Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma

Circulating long non‐coding RNAs (lncRNAs) are a new class of cancer biomarkers. However, their significance in predicting outcomes in glioblastoma patients is unclear. We measured the levels of six known oncogenic lncRNAs—CRNDE, GAS5, H19, HOTAIR, MALAT1, and TUG1 in serum samples from 106 patients with primary glioblastoma and analyzed their association with outcomes. High levels of HOTAIR were associated with decreased probability of 2‐year overall survival (adjusted hazard ratio [HR] = 2.04; 95% confidence interval [CI] = 1.08‐9.76), and disease‐free survival (adjusted HR = 1.82; 95% CI = 1.04‐6.17). High levels of GAS5 were associated with increased probability of 2‐year overall survival (adjusted HR = 0.44; 95% CI = 0.18‐0.99), and disease‐free survival (adjusted HR = 0.46; 95% CI = 0.16‐0.98). HOTAIR and GAS5 levels could serve as reciprocal prognostic predictors of survival and disease progression in patients with glioblastoma.     

Prevalence,predictors, and characteristics of off‐treatment fatigue in breast cancer survivors

BACKGROUND:

Lack of consensus regarding how to identify cancer patients with significant fatigue has hampered research regarding cancer‐related fatigue (CRF).

METHODS:

Specific criteria were used to identify CRF cases in women with stage 0‐II breast cancer (BC group, n = 304). Women completed assessments before adjuvant therapy (baseline), end of adjuvant therapy (Post‐Tx), and 6 and 42 months after end of adjuvant therapy (6 and 42 Month Post‐Tx). At each, women completed a clinical interview and questionnaires assessing physical and mental health. A healthy control (HC) group with no history of BC (n = 337) completed 2 similar assessments 36 months apart.

RESULTS:

Off‐treatment CRF prevalence was 9% and 13% at the 6 and 42 Month Post‐Tx assessments, respectively. Thus, 15% of the sample evidenced off‐treatment CRF with 7% evidencing delayed onset CRF. CRF at the 6 Month Post‐Tx assessment was associated only with CRF at baseline (OR = 3.2) and Post‐Tx assessments (OR = 3.9). CRF at the 42 Month Post‐Tx assessment was associated with CRF at the Post‐Tx assessment (OR = 6.1), obesity at baseline, and several baseline measures of coping in response to fatigue. Off‐treatment CRF cases differed markedly from CRF noncases and healthy controls on a spectrum of health status indices (mean effect size >1.0 SD).

CONCLUSIONS:

Results document the prevalence of off‐treatment and delayed onset CRF, suggest the utility of a cognitive‐behavioral model of CRF, and support NCCN guidelines recommending monitoring fatigue across the cancer trajectory. Cancer 2010. © 2010 American Cancer Society.     

Multicenter imaging outcomes study of The Cancer Genome Atlas glioblastoma patient cohort: imaging predictors of overall and progression-free survival

BackgroundDespite an aggressive therapeutic approach, the prognosis for most patients with glioblastoma (GBM) remains poor. The aim of this study was to determine the significance of preoperative MRI variables, both quantitative and qualitative, with regard to overall and progression-free survival in GBM.MethodsWe retrospectively identified 94 untreated GBM patients from the Cancer Imaging Archive who had pretreatment MRI and corresponding patient outcomes and clinical information in The Cancer Genome Atlas. Qualitative imaging assessments were based on the Visually Accessible Rembrandt Images feature-set criteria. Volumetric parameters were obtained of the specific tumor components: contrast enhancement, necrosis, and edema/invasion. Cox regression was used to assess prognostic and survival significance of each image.ResultsUnivariable Cox regression analysis demonstrated 10 imaging features and 2 clinical variables to be significantly associated with overall survival. Multivariable Cox regression analysis showed that tumor-enhancing volume (P = .03) and eloquent brain involvement (P < .001) were independent prognostic indicators of overall survival. In the multivariable Cox analysis of the volumetric features, the edema/invasion volume of more than 85 000 mm³ and the proportion of enhancing tumor were significantly correlated with higher mortality (Ps = .004 and .003, respectively).ConclusionsPreoperative MRI parameters have a significant prognostic role in predicting survival in patients with GBM, thus making them useful for patient stratification and endpoint biomarkers in clinical trials.     

