there were diffuse vitreous pigmented seeds of presumed melanoma origin, emanating from the site of retinal necrosis. This progressively worsened over the following 18 months, suspicious for viable melanoma cells, as visual acuity concurrently declined to 20/100. Treatment with intravitreal melphalan (10 µg/0.05 mL) was delivered on a monthly basis for 12 cycles, resulting in vitreous seeds regression, and preservation of the eye. Final visual acuity was 20/200. There were no treatment-related complications. CONCLUSION: Intravitreal melphalan can be considered in cases of vitreous seeding from uveal melanoma.

131 I-Meta-iodobenzylguanidine followed by busulfan and melphalan and autologous stem cell rescue in high-risk neuroblastoma.

INTRODUCTION: Despite the progress in current treatments, the event-free survival of high-risk neuroblastoma (HR-NB) patients does not exceed 40%-50%, and the prognosis of refractory or relapsed patients is poor, still representing a challenge for pediatric oncologist. Therapeutic Iodine-131 meta-iodobenzylguanidine (Th-131 I-MIBG) is a recognized safe and potentially effective treatment for NB. MATERIALS: This retrospective study reports the outcomes of 28 MIBG-avid NB patients with advanced disease either refractory or relapsed, which was undertaken from 1996 to 2014. Th-131 I-MIBG was administered shortly before (median: 17 days) high-dose chemotherapy with busulfan and melphalan (HD-BuMel) and autologous stem cell rescue (ASCR) at the Gaslini Institute in Genoa, with the aim of analyzing the feasibility, safety, and efficacy of this approach. RESULTS: Engraftment occurred in all patients after a median of 14 (11-29) and 30 days (13-80) from ASCR for neutrophils and platelets, respectively. No treatment-related deaths were observed. The main high-grade (3-4) toxicity observed was oral and gastrointestinal mucositis in 78.6% and 7.1% of patients, respectively, whereas high-grade hepatic toxicity was observed in 10.7%. Two patients developed veno-occlusive-disease (7.1%), completely responsive to defibrotide. Hypothyroidism was the main late complication that occurred in nine patients (31.1%). After Th-131 MIBG and HD-BuMel, 19 patients (67.8%) showed an improvement in disease status. Over a median follow-up of 15.9 years, the three-year and five-year overall survival (OS) probabilities were 53% (CI 0.33-0.69) and 41% (CI 0.22-0.59), and the three-year and five-year rates of cumulative risk of progression/relapse were 64% (CI 0.47-0.81) and 73% (CI 0.55-0.88), respectively. MYCN amplification emerged as the only risk factor significantly associated with OS (HR, 3.58;P = 0.041). CONCLUSION: Th-131 I-MIBG administered shortly before HD-BuMel is a safe and effective regimen for patients with advanced MIBG-avid NB. These patients should be managed in centers with proven expertise.

Efficacy of hyperthermic isolated limb perfusion in the treatment of locally recurrent high-grade soft tissue sarcoma of the extremities.

BACKGROUND: This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities. METHODS: We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed. RESULTS: Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival. CONCLUSIONS: TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.

Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment.

Although lower grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1-mutant patients are increasingly being treated with temozolomide, but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to temozolomide in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in temozolomide-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1-13C]glucose and [3-13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following temozolomide treatment. In line with these results, hyperpolarized [5-13C]glutamate produced from [2-13C]pyruvate and hyperpolarized [1-13C]glutamate produced from [1-13C]α-ketoglutarate were significantly higher in temozolomide-treated cells compared with controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to temozolomide treatment in mutant IDH1 glioma. SIGNIFICANCE: These findings show that glutamate can be used as a noninvasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.

Long term follow-up and outcomes in adult patients with thalamic gliomas.

OBJECTIVES: To investigate the optimal treatment and prognosis of thalamic glioma in adult patients. PATIENTS AND METHODS: We retrospectively analyzed the adult patients with thalamic glioma admitted to our hospital from May 2005 to September 2016. Patients were divided into two groups according to their treatment: surgery-based combined treatment and intensity modulated radiation therapy (IMRT)-based treatment. Univariate chi-square test and multivariate logistic regression were used to identify independent factors for the treatment modality. A log-rank test, adjusting for propensity score, was used to compare the overall survival (OS) and progression-free survival (PFS) of patients between the two groups. RESULTS: Fifty-eight adult patients with thalamic gliomas were included in the analysis. Of them, 31 were treated with surgery-based treatment, and 27 were treated with IMRT-based treatment. The overall survival (OS) and progression-free survival (PFS) of patients between the two groups were not significantly different (median OS 16.0 (range 1.0-163.0) months vs. 10.0 (range 1.0-118.0) months, p = 0.344 and median PFS 10.0 (range 1.0-163.0) months vs. 6.0 (range 1.0-118.0) months, p = 0.464, respectively) even after adjusting for potential confounding factors. CONCLUSIONS: The OS and PFS of adult patients with thalamic glioma were not significantly different between patients in the surgical group and in the IMRT group. IMRT might be an acceptable alternative to surgery for adult patients with unresectable thalamic glioma.

Temozolomide in secondary prevention of HER2-positive breast cancer brain metastases.

Brain metastases occur in up to 25-55% of patients with metastatic HER2-positive breast cancer. Standard treatment has high rates of recurrence or progression, limiting survival and quality of life in most patients. Temozolomide (TMZ) is known to penetrate the blood-brain barrier and is US FDA approved for treatment of glioblastoma. Our group has demonstrated that low doses of TMZ administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases in murine models of breast cancer. Based on these findings, we initiated a secondary-prevention clinical trial with oral TMZ given to HER2-positive breast cancer patients with brain metastases after recent local treatment in combination with T-DM1 for systemic control of disease. Primary end point is freedom from new brain metastases at 1 year. (NCT03190967).