ABSTRACT
BACKGROUND: MRI-Linac systems enable daily diffusion-weighed imaging (DWI) MRI scans for assessing glioblastoma tumor changes with radiotherapy treatment. PURPOSE: Our study assessed the image quality of echoplanar imaging (EPI)-DWI scans compared with turbo spin echo (TSE)-DWI scans at 0.35 Tesla (T) and compared the apparent diffusion coefficient (ADC) values and distortion of EPI-DWI on 0.35 T MRI-Linac compared to high-field diagnostic MRI scanners. METHODS: The calibrated National Institute of Standards and Technology (NIST)/Quantitative Imaging Biomarkers Alliance (QIBA) Diffusion Phantom was scanned on a 0.35 T MRI-Linac, and 1.5 T and 3 T MRI with EPI-DWI. Five patients were scanned on a 0.35 T MRI-Linac with a TSE-DWI sequence, and five other patients were scanned with EPI-DWI on a 0.35 T MRI-Linac and a 3 T MRI. The quality of images was compared between the TSE-DWI and EPI-DWI on the 0.35 T MRI-Linac assessing signal-to-noise ratios and presence of artifacts. EPI-DWI ADC values and distortion magnitude were measured and compared between 0.35 T MRI-Linac and high-field MRI for both phantom and patient studies. RESULTS: The average ADC differences between EPI-DWI acquired on the 0.35 T MRI-Linac, 1.5 T and 3 T MRI scanners and published references in the phantom study were 1.7%, 0.4% and 1.0%, respectively. Comparing the ADC values based on EPI-DWI in glioblastoma tumors, there was a 3.36% difference between 0.35 and 3 T measurements. Susceptibility-induced distortions in the EPI-DWI phantoms were 0.46 ± 1.51 mm for 0.35 MRI-Linac, 0.98 ± 0.51 mm for 1.5 T MRI and 1.14 ± 1.88 mm for 3 T MRI; for patients -0.47 ± 0.78 mm for 0.35 T and 1.73 ± 2.11 mm for 3 T MRIs. The mean deformable registration distortion for a phantom was 1.1 ± 0.22 mm, 3.5 ± 0.39 mm and 4.7 ± 0.37 mm for the 0.35 T MRI-Linac, 1.5 T MRI, and 3 T MRI scanners, respectively; for patients this distortion was -0.46 ± 0.57 mm for 0.35 T and 4.2 ± 0.41 mm for 3 T. EPI-DWI 0.35 T MRI-Linac images showed higher SNR and lack of artifacts compared with TSE-DWI, especially at higher b-values up to 1000 s/mm2. CONCLUSION: EPI-DWI on a 0.35 T MRI-Linac showed superior image quality compared with TSE-DWI, minor and less distortions than high-field diagnostic scanners, and comparable ADC values in phantoms and glioblastoma tumors. EPI-DWI should be investigated on the 0.35 T MRI-Linac for prediction of early response in patients with glioblastoma.
Subject(s)
Diffusion Magnetic Resonance Imaging , Glioblastoma , Phantoms, Imaging , Radiotherapy, Image-Guided , Glioblastoma/diagnostic imaging , Glioblastoma/radiotherapy , Humans , Radiotherapy, Image-Guided/methods , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/radiotherapy , Signal-To-Noise Ratio , Image Processing, Computer-Assisted/methodsABSTRACT
OBJECTIVE: This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily practice of the general neurologist. LATEST DEVELOPMENTS: The advances in molecular characterization of gliomas have translated into more accurate prognostication and tumor classification. Gliomas previously categorized by histological appearance solely as astrocytomas or oligodendrogliomas are now also defined by molecular features. Furthermore, ongoing clinical trials have incorporated these advances to tailor more effective treatments for specific glioma subtypes. ESSENTIAL POINTS: Despite recent insights into the molecular aspects of gliomas, these tumors remain incurable. Care for patients with these complex tumors requires a multidisciplinary team in which the general neurologist has an important role. Efforts focus on translating the latest data into more effective therapies that can prolong survival.