Tumor mutational burden and purity adjustment before and after treatment with temozolomide in 27 paired samples of glioblastoma: a prospective study

Treatment of glioblastoma (GBM) remains a challenging task, with limited treatment options, none offering a cure. Immune therapy has proven effective across different cancers with remarkable response rates. Tumor mutational burden (TMB) is a marker of response, but technical and methodological differences in TMB estimates have made a proper assessment and comparison challenging. Here, we analyzed a prospective collection of paired samples from 35 patients with newly diagnosed GBM, all of whom were wild‐type (WT) for isocitrate dehydrogenase, before and after treatment with radiotherapy and temozolomide. Seven patients (20%) had O6‐methylguanine‐DNA methyltransferase‐methylated tumors. Six patients (17%) had two relapse surgeries, and tissue from all three surgeries was collected. We found that accurate evaluation of TMB was confounded by high variability in the cancer cell fraction of relapse samples. To ameliorate this, we developed a model to adjust for tumor purity based on the relative density distribution of variant allele frequencies in each primary–relapse pair. Additionally, we examined the mutation spectra of shared and private mutations. After tumor purity adjustment, we found TMB comparison reliable in tumors with tumor purity between 15% and 40%, resulting in 27/35 patients (77.1%). TMB remained unchanged from 0.65 mutations per megabase (Mb) to 0.67/Mb before and after treatment, respectively. Examination of the mutation spectra revealed a dominance of C > T transitions at CpG sites in both shared and relapse‐private mutations, consistent with cytosine deamination and the clock‐like mutational signature 1. We present and apply a cellularity correction approach that enables more accurate assessment of TMB in paired tumor samples. We did not find a significant increase in TMB after correcting for cancer cell fraction. Our study raises significant concerns when determining TMB. Although a small sample size, corrected TMB can have a clinical significance when stratifying patients to experimental treatment, for example, immune checkpoint therapy.     

Prospective study of depression and fatigue in men with advanced prostate cancer receiving hormone therapy

PURPOSE: We prospectively examined the development of depressive symptoms and fatigue among men with locally advanced prostate cancer receiving hormone therapy. METHODS: Fifty-two men with advanced or recurrent prostate cancer were randomly assigned to receive either parenteral leuprolide or oral bicalutamide. Patients completed the Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) at pretreatment baseline, 6 months, and 12 months. RESULTS: Rates of at least mild depression ranged from 10.4 to 16.3% over the 12 months and were not significantly different at each time point. Mean change in BDI scores from baseline to 6 months for the entire sample was 0.91 (SE = 0.73), and from baseline to 12 months was 0.35 (SE = 0.67). Mean FSS scores increased significantly from baseline (M = 24.43, SD = 11.75) to 6 months (M = 27.93, SD = 13.52) and remained steady at 12 months (M = 27.80, SD = 14.44). There were no significant differences in depression between the two types of hormone therapy. CONCLUSION: Hormone therapy does not appear to cause clinically significant changes in depression among men with locally advanced prostate cancer. However, fatigue increased significantly over the study period.     

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

BackgroundThe optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy.MethodsThis was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0–2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS).ResultsOne hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64–1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82–1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately.ConclusionsAdding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

Clinical trials registration nr

ACTRN12610000915055.     

Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study

We explored the feasibility of concurrent palliative chemotherapy and low-dose fractionated radiotherapy (LD-FRT) in glioblastoma multiforme (GBM). Patients with recurrent/progressive GBM at least 3 months after the end of primary radiotherapy received 0.3 Gy twice daily with cisplatin and fotemustine if progressing on temozolomide, or 0.4 Gy twice daily with temozolomide if recurrent 4-6 months later (retreatment group). Newly diagnosed GBM with gross residual mass received 30 Gy with concomitant and adjuvant temozolomide and 0.4 Gy twice daily from the second adjuvant cycle (naive group) for 2-4 cycles. Twenty-six patients were enrolled. In the retreatment group (n = 17; median LD-FRT total dose 7.2 Gy [range 2.4-11.6]), grade 3 or 4 hematological toxicity was observed in 5.9% of patients. Median follow-up time was 20 months (range 4-35). Median progression-free survival (PFS) and overall survival (OS) from the time of recurrence or progression were 4 and 8 months, respectively (OS at 6 months, 69%; at 12 months, 16.7%). In the naive group (n = 9; median LD-FRT total dose 8 Gy [range 3.2-16]), grade 3 or 4 hematological toxicity was observed in 11.1% of patients. Median follow-up time was 17 months (range 8-20)-median PFS was 9 months, with PFS at 6 months and at 1 year of 66.7% and 26.7%, respectively; and median OS was 12 months, with OS at 6 months and at 1 year of 77.8% and 34.6%, respectively. LD-FRT with concurrent chemotherapy was well tolerated.     

