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PURPOSE: Glioblastoma (GBM) is the most common primary brain cancer in adults with a very poor prognosis. Metabolic drivers of tumorigenesis are highly relevant within the central nervous system, where glucose is the critical source of energy. The impact of obesity on survival outcomes in patients with GBM is not well established. This study investigates the prognostic value of body mass index (BMI) in patients diagnosed with GBM. METHODS: Adult patients with newly diagnosed GBM treated at Thomas Jefferson University Hospital between January 1, 2008, and December 31, 2022, were included in the study. BMI was calculated using the formula BMI = kg/m2. Patients BMI groups were underweight (BMI < 19.00), normal weight (BMI 19.00-24.99), overweight (BMI 25-29.99), and obese (BMI > 30.00). All patients received 60 Gy of radiation therapy with concurrent and adjuvant temozolomide following maximal safe resection. A difference in clinical outcomes of overall survival (OS) and progression-free survival (PFS) were evaluated between the groups using Kaplan-Meier and log-rank tests. RESULTS: A total of 392 patients met inclusion criteria. The median age was 60.3 (range 18.9-86.7), with 144 females and 248 males. Median BMI was 27.0 (Range; 17.7-52.9). Non-overweight GBM patients (BMI < 25.00, OS 2.1 years, CI 1.7-2.4 years) had increased overall survival compared to overweight patients (BMI ≥ 25.00, OS 1.5 years, CI 1.4-1.6 years) (p < 0.001). Patients with MGMT-methylated GBM also had significantly greater OS and PFS compared to MGMT-unmethylated patients (p < 0.001). Non-overweight GBM patients (BMI < 25.00, median PFS 1.5 years, CI 1.3-2.0 years) also had increased progression-free survival compared to overweight patients (BMI ≥ 25.00, median PFS 1.1 years, CI 0.9-1.2 years) (p < 0.001). CONCLUSIONS: Our study indicates normal BMI (19.00-24.99) at the time of GBM diagnosis is a favorable prognostic indicator for overall and progression-free survival. Additional studies are warranted for further analysis of BMI and survival outcomes in GBM patients.
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Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.
Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).
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Neoplasias Encefálicas , Combinação de Medicamentos , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , Intervalo Livre de Doença , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Imunoterapia , Antineoplásicos Alquilantes/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Previous work has reported the design of a novel thermobrachytherapy (TBT) balloon implant to deliver magnetic nanoparticle (MNP) hyperthermia and high-dose-rate (HDR) brachytherapy simultaneously after brain tumor resection, thereby maximizing their synergistic effect. This paper presents an evaluation of the robustness of the balloon device, compatibility of its heat and radiation delivery components, as well as thermal and radiation dosimetry of the TBT balloon. TBT balloon devices with 1 and 3 cm diameter were evaluated when placed in an external magnetic field with a maximal strength of 8.1 kA/m at 133 kHz. The MNP solution (nanofluid) in the balloon absorbs energy, thereby generating heat, while an HDR source travels to the center of the balloon via a catheter to deliver the radiation dose. A 3D-printed human skull model was filled with brain-tissue-equivalent gel for in-phantom heating and radiation measurements around four 3 cm balloons. For the in vivo experiments, a 1 cm diameter balloon was surgically implanted in the brains of three living pigs (40-50 kg). The durability and robustness of TBT balloon implants, as well as the compatibility of their heat and radiation delivery components, were demonstrated in laboratory studies. The presence of the nanofluid, magnetic field, and heating up to 77 °C did not affect the radiation dose significantly. Thermal mapping and 2D infrared images demonstrated spherically symmetric heating in phantom as well as in brain tissue. In vivo pig experiments showed the ability to heat well-perfused brain tissue to hyperthermic levels (≥40 °C) at a 5 mm distance from the 60 °C balloon surface.
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PURPOSE: Owing to their vicinity near the superior sagittal sinus, parasagittal and parafalcine meningiomas are challenging tumors to surgically resect. In this study, we investigate key factors that portend increased risk of recurrence after surgery. METHODS: This is a retrospective study of patients who underwent resection of parasagittal and parafalcine meningiomas at our institution between 2012 and 2018. Relevant clinical, radiographic, and histopathological variables were selected for analysis as predictors of tumor recurrence. RESULTS: A total of 110 consecutive subjects (mean age: 59.4 ± 15.2 years, 67.3% female) with 74 parasagittal and 36 parafalcine meningiomas (92 WHO grade 1, 18 WHO grade 2/3), are included in the study. A total of 37 patients (33.6%) exhibited recurrence with median follow-up of 42 months (IQR: 10-71). In the overall cohort, parasagittal meningiomas exhibited shorter progression-free survival compared to parafalcine meningiomas (Kaplan-Meier log-rank p = 0.045). On univariate analysis, predictors of recurrence include WHO grade 2/3 vs. grade 1 tumors (p < 0.001), higher Ki-67 indices (p < 0.001), partial (p = 0.04) or complete sinus invasion (p < 0.001), and subtotal resection (p < 0.001). Multivariable Cox regression analysis revealed high-grade meningiomas (HR: 3.62, 95% CI: 1.60-8.22; p = 0.002), complete sinus invasion (HR: 3.00, 95% CI: 1.16-7.79; p = 0.024), and subtotal resection (HR: 3.10, 95% CI: 1.38-6.96; p = 0.006) as independent factors that portend shorter time to recurrence. CONCLUSION: This study identifies several pertinent factors that confer increased risk of recurrence after resection of parasagittal and parafalcine meningiomas, which can be used to devise appropriate surgical strategy to achieve improved patient outcomes.
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Neoplasias Meníngeas , Meningioma , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Estudos Retrospectivos , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia , Seio Sagital Superior/cirurgiaRESUMO
OBJECTIVE: The clinical behavior of meningiomas is not entirely captured by its designated WHO grade, therefore other factors must be elucidated that portend increased tumor aggressiveness and associated risk of recurrence. In this study, the authors identify multiparametric MRI radiomic signatures of meningiomas using Ki-67 as a prognostic marker of clinical outcomes independent of WHO grade. METHODS: A retrospective analysis was conducted of all resected meningiomas between 2012 and 2018. Preoperative MR images were used for high-throughput radiomic feature extraction and subsequently used to develop a machine learning algorithm to stratify meningiomas based on Ki-67 indices < 5% and ≥ 5%, independent of WHO grade. Progression-free survival (PFS) was assessed based on machine learning prediction of Ki-67 strata and compared with outcomes based on histopathological Ki-67. RESULTS: Three hundred forty-three meningiomas were included: 291 with WHO grade I, 43 with grade II, and 9 with grade III. The overall rate of recurrence was 19.8% (15.1% in grade I, 44.2% in grade II, and 77.8% in grade III) over a median follow-up of 28.5 months. Grade II and III tumors had higher Ki-67 indices than grade I tumors, albeit tumor and peritumoral edema volumes had considerable variation independent of meningioma WHO grade. Forty-six high-performing radiomic features (1 morphological, 7 intensity-based, and 38 textural) were identified and used to build a support vector machine model to stratify tumors based on a Ki-67 cutoff of 5%, with resultant areas under the curve of 0.83 (95% CI 0.78-0.89) and 0.84 (95% CI 0.75-0.94) achieved for the discovery (n = 257) and validation (n = 86) data sets, respectively. Comparison of histopathological Ki-67 versus machine learning-predicted Ki-67 showed excellent performance (overall accuracy > 80%), with classification of grade I meningiomas exhibiting the greatest accuracy. Prediction of Ki-67 by machine learning classifier revealed shorter PFS for meningiomas with Ki-67 indices ≥ 5% compared with tumors with Ki-67 < 5% (p < 0.0001, log-rank test), which corroborates divergent patient outcomes observed using histopathological Ki-67. CONCLUSIONS: The Ki-67 proliferation index may serve as a surrogate marker of increased meningioma aggressiveness independent of WHO grade. Machine learning using radiomic feature analysis may be used for the preoperative prediction of meningioma Ki-67, which provides enhanced analytical insights to help improve diagnostic classification and guide patient-specific treatment strategies.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Antígeno Ki-67 , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Estudos Retrospectivos , Prognóstico , Proliferação de CélulasRESUMO
BACKGROUND: Hemangioblastoma of the central nervous system is an uncommon benign neoplasm, with about 25% of cases in patients with von Hippel-Lindau disease. The incidence of metastasis is rare, particularly in patients without von Hippel-Lindau disease. We report a case of hemangioblastoma with leptomeningeal dissemination as a late recurrence. CASE PRESENTATION: A 65-year-old Caucasian man with a history of World Health Organization grade I hemangioblastoma of the cerebellar vermis underwent gross total resection in 1997. In early 2018, he developed intracranial recurrences with diffuse leptomeningeal disease of the entire spine. The patient underwent resection of intracranial recurrence, followed by palliative craniospinal irradiation. The disease progressed quickly, and he died 8 months after recurrence. CONCLUSIONS: Despite a benign pathology, hemangioblastoma has a low risk of metastasis. The outcome for hemangioblastoma patients with metastasis is poor. Multidisciplinary care for patients with metastatic hemangioblastoma warrants further investigation, and an effective systemic option is urgently needed. Regular lifelong follow-up of at-risk patients is recommended.
