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Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10-10 and p = 8.5 × 10-9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10-4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10-8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.
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Pérdida de Heterocigocidad , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Pérdida de Heterocigocidad/genética , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Estudios Retrospectivos , Mutación/genética , Estudios ProspectivosRESUMEN
PURPOSE: Papillary craniopharyngiomas can cause considerable morbidity due to mass effect and potential surgical complications. These tumors are known to harbor BRAF V600 mutations, which make them exquisitely sensitive to BRAF inhibitors. METHODS: The patient is a 59 year old man with a progressive suprasellar lesion that was radiographically consistent with a papillary craniopharyngioma. He was consented to an Institution Review Board-approved protocol, which permits sequencing of cell free DNA in plasma and the collection and reporting of clinical data. RESULTS: The patient declined surgical resection and was empirically treated with dabrafenib at 150 mg twice daily. Treatment response was demonstrated after 19 days, confirming the diagnosis. After achieving a near complete response after 6.5 months on drug, a decision was made to deescalate treatment to dabrafenib 75 mg twice daily with subsequent tumor stability for 2.5 months. CONCLUSION: Patients with a suspected papillary craniopharyngioma can be challenged with dabrafenib as a potentially effective diagnostic and therapeutic strategy, given that rapid regression with dabrafenib is only observed in tumors harboring a BRAF V600 mutation. Further work is needed to explore the optimal regimen and dose of the targeted therapy.
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Craneofaringioma , Neoplasias Hipofisarias , Masculino , Humanos , Persona de Mediana Edad , Craneofaringioma/patología , Proteínas Proto-Oncogénicas B-raf/genética , Mutación , Neoplasias Hipofisarias/cirugíaRESUMEN
INTRODUCTION: Aggressive prolactinomas are life-limiting tumors without a standard of care treatment option after the oral alkylator, temozolomide, fails to provide tumor control. METHODS: We reviewed an institutional database of pituitary tumors for patients with aggressive prolactinomas who progressed following treatment with a dopamine receptor agonist, radiotherapy and temozolomide. Within this cohort, we identified four patients who were treated with everolimus and we report their response to this therapy. Treatment response was determined by a neuroradiologist, who manually performed volumetric assessment and determined treatment response by Response Assessments in Neuro-Oncology (RANO) criteria. RESULTS: Three of four patients who were treated with everolimus had a biochemical response to therapy and all patients derived a clinically meaningful benefit based upon suppression of tumor growth. While the best overall response as assessed by RANO criteria was stable disease for the four patients, a minor regression in tumor size was appreciated in two of the four patients. CONCLUSION: Everolimus is an active agent in the treatment of prolactinomas that warrants further investigation.
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Neoplasias Hipofisarias , Prolactinoma , Humanos , Prolactinoma/patología , Everolimus/uso terapéutico , Temozolomida/uso terapéutico , Neoplasias Hipofisarias/patología , Agonistas de DopaminaRESUMEN
PURPOSE: Understanding the molecular landscape of glioblastoma (GBM) is increasingly important in the age of targeted therapy. O-6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation and EGFR amplification are markers that may play a role in prognostication, treatment, and/or clinical trial eligibility. Quantification of MGMT and EGFR protein expression may offer an alternative strategy towards understanding GBM. Here, we quantify baseline expression of MGMT and EGFR protein in newly diagnosed GBM samples using mass spectrometry. We correlate findings with MGMT methylation and EGFR amplification statuses and survival. METHODS: We retrospectively identified adult patients with newly diagnosed resected GBM. MGMT and EGFR protein expression were quantified using a selected reaction monitoring mass spectrometry assay. Protein levels were correlated with MGMT methylation and EGFR amplification and survival data. RESULTS: We found a statistically significant association between MGMT protein expression and promoter methylation status (p = 0.02) as well as between EGFR protein expression and EGFR amplification (p < 0.0001). EGFR protein expression and amplification were more tightly associated than MGMT protein expression and methylation. Only MGMT promoter methylation was statistically significantly associated with progression-free and overall survival. CONCLUSIONS: Unlike EGFR protein expression and EGFR amplification which are strongly associated, only a weak association was seen between MGMT protein expression and promoter methylation. Quantification of MGMT protein expression was inferior to MGMT methylation for prognostication in GBM. Discordance was observed between EGFR amplification and EGFR protein expression; additional study is warranted to determine whether EGFR protein expression is a better biomarker than EGFR amplification for clinical decisions and trial enrollment.
