To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors.
ASCO convened an Expert Panel and conducted a systematic review of the literature.
Thirty-two ...randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base.
Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.
Aβ Immunotherapy is a promising therapeutic approach for Alzheimer's disease. Preclinical studies demonstrate that plaque prevention is possible; however, the more relevant therapeutic removal of ...existing plaque has proven elusive. Monoclonal antibodies in development target both soluble and insoluble Aβ peptide. We hypothesized that antibody specificity for deposited plaque was critical for plaque removal since soluble Aβ peptide would block recognition of deposited forms. We developed a plaque-specific antibody that targets a modified Aβ peptide (Aβp3-42), which showed robust clearance of pre-existing plaque without causing microhemorrhage. Interestingly, a comparator N-terminal Aβ antibody 3D6, which binds both soluble and insoluble Aβ1-42, lacked efficacy for lowering existing plaque but manifested a significant microhemorrhage liability. Mechanistic studies suggested that the lack of efficacy for 3D6 was attributed to poor target engagement in plaques. These studies have profound implications for the development of therapeutic Aβ antibodies for Alzheimer's disease.
► Antibodies that bind soluble and insoluble Aβ lack therapeutic plaque lowering ► Plaque-specific anti-Aβp3-42 antibody removes pre-existing plaque ► Anti-Aβp3-42 antibody does not increase microhemorrhage ► Soluble Aβ binding will block target engagement in existing plaque
DeMattos et al. report a plaque-specific antibody that targets a modified Aβ peptide and shows robust clearance of pre-existing plaque without causing microhemorrhage. These findings have important implications for the possibility of using therapeutic Aβ antibodies in the treatment of Alzheimer's disease.
By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic ...criteria for Legius syndrome (LGSS).
We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.
We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.
The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
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While distinct stages of natural killer (NK) cell development have been defined, the molecular interactions that shape human NK cell maturation are poorly understood. Here we define intercellular ...interactions between developing NK cells and stromal cells which, through contact-dependent mechanisms, promote the generation of mature, functional human NK cells from CD34(+) precursors. We show that developing NK cells undergo unique, developmental stage-specific sustained and transient interactions with developmentally supportive stromal cells, and that the relative motility of NK cells increases as they move through development in vitro and ex vivo. These interactions include the formation of a synapse between developing NK cells and stromal cells, which we term the developmental synapse. Finally, we identify a role for CD56 in developmental synapse structure, NK cell motility and NK cell development. Thus, we define the developmental synapse leading to human NK cell functional maturation.
Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening ...adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell–mediated neurotoxicity warrants evaluation in prospective clinical trials.
•Neurotoxicity after CAR T cells is associated with cytokine release syndrome; serum levels of inflammatory markers correlate with severity.•Grade 3-4 neurotoxicity is a negative prognostic factor for OS, and a short course of steroids does not appear to alter outcome.
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VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.
Eighty ...bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A,
= 50) or pembrolizumab monotherapy (cohort B,
= 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.
Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% 95% confidence interval (CI), 16.3-41.5, median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant
, unmethylated
, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.
Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
BACKGROUND:Postoperative pain is a frequent cause for delayed discharge following outpatient procedures, including anorectal surgery. Both central and peripheral pain receptor sensitization are ...thought to contribute to postoperative pain. Blocking these receptors and preempting sensitization prevents hyperalgesia leading to lower pain medication requirements. Studies in the orthopedic, urologic, and gynecologic literature support this practice, but the use of preemptive analgesia in anorectal surgery is understudied.
OBJECTIVE:This study aimed to evaluate the effectiveness of preemptive analgesia in decreasing postoperative pain.
DESIGN:This is a randomized, double-blinded, placebo-controlled trial.
SETTING:This study was conducted at the University of Vermont Medical Center, a tertiary care referral center in Burlington, Vermont.
PATIENTS:Patients who were over 18 years of age, ASA Physical Status Classes I, II, or III, and undergoing surgery for anal fissure, fistula or condyloma or hemorrhoids were selected.
INTERVENTIONS:Preoperative oral acetaminophen and gabapentin followed by intravenous ketamine and dexamethasone were given before incision compared with oral placebos.
MAIN OUTCOME MEASURES:The primary outcomes measured were postoperative pain scores, percentage of patients utilizing breakthrough narcotics, and rates of side effects.
RESULTS:Ninety patients were enrolled. Because of patient withdrawal, screen failures, and loss to follow-up, 61 patients were analyzed (30 in the preemptive analgesia group and 31 in the control group). Patients in the active group had significantly less pain in the postanesthesia care unit and at 8 hours postoperatively. Significantly fewer participants in the active group used narcotics in the postanesthesia care unit and at 8 hours postoperatively. Average pain scores were excellent for both groups. There was no difference in the number of medication-related side effects between the 2 groups.
LIMITATIONS:This study was limited by the small sample size and excellent pain control in both groups.
CONCLUSIONS:Preemptive analgesia is safe and results in decreased pain in the early postoperative period following anorectal surgery. It should be implemented by surgeons performing these procedures. See Video Abstract at http://links.lww.com/DCR/A588.
Early‐phase clinical trials using oral inhibitors of MEK, the mitogen‐activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)‐associated tumors, ...particularly progressive low‐grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side‐effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients.
Implications for Practice
Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low‐grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1‐related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.
As treatment for neurofibromatosis type 1 (NF1)‐associated complex and inoperable tumors, MEK inhibitor therapy is likely to become more widely used. To aid clinicians who may not have experience with the use of this class of agents, the Clinical Care Advisory Board of the Children's Tumor Foundation presents an overview of the use of MEK inhibitors in the NF1 population, covering relevant clinical trial results, common side effects, basic symptom management, recommended screening guidelines, and patient counseling approaches.
Higher-order cognition emerges through the flexible interactions of large-scale brain networks, an aspect of temporal coordination that may be impaired in psychosis. Here, we map the dynamic ...functional architecture of the cerebral cortex in healthy young adults, leveraging this atlas of transient network configurations (states), to identify state- and network-specific disruptions in patients with schizophrenia and psychotic bipolar disorder. We demonstrate that dynamic connectivity profiles are reliable within participants, and can act as a fingerprint, identifying specific individuals within a larger group. Patients with psychotic illness exhibit intermittent disruptions within cortical networks previously associated with the disease, and the individual connectivity profiles within specific brain states predict the presence of active psychotic symptoms. Taken together, these results provide evidence for a reconfigurable dynamic architecture in the general population and suggest that prior reports of network disruptions in psychosis may reflect symptom-relevant transient abnormalities, rather than a time-invariant global deficit.
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