Reirradiation versus systemic therapy versus combination therapy for recurrent high-grade glioma: a systematic review and meta-analysis of survival and toxicity

Purpose: This review compares reirradiation (reRT), systemic therapy and combination therapy (reRT & systemic therapy) with regards to overall survival (OS), progression-free survival (PFS), adverse effects (AEs) and quality of life (QoL) in patients with recurrent high-grade glioma (rHGG). Methods: A search was performed on PubMed, Scopus, Embase and CENTRAL. Studies reporting OS, PFS, AEs and/or QoL and encompassing the following groups were included; reirradiation vs systemic therapy, combination therapy vs systemic therapy, combination therapy vs reRT, and bevacizumab-based combination therapy vs reRT with/without non-bevacizumab-based systemic therapy. Meta-analyses were performed utilising a random effects model. Certainty of evidence was assessed using GRADE. Results: Thirty-one studies (three randomised, twenty-eight non-randomised) comprising 2084 participants were included. In the combination therapy vs systemic therapy group, combination therapy improved PFS (HR 0.57 (95% CI 0.41–0.79); low certainty) and OS (HR 0.73 (95% CI 0.56–0.95); low certainty) and there was no difference in grade 3 + AEs (RR 1.03 (95% CI 0.57–1.86); very low certainty). In the combination therapy vs reRT group, combination therapy improved PFS (HR 0.52 (95% CI 0.38–0.72); low certainty) and OS (HR 0.69 (95% CI 0.52–0.93); low certainty). In the bevacizumab-based combination therapy vs reRT with/without non-bevacizumab-based systemic therapy group, adding bevacizumab improved PFS (HR 0.46 (95% CI 0.27–0.77); low certainty) and OS (HR 0.42 (95% CI 0.24–0.72; low certainty) and reduced radionecrosis (RR 0.17 (95% CI 0.06–0.48); low certainty). Conclusions: Combination therapy may improve OS and PFS with acceptable toxicities in patients with rHGG compared to reRT or systemic therapy alone. Particularly, combining bevacizumab with reRT prophylactically reduces radionecrosis. Registration: CRD42022291741

Lumbar Kinematics, Functional Disability and Fear Avoidance Beliefs Among Adults with Nonspecific Chronic Low Back Pain

Objectives: This study aimed to examine correlations between lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain (LBP). Methods: This crosssectional study was conducted between March and December 2014. A total of 32 adults diagnosed with nonspecific chronic LBP were recruited from outpatients attending either an orthopaedic clinic at a university hospital or a private physiotherapy clinic in Malaysia. Lumbar kinematics were measured using sensors attached at the first lumbar (L1) and second sacral (S2) vertebrae levels. The Oswestry Disability Index (ODI) and Fear-Avoidance Beliefs Questionnaire (FABQ) were used to assess degree of functional disability and fear avoidance beliefs, respectively. Results: For maximum range of motion, positive correlations were observed between ODI scores and right lateral flexion and right rotation (P = 0.01 each), although there was a negative correlation with left rotation (P = 0.03). With maximum angular velocity, ODI scores were positively correlated with right and left lateral flexion L1 (P = 0.01 and <0.01, respectively) but negatively correlated with left lateral flexion L2 (P= 0.04). Regarding minimum angular velocity, ODI scores were positively correlated with left lateral flexion S2 (P <0.01) but negatively correlated with right and left lateral flexion L1 (P = 0.02 each), right rotation L1 (P = 0.02) and left rotation S2 (P = 0.01). No significant correlations were found between lumbar kinematics and FABQ scores. Conclusion: These findings suggest that certain lumbar kinematic parameters are correlated with functional disability, but not with fear avoidance beliefs

Supersymmetric Electroweak Corrections to the Higgs Boson Decays into Chargino or Neutralino Pair

We investigate the supersymmetric electroweak corrections to the decay widths of the CP-odd and the heavy CP-even Higgs bosons into chargino or neutralino pair in the framework of the Minimal Supersymmetric Standard Model. The corrections involve the contributions of the order $O(\alpha_{ew} m_{t(b)}^3/m_W^3)$, $O(\alpha_{ew} m_{t(b)}^2/m_W^2)$ and $O(\alpha_{ew} m_{t(b)}/m_W)$. The detailed calculations of the electroweak corrections to the following decay processes: $A^0/H^0 \to \tilde{\chi}^+_1 \tilde{\chi}^-_1$ and $A^0/H^0 \to \tilde{\chi}^0_2 \tilde{\chi}^0_2$ are presented in this paper. We find that these relative corrections maybe rather large quantitatively, and can exceed 10% in some regions of parameter space. The corrections to the decay $A^0/H^0 \to \tilde{\chi}^0_1 \tilde{\chi}^0_2$ can be obtained analogously, but our results show that they are very small and can be neglected.Comment: 25 pages, 9 figures,accepted by Physical Review

Single gluino production in the R-parity lepton number violating MSSM at the LHC

We examine the $R_{p}$-violating signal of single gluino production associated with a charged lepton or neutrino at the large hadron collider (LHC), in the model of R-parity relaxed supersymmetric model. If the parameters in the ${\rlap/R}_p$ supersymmetric interactions are not too small, and the mass of gluino is considered in the range from several GeV (as the Lightest Supersymmetric Particle) to 800 GeV, the cross section of the single gluino production via Drell-Yan processes can be in the order of $10^2 \sim 10^3$ femto barn, and that via gluon fusion in the order of $10^{-1} \sim 10^3$ femto barn. If the gluino decay can be well detected in the CERN LHC, this process provides a prospective way to probe supersymmetry and $R_p$ violation.Comment: LaTex, 22 pages, 5 EPS file

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors

Background GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. Patients and Methods Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. Results Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). Conclusion GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. Implications for Practice This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials

Effects of the R-parity violation in the minimal supersymmetric standard model on dilepton pair production at the CERN LHC

We investigate in detail the effects of the R-parity lepton number violation in the minimal supersymmetric standard model (MSSM) on the parent process $pp \to e^+ e^- + X$ at the CERN Large Hadron Collider (LHC). The numerical comparisons between the contributions of the R-parity violating effects to the parent process via the Drell-Yan subprocess and the gluon-gluon fusion are made. We find that the R-violating effects on $e^+ e^-$ pair production at the LHC could be significant. The results show that the cross section of the $e^+ e^-$ pair productions via gluon-gluon collision at the LHC can be of the order of $10^2$ fb, and this subprocess maybe competitive with the production mechanism via the Drell-Yan subprocess. We give also quantitatively the analysis of the effects from both the mass of sneutrino and coupling strength of the R-parity violating interactions.Comment: 18 pages, 10 figures, accepted by Phys. Rev.

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

BACKGROUND: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. METHODS: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. RESULTS: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. CONCLUSIONS: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations

The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype