Alkaline exonuclease and single-strand DNA (ssDNA) annealing proteins (SSAPs) are key components of DNA recombination and repair systems within many prokaryotes, bacteriophages and virus-like genetic ...elements. The recently sequenced β-proteobacterium Laribacter hongkongensis (strain HLHK9) encodes putative homologs of alkaline exonuclease (LHK-Exo) and SSAP (LHK-Bet) proteins on its 3.17 Mb genome. Here, we report the biophysical, biochemical and structural characterization of recombinant LHK-Exo protein. LHK-Exo digests linear double-stranded DNA molecules from their 5′-termini in a highly processive manner. Exonuclease activities are optimum at pH 8.2 and essentially require Mg2+ or Mn2+ ions. 5′-phosphorylated DNA substrates are preferred over dephosphorylated ones. The crystal structure of LHK-Exo was resolved to 1.9 Å, revealing a 'doughnut-shaped' toroidal trimeric arrangement with a central tapered channel, analogous to that of λ-exonuclease (Exo) from bacteriophage-λ. Active sites containing two bound Mg2+ ions on each of the three monomers were located in clefts exposed to this central channel. Crystal structures of LHK-Exo in complex with dAMP and ssDNA were determined to elucidate the structural basis for substrate recognition and binding. Through structure-guided mutational analysis, we discuss the roles played by various active site residues. A conserved two metal ion catalytic mechanism is proposed for this class of alkaline exonucleases.
Learning Objectives
After completing this course, the reader will be able to:
Explain the considerations of beneficence, nonmaleficence, autonomy, and justice necessary to the care and counseling of ...patients with glioblastoma receiving treatment with bevacizumab.
Identify the ethical issues inherent to bevacizumab discontinuation in patients with glioblastoma whose tumors have progressed on the drug.
This article is available for continuing medical education credit at CME.TheOncologist.com
Glioblastoma (GBM) is a highly lethal malignant brain tumor that expresses proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA), a monoclonal antibody against VEGF, is routinely used in the U.S. to treat GBM patients whose tumors have progressed following initial therapy. The Ethics Advisory Committee at the Dana‐Farber Cancer Institute was asked to provide consultation on two cases involving patients with recurrent GBM who were receiving bevacizumab. Despite evidence of disease progression, family members advocated for the continued use of bevacizumab because of its mild toxicity profile and concern that discontinuation would impair quality of life. However, continuing bevacizumab in this setting posed physical and financial risks to the patients and raised ethical concerns about resource allocation and justice.
We analyze the ethical questions regarding bevacizumab discontinuation in the setting of progressive GBM. We articulate the potential benefits and harms of continuing the drug and identify guiding principles for drug discontinuation that should be made transparent to patients and families. With the increasing availability of new, modestly toxic, expensive drugs for patients with advanced cancer, questions of when to stop these drugs will become increasingly relevant.
摘要
胶质母细胞瘤（GBM）是一种高度致死的恶性脑部肿瘤，并且能表达包括血管内皮生长因子（VEGF）在内的促血管生成因子。贝伐珠单抗（Avastin®；Genentech, Inc., South San Francisco, CA）是一种抗VEGF单克隆抗体，在美国常规用于经初始治疗后肿瘤出现进展的GBM患者。Dana‐Farber癌症研究所伦理咨询委员会应邀为两例接受贝伐珠单抗的复发性GBM患者提供建议。尽管有证据显示疾病进展，但家属主张继续使用贝伐珠单抗，因为其毒性轻，且考虑停药可能影响生活质量。然而，在这种情况下继用贝伐珠单抗会为患者带来生理和经济方面的风险，并可引发对资源分配与公平性的伦理担忧。
研究者分析了关于在进展性GBM情况下停用贝伐珠单抗的伦理问题，表述了继续使用该药的潜在效益与风险，并确定了患者及其家属明确易懂的停药指导原则。随着可用于晚期癌症患者的毒性适度但价格昂贵的新药增多，何时停用这些药物的问题将日益多见。
Ethical questions regarding bevacizumab discontinuation in the setting of progressive glioblastoma are evaluated.
