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Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinomatosis Meníngea , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinomatosis Meníngea/terapia , Carcinomatosis Meníngea/tratamiento farmacológico , Antineoplásicos/uso terapéutico , PronósticoRESUMEN
Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.
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Mieloma Múltiple , Mieloma Múltiple Quiescente , Humanos , Biomarcadores , Progresión de la Enfermedad , Factores Inmunológicos , Inmunoterapia , Lenalidomida/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple Quiescente/terapia , Ensayos Clínicos Fase II como AsuntoRESUMEN
PURPOSE: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. RESULTS: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001). CONCLUSIONS: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.
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Neoplasias Encefálicas , Glioblastoma , Bevacizumab , Vacunas contra el Cáncer , Método Doble Ciego , Receptores ErbB , Humanos , Recurrencia Local de Neoplasia , Pacientes , Vacunas de SubunidadRESUMEN
Meningiomas are primary CNS tumors that arise from the arachnoid layer of the meninges. Genomic sequencing has revealed that NF2 mutations are the most common genetic alteration seen in meningiomas. Meningiomas although usually low grade, can sometimes progress to high grade. A patient who had several recurrences of meningiomas since childhood presented with recurrent headaches. Imaging showed that he had another recurrence of a meningioma. He underwent surgery for resection of the meningioma and histopathology showed NF2 mutation. He was started on everolimus and bevacizumab with good effect. Studies have shown that NF-2 mutated meningiomas have a good response to everolimus and bevacizumab with increased progression-free survival time and progression-free survival time at 6 months.
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PURPOSE: Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity. MATERIALS AND METHODS: A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL. RESULTS: A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL-DEX treatment-related toxicities. CONCLUSION: Data suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.
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BACKGROUND: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control. METHODS: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. RESULTS: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %. CONCLUSION: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.
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Antineoplásicos/uso terapéutico , Quimioradioterapia/métodos , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Glioma/radioterapia , Isoquinolinas/uso terapéutico , Calidad de Vida/psicología , Quinuclidinas/uso terapéutico , Administración Intravenosa , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Dacarbazina/efectos adversos , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Femenino , Glioma/patología , Humanos , Isoquinolinas/efectos adversos , Isoquinolinas/farmacología , Masculino , Persona de Mediana Edad , Palonosetrón , Quinuclidinas/efectos adversos , Quinuclidinas/farmacología , Encuestas y Cuestionarios , TemozolomidaRESUMEN
Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc.
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Astrocitoma/diagnóstico , Astrocitoma/etiología , Neurofibromatosis 1/complicaciones , Adulto , Astrocitoma/mortalidad , Astrocitoma/terapia , Biopsia , Encéfalo/patología , Estudios de Casos y Controles , Terapia Combinada , Diagnóstico por Imagen , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Clasificación del Tumor , Neurofibromatosis 1/diagnóstico , Fenotipo , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare yet highly aggressive malignancy with a poor prognosis. Currently, there are no SCCOHT treatment guidelines. After surgery, many patients with SCCOHT receive adjuvant cisplatin and etoposide (CE), based on its efficacy in small cell lung cancer (SCLC). Nonetheless, CE-refractory SCCOHT is still common. Novel therapies (ie, histone deacetylase [HDAC] inhibitors) are being studied as they may target abnormal chromatin remodeling known to be associated with SCCOHT. We present the case of a 21-year-old female with Stage IC SCCOHT status after unilateral oophorectomy. Despite adjuvant CE, the patient developed disease progression. This is the first case report of a patient with CE-refractory SCCOHT treated with second-line topotecan (a topoisomerase-1 inhibitor) and romidepsin (an HDAC inhibitor). Although our patient's SCCOHT further progressed and lead to her death, her story highlights the importance of discovering better therapeutic targets for the treatment of SCCOHT.
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Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/terapia , Depsipéptidos/uso terapéutico , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Topotecan/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Ovariectomía , Inhibidores de Topoisomerasa I/uso terapéutico , Adulto JovenRESUMEN
Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis (HNL), is a rare, self-limiting disease most commonly reported in young Asian women worldwide. We present the case of a 27-year-old African American male who had three weeks of high-grade fevers, night sweats, a 10-pound weight loss, and tender unilateral posterior cervical lymphadenopathy. A complete workup of infectious, rheumatologic, and neoplastic diseases was pursued. Lymph node biopsies revealed histiocyte proliferation with areas of necrosis. These findings were diagnostic of KFD. While KFD has been reported most commonly in young Asian women, in the US, this disease must be considered in both males and females and in diverse ethnicities.