Response to chemotherapy of a radiation-induced glioblastoma multiforme

Summary Background Radiation-induced glioblastoma multiforme (GBM) is particularly resistant to treatment and therapeutic options are limited. We report a patient with a radiation-induced GBM who had a complete response to carmustine and survived for 44 months. Patients and Methods Case report of a 38-year-old man with a radiation-induced GBM that responded to carmustine. Results Our patient developed a left occipital GBM 35 years after a left cerebellar astrocytoma was treated with surgery and radiation therapy (4500 rad). The GBM was treated with subtotal resection followed by four cycles of carmustine; a complete response was achieved. He relapsed 34 months after diagnosis and with further surgery survived 44 months from his diagnosis of GBM. Conclusion GBMs may be a late complication of radiation treatment for pediatric brain tumors. If further radiotherapy is not a therapeutic option, chemotherapy may result in prolonged survival.     

Fast neutrons compared with megavoltage x-rays in the treatment of patients with supratentorial glioblastoma: a controlled pilot study

The radioresistance of glioblastoma presumably results from the presence of hypoxic cells. In an attempt to overcome this problem, fast neutrons were compared in a controlled pilot study with conventional megavoltage X-rays (photons). 63 patients entered the study between January, 1973 and July, 1976, 30 patients received neutron and 33 received X-ray therapy. The overall mean survival was 11.4 months for those who received photon and 10 months for those who received neutron therapy. Survival rates at 6 and 12 months were 72 % and 36 % respectively for photon treated patients, and 77 % and 30 % for those treated with neutrons. Although neutron therapy did not improve overall survival, examination of the histological material indicated a considerably greater antitumor effect after neutron therapy than after treatment with photons. In the neutron treated group, at post-mortem examination no tumor or only minimal tumor was found in 10 of 12 patients and in one of 4 patients where tissue was obtained from a second craniotomy. In some cases, there was evidence of diffuse damage to normal brain which was in keeping with a clinical syndrome of progressive dementia without localizing signs. Dose, time, and volume factors for neutron therapy to the brain and possible ways of improving results are discussed.     

Phase 2 study of dose-intense temozolomide in recurrent glioblastoma

Background

Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O⁶-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.

Methods

This was a multicenter, phase 2, single-arm study of temozolomide (75–100 mg/m²/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).

Results

Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25–79 years) and a median Karnofsky performance score of 90 (range, 60–100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).

Conclusions

Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.     

Pediatric giant cell glioblastoma: New insights into a rare tumor entity

Little is known about giant cell glioblastoma (GCG) in pediatric patients. The present study identified 18 pediatric patients with centrally reviewed GCG from the HIT-GBM database of the Gesellschaft für Paediatrische Onkologie und Haematologie in Germany, Austria, and Switzerland. Clinical and epidemiological data were compared with those of 178 pediatric patients with centrally reviewed glioblastoma multiforme (GBM) from the same database. In this unique series, median age, male preference, and median clinical history did not differ significantly between pediatric GCG and GBM patients. GCG showed a stronger predilection for cerebral hemispheres than did GBM, which may only partly explain the higher percentage of gross total tumor resections in GCG patients. Most surprising, the widely distributed hypothesis that GCG may imply a better prognosis than GBM could not be substantiated for our pediatric series. Future studies with larger patient numbers and molecular pathological analyses are still needed to corroborate the present findings and further elucidate the biology of GCG in children.     

