Induction of cytotoxic T lymphocytes by CEA peptide-pulsed γδ T-cells isolated from patients with advanced cancer

Cytotoxic γδ T-cells recognize antigens directly without the need for antigen processing and presentation. Recently, it was reported that they can also present antigens and proliferate in vitro. In this study, we examined whether γδ T-cells isolated from patients with advanced cancer can be used for immunotherapy. Twenty-two inoperable patients with multiple cancer metastases were enrolled in the study. There was no significant difference in the ratio of γδ T-cells within the peripheral blood mononuclear cell population isolated from healthy volunteers and cancer patients. γδ T-Cells isolated from cancer patients were expanded 2- to 5-fold using zoledronic acid or 2-methyl-3butenyl-1-pyrophosphate and IL-2. Autologous CD8(+) T-cells co-cultured with expanded CEA peptide-pulsed γδ T-cells from cancer patients with HLA-A24 killed more CEA-positive HLA-A24-matched gastric cancer cells and secreted higher levels of interferon-γ. These results suggest that γδ T-cells from cancer patients may be ideal candidates for adoptive immunotherapy.     

Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma?

Glioblastoma progenitor or stem cells residing in the stem-cell niche in the subventricular zones (SVZ) can initiate or promote tumorigenesis. They can also migrate throughout the brain, resulting in disease progression. Irradiation of potential cancer stem-cell niche in the SVZ may influence survival. To analyze radiotherapy dose-volume parameters to the SVZ that correlate with survival in adequately treated patients with newly diagnosed glioblastoma, 40 adults with histopathologically proven supratentorial glioblastoma with available baseline imaging treated with postoperative conventionally fractionated focal conformal radiotherapy plus chemotherapy, available radiotherapy planning dataset, and documented event of progression or death or minimum 6-month follow-up were included in this retrospective study. Dose-volume parameters to the SVZ were extracted from treatment planning system and analyzed in relation to survival outcomes. Mean ipsilateral and contralateral SVZ volumes were 5.6 and 6.4 cc, respectively. With median follow-up of 15 months (interquartile range 12-18 months), median [95 % confidence interval (CI)] progression-free survival (PFS) and overall survival (OAS) was 11 months (95 % CI 8.9-13.0 months) and 17 months (95 % CI 11.6-22.4 months), respectively. Older age (>50 years), poor recursive partitioning analysis (RPA) class, and higher than median of mean contralateral SVZ dose were associated with significantly worse PFS and OAS. Multivariate analysis identified RPA class, Karnofsky performance status, and mean ipsilateral SVZ dose as independent predictors of survival. Increasing mean dose to the ipsilateral SVZ was associated with significantly improved OAS. Irradiation of potential cancer stem-cell niche influences survival outcomes in patients with newly diagnosed glioblastoma.     

Patterns of care and outcome for patients with glioblastoma diagnosed during 2008–2010 in Spain

Background

To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008–2010 in Spain.

Methods

Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals.

Results

We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01–1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64–0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62–1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8–14.9 months), compared with 17.0 months (95% CI, 15.5–18.4 months; P = .034) among younger patients with GBM treated with the same regimen.

Conclusions

In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival.     

Increased concentrations of transforming growth factor β1 and β2 in the plasma of patients with glioblastoma

Summary Recently, several in vitro studies have demonstrated production of the potent immunosuppressive cytokine transforming growth factor β (TGF-β)2 in glioblastoma cell lines. Systematic studies of the concentration of TGF-β isoforms in the plasma of patients harboring intracerebral tumors do not exist.In the present study, the concentrations of TGF-β1 and TGF-β2 in platelet-poor plasma of 21 patients with glioblastoma before and after extensive resection were measured by specific ELISA systems and related to survival.The plasma concentrations of latent TGF-β1 of patients with glioblastoma prior to surgery were significantly higher in comparison to healthy control probands, but not to patients with multiple sclerosis (MS). Furthermore, latent TGF-β2 was found to be significantly increased in the plasma of patients with glioblastoma in comparison to healthy control probands and patients with MS. After extensive resection of the tumor, the value of latent TGF-β2 evidently decreased.Interestingly, the concentration of latent TGF-β2 prior to surgery was correlated with survival and a strong relationship was found between the survival and the difference of latent TGF-β2 levels prior to surgery minus the TGF-β2 concentrations 7 days after surgery. A higher difference in these plasma concentrations >6 ng/ml vs. <6 ng/ml clearly correlates with a longer survival time. In conclusion, this study suggests that glioblastoma does secret TGF-β2 in vivo and that TGF-β2 may play an important role in glioblastoma patients.     