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Neoplasias Encefálicas/mortalidad , Quimioradioterapia/mortalidad , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Glioblastoma/mortalidad , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Terapia Combinada , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Estudios de Seguimiento , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Estudios Retrospectivos , Tasa de Supervivencia , Temozolomida/uso terapéutico , Proteínas Supresoras de Tumor/genéticaRESUMEN
Neurologic complications of cancer are common and are frequently life-threatening events. Certain neurologic emergencies occur more frequently in the cancer population, specifically elevated intracranial pressure, epidural cord compression, status epilepticus, ischemic and hemorrhagic stroke, central nervous system infection, and treatment-associated neurologic dysfunction. These emergencies require early diagnosis and prompt treatment to ensure the best possible outcome and are best managed in the intensive care unit. This article reviews the presentation, pathophysiology, and management of the most common causes of acute neurologic decompensation in the patient with cancer.
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Antineoplásicos/efectos adversos , Cuidados Críticos , Neoplasias/complicaciones , Enfermedades del Sistema Nervioso/etiología , Compresión de la Médula Espinal/etiología , Estado Epiléptico/etiología , Accidente Cerebrovascular/etiología , Cuidados Críticos/métodos , Humanos , Presión Intracraneal , Imagen por Resonancia Magnética , Neoplasias/fisiopatología , Neoplasias/terapia , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Guías de Práctica Clínica como Asunto , Compresión de la Médula Espinal/diagnóstico , Compresión de la Médula Espinal/terapia , Estado Epiléptico/diagnóstico , Estado Epiléptico/terapia , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapiaRESUMEN
During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8 %). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11 %). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21 %. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90 %) and had a low rate of IDH1 R132H mutation (50 %). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/patología , Mutación/genética , Proteínas de Neoplasias/genética , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Receptores ErbB/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Recurrencia Local de Neoplasia/genética , Pronóstico , Proteína p53 Supresora de Tumor/genética , Proteína Nuclear Ligada al Cromosoma X/genéticaRESUMEN
Background: The 2016 WHO classification described a subtype of midline gliomas harboring histone 3 (H3) K27M alterations, and the 2021 edition added a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. The incidence and clinical behavior of leptomeningeal disease (LMD) in these patients is not well defined. Methods: Retrospective study of patients with H3-altered gliomas diagnosed from 01/2012 to 08/2021; histone mutations were identified through next-generation sequencing (NGS) of tumor biopsy and/or cerebrospinal fluid (CSF). Results: We identified 42 patients harboring H3 mutations (K27M mutations in 33 patients, G34R/V in 8, and both in one). Median age was 21 (4-70); 27 were male. LMD was diagnosed in 21/42 (50%) patients, corresponding to a 3-year cumulative incidence of 44.7% (95% confidence interval (CI): 26.1%-63.4%) for the K27-mutant group and a 1-year cumulative incidence of 37.5% in the G34-mutant group (95% CI: 0.01%-74.4%; no events after 1 year). Median time from tumor diagnosis to LMD was 12.9 months for H3-K27 patients and 5.6 months for H3-G34 patients. H3 mutation was detected in CSF in all patients with LMD who had NGS (8 H3-K27-mutant patients). In the H3-K27-mutant group, modeled risk of death was increased in patients who developed LMD (hazard ratio: 7.37, 95% CI: 2.98-18.23, P < .0001). Conclusions: In our cohort, 50% of patients developed LMD. Although further studies are needed, CSF ctDNA characterization may aid in identifying molecular tumor profiles in glioma patients with LMD, and neuroaxis imaging and CSF NGS should be considered for early LMD detection.