Subject(s)
Astrocytoma , Brain Neoplasms , Glioma , Oligodendroglioma , Adult , Humans , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Glioma/diagnosis , Glioma/genetics , Glioma/therapy , Prognosis , Mutation/genetics , Isocitrate Dehydrogenase/geneticsABSTRACT
Glioblastoma changes during chemoradiotherapy are inferred from high-field MRI before and after treatment but are rarely investigated during radiotherapy. The purpose of this study was to develop a deep learning network to automatically segment glioblastoma tumors on daily treatment set-up scans from the first glioblastoma patients treated on MRI-linac. Glioblastoma patients were prospectively imaged daily during chemoradiotherapy on 0.35T MRI-linac. Tumor and edema (tumor lesion) and resection cavity kinetics throughout the treatment were manually segmented on these daily MRI. Utilizing a convolutional neural network, an automatic segmentation deep learning network was built. A nine-fold cross-validation schema was used to train the network using 80:10:10 for training, validation, and testing. Thirty-six glioblastoma patients were imaged pre-treatment and 30 times during radiotherapy (n = 31 volumes, total of 930 MRIs). The average tumor lesion and resection cavity volumes were 94.56 ± 64.68 cc and 72.44 ± 35.08 cc, respectively. The average Dice similarity coefficient between manual and auto-segmentation for tumor lesion and resection cavity across all patients was 0.67 and 0.84, respectively. This is the first brain lesion segmentation network developed for MRI-linac. The network performed comparably to the only other published network for auto-segmentation of post-operative glioblastoma lesions. Segmented volumes can be utilized for adaptive radiotherapy and propagated across multiple MRI contrasts to create a prognostic model for glioblastoma based on multiparametric MRI.
ABSTRACT
BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).
Subject(s)
Antineoplastic Agents , Craniopharyngioma , Pituitary Neoplasms , Humans , Craniopharyngioma/drug therapy , Craniopharyngioma/genetics , Disease Progression , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/genetics , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Vemurafenib/adverse effects , Vemurafenib/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Remission InductionABSTRACT
During radiation therapy (RT) of glioblastoma, daily MRI with combination MRI-linear accelerator (MRI-Linac) systems has demonstrated significant anatomic changes, including evolving post-surgical cavity shrinkage. Cognitive function RT for brain tumors is correlated with radiation doses to healthy brain structures, especially the hippocampi. Therefore, this study investigates whether adaptive planning to the shrinking target could reduce normal brain RT dose with the goal of improving post-RT function. We evaluated 10 glioblastoma patients previously treated on a 0.35T MRI-Linac with a prescription of 60 Gy delivered in 30 fractions over six weeks without adaptation ("static plan") with concurrent temozolomide chemotherapy. Six weekly plans were created per patient. Reductions in the radiation dose to uninvolved hippocampi (maximum and mean) and brain (mean) were observed for weekly adaptive plans. The dose (Gy) to the hippocampi for static vs. weekly adaptive plans were, respectively: max 21 ± 13.7 vs. 15.2 ± 8.2 (p = 0.003) and mean 12.5 ± 6.7 vs. 8.4 ± 4.0 (p = 0.036). The mean brain dose was 20.6 ± 6.0 for static planning vs. 18.7 ± 6.8 for weekly adaptive planning (p = 0.005). Weekly adaptive re-planning has the potential to spare the brain and hippocampi from high-dose radiation, possibly reducing the neurocognitive side effects of RT for eligible patients.