Spinal canal metastases: a late complication of glioblastoma

Summary The case of a 41 year old woman with a cerebral glioblastoma is reported who developed paraplegia due to a pathologically confirmed spinal metastasis. This and 22 other case histories from the literature suggest that spinal seeding is a rather late complication of cerebral glioblastomas that can be diagnosed on clinical grounds with the help of myelography, CSF cytology and MR imaging.     

Epithelial and pseudoepithelial differentiation in glioblastoma and gliosarcoma: a comparative morphologic and molecular genetic study

BACKGROUND: Glioblastomas exhibit a remarkable tendency toward morphologic diversity. Although rare, pseudoepithelial components (adenoid or epithelioid) or true epithelial differentiation may occur, posing a significant diagnostic challenge. METHODS: Hematoxylin and eosin-stained slides were reviewed, and immunohistochemistry and fluorescence in situ hybridization were performed. RESULTS: The patients included 38 men and 20 women. The median age at diagnosis was 57 years (interquartile range [IQR], 50 years-67 years), and the median overall survival was 7 months (IQR, 4 months-11 months). "Adenoid" glioblastomas (A-GBM) predominated (48%). True epithelial glioblastomas (TE-GBM) were next most frequent based on morphology and immunohistochemistry (35%), followed by epithelioid glioblastomas (E-GBM) (17%). Overall, 25 (43%) tumors featured a sarcomatous component. Molecular cytogenetic abnormalities identified by fluorescent in situ hybridization in A-GBM, E-GBM, and TE-GBM, respectively, included p16 deletion/-9 (60%, 71%, 64%); chromosome 10 loss (40%, 63%, 57%), chromosome 7 gain without EGFR amplification (70%, 38%, 40%), EGFR amplification (10%, 50%, 27%), PTEN deletion (10%, 25%, 29%), PDGFRA amplification (10%, 25%, 0%), and RB1 deletion/-13q (50%, 0%, 14%). Abnormalities identified by immunohistochemistry included p21 immunonegativity (60%, 25%, 93%), which was most frequent in TE-GBM (P = .008), strong nuclear p53 staining (29%, 29%, 41%), strong membranous staining for epidermal growth factor receptor (EGFR) (21%, 63%, 19%), which was most frequent in E-GBM (P = .03), and an increased frequency of p27 immunonegativity in gliosarcomas (15% negative, 85% focal) compared with tumors without sarcoma (38% strongly positive) (P = .009). CONCLUSIONS: Pseudoepithelial and true epithelial morphology are rare phenomena in GBM and may be associated with a similar poor prognosis. These tumors demonstrate proportions of molecular genetic abnormalities varying somewhat from conventional GBM.     

Prevalence of acute and post-traumatic stress disorder and comorbid mental disorders in breast cancer patients during primary cancer care: a prospective study

This study aimed at the identification of acute and post-traumatic stress responses, and comorbid mental disorders in breast cancer patients. Structured clinical interviews for DSM-IV (SCID) were conducted post-surgery with 127 patients (t1). Screening measures were used to assess post-traumatic stress responses, anxiety, and depression at t1 and at 6 months follow-up (t2). Based on the SCID, prevalence rates were 2.4% for both, cancer-related ASD and PTSD. Experiences most frequently described as traumatic were the cancer diagnosis itself and subsequent feelings of uncertainty. Patients with lifetime PTSD (8.7%) were more likely to meet the criteria for cancer-related ASD or PTSD (OR=14.1). Prevalence estimates were 7.1% for Adjustment Disorder, 4.7% for Major Depression, 3.1% for Dysthymic Disorder and 6.3% for Generalized Anxiety Disorder. Using the screening instruments, IES-R, PCL-C and HADS, we found PTSD in 18.5% at t1 and 11.2-16.3% at t2. The estimates of anxiety and depression reveal rates of 39.6% (t1) and 32.7% (t2) for anxiety, as well as 16.0% (t1) and 13.3% (t2) for depression (t1) (cut-off> or =8). The diagnosis of a life-threatening illness has been included as a potential trauma in the DSM-IV. However, it has to be critically evaluated whether subjective feelings of uncertainty like fears of treatment count among traumatic stressors, and thus, whether the diagnosis of PTSD is appropriate in this group of cancer patients. However, a large number of women with emotional distress illustrate the need for psychosocial counseling and support in this early treatment phase.