In patients with glioblastoma, the addition of bevacizumab to radiotherapy and temozolomide induction therapy and the use of bevacizumab maintenance therapy did not influence overall survival. ...Freedom from progression was slightly increased but at the cost of increased toxic effects.
Tumor progression in glioblastoma, the most common primary brain cancer,
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,
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is associated with deterioration in neurocognitive function,
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,
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decreased functional independence,
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and a progressive decrease in health-related quality of life.
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,
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After surgical resection, the standard of care for patients with newly diagnosed glioblastoma and a good Karnofsky performance score (≥70, on a scale of 0 to 100, with higher numbers indicating better functioning) is concurrent radiotherapy and temozolomide, followed by adjuvant temozolomide.
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–
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The prognosis remains poor; no further improvements in outcomes have been documented since the introduction of radiotherapy–temozolomide therapy in 2005.
Glioblastomas are characterized by overexpression . . .
Older patients with glioblastoma appear to benefit more from treatment combining a shorter course (3 weeks rather than 6 weeks) of radiotherapy together with temozolomide than from radiotherapy ...alone.
Glioblastoma is a fatal illness that is associated with a median survival of less than 2 years. Population studies of glioblastoma have shown that survival declines with increasing age,
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,
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and the incidence of glioblastoma is increasing, especially among the elderly.
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Older patients have been underrepresented in most randomized trials, in which the average age of participants is approximately 55 years, as compared with the population-based median for patients with glioblastoma of 65 years of age.
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In 2005, a phase 3 trial of radiotherapy alone (60 Gy over a period of 6 weeks) versus radiotherapy plus temozolomide showed longer survival . . .
Abstract
Background
The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for ...relapsed/refractory primary central nervous system lymphoma (PCNSL).
Methods
Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.
Results
Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.
Conclusion
These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.
Trial registration
JapicCTI-173646.
Programmed death ligand-1 (PD-L1), encoded by the
gene, is a target for immune checkpoint blockade; however, little is known about genomic
alterations. A subset of small-cell lung cancer (SCLC) ...exhibits increased copy number of chromosome 9p24, on which
resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether
is a target of recurrent genomic alterations.
We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.
By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where
resides) and focal, high-level amplification of
We found evidence for genomic targeting of
, suggesting selection during oncogenic transformation.
amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased
transcripts and high level expression of PD-L1.
A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of
Such tumors may be particularly susceptible to immune checkpoint blockade.
.
Clinical trial data of Carmustine implant (Gliadel Wafer) in Japanese patients with malignant glioma are limited; thus, we conducted a postmarketing surveillance study to evaluate the safety of ...Gliadel in real-world clinical practice in Japan. In this postmarketing surveillance study, all patients who received Gliadel placement for malignant glioma surgeries from its market launch (January 9, 2013) to July 10, 2013 were enrolled from 229 institutions using a central registration system. Up to eight wafers of Gliadel (containing 61.6 mg of carmustine) were used to cover the site of brain tumor resection intraoperatively according to the size and shape of the tumor resection cavity. The observation period lasted 3 months after Gliadel placement. Patients were followed up for 1 year postoperatively. Safety was assessed by the incidence of adverse events (AEs) and adverse drug reactions (ADRs). In total, 558 patients were included. Most patients (66.7%) received eight Gliadel wafers. The percentage of patients with ADRs was 35.7% (365 ADR episodes in 199 patients). Of the AEs of special interest, the most common were cerebral edema (22.2%, 124/558 patients), convulsion (9.9%, 55/558 patients), impaired healing (4.8%, 27/558 patients), and infection (3.4%, 19/558 patients). This first all-case postmarketing surveillance report of the safety of Gliadel in real-world clinical practice in Japan suggests that the risk of toxicity with Gliadel placement is relatively tolerable. The survival benefits of Gliadel placement should be evaluated and considered carefully by the clinician taking into account possible toxicities.
Summary The management of intracranial germ-cell tumours is complex because of varied clinical presentations, tumour sites, treatments and outcomes, and the need for multidisciplinary input. ...Participants of the 2013 Third International CNS Germ Cell Tumour Symposium (Cambridge, UK) agreed to undertake a multidisciplinary Delphi process to identify consensus in the clinical management of intracranial germ-cell tumours. 77 delegates from the symposium were selected as suitable experts in the field and were invited to participate in the Delphi survey, of which 64 (83%) responded to the invitation. Invited participants represented multiple disciplines from Asia, Australasia, Europe, and the Americas. 38 consensus statements encompassing aspects of intracranial germ-cell tumour work-up, staging, treatment, and follow-up were prepared. To achieve consensus, statements required at least 70% agreement from at least 60% of respondents. Overall, 34 (89%) of 38 statements met consensus criteria. This international Delphi approach has defined key areas of consensus that will help guide and streamline clinical management of patients with intracranial germ-cell tumours. Additionally, the Delphi approach identified areas of different understanding and clinical practice internationally in the management of these tumours, areas which should be the focus of future collaborative studies. Such efforts should translate into improved patient outcomes.
Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre–clinical study shows that eribulin, a specific inhibitor of ...telomerase reverse transcriptase (TERT)‐RNA‐dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation‐harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix‐assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA‐approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator‐initiated registration‐directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.
Eribulin inhibited the growth of TERT promoter mutation‐harboring glioblastoma cell lines in vitro. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma.
Glioblastoma is the most common primary malignant brain tumor in adults and is a challenging disease to treat. The current standard therapy includes maximal safe surgical resection, followed by a ...combination of radiation and chemotherapy with temozolomide. However, recurrence is quite common, so we continue to search for more effective treatments both for initial therapy and at the time of recurrence. This article will review the current standard of care and recent advances in therapy for newly-diagnosed and recurrent glioblastomas, based on the most authoritative guidelines, the National Cancer Institute's comprehensive cancer database Physician Data Query (PDQ®), and the National Comprehensive Cancer Network Clinical Practice Guidelines in OncologyTM for central nervous system cancers (V.1.2010), to elucidate the current position and in what direction we are advancing.
Background:How the time sequence of cardiopulmonary resuscitation (CPR) procedures is related to clinical outcomes in patients with out-of-hospital cardiac arrest (OHCA) remains unclear. This study ...examined the impact of the time interval from collapse to start of CPR (no-flow time, NF time) and the time interval from start of CPR to implementation of extracorporeal CPR (ECPR) (low-flow time, LF time) on neurological outcomes.Methods and Results:During the period from 2010 to 2015, we enrolled 85 patients who received ECPR. Fourteen patients (16.5%) showed favorable 30-day neurological recovery. NF time was shorter in the favorable neurological recovery group than in the unfavorable recovery group (1.4±3.0 vs. 5.2±5.8 min, P<0.05), though combined NF+LF times were similar in the 2 groups (50.1±13.2 vs. 55.1±14.8 min, P=0.25). Multivariate logistic regression analysis indicated that pupil diameter at arrival and NF time were independently associated with favorable neurological recovery. The optimal cut-off value of NF time to predict favorable neurological recovery was 5 min (area under curve: 0.70, P<0.05; sensitivity, 85.7%; specificity, 52.1%).Conclusions:The results suggest that NF time is a better predictor than NF+LF time for neurological outcomes in OHCA patients who received ECPR, and that start of CPR within 5 min after collapse is crucial for improving neurological outcomes followed by use of ECPR.
ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 ...phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.
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•MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells•MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383•Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy•Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models
Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.
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