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We report a case of a 72-year-old man presenting with a 2-month history of a persistent, painful rash of the chest, axilla, and back. He had a history of recently resolved varicella zoster virus reactivation in the same distribution of the current rash and metastatic malignant melanoma treated with nivolumab and ipilimumab. The histopathology was consistent with granulomatous dermatitis (GD), and a diagnosis of postherpetic isotopic response manifesting as GD was made. Given the paucity of reported cases of postherpetic GD in the setting of treatment with immune checkpoint inhibitors (ICIs), we discuss the clinicopathologic features of this case and potential mechanisms by which ICIs may contribute to the development of granulomatous disease.
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Doenças Autoimunes , Dermatite , Exantema , Melanoma , Masculino , Humanos , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Dermatite/etiologia , Dermatite/patologia , Melanoma/patologia , Nivolumabe/efeitos adversos , Ipilimumab/uso terapêutico , Doenças Autoimunes/complicaçõesRESUMO
Background: Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome with varying manifestations and severity. Adult NF1 patients often experience fragmented care, so we sought to characterize the health and demographic features of a community-based population of adults with NF1 and hypothesized that lack of a specialty clinic for adult NF1 patients correlates with unmet needs. Methods: Retrospective case-control study of all adult cases of NF1 among 4.06 million medical records in a Pacific Northwest population. 122 case charts were reviewed to ascertain NF1 disease features, comorbidities, and severity of disease. A 1:1 control cohort was selected by matching case/control by age, sex, and ZIP code to compare demographic features and health status. Results: Adult NF1 patients were less likely to have private insurance, be employed, and have children, but were equally likely to be married. One half of cases had disease features compromising health and well-being, and care involved 26 different specialties. Excluding neurofibromas, 43% of cases had cancer compared to 10% of controls [P < .0001, OR 5.38 (2.53-11.4)]. Only 27% of women ages 30-50 had undergone age-appropriate enhanced breast cancer surveillance. Behavioral health problems were found in 60% of NF1 patients compared to 37% of controls [P < .001, OR 2.61 (1.52-4.50)]. 93% of cases referred to a NF1 specialty center underwent a change in management upon establishing care. Conclusions: NF1 patients may benefit from coordinated management of care in a specialty center.
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OBJECTIVE: To better understand the relationship between cancer patient distress and psychosocial variables, including problem types, to improve ability to predict and address psychosocial need. METHODS: A variation of National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) was administered and collected at four sites from an Integrated Network Cancer Program (INCP). The presence of moderate/severe distress was examined relative to patient demographics, disease characteristics, and psychosocial problems. RESULTS: Distress scores were positively correlated with all problem counts. For every count increase of practical, emotional, and physical problems, and for every cancer stage increase the odds of reporting a moderate/severe distress score was significantly higher. Relative to patients with one cancer treatment type, patients with three cancer treatment types were significantly less likely to report moderate/severe distress. CONCLUSION: Problem count could be a useful indicator for clinical intervention. Stage and number of treatment types may also be considered clinically relevant distress predictors.
Implications for Psychosocial ResearchThis study found that NCCN Distress Thermometer distress levels and problem counts are highly correlated in most cancer patients.In addition to distress level, problem count on NCCN Distress Thermometer should be considered a potential trigger for psychosocial intervention.NCCN Distress Thermometer problem count may be a more durable indicator of need for psychosocial intervention then distress level alone. Psychosocial problems are rarely transient, while distress level can fluctuate day-to-day.Future research should examine the role of psychosocial problems on continuous distress scores and the relative contribution of each set of problem types on distress.