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Neoplasias Cerebelares , Hemangioblastoma , Doença de von Hippel-Lindau , Masculino , Humanos , Idoso , Hemangioblastoma/cirurgia , Neoplasias Cerebelares/cirurgia , Coluna VertebralRESUMO
Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression. MATERIALS AND METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion. RESULTS: Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 15.2 months (1.7-23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26-6.95 cm). One infratentorial progression was noted. CONCLUSIONS: We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.
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Neoplasias Encefálicas , Terapia por Estimulação Elétrica , Glioblastoma , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Terapia Combinada , Glioblastoma/tratamento farmacológico , Projetos Piloto , Temozolomida/uso terapêutico , Adulto Jovem , IdosoRESUMO
Glioblastoma (GBM) with deep-supratentorial extension (DSE) involving the thalamus, basal ganglia and corpus collosum, poses significant challenges for clinical management. In this study, we present our outcomes in patients who underwent resection of supratentorial GBM with associated involvement of deep brain structures. We conducted a retrospective review of patients who underwent resection of GBM at our institution between 2012 and 2018. A total of 419 patients were included whose pre-operative MRI scans were reviewed. Of these, 143 (34.1%) had GBM with DSE. There were similar rates of IDH-1 mutation (9% versus 7.6%, p = 0.940) and MGMT methylation status (35.7% versus 45.2%, p = 0.397) between the two cohorts. GBM patients without evidence of DSE had higher rates of radiographic gross total resection (GTR) compared to those with DSE: 70.6% versus 53.1%, respectively (p = 0.002). The presence of DSE was not associated with decreased progression-free survival (PFS) compared to patients without DSE (mean 7.24 ± 0.97 versus 8.89 ± 0.76 months, respectively; p = 0.276), but did portend a worse overall survival (OS) (mean 10.55 ± 1.04 versus 15.02 ± 1.05 months, respectively; p = 0.003). There was no difference in PFS or OS amongst DSE and non-DSE patients who underwent GTR, but patients who harbored DSE and underwent subtotal resection had worse OS (mean 8.26 ± 1.93 versus 12.96 ± 1.59 months, p = 0.03). Our study shows that GBM patients with DSE have lower OS compared to those without DSE. This survival difference appears to be primarily related to the limited surgical extent of resection owing to the neurological deficits that may be incurred with involvement of eloquent deep brain structures.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Supratentoriais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Humanos , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Supratentoriais/diagnóstico por imagem , Neoplasias Supratentoriais/cirurgiaRESUMO
BACKGROUND: Although World Health Organization (WHO) grade I meningiomas are considered "benign" tumors, an elevated Ki-67 is one crucial factor that has been shown to influence tumor behavior and clinical outcomes. The ability to preoperatively discern Ki-67 would confer the ability to guide surgical strategy. OBJECTIVE: In this study, we develop a machine learning (ML) algorithm using radiomic feature analysis to predict Ki-67 in WHO grade I meningiomas. METHODS: A retrospective analysis was performed for a cohort of 306 patients who underwent surgical resection of WHO grade I meningiomas. Preoperative magnetic resonance imaging was used to perform radiomic feature extraction followed by ML modeling using least absolute shrinkage and selection operator wrapped with support vector machine through nested cross-validation on a discovery cohort (n = 230), to stratify tumors based on Ki-67 <5% and ≥5%. The final model was independently tested on a replication cohort (n = 76). RESULTS: An area under the receiver operating curve (AUC) of 0.84 (95% CI: 0.78-0.90) with a sensitivity of 84.1% and specificity of 73.3% was achieved in the discovery cohort. When this model was applied to the replication cohort, a similar high performance was achieved, with an AUC of 0.83 (95% CI: 0.73-0.94), sensitivity and specificity of 82.6% and 85.5%, respectively. The model demonstrated similar efficacy when applied to skull base and nonskull base tumors. CONCLUSION: Our proposed radiomic feature analysis can be used to stratify WHO grade I meningiomas based on Ki-67 with excellent accuracy and can be applied to skull base and nonskull base tumors with similar performance achieved.