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Histiocitos/patología , Linfadenitis Necrotizante Histiocítica , Ibuprofeno/administración & dosificación , Ganglios Linfáticos , Linfadenopatía/diagnóstico , Adulto , Negro o Afroamericano , Antiinflamatorios no Esteroideos/administración & dosificación , Biopsia/métodos , Diagnóstico Diferencial , Linfadenitis Necrotizante Histiocítica/diagnóstico , Linfadenitis Necrotizante Histiocítica/patología , Linfadenitis Necrotizante Histiocítica/fisiopatología , Linfadenitis Necrotizante Histiocítica/terapia , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Masculino , Cuello , NecrosisRESUMEN
Identification of targetable oncogenic mutations in non-small cell lung cancer (NSCLC) has been a major advance in cancer treatment. Laboratory techniques to assess human epidermal growth factor receptor 2 (HER2) positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for HER2 gene mutations. These tests have a controversial prognostic and predictive value, with an emerging association between HER2 gene mutations and treatment response to HER2 targeted therapy. We present a case of a woman with metastatic lung adenocarcinoma with HER2 positivity assessed by IHC and FISH, as well as a high gene copy number noted on NGS. She was observed to have significant disease progression following standard first-line platinum doublet chemotherapy. She was started on dual HER2 blockade in the second-line setting, which yielded a great response in the liver with stable disease elsewhere. To our knowledge, this is the first report describing successful use of dual HER2 blockade in metastatic HER2 positive NSCLC. We also review common laboratory techniques for determining HER2 positivity in NSCLC and their clinical applications.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor ErbB-2/antagonistas & inhibidores , Anciano , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/secundario , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/patología , Mutación , Receptor ErbB-2/genéticaRESUMEN
Vredenburgh and colleagues conducted the first phase II study of bevacizumab plus irinotecan in recurrent malignant glioma, confirming the safety and efficacy of bevacizumab. This study, which was published in the February 15, 2007, issue of Clinical Cancer Research, was a stepping stone for subsequent research, leading to regulatory approval of bevacizumab for recurrent glioblastoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Femenino , Humanos , MasculinoRESUMEN
LESSONS LEARNED: Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. BACKGROUND: Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. METHODS: Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. RESULTS: Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months). CONCLUSION: Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Bevacizumab/administración & dosificación , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Esquema de Medicación , Femenino , Glioblastoma/mortalidad , Glioblastoma/radioterapia , Glioblastoma/cirugía , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Temozolomida , Resultado del TratamientoRESUMEN
After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
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Vacunas contra el Cáncer/inmunología , Quimiocina CCL3/inmunología , Células Dendríticas/efectos de los fármacos , Glioblastoma/inmunología , Glioblastoma/terapia , Toxoide Tetánico/administración & dosificación , Toxoide Tetánico/farmacología , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/uso terapéutico , Movimiento Celular/efectos de los fármacos , Células Dendríticas/citología , Células Dendríticas/inmunología , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Inmunoterapia/métodos , Ganglios Linfáticos/citología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Especificidad por Sustrato , Tasa de Supervivencia , Toxoide Tetánico/uso terapéutico , Resultado del Tratamiento , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunologíaRESUMEN
Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Receptor ErbB-2/antagonistas & inhibidores , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Amplificación de Genes , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Mutación , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacosAsunto(s)
Examen de la Médula Ósea , Coagulación Intravascular Diseminada/etiología , Isquemia/etiología , Leucemia Mieloide Aguda/diagnóstico , Trombosis/etiología , Dedos del Pie/irrigación sanguínea , Anticoagulantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aorta Abdominal/cirugía , Arteriopatías Oclusivas/tratamiento farmacológico , Arteriopatías Oclusivas/etiología , Arteriopatías Oclusivas/cirugía , Terapia Combinada , Cianosis , Citarabina/administración & dosificación , Diagnóstico Diferencial , Coagulación Intravascular Diseminada/diagnóstico , Resultado Fatal , Femenino , Humanos , Idarrubicina/administración & dosificación , Isquemia/tratamiento farmacológico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Imagen por Resonancia Magnética , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/diagnóstico , Zapatos/efectos adversos , Trombectomía , Trombocitopenia/etiología , Trombosis/diagnóstico por imagen , Trombosis/tratamiento farmacológico , Trombosis/cirugía , UltrasonografíaRESUMEN
PURPOSE: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Recurrencia Local de Neoplasia/terapia , Radiocirugia/métodos , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Neoplasias Encefálicas/patología , Terapia Combinada/métodos , Femenino , Glioma/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estudios Prospectivos , Calidad de Vida , Radiocirugia/efectos adversos , Dosificación Radioterapéutica , Carga TumoralRESUMEN
Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.
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Antineoplásicos Alquilantes/efectos adversos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/metabolismo , Dacarbazina/análogos & derivados , Linfoma/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Dacarbazina/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Estudios Longitudinales , Linfoma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , TemozolomidaRESUMEN
Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Dacarbazina/uso terapéutico , Femenino , Glioblastoma/diagnóstico por imagen , Glioblastoma/radioterapia , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiografía , Temozolomida , Resultado del TratamientoRESUMEN
Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Recurrencia Local de Neoplasia/terapia , Radiocirugia , Bevacizumab , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Terapia Combinada , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Resultado del TratamientoRESUMEN
Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.