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Neoplasias , Estresse Psicológico , Emoções , Humanos , Estadiamento de Neoplasias , Neoplasias/terapia , Estresse Psicológico/epidemiologiaRESUMO
OPINION STATEMENT: Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Terapia de Alvo Molecular , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Medicina de Precisão , Biomarcadores Tumorais , Neoplasias Encefálicas/etiologia , Tomada de Decisão Clínica , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Síndromes Neoplásicas Hereditárias/etiologia , Síndromes Neoplásicas Hereditárias/metabolismo , Medicina de Precisão/métodos , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the molecular alterations in adult PA are associated with MAPK pathway dysregulation. The most common alterations are fusions of BRAF. Understanding of the mechanisms underlying this pathway has evolved substantially, heralding advancements in specific targeted therapy. Here, we review clinical and molecular features of adult PA, characteristics predicting aggressive behavior and approaches to standard and investigational therapies. We highlight epigenetic profiling and integrated diagnosis as an essential component of classifying PA.
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Astrocitoma , Neoplasias Encefálicas , Adulto , Astrocitoma/diagnóstico , Astrocitoma/genética , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Criança , Humanos , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Mutations in histone H3 are key molecular drivers of pediatric and young adult high-grade gliomas. Histone H3 G34R mutations occur in hemispheric high-grade gliomas and H3 K27M mutations occur in aggressive, though histologically diverse, midline gliomas. Here, we report 2 rare cases of histologically low-grade gliomas with gemistocytic morphology and sequencing-confirmed histone H3 G34R mutations. One case is a histologically low-grade gemistocytic astrocytoma with a G34R-mutation in H3F3A. The second case is a histologically low-grade gemistocytic astrocytoma with co-occurring K27M and G34R mutations in HIST1H3B. Review of prior histone H3-mutant gliomas sequenced at our institution shows a divergent clinical and immunohistochemical pattern in the 2 cases. The first case is similar to prior histone H3 G34R-mutant tumors, while the second case most closely resembles prior histone H3 K27M-mutant gliomas. These represent novel cases of sequencing-confirmed histone H3 G34R-mutant gliomas with low-grade histology and add to the known rare cases of G34R-mutant tumors with gemistocytic morphology. Although K27M and G34R mutations are thought to be mutually exclusive, we document combined K27M and G34R mutations in HIST1H3B and present evidence suggesting the K27M-mutation drove tumor phenotype in this dual mutant glioma.
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Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Histonas/genética , Adulto , Humanos , Masculino , Mutação , Adulto JovemRESUMO
OBJECTIVE: A new case of brainstem ischemic necrosis in a young woman with de novo neurofibromatosis type 2 (NF2) is reported, and given notable similarities to 7 prior cases of brainstem stroke in the literature, features defining a possible syndrome were sought. METHODS: Case review including detailed clinical assessment, neuroimaging analysis, genetic testing, and brain biopsy, followed by a multicase analysis. RESULTS: Brainstem ischemia in juvenile NF2 typically occurs in teenagers without previously known NF2 as an acute, monophasic presentation with restricted diffusion in the midbrain or pons following a recent hypoperfusion event, normal vascular imaging, obvious intracranial imaging features of NF2, typical inactivating NF2 alterations, biopsy showing necrosis without small vessel pathology, and subsequent aggressive NF2 lesion progression. CONCLUSIONS: Brainstem ischemia in juvenile NF2 is a rare syndrome of unclear etiology, possibly reflecting an unknown underlying vascular abnormality; a digenic effect is not excluded.
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We present a case of a 43-year-old woman with a history of headaches and blurry vision. Ophthalmologic examination identified papilledema. MR imaging demonstrated a right parietal region mass with patchy areas of contrast enhancement and focal calcifications. Intraoperative examination and exploration revealed an extra-axial mass with no apparent parenchymal involvement. Microscopic examination revealed solid sheets of tumor cells with clear cell cytologic features and no discernable intra-parenchymal tumor component. Molecular studies demonstrated the presence of IDH1 IDH1 c.395G>A p.R132H and CIC c.601C>T p.R281W mutations and 1p/19q codeletion. The radiographic features, gross appearance, and microscopic and molecular characteristics of the mass support the diagnosis of primary leptomeningeal oligodendroglioma, IDH-mutant, 1p/19-codeleted. This case represents one of a very few reported instances of molecularly-defined solitary, primary, intracranial oligodendroglioma, without definitive involvement of the brain parenchyma.