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Antígeno Ki-67/análise , Neoplasias Meníngeas , Meningioma , Imageamento por Ressonância Magnética Multiparamétrica , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Estudos RetrospectivosRESUMO
PURPOSE: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. PATIENTS AND METHODS: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. RESULTS: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine-DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. CONCLUSIONS: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
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Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Adulto , Idoso , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/imunologia , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Receptor IGF Tipo 1/genéticaRESUMO
AIM: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant. METHODS: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (>0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz. RESULTS: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies. CONCLUSIONS: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme.
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Braquiterapia , Neoplasias Encefálicas , Hipertermia Induzida , Nanopartículas de Magnetita , Neoplasias Encefálicas/radioterapia , Estudos de Viabilidade , Calefação , Humanos , Qualidade de VidaRESUMO
BACKGROUND AND PURPOSE: We conducted a phase I trial of alisertib, an oral aurora kinase inhibitor, with fractionated stereotactic re-irradiation therapy (FSRT) for patients with recurrent high grade glioma (HGG). MATERIALS AND METHODS: Adult patients with recurrent HGG were enrolled from Feb 2015 to Feb 2017. Patients were treated with concurrent FSRT and alisertib followed by maintenance alisertib. Concurrent alisertib dose was escalated from 20â¯mg to 50â¯mg twice daily (BID). RESULTS: 17 patients were enrolled. Median follow-up was 11â¯months. Median FSRT dose was 35â¯Gy. There were 6, 6, 3, and 2 patients enrolled in 20â¯mg, 30â¯mg, 40â¯mg, and 50â¯mg cohort, respectively. Only one DLT was observed. One patient in the 20â¯mg cohort had severe headache (Grade 3) resolved with steroids. There was no non-hematological grade 3 or higher toxicity. There were two Grade 4 late toxicities (one with grade 4 neutropenia and leukopenia, one with pulmonary embolism). One patient developed radiation necrosis (Grade 3). Sixteen patients finished concurrent treatment and received maintenance therapy (median cycles was 3, range 1-9). OS for all cohorts at 6â¯months was 88.2% with median survival time of 11.1â¯months. PFS at 6â¯months was 35.3% with median time to progression of 4.9â¯months. The trial stopped early due to closure of alisertib program with only 2 of 3 planned patients enrolled in the 50â¯mg cohort. CONCLUSION: Re-irradiation with FSRT combined with alisertib is safe and well tolerated for HGG with doses up to 40â¯mg BID. Although no DLT observed in the 50â¯mg cohort, this cohort was not fully enrolled and MTD was not reached. Clinical outcomes appear comparable to historical results. (NCT02186509).
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Azepinas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioma/tratamento farmacológico , Glioma/radioterapia , Pirimidinas/uso terapêutico , Radiocirurgia/métodos , Adulto , Idoso , Neoplasias Encefálicas/patologia , Quimiorradioterapia , Estudos de Coortes , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Reirradiação , Resultado do TratamentoRESUMO
PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.
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Anticorpos Monoclonais/administração & dosagem , Neoplasias Encefálicas/radioterapia , Irradiação Craniana/métodos , Melanoma/radioterapia , Radiocirurgia , Anticorpos Monoclonais/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Irradiação Craniana/efeitos adversos , Irradiação Craniana/estatística & dados numéricos , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Ipilimumab , Masculino , Dose Máxima Tolerável , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Radiocirurgia/estatística & dados numéricos , Fatores de TempoRESUMO
The standard treatment of hydrocephalus is placement of a ventriculoperitoneal (VP) shunt. While infection is a common complication, rarely are fungal organisms implicated. Cryptococcus neoformans has been reported in only nine cases of shunt infection to our knowledge. The timing from shunt placement to symptom onset varies widely from 10 days to 15 months. We present a patient who developed a cryptococcal infection of his VP shunt more than two decades following shunt placement.