ABSTRACT
BACKGROUND: Glioblastoma (GBM) cellularity correlates with whole brain spectroscopic MRI (sMRI) generated relative choline to N-Acetyl-Aspartate ratio (rChoNAA) mapping. In recurrent GBM (rGBM), tumor volume (TV) delineation is challenging and rChoNAA maps may assist with re-RT targeting. METHODS: Fourteen rGBM patients underwent sMRI in a prospective study. Whole brain sMRI was performed to generate rChoNAA maps. TVs were delineated by the union of rChoNAA ratio over 2 (rChoNAA > 2) on sMRI and T1PC. rChoNAA > 2 volumes were compared with multiparametric MRI sequences including T1PC, T2/FLAIR, diffusion-restriction on apparent diffusion coefficient (ADC) maps, and perfusion relative cerebral blood volume (rCBV). RESULTS: rChoNAA > 2 (mean 27.6 cc, range 6.6-79.1 cc) was different from other imaging modalities (P ≤ 0.05). Mean T1PC volumes were 10.7 cc (range 1.2-31.4 cc). The mean non-overlapping volume of rChoNAA > 2 and T1PC was 29.2 cm3. rChoNAA > 2 was 287% larger (range 23% smaller-873% larger) than T1PC. T2/FLAIR volumes (mean 111.7 cc, range 19.0-232.7 cc) were much larger than other modalities. rCBV volumes (mean 6.2 cc, range 0.2-19.1 cc) and ADC volumes were tiny (mean 0.8 cc, range 0-3.7 cc). Eight in-field failures were observed. Three patients failed outside T1PC but within rChoNAA > 2. No grade 3 toxicities attributable to re-RT were observed. Median progression-free and overall survival for re-RT patients were 6.5 and 7.1 months, respectively. CONCLUSIONS: Treatment of rGBM may be optimized by sMRI, and failure patterns suggest benefit for dose-escalation within sMRI-delineated volumes. Dose-escalation and radiologic-pathologic studies are underway to confirm the utility of sMRI in rGBM.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/pathology , Prospective Studies , Brain Neoplasms/pathology , Magnetic Resonance Imaging/methods , Brain/pathology , Diffusion Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. METHODS: This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. RESULTS: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3â19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3â4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). CONCLUSIONS: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.
Subject(s)
Glioma , Quinolines , Humans , Pyridines , Glioma/drug therapy , Glioma/genetics , Isocitrate Dehydrogenase/geneticsABSTRACT
PURPOSE OF REVIEW: Somatic point mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) are a defining feature of the majority of WHO grade 2-3 diffuse glioma and the most powerful positive prognostic factor for survival in gliomas. The purpose is to review experimental therapeutic approaches targeting IDH mutations in gliomas including small-molecule inhibitors, immunotherapies, and agents targeting mutant IDH-induced epigenetic and metabolic vulnerabilities. RECENT FINDINGS: Extensive preclinical work supports targeting mutant IDH (mIDH) in glioma. In heavily pretreated patients with mIDH glioma, enzyme inhibitors demonstrated to be well tolerated with preliminary evidence of clinical activity in nonenhancing tumors and enhancing tumors when used as single agents. In patients with newly diagnosed WHO grade 3 or 4 astrocytomas, a phase 1 study of a vaccine-targeting IDH1 R132H showed to be well tolerated and demonstrated immunogenicity with a 3-year progression-free and overall survival rates of 0.63 and 0.84, respectively. A variety of ongoing trials aim to target mIDH, including treatments with single agents or combinatory approaches in the upfront or recurrent setting. SUMMARY: mIDH are commonly found in gliomas and play a key role in gliomagenesis. This has led to studies using agents to directly inhibit them, immunotherapies, and epigenetic/metabolic drugs with varying and promising results. Ongoing studies may elucidate the precise role of these therapies and the best timing for treatment within the disease course.
Subject(s)
Brain Neoplasms , Glioma , Humans , Glioma/drug therapy , Glioma/genetics , Isocitrate Dehydrogenase/genetics , Mutation , Enzyme Inhibitors , Brain Neoplasms/drug therapy , Brain Neoplasms/geneticsABSTRACT
BACKGROUND: Neuro-oncology has grown tremendously since 2010, marked by increasing society membership, specialized clinical expertise, and new journals. Yet, modest improvement in racial/ethnic diversity amongst clinical trial participants, researchers, and clinicians led us to conduct a survey to identify opportunities to enhance diversity and inclusiveness amongst neuro-oncology professionals. METHODS: In summer 2020, the Women and Diversity Committee of the Society for Neuro-Oncology (SNO) distributed an anonymous online survey to members and affiliates including the European Association of Neuro-Oncology (EANO), Asian Society for Neuro-Oncology (ASNO), Society for Neuro-Oncology Latin America (SNOLA) and Society for Neuro-Oncology Sub-Saharan Africa (SNOSSA). The survey captured personal and professional characteristics, biases, effective mentorship qualities, career service metrics, and suggested field/society changes. Results were analyzed by geography, profession, age, racial/ethnic, and sexual identity. Standard descriptive statistics characterized the study population. RESULTS: The 386 respondents were predominantly female (58%) with a median age range of 40-49 years (31%), White (65%), and SNO members (97%). Most worked in North America (77%) in a research profession (67%). A majority of White respondents reported never experiencing biases (64%), while the majority of non-White respondents reported unconscious biases/microaggressions, followed by a lack of/limited mentorship. Qualitative assessments showcased that personal/professional success metrics were linked to needed improvements in diversity and inclusion efforts within the neuro-oncology field. CONCLUSIONS: The prevalence of racial/ethnic biases and poor mentorship rates amongst underrepresented groups in neuro-oncology is high and potentially linked to the limited diverse representation amongst members and affiliates. These findings warrant a swift implementation of equity and inclusion practices within the neuro-oncology field.