To resect or not to resect? Risks and benefits of surgery in older patients with glioblastoma

IntroductionGlioblastoma multiforme (GBM) has a peak incidence in patients older than 65 years. The aim of the present study is to evaluate the impact of surgical strategy on short- and long-term outcomes of older GBM patients.MethodsA total of 273 older patients (65–84 years) from 2006 to 2014 were operated in our neurosurgical center. The study endpoints were postoperative change of the Karnofsky performance status scale (KPS) and overall survival (OS). The extent of resection (EOR) was categorized into gross total resection (GTR, >95% by volume), subtotal resection (STR, ≤95%) and stereotactic biopsy (SB). The subgroup analyses were performed in two age groups dichotomized at 75 years.ResultsEOR was associated with the risk of postoperative decline of KPS only in patients aged ≥75 years (p = 0.0002/p = 0.0014 for SB vs. GTR and STR respectively), but not in the age group 65–74 years (p = 0.1511/p = 0.2701). The mean OS in the whole cohort was 8.4 months (±9.6). GTR was superior to SB with regards to OS (p < 0.0001/p = 0.0017). STR revealed a more favorable OS than SB only in patients aged 65–74 years (p = 0.0077). Multivariate analysis confirmed that only GTR was independently associated with OS (p < 0.0001/p = 0.013).ConclusionsGTR may provide a better OS even in GBM patients with advanced age. STR still shows a benefit over SB for OS in older patients <75 years. For older individuals, SB presents a safer option with regards to the risk of postoperative morbidity and should be favored in cases, when the surgical alternative is limited to STR.     

LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis

Long non-coding RNAs (lncRNAs) have recently emerged as a major class of regulatory molecules involved in a broad range of biological processes and complex diseases. Our aim was to identify important lncRNAs that might play an important role in contributing to glioblastoma (GBM) pathogenesis by conducting lncRNA and mRNA pro?le comparison between GBM and normal brain tissue. The differentially expressed lncRNA and mRNA pro?les of the tissue between GBM patient and age-matched donor without GBM diseases were analyzed using microarrays. We propose a novel model for the identification of lncRNA-mRNA targeting relationships that combine the potential targets of the differentially expressed lncRNAs with the differentially expressed mRNA abundance data. Bioinformatic analysis of the predicted target genes (gene ontology, pathway and network analysis) was performed for further research. The lncRNA microarray reveals differentially expressed lncRNAs between GBM and normal brain tissues. In the GBM group, 654 lncRNAs were upregulated and 654 were downregulated (fold change ≥4.0 or ≤0.25, P<0.01). We found 104 matched lncRNA-mRNA pairs for 91 differentially expressed lncRNAs and 84 differentially expressed genes. Target gene-related pathway analysis showed signi?cant changes in PPAR pathways in the GBM group compared with the normal brain group (P<0.05). By further conducting lncRNA gene network analysis, we found that ASLNC22381 and ASLNC2081 were likely to play roles in the regulation of glioma signaling pathways. In conclusion, our results indicated that the lncRNA expression pro?le in GBM tissue was signi?cantly altered. These results may provide important insights into the mechanisms responsible for GBM progression and pathogenesis. This study also suggests that ASLNC22381 and ASLNC20819 may play important roles via their target IGF-1 in the recurrence and malignant progression of GBM.     