Gimatecan is a lipophilic oral camptothecin analogue with preclinical activity in glioma models. We conducted a multicenter phase II trial to evaluate the efficacy of gimatecan in adults with ...recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, Eastern Cooperative Oncology Group performance status 0–1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m
2
was given orally once daily for 5 consecutive days during each 28-day cycle. The primary endpoint was progression-free survival at 6 months. A Simon 2-stage optimal design was used in which 19 patients were evaluated in the 1st stage, with an additional 36 patients accrued if
>
4 patients in stage 1 achieved PFS at 6 months. 29 patients were enrolled in the study, with median age of 58 years (range, 25–77 years); 58.6 % female. All patients received prior surgery, radiation therapy, and at least one chemotherapy regimen. The daily dose was reduced to 1.0 mg/m
2
after four of the first 10 patients experienced grade 4 hematologic toxicity. Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2 %), leukopenia (17.2 %) and neutropenia (10.3 %). None of the 19 patients treated at 1.0 mg/m
2
/day experienced grade 4 hematologic toxicity. One patient had a partial radiographic response by modified Macdonald criteria. Only 3 patients (12 %) were progression-free at 6 months. Median time to progression was 12.0 weeks (7.0, 17.0).Treatment with gimatecan 1.0 mg/m
2
/day for 5 days, repeated every 28-days showed minimal efficacy.
Over the past few years, understanding the genetic abnormalities associated with glioblastoma, the most common malignant primary tumor of the central nervous system, has increased dramatically. ...Mutation types and frequencies have been comprehensively assessed, glioblastoma subclasses have been defined based on gene expression and methylation analyses, and novel mutations implicated in gliomagenesis have been identified. Nonetheless, a critical disconnect exists between achieved scientific advances and failure to improve patient outcome. Currently, standard therapy incorporating surgery, cranial irradiation, and temozolomide chemotherapy is uniformly applied for all patients. With this approach, median survival remains unacceptably poor including fewer than 10% of patients surviving 5 years after diagnosis. Salvage therapies are ineffective with PFS-6 rates under 10% for non-bevacizumab regimens and 40% for bevacizumab. Furthermore, all patients ultimately progress on bevacizumab, and then typically die from rapidly progressive tumor. Innovative treatment strategies directed to distinct patient subsets defined by specific genetic and gene expression analyses represent an attractive therapeutic paradigm shift for this highly challenging complex tumor, offering promise to ultimately improve outcome.
Opinion Statement
Glioblastoma (GBM), the most common malignant primary tumor in adults, carries a dismal prognosis with an average median survival of 14–16 months. The current standard of care for ...newly diagnosed GBM consists of maximal safe resection followed by fractionated radiotherapy combined with concurrent temozolomide and 6 to 12 cycles of adjuvant temozolomide. The determination of treatment response and clinical decision-making in the treatment of GBM depends on accurate radiographic assessment. Differentiating treatment response from tumor progression is challenging and combines long-term follow-up using standard MRI, with assessing clinical status and corticosteroid dependency. At progression, bevacizumab is the mainstay of treatment. Incorporation of antiangiogenic therapies leads to rapid blood-brain barrier normalization with remarkable radiographic response often not accompanied by the expected survival benefit, further complicating imaging assessment. Improved radiographic interpretation criteria, such as the Response Assessment in Neuro-Oncology (RANO) criteria, incorporate non-enhancing disease but still fall short of definitely distinguishing tumor progression, pseudoresponse, and pseudoprogression. With new evolving treatment modalities for this devastating disease, advanced imaging modalities are increasingly becoming part of routine clinical care in a field where neuroimaging has such essential role in guiding treatment decisions and defining clinical trial eligibility and efficacy.
Abstract
Background
The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures ...should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.
Methods
A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living (I)ADL or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.
Results
A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).
Conclusion
Many different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
Neurologic side effects of cancer therapy can inhibit treatment, can be dose-limiting and can diminish quality-of-life. Neurotoxicity related to cancer therapy is a common problem in oncology ...practice and in clinical neurology. Recognition of neurologic complications of anticancer therapy is necessary due to potential confusion with metastatic disease, paraneoplastic syndromes or comorbid neurologic disorders that do not require reduction or discontinuation of therapy. Neurologic Complications of Cancer Therapy provides comprehensive coverage of the recognition and management of neurologic symptoms related to cancer therapy. The book includes sections on systemic therapy discussed by both agent and adverse event. The section on adverse events is particularly valuable to clinicians, allowing them to consult by symptom in cases where multiple agents have been administered and the source of the complication is uncertain. The systemic therapy section includes coverage of immunologic agents, biologics, and targeted therapies. The book also features sections on the complications of radiation therapy, complications of surgery and high-dose chemotherapy, and stem cell transplantation.
PDF