Subject(s)
Benchmarking , Medical Oncology , Adult , Ethnicity , Female , Humans , Middle Aged , Societies , Surveys and QuestionnairesABSTRACT
PURPOSE: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. RESULTS: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. CONCLUSIONS: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.
Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Diamines/therapeutic use , Glioma/drug therapy , Glioma/genetics , Isocitrate Dehydrogenase/genetics , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Pyridines/therapeutic use , Adolescent , Adult , Aged , Brain Neoplasms/pathology , Disease Progression , Female , Glioma/pathology , Humans , Male , Middle Aged , Young AdultABSTRACT
Glioblastoma is the most common and aggressive primary brain tumor. Despite standard multimodality therapy, median overall survival remains poor with a 5-year survival rate of approximately 5% in most studies (range 4.7-13.0%). Strong interest in targeting IDH mutations has led to a variety of studies in both hematologic malignancies and solid tumors and to the approval of IDH inhibitors such as ivosidenib, an IDH1 inhibitor, in hematologic malignancies. Here, we present the first case study of a patient with a recurrent IDH1-mutant glioblastoma who experienced improved seizure control and radiographic stable disease for more than 4 years while treated with ivosidenib. Such findings support the further development of IDH inhibitors as single agents and/or in combination for the treatment of IDH-mutant glioma.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Glycine/analogs & derivatives , Isocitrate Dehydrogenase/antagonists & inhibitors , Neoplasm Recurrence, Local/drug therapy , Pyridines/therapeutic use , Adult , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Clinical Trials, Phase I as Topic , Female , Glioblastoma/genetics , Glioblastoma/pathology , Glycine/therapeutic use , Humans , Isocitrate Dehydrogenase/genetics , Mutation , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , PrognosisABSTRACT
PURPOSE: Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS: We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with mIDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS: In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION: In patients with mIDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
Subject(s)
Brain Neoplasms/drug therapy , Glioma/drug therapy , Glycine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Pyridines/administration & dosage , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Female , Glioma/enzymology , Glioma/genetics , Glioma/pathology , Glycine/administration & dosage , Glycine/adverse effects , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Male , Middle Aged , Mutation , Pyridines/adverse effects , Young AdultABSTRACT
OBJECT: Diffuse tumor invasion in multifocal/multicentric GBM (mGBM) often foreshadows poor survival outcome. The correlation between extent of resection in gliomas and patient outcome is well described. The objective of this study was to assess the effect of gross total resection compared to biopsy for mGBM on patient overall survival and progression free survival. METHODS: Thirty-four patients with mGBM received either biopsy or resection of their largest enhancing lesion from 2011 to 2019. Relevant demographic, peri-operative, and radiographic data were collected. Tumor burden and extent of resection was assessed through measurement of pre-operative and post-operative contrast-enhancing volume. An adjusted Kaplan-Meier survival analysis was conducted using inverse probability of treatment weighting (IPTW) to account for the covariates of age, number of lesions, satellite tumor volume, total pre-operative tumor volume, degree of spread, and location. RESULTS: Thirty-four patients were identified with sixteen (47.1%) and eighteen (52.9%) patients receiving resection and biopsy respectively. Patients receiving resection exhibited greater median overall survival but not progression free survival compared to biopsy on IPTW analysis (p = 0.026, p = 0.411). Greater than or equal to 85% extent of resection was significantly associated with increased median overall survival (p = 0.016). CONCLUSION: Overall, our study suggests that resection of the largest contrast-enhancing lesion may provide a survival benefit. Our volumetric analysis suggests that a greater degree of resection results in improved survival. Employing IPTW analysis, we sought to control for selection bias in our retrospective analysis. Thus, aggressive surgical treatment of mGBM may offer improved outcomes. Further clinical trials are needed.