Anti-tumor cytotoxicity of γδ T cells expanded from peripheral blood cells of patients with myeloma and lymphoma

In order to establish an efficient gammadelta T cell-mediated immunotherapy for hematological malignancies, we attempted to evaluate cytotoxicity against tumor cells by gammadelta T cells, which were generated from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and a low dose of IL-2. Although gammadelta T cells were expanded in patients with myeloma and lymphoma as well as normal persons, the amplification rates of gammadelta T cells before and after culturing varied from patient to patient in myeloma and lymphoma. gammadelta T cells generated in patients with myeloma and lymphoma showed a potent cytotoxic ability against myeloma/lymphoma cell lines as shown in gammadelta T cells generated in normal subjects. In addition, gammadelta T cells generated in a patient with myeloma showed a cytotoxic ability against self myeloma cells freshly prepared from bone marrow. However, the same gammadelta T cells were demonstrated to be non-cytotoxic to normal cells of the patient. These data demonstrated that gammadelta T cells, which could be expanded in vitro from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and IL-2, possess a sufficient cytotoxic ability against tumor cells. These findings suggested that in vitro generated patients' gammadelta T cells could be applied to gammadelta T cell-mediated immunotherapy for hematological malignancies.     

Two phase II trials of temozolomide with interferon-��2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme

Background:

Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon α2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls.

Methods:

Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150–200 mg m⁻² per day × 5 days every month) combined with either 4 million units per m² subcutaneously (SQ) three times weekly of IFN or 0.5 μg kg⁻¹ SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks.

Results:

On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35–38% and 18–21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study.

Conclusion:

In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.     

Salvage therapy in patients with glioblastoma: is there any benefit?

BACKGROUND: Survival after first-line therapy is poor for patients with glioblastoma. The role of second-line treatment for recurrent disease is controversial. The authors studied the outcome in a subset of patients with glioblastoma who were selected for an aggressive reintervention strategy at the time of progression. Their objectives were to improve patients' overall survival with sustained quality of life and to make comparisons with overall survival in unselected patients. METHODS: Overall, 168 patients were eligible for retrospective analysis. Ninety patients received specific therapy for disease recurrence (reintervention group) by specific criteria. RESULTS: In the reintervention group, promising median overall survival (mOS) results after diagnosis (61.5 weeks) and progression (33 weeks) were obtained. The progression-free survival (PFS) rate at 12 months and the overall survival rate were superior in the reintervention group (71% at 12 months and 32% at 24 months) compared with the total cohort (45% and 20%, respectively) and the standard group (15% and 5%, respectively). A matched-pair analysis (n = 46 in each group), with an mOS period of 65.5 versus 28.5 weeks, confirmed these data. Quality of life was stable or slightly improved during reinterventions in a subset of patients treated within clinical studies. CONCLUSIONS: The majority of patients in the current series were treated with a reintervention strategy, which had an impact on PFS and mOS. A second resection, focal radiotherapy (in selected cases), and additional chemotherapeutic regimens should be considered for patients with recurrent glioblastoma.     

Is the long-term survival of patients with intracranial glioblastoma multiforme overstated?

BACKGROUND: The 5-year survival rate for intracranial glioblastoma multiforme (GBM) has remained at 4-5% for the last 30 years, in spite of multiple randomized prospective trials. The authors hypothesized, based on the literature, that even this remarkably poor survival rate is an overstatement. They investigated this hypothesis using the the Duke University Medical Center Tumor Registry. METHODS: The authors reviewed all patients with the diagnosis of intracranial GBM recorded in the Duke University Medical Center Tumor Registry from the registry's inception in 1976 through 1996. This search identified a population of patients with a minimum of 5 years of follow-up. Each of the long-term survivors was assigned a code number for clinical information. The pathology slides were provided to a neuropathologist in a coded fashion so that the patients could not be identified. The neuropathologist reviewed the slides to analyze the presence or absence of nine histologic factors. A match technique was used to identify a control population of patients with GBM who were not 5-year survivors and were all deceased. The control population was compared with the study population to ascertain if there are histologic correlates associated with long-term survivorship. RESULTS: The authors identified 766 patients recorded by the tumor registry as having an intracranial GBM with a minimum of 5 years of follow up. Of the total population, 32 patients initially appeared to be 5-year survivors (4%). Upon review of the medical records for these 32 patients, however, the authors found only 17 patients who were truly 5-year survivors. The most common reason for miscoding was the presence of a low-grade astrocytoma that subsequently dedifferentiated into GBM. The 17 long-term survivors included 11 males and 6 females. Their mean age at diagnosis was 40.2 years. Therapy consisted of a macroscopic total resection in 4 patients (22%), a biopsy in 1 patient (6%), a subtotal resection in 10 patients (56%), and unknown extent of resection in 2 patients (11%). All patients received partial brain irradiation (mean dose, 62.6 Gy) and chemotherapy. Thirteen different single-agent or combination chemotherapy programs were used. Two patients also received I-131 monoclonal antibody therapy. Analysis of the nine histopathologic factors studied showed that intermediate fibrillary elements were more common and small anaplastic elements were less common in the long-term survivors than in the control population. CONCLUSIONS: Survival data on intracranial GBM, based on tumor registry data, should be interpreted cautiously. Reliable conclusions can only be drawn when such data are supplemented with clinical information and the histopathology is reviewed carefully. The group of long-term survivors in the current study were younger than the typical GBM population. Conventionally treated patients with GBM, chosen from an unselected population from a tumor registry, have a smaller chance of long-term survival than is generally believed.     