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Evidence-based enhanced recovery after surgery (ERAS) programs aim to improve patient outcomes and shorten hospital stays. The objective of this study is to describe the development, implementation, and evolution of an ERAS protocol to optimize the perioperative management for patients undergoing endoscopic skull base surgery for pituitary tumors. A systematic review of the literature was performed, best practices were discussed with stakeholders, and institutional guidelines were established and implemented. Key performance indicators (KPI) were measured and patient-reported outcome surveys were collected. The ERAS protocol was introduced successfully at our institution. We describe the process of initiation of the program and the perioperative management of our patients. We demonstrated the feasibility of integration of ERAS protocols for pituitary tumors with multidisciplinary engagement, with a particular emphasis on the use of data informatics and metrics to monitor outcomes. We expect that this approach will translate to improved quality of care for these often-complex patients.
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OBJECTIVES: To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma METHODS: Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021 RESULTS: Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively. DISCUSSION: Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH-mutant grade 2-3 gliomas with encouraging PFS and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population. CLASSIFICATION OF EVIDENCE: This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.
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BACKGROUND AND IMPORTANCE: Aggressive pituitary adenomas (APAs) are pituitary tumors that are refractory to standard treatments and carry a poor prognosis. Current treatment guidelines are not standardized but combine surgical resection, radiation therapy, and chemotherapy. Temozolomide is the only chemotherapeutic agent with documented effectiveness and is recommended for APA in European Society of Endocrinology clinical guidelines. CLINICAL PRESENTATION: A 57-year-old man presented with visual deterioration and bitemporal hemianopsia. MRI of the brain demonstrated a sellar mass suspected to be pituitary macroadenoma with displacement of the stalk and optic nerve impingement. The patient underwent stereotactic endoscopic transsphenoidal resection of the mass. Postoperative MRI demonstrated gross total resection. Pathology revealed a sparsely granulated corticotroph adenoma with malignant transformation. Immunohistochemistry showed loss of expression of MLH1 and PMS2 in the tumor cells. Proton therapy was recommended given an elevated Ki67 index and p53 positivity. Before radiotherapy, there was no radiographic evidence of residual tumor. Temozolomide therapy was initiated after surveillance MRI showed recurrence at 16 months postoperatively. However, MRI demonstrated marked progression after 3 cycles. Next-generation sequencing using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C . Immunotherapy with ipilimumab/nivolumab was initiated, and MRI demonstrated no residual tumor burden 34 months postoperatively. CONCLUSION: APA is a tumor with frequent recurrence and a short median expected length of survival. Here, we demonstrate the utility of immunotherapy in a single case report of APA, with complete resolution of recurrent APA and improved survival compared with life expectancy.
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Adenoma , Neoplasias Hipofisarias , Adenoma/diagnóstico por imagen , Adenoma/tratamiento farmacológico , Adenoma/genética , Reparación de la Incompatibilidad de ADN , Humanos , Inhibidores de Puntos de Control Inmunológico , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/genética , Temozolomida/uso terapéuticoRESUMEN
CONTEXT: Aggressive pituitary tumors that have progressed following temozolomide have limited treatment options. Peptide receptor radionuclide therapy and immunotherapy may have a complementary role in the management of these tumors. METHODS: We provide follow-up data on a previously reported patient with a hypermutated recurrent tumor. The patient in this report provided written informed consent for tumor sequencing and review of medical records on an institutional review board-approved research protocol (NCT01775072). RESULTS: This patient with a corticotroph pituitary carcinoma with alkylator-induced somatic hypermutation has remained on treatment with ipilimumab and nivolumab for 3.5 years and remains clinically well. After an initial partial response to checkpoint inhibitors, she has had several recurrences that have undergone immunoediting of subclonal mutations, which have been effectively treated with continuation of immunotherapy, surgery, external beam radiation, and 177Lu-DOTATATE. Following external beam radiotherapy (RT), she had radiographic evidence of an abscopal response at a distant site of disease suggesting a synergism between checkpoint inhibitors and RT. Following treatment with 177Lu-DOTATATE, the patient had a partial response with a 61% reduction in volume of the target lesion. CONCLUSION: In patients with aggressive pituitary tumors, treatment with checkpoint inhibitors may trigger an abscopal response from RT. With appropriate selection, an additional efficacious treatment, 177Lu-DOTATATE, may be available for a limited number of patients with aggressive pituitary tumors, including patients who have progressed on temozolomide and exhibit increased somatostatin receptor expression on 68Ga-DOTATATE positron emission tomography.