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Criptococose/diagnóstico , Criptococose/etiologia , Cryptococcus neoformans , Hidrocefalia/cirurgia , Derivação Ventriculoperitoneal/efeitos adversos , Idoso , Criptococose/microbiologia , Criptococose/terapia , Cryptococcus neoformans/isolamento & purificação , Humanos , MasculinoRESUMO
Perform a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) in patients with brain metastasis. A multi-institutional phase I clinical trial enrolled patients with a histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 to 400 mg daily using a 3+3 trial design. Seventeen patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n = 1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 and 300 mg dose levels. In the 400 mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Both events were most likely related to disease progression rather than treatment; nonetheless, we conservatively classified the death as a dose limiting toxicity. We found Vorinostat administered with concurrent WBRT to be well tolerated to a dose of 300 mg once daily. This is the recommended dose for phase II study.
Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Ácidos Hidroxâmicos/uso terapêutico , Radiossensibilizantes/uso terapêutico , Idoso , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Progressão da Doença , Neoplasias das Tubas Uterinas/patologia , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Radiossensibilizantes/efeitos adversos , Resultado do Tratamento , VorinostatRESUMO
OBJECTIVE: Somatotroph adenomas are typically recognized when they secrete GH excessively and cause acromegaly. Both 'silent' somatotroph adenomas (immunohistochemical evidence of GH excess without biochemical or clinical evidence) and 'clinically silent' somatotroph adenomas (immunohistochemical and biochemical evidence but no clinical evidence) have occasionally been reported. The relative frequency of each presentation is unknown. The goal of this study was, therefore, to determine the frequency of clinically silent somatotroph adenomas, a group that is potentially recognizable in vivo. DESIGN: We retrospectively identified 100 consecutive patients who had surgically excised and histologically confirmed pituitary adenomas. METHODS: Each pituitary adenoma was classified immunohistochemically by pituitary cell type. Somatotroph adenomas were further classified as 'classic' (obvious clinical features of acromegaly and elevated serum IGF1), 'subtle' (subtle clinical features of acromegaly and elevated IGF1), 'clinically silent' (no clinical features of acromegaly but elevated IGF1), and 'silent' (no clinical features of acromegaly and normal IGF1). RESULTS: Of the 100 consecutive pituitary adenomas, 29% were gonadotroph/glycoprotein, 24% somatotroph, 18% null cell, 15% corticotroph, 6% lactotroph, 2% thyrotroph, and 6% not classifiable. Of the 24 patients with somatotroph adenomas, classic accounted for 45.8%, subtle 16.7%, clinically silent 33.3%, and silent 4.2%. CONCLUSIONS: Clinically silent somatotroph adenomas are more common than previously appreciated, representing one-third of all somatotroph adenomas. IGF1 should be measured in all patients with a sellar mass, because identification of a mass as a somatotroph adenoma expands the therapeutic options and provides a tumor marker to monitor treatment.
Assuntos
Adenoma/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/etiologia , Adulto , Idoso , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Somatotrofos/patologiaRESUMO
PURPOSE: The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of (18)F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies. METHODS: (18)F-EF5 was synthesized by electrophilic addition of (18)F(2) gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus. Three whole-body images were collected for each of ten patients using an Allegro (Philips) scanner. Gamma counts were determined in blood, drawn during each image, and urine, pooled as a single sample. PET images were analyzed to determine radiotracer uptake in several tissues and the resulting radiation dose calculated using OLINDA software and standard phantom. For three patients, 21 mg/kg unlabeled EF5 was administered after the PET scans, and tissue samples obtained the next day at surgery to determine EF5 binding using immunohistochemistry techniques (IHC). RESULTS: EF5 distributes evenly throughout soft tissue within minutes of injection. Its concentration in blood over the typical time frame of the study (â¼3.5 h) was nearly constant, consistent with a previously determined EF5 plasma half-life of â¼13 h. Elimination was primarily via urine and bile. Radiation exposure from labeled EF5 is similar to other (18)F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of (18)F-EF5 was confirmed by IHC. CONCLUSION: These results confirm predictions of biodistribution and safety based on EF5's characteristics (high biological stability, high lipophilicity). EF5 is a novel hypoxia marker with unique pharmacological characteristics allowing both noninvasive and invasive measurements.