Subject(s)
Brain Neoplasms/mortality , Brain Neoplasms/surgery , Glioblastoma/mortality , Glioblastoma/surgery , Biopsy , Female , Humans , Kaplan-Meier Estimate , Male , Retrospective Studies , Treatment OutcomeABSTRACT
HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms, Male/drug therapy , Breast Neoplasms/drug therapy , Receptor, ErbB-2/antagonists & inhibitors , Receptors, Estrogen/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms, Male/genetics , Breast Neoplasms, Male/pathology , Cell Line, Tumor , DNA Mutational Analysis , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Drug Synergism , Estrogen Receptor Antagonists/pharmacology , Estrogen Receptor Antagonists/therapeutic use , Female , Fulvestrant/pharmacology , Fulvestrant/therapeutic use , Humans , Male , Middle Aged , Mutation , Prospective Studies , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Treatment OutcomeABSTRACT
Neurological emergencies are frequently catastrophic events in the course of haematological malignancies (HM) that, if not promptly recognized and treated, may lead to lethal outcomes or chronic sequelae. They may occur at any time during the disease course, but are more frequently observed following relapse. Practice guidelines are lacking in the management of most central nervous system (CNS) complications in HM. Herein we review the pathophysiology, presentation and treatment of elevated intracranial pressure, spinal cord compression, status epilepticus, neurovascular complications, CNS infection, leucostasis and hyperviscosity. Further, we discuss the expanding spectrum of neurological complications of old and novel treatments in HM.
Subject(s)
Hematologic Neoplasms , Intracranial Hypertension , Spinal Cord Compression , Status Epilepticus , Hematologic Neoplasms/complications , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Humans , Intracranial Hypertension/diagnosis , Intracranial Hypertension/pathology , Intracranial Hypertension/therapy , Practice Guidelines as Topic , Spinal Cord Compression/etiology , Spinal Cord Compression/pathology , Spinal Cord Compression/therapy , Status Epilepticus/etiology , Status Epilepticus/pathology , Status Epilepticus/therapyABSTRACT
Between 11 and 37% of extranodal marginal zone lymphoma (EMZL) patients present with disease involvement in multiple mucosal sites (MMS). We analyzed 405 EMZL patients seen between 1995 and 2017: 265 (65.4%) patients presented with stage I disease, 49 of 309 (15.8%) patients with bone marrow involvement, and 35 of 328 (10.7%) patients with monoclonal gammopathy (MG). Forty-three (10.6%) patients had MMS presentation, which was more frequently seen in patients aged >60 years (55.8%). Five (17.9%) of 28 MMS patients had MG. MMS patients commonly exhibited the International Prognostic Index (IPI) >2 (79.1%), Follicular Lymphoma International Prognostic Index (FLIPI) >2 (39.5%), and Mucosa-Associated Lymphoid Tissue Lymphoma International Prognostic Index (MALT-IPI) 2-3 (60.5%). Both MMS presentation and MG were associated with shorter survival univariately. In multivariable Cox regression models, shorter progression-free survival (PFS) and overall survival (OS) were observed in patients with MMS (hazard ratio [HR] = 3.08 and 2.92, respectively), age ≥60 years (HR = 1.52 and 2.45, respectively), and in patients who failed to attain a complete remission following initial therapy (HR = 3.27 and 2.13, respectively). Elevated lactate dehydrogenase was associated with shorter PFS (HR = 1.92), while anemia (HR = 2.46) was associated with shortened OS. MALT-IPI ≥2 (HR = 2.47 and 4.75), FLIPI >2 (HR = 1.65 and 2.09), and IPI >2 (HR = 2.09 and 1.73) were associated with shorter PFS and OS, respectively. Higher grade transformation (HGT) occurred in 11 (25.6%) MMS patients with a 5-year cumulative incidence of 13.2% (95% CI 4.7-26.1%). EMZL patients with MMS presentation represent a novel clinical subset associated with shorter PFS, OS, and higher incidence of HGT that needs novel therapeutic approaches.