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A small subset of pituitary adenomas grows despite maximal treatment with standard therapies; namely, surgery and radiotherapy. These aggressive tumors demonstrate 2 patterns of growth: they may be locally aggressive or metastasize distantly, either hematogenously or through the spinal fluid. Further surgery and radiotherapy may be helpful for palliation of symptoms, but they are rarely definitive in the management of these malignant tumors. The only chemotherapy with established activity in the treatment of pituitary tumors is the alkylating agent temozolomide. At most, 50% of patients exhibit an objective response to temozolomide and the median time to progression is short; thus, there remains a significant unmet need for effective treatments within this patient population. Several targeted agents have reported activity in this tumor type-including small molecule inhibitors, checkpoint inhibitors, and other biologics-but remain investigational at this time.
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Adenoma/patología , Adenoma/terapia , Recurrencia Local de Neoplasia/terapia , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Quimioradioterapia Adyuvante , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Procedimientos Neuroquirúrgicos , Resultado del TratamientoRESUMEN
BACKGROUND: In the molecular era, the relevance of tumor grade for prognostication of IDH1/2-wildtype (WT) gliomas has been debated. It has been suggested that histologic grade II and III astrocytomas with molecular features of glioblastoma, IDH1/2-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. METHODS: We integrated prospective clinical sequencing from 564 patients with IDH1/2-WT gliomas (26 grade II, 71 grade III and 467 grade IV) with clinical and radiographic data to assess associations between molecular features, grade and outcome. RESULTS: Compared to histologic grade IV IDH1/2-WT astrocytomas, histologic grade II astrocytomas harbor fewer chromosome 7/10 alterations (P = 0.04), EGFR amplifications (P = 0.022) and alterations in cell-cycle effectors (P = 1.9e-11), but a similar frequency of TERT promoter mutations. In contrast, there is no difference in the frequency of these canonical molecular features in histologic grade III vs. IV IDH1/2-WT disease. Progression-free (PFS) and overall survival (OS) for histologic grade II tumors were significantly longer than grade III tumors (P = 0.02 and P = 0.008, respectively), whereas there was no difference in PFS and OS for histologic grade III compared to grade IV tumors. Median PFS for histologic grade II, III and IV tumors was 19, 11 and 9 months, respectively. Median OS for the same tumors was 44, 23 and 23 months, respectively. In histologic grade II and III IDH1/2 WT tumors, gliomatosis is associated with the absence of cell-cycle alterations (P = 0.008) and enriched in grade II features (P = 0.1) and alterations in the PI3K-AKT pathway (P = 0.09). CONCLUSIONS: Grade II histology has genotypic and phenotypic associations with prognostic implications in IDH1/2-WT astrocytomas.
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Astrocitoma/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Isocitrato Deshidrogenasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación de ADN , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Pronóstico , Regiones Promotoras Genéticas , Estudios Prospectivos , Adulto JovenRESUMEN
A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.