Assuntos
Neoplasias Encefálicas/metabolismo , Etanidazol/análogos & derivados , Radioisótopos de Flúor , Glioblastoma/metabolismo , Hidrocarbonetos Fluorados/metabolismo , Hidrocarbonetos Fluorados/farmacocinética , Transporte Biológico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Hipóxia Celular , Etanidazol/metabolismo , Etanidazol/farmacocinética , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Radiometria , Distribuição Tecidual , Imagem Corporal TotalRESUMO
The hypoxia and proliferation index increase with grade in human glial tumors, but there is no agreement whether either has prognostic importance in glioblastomas. We evaluated these end points individually and together in 16 de novo human glioblastomas using antibodies against the 2-nitroimidazole hypoxia detection agent EF5 and the proliferation detection agent Ki-67. Frozen tumor tissue sections were fluorescence-stained for nuclei (Hoechst 33342), hypoxia (anti-EF5 antibodies), and proliferation (anti-Ki-67 antibodies). EF5 binding adjacent to Ki-67+ cells, overall EF5 binding, the ratio of these values, and the proliferation index were evaluated. Patients were classified using recursive partitioning analysis and followed up until recurrence and/or death. Recursive partitioning analysis was statistically significant for survival (P = .0026). Overall EF5 binding, EF5 binding near Ki-67+ cells, and proliferation index did not predict recurrence. Two additional survival analyses based on ratios of the overall EF5 binding to EF5 binding near Ki-67+ cells were performed. High and low ratio values were determined by two cutoff points: (a) the 50% value for the ratio [EF5/Ki-67(Binding)]/[Tumor(binding)] = Ratio(EF5 50%) and (b) the median EF5 value (75.6%) of the ratio [EF5/Ki-67(Binding)]/[Tumor(binding)] = Ratio(patients median). On the basis of the Ratio(EF5 50%), recurrence (P = .0074) and survival (P = .0196) could be predicted. Using the Ratio(patients median), only survival could be predicted (P = .0291). In summary, patients had a worse prognosis if the [EF5/Ki-67(Binding)]/[Tumor(binding)] ratio was high. A hypothesis for the mechanisms and translational significance of these findings is discussed.
RESUMO
A 72-year-old man with a known left acoustic neuroma, left-sided deafness, and a recently diagnosed right infratemporal fossa (ITF) hemangiopericytoma, presented with sudden deafness in his right ear. Imaging revealed right-sided skull base extension and a large intracranial tumor component. The patient underwent a frontotemporal crainiotomy with concomitant ITF approach. Complete tumor resection was possible, though invasion of the otic capsule was present. Immediately postresection, a cochlear implant (CI) was performed via a transmastoid approach. Full electrode insertion was achieved and confirmed by visualization through the dehiscent middle fossa floor. Mastoid obliteration was then performed with a free fat graft. Postoperative imaging confirmed complete tumor resection (Simpson grade I) and adequate CI placement. Follow-up magnetic resonance imaging was performed at 6 and 12 months, and no tumor recurrence was seen. Prior to CI activation, the patient was completely deaf bilaterally. At 18-month follow-up, however, excellent hearing was achieved with the right CI (16 of 22 electrodes active), and the patient is now conversational with no obvious deficit. His cognitive function is excellent, corresponding to preoperative status, and he is independent in his activities of daily living. Following adjuvant radiation, our patient remains disease free at 18 months.
RESUMO
BACKGROUND AND PURPOSE: Preoperative differentiation of astrocytomas from oligodendrogliomas is clinically important, as oligodendrogliomas are more sensitive to chemotherapy. The purpose of this study was to assess the role of proton magnetic resonance spectroscopy in distinguishing astrocytomas from oligodendrogliomas. METHODS: Forty-six patients [astrocytomas (n= 17) and oligodendrogliomas (n= 29)] underwent magnetic resonance imaging and multi voxel proton magnetic resonance spectroscopic imaging before treatment. Peak areas for N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (mI), glutamate/glutamine (Glx), and lipids + lactate (Lip+Lac) were analyzed from voxels that exhibited hyperintensity on fluid-attenuated inversion recovery images and were normalized to Cr from each voxel. The average metabolite/Cr ratios from these voxels were then compared between astrocytomas and oligodendrogliomas. Receiver-operating curve analyses were used as measures of differentiation accuracy of metabolite ratios. A threshold value for a metabolite ratio was estimated by maximizing the sum of sensitivity and specificity. RESULTS: A significant difference in mI/Cr was observed between astrocytomas and oligodendrogliomas (.50 +/- .18 vs. 0.66 +/- 0.20, P < .05). Using a threshold value of .56 for mI/Cr ratio, it was possible to differentiate oligodendrogliomas from astrocytomas with a sensitivity of 72.4% and specificity of 76.4%. CONCLUSION: These results suggest that mI/Cr might aid in distinguishing oligodendrogliomas from astrocytomas.