Has the survival of patients with glioblastoma changed over the years?

Background:

Over the last decade, the approach to the management of brain tumours and the understanding of glioblastoma tumour biology has advanced and a number of therapeutic interventions have evolved, some of which have shown statistically significant effects on overall survival (OS) and progression-free survival in glioblastoma. The aim of this study is to compare survival in glioblastoma patients over a 10-year period (1999–2000 and 2009–2010).

Methods:

A retrospective cohort study was performed. Identification of all histologically confirmed glioblastoma in a single centre in years 1999, 2000, 2009 and 2010, and production of survival analysis comparing 1999–2000 and 2009–2010 were achieved.

Results:

A total of 317 patients were included in the analysis (133 in year 1999–2000, and 184 in year 2009–2010). Cox regression analysis showed that the survival was significantly longer in patients in years 2009–2010 than those in 1999–2000 at P<0.001 with HR=0.56, confidence interval (CI) (0.45–0.71). The 1- and 3-year survival rates were 20.7% and 4.4%, respectively, for patients in 1999–2000, improving to 40.0% and 10.3%, respectively, for patients in 2009–2010. The comparisons between the two groups in survival at 1, 2 and 3 years are all statistically significant at P<0.001, respectively. The median OS was 0.36 and 0.74 in 1999–2000 and 2009–2010 groups, respectively.

Conclusions:

Over this period, OS from glioblastoma has increased significantly in our unit. We believe this is due to the institution of evidence-based surgical and oncological strategies practised in a multidisciplinary setting.     

Targeted therapies in patients with newly diagnosed glioblastoma—A systematic meta-analysis of randomized clinical trials

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov , WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86-1.11, P = .7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74-0.94, P = .0037]), especially for patients with an unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, P = .0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61-0.80, P = .0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents.     

Walking ability in patients with glioblastoma: prognostic value of the Berg Balance Scale and the 10 meter walk test

Primary brain tumors frequently cause considerable functional impairments and the survival time when diagnosed with glioblastoma is 14.6 months. The aim of this study was to examine if baseline postural control and walking ability in patients with glioblastoma could predict long term walking ability and 1 year mortality. Data were gathered from prospective recordings in a brain cancer database supplemented by retrospective review of electronic patient records. We included 109 patients with glioblastoma, 47 women and 62 men with mean age 65 years. At admission 84 patients were tested with Berg Balance Scale and 57 were tested with 10 meter walk test. Binary logistic regression analysis showed no statistical significance in favour of the 10 meter walk test. Berg Balance Scale showed an ability to predict walking ability 4–8 months after admission. The risk of dying within a year was 6.9 times higher in patients who lost their ability to walk within 4–8 months of the first admission. This study showed that Berg Balance Scale has some ability to predict the loss of walking ability 4–8 months after admission. This could be an important indicator pin pointing patients most in need of more intensive specialized neurorehabilitation efforts early in the disease course.