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Neoplasias Encefálicas/genética , Quimioradioterapia Adyuvante , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Proteínas Asociadas a Microtúbulos/genética , Procedimientos Neuroquirúrgicos , Fusión de Oncogenes , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Proteínas Supresoras de Tumor/genética , Anciano , Neoplasias Encefálicas/terapia , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/genética , Femenino , Glioblastoma/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Estudios RetrospectivosRESUMEN
PURPOSE: Recurrent meningiomas remain therapeutically challenging, often progressive despite multimodality salvage. There are limited data guiding reirradiation (reRT), and proton beam radiation therapy (PBRT) offers a potential advantage owing to lower integral brain dose. PATIENTS AND METHODS: We retrospectively conducted a review of 16 patients who received PBRT reRT for recurrent meningiomas. Kaplan-Meier and proportional hazards were used to determine post-PBRT progression-free survival (PFS) and overall survival (OS) and to evaluate clinical predictors. RESULTS: At diagnosis, 7 (44%), 8 (50%), and 1 (6%) patient had World Health Organization (WHO) grade I, II and III tumors, respectively. All received prior radiation therapy (RT) to a median of 54 Gy (range 13-65.5). Median time to PBRT reRT after prior RT was 5.8 years (range 0.7-18.7). Median PBRT dose was 60 Gy(RBE) (range 30-66.6), and median planning tumor volume (PTV) was 76 cm3 (range 8-249). Median follow-up was 18.8 months. At last follow-up, 7 intracranial recurrences (44%) and 3 disease-related deaths (19%) were found. Median cohort PFS was 22.6 months, with 1- and 2-year PFS of 80% and 43%, respectively. Median OS was not achieved, with 1- and 2-year OS of 94% and 73%; all deaths were felt to be related to meningioma. Patients with initially grade I tumors had improved PFS versus higher grade (Hazard Ratio, HR = 0.23, P = .03) with 1- and 2-year PFS estimates of 100% versus 71% and 75% versus 29%, respectively. Longer interval between prior RT and PBRT also predicted improved PFS (P = .03) and OS (P = .049). Overall late grade 3+ toxicity rate was 31%. Two patients (13%) developed radionecrosis at 6 and 16 months after PBRT; only 1 was symptomatic. CONCLUSIONS: This is the first series specifically analyzing PBRT alone as a reRT strategy for recurrent meningioma. We report fair intracranial control with low rates of radionecrosis at 1 year after reRT. However, strategies to achieve durable outcomes are needed, particularly for high-grade tumors.
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CONTEXT: Pituitary adenomas (PA) are often irregularly shaped, particularly posttreatment. There are no standardized radiographic criteria for assessing treatment response, substantially complicating interpretation of prospective outcome data. Existing imaging frameworks for intracranial tumors assume perfectly spherical targets and may be suboptimal. OBJECTIVE: To compare a three-dimensional (3D) volumetric approach against accepted surrogate measurements to assess PA posttreatment response (PTR). DESIGN: Retrospective review of patients with available pre- and postradiotherapy (RT) imaging. A neuroradiologist determined tumor sizes in one dimensional (1D) per Response Evaluation in Solid Tumors (RECIST) criteria, two dimensional (2D) per Response Assessment in Neuro-Oncology (RANO) criteria, and 3D estimates assuming a perfect sphere or perfect ellipsoid. Each tumor was manually segmented for 3D volumetric measurements. The Hakon Wadell method was used to calculate sphericity. SETTING: Tertiary cancer center. PATIENTS OR OTHER PARTICIPANTS: Patients (n = 34, median age = 50 years; 50% male) with PA and MRI scans before and after sellar RT. INTERVENTIONS: Patients received sellar RT for intact or surgically resected lesions. MAIN OUTCOME MEASURES: Radiographic PTR, defined as percent tumor size change. RESULTS: Using 3D volumetrics, mean sphericity = 0.63 pre-RT and 0.60 post-RT. With all approaches, most patients had stable disease on post-RT scan. PTR for 1D, 2D, and 3D spherical measurements were moderately well correlated with 3D volumetrics (e.g., for 1D: 0.66, P < 0.0001) and were superior to 3D ellipsoid. Intraclass correlation coefficient demonstrated moderate to good reliability for 1D, 2D, and 3D sphere (P < 0.001); 3D ellipsoid was inferior (P = 0.009). 3D volumetrics identified more potential partially responding and progressive lesions. CONCLUSIONS: Although PAs are irregularly shaped, 1D and 2D approaches are adequately correlated with volumetric assessment.