Subject(s)
Lymphoma, B-Cell, Marginal Zone/mortality , Models, Biological , Age Factors , Aged , Disease-Free Survival , Female , Humans , Incidence , L-Lactate Dehydrogenase/blood , Lymphoma, B-Cell, Marginal Zone/blood , Lymphoma, B-Cell, Marginal Zone/therapy , Male , Middle Aged , Neoplasm Proteins/blood , Neoplasm Staging , Survival RateABSTRACT
Primary vitreoretinal lymphoma (PVRL) is a subset of primary CNS lymphoma that presents as isolated ocular disease without brain involvement. Although ocular radiotherapy (RT) is an effective treatment for PVRL, the optimal treatment is uncertain. PVRL may later involve the brain in 56%-85% of patients. We report on 12 PVRL patients treated with a combination of bilateral RT and a systemic chemotherapy (CT) regimen containing high-dose methotrexate (M). Ten received RT (30-40 Gy) followed by CT, one received RT, and one was treated with intravitreal M; all achieved a complete response (CR). Three patients had tumor recurrence in the brain and received CT and one patient relapsed in the eye with a second recurrence in the brain. Three patients achieved CR-2 remain alive and one died of dementia. One died from recurrent CNS disease. With a median follow of 68 months (range, 17-154 months), median progression-free and overall survival have not been reached. Bilateral RT followed by M-based CT is an effective treatment for reducing CNS progression and prolonging survival.
Subject(s)
Brain Neoplasms , Chemoradiotherapy , Intraocular Lymphoma , Methotrexate/administration & dosage , Neoplasm Recurrence, Local , Retinal Neoplasms , Adult , Aged , Aged, 80 and over , Brain Neoplasms/mortality , Brain Neoplasms/therapy , Disease-Free Survival , Female , Follow-Up Studies , Humans , Intraocular Lymphoma/mortality , Intraocular Lymphoma/therapy , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/therapy , Retinal Neoplasms/mortality , Retinal Neoplasms/therapy , Survival Rate , Time FactorsABSTRACT
PURPOSE: Given the paucity of data on higher-grade transformation (HGT) to aggressive lymphoma in patients with marginal zone lymphoma (MZL), we report on a large cohort of patients, identify risk factors, and determine HGT impact on overall survival (OS). METHODS: We analyzed 453 patients with biopsy-proven MZL seen at our institution between 1995 and 2016. Kaplan-Meier, Cox proportional hazards regression, and competing risk methods were used in analyses of time-to-event outcomes. RESULTS: Thirty-four patients (7.5%) had biopsy-proven HGT to diffuse large B-cell lymphoma, including seven (21%) diagnosed at the time of initial MZL diagnosis. Among 27 incident patients, median time to HGT was 29 months (range, 1.3 to 135 months). Higher risk of HGT was observed in those with nodal/splenic MZL (subdistribution hazard ratio [SHR], 2.60; P = .023). On multivariable competing risk analysis, elevated lactate dehydrogenase (SHR, 2.71), more than four nodal sites (SHR, 2.97), and failure to achieve complete remission (CR) after initial treatment (SHR, 3.76) conveyed significantly higher risk for HGT ( P < .02). International Prognostic Index (IPI), Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were only significant predictors of HGT univariably. Patients with HGT had shorter OS (5-year rate, 65% v 86%; P < .001). Patients who presented with HGT within 12 months since MZL diagnosis had shorter OS than those with HGT at MZL diagnosis combined with those with HGT more than 12 months later (4-year rate, 43% v 81%, P < .001). Non-CR and higher scores of IPI, Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were the main significant predictors for shorter progression-free survival and OS. CONCLUSION: Failure to achieve CR after initial treatment, elevated lactate dehydrogenase, and more than four nodal sites at the time of MZL diagnosis are the main predictors of increased risk of HGT. Patients with HGT have shorter OS.