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PURPOSE: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Variación Genética , Genómica , Glioma/genética , Glioma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Niño , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Progresión de la Enfermedad , Femenino , Genómica/métodos , Mutación de Línea Germinal , Glioma/diagnóstico por imagen , Glioma/terapia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Aumento de la Imagen , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Biológicos , Mutación , Medicina de Precisión/métodos , Pronóstico , Regiones Promotoras Genéticas , Resultado del Tratamiento , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. Case: A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Molecular Evaluation: Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. Conclusion: Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adenoma Hipofisario Secretor de ACTH/diagnóstico por imagen , Adenoma Hipofisario Secretor de ACTH/genética , Adenoma Hipofisario Secretor de ACTH/metabolismo , Adenoma/diagnóstico por imagen , Adenoma/genética , Adenoma/metabolismo , Hormona Adrenocorticotrópica/sangre , Adulto , Femenino , Humanos , Ipilimumab/administración & dosificación , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Imagen por Resonancia Magnética , Mutación , Nivolumab/administración & dosificaciónRESUMEN
Pituitary adenomas are benign intracranial neoplasms that are frequently well-controlled with standard treatments that include surgical resection, radiotherapy, and agents that modulate hormonal excess. Unfortunately, a subset of patients remains uncontrolled or develops complications from these interventions. For these patients, chemotherapy is an additional treatment option that could improve outcomes. Temozolomide is an oral chemotherapy with a favorable side-effect profile that has shown activity against pituitary adenomas. Its non-overlapping toxicity and ability to induce rapid tumor regression renders it a potentially important adjunctive treatment. In patients with tumors that cannot be optimally addressed with standard treatments, there may be a role for early initiation of temozolomide.
Asunto(s)
Adenoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Dacarbazina/análogos & derivados , Neoplasias Hipofisarias/tratamiento farmacológico , Dacarbazina/uso terapéutico , Humanos , TemozolomidaRESUMEN
BACKGROUND: Pseudoprogression (PsP) occurs at a higher rate in glioblastoma multiforme with a methylated MGMT promoter-a subset with increased sensitivity to chemoradiotherapy and better overall prognosis. In oligodendroglioma (OG) and oligoastrocytoma (OA), presence of 1p/19q codeletions is highly predictive of response to treatment and is often associated with the methylated MGMT promoter; hence, this study queries whether the presence of 1p/19q codeletions in OG/OA correlates with a higher rate of PsP following therapy. METHODS: A retrospective analysis was performed on all OG/OA in a database of patients with brain tumors who underwent resection of their tumor since 1998. Eighty-eight cases (37 with and 51 without 1p/19q codeletions) met inclusion criteria, and their patient data were analyzed to determine whether the presence of 1p/19q codeletions was associated with PsP and survival. RESULTS: OG/OA (World Health Organization grades II and III) with 1p/19q codeletions had a significantly improved survival (P = .041). Multivariate analysis found that PsP occurred less frequently in OG/OA with 1p/19q codeletions compared with tumors without codeletions (odds ratio, 0.047; 95% confidence interval, 0.005-0.426; P = .0066). The rate of PsP was 19% for the entire cohort, 31% for tumors without codeletions, and 3% for tumors with codeletions. When early posttreatment contrast enhancement developed in tumors with 1p/19q codeletions, it occurred exclusively in tumors that were histologically OA and not OG. CONCLUSION: Codeletions of 1p/19q are a marker of good prognosis but are unexpectedly associated with a lower likelihood of PsP. PsP does not correlate with sensitivity to treatment and improved survival in OG/OA.