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An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.
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Appropriate management of adult gliomas requires an accurate histopathological diagnosis. However, the heterogeneity of gliomas can lead to misdiagnosis and undergrading, especially with biopsy. We evaluated the role of preoperative relative cerebral blood volume (rCBV) analysis in conjunction with histopathological analysis as a predictor of overall survival and risk of undergrading. We retrospectively identified 146 patients with newly diagnosed gliomas (WHO grade II-IV) that had undergone preoperative MRI with rCBV analysis. We compared overall survival by histopathologically determined WHO tumor grade and by rCBV using Kaplan-Meier survival curves and the Cox proportional hazards model. We also compared preoperative imaging findings and initial histopathological diagnosis in 13 patients who underwent biopsy followed by subsequent resection. Survival curves by WHO grade and rCBV tier similarly separated patients into low, intermediate, and high-risk groups with shorter survival corresponding to higher grade or rCBV tier. The hazard ratio for WHO grade III versus II was 3.91 (p = 0.018) and for grade IV versus II was 11.26 (p < 0.0001) and the hazard ratio for each increase in 1.0 rCBV units was 1.12 (p < 0.002). Additionally, 3 of 13 (23%) patients initially diagnosed by biopsy were upgraded on subsequent resection. Preoperative rCBV was elevated at least one standard deviation above the mean in the 3 upgraded patients, suggestive of undergrading, but not in the ten concordant diagnoses. In conclusion, rCBV can predict overall survival similarly to pathologically determined WHO grade in patients with gliomas. Discordant rCBV analysis and histopathology may help identify patients at higher risk for undergrading.
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Neoplasias Encefálicas/irrigação sanguínea , Volume Sanguíneo Cerebral , Glioma/irrigação sanguínea , Adulto , Idoso , Biópsia , Determinação do Volume Sanguíneo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Feminino , Glioma/diagnóstico , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Período Pré-Operatório , Fatores de RiscoRESUMO
Tumor predisposition syndromes may be under-recognized in neuro-oncology practice. Identifying patients with a hereditary tumor predisposition permits appropriate tumor management as well as surveillance and risk-reduction measures for patients and their families. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recently published referral guidelines for tumor predisposition assessment, providing an impetus to review the use of genetic counseling in neuro-oncology and to describe features of the less stereotypic conditions from the perspective of neuro-oncology practice. This review also provides a framework for the identification and management of these conditions, as well as references to guidelines and resources for providers and patients.
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IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Terapia por Estimulação Elétrica/métodos , Glioblastoma/terapia , Quimioterapia de Manutenção/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Canadá , Carmustina/uso terapêutico , Quimiorradioterapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Dacarbazina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Término Precoce de Ensaios Clínicos , Terapia por Estimulação Elétrica/efeitos adversos , Europa (Continente) , Feminino , Glioblastoma/mortalidade , Humanos , Israel , Masculino , Pessoa de Meia-Idade , República da Coreia , Temozolomida , Estados Unidos , Adulto JovemRESUMO
The clinical manifestations of intracranial tumors are usually referable to the anatomic area of the brain involved or adjacent structures. Some anatomic regions may allow a tumor to reach substantial size while remaining clinically silent. In contrast, small lesions in critical areas are more likely to present early. The initial diagnosis of intracranial tumors is most efficiently made by imaging. This article discusses the clinicoanatomic features and imaging characteristics of brain tumors, including the use of dynamic susceptibility-weighted, T1 dynamic, diffusion, functional, and diffusion tensor imaging.
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Neoplasias Encefálicas/diagnóstico , Diagnóstico por Imagem/métodos , Encéfalo/patologia , Humanos , RecidivaRESUMO
We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and celecoxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O(6)-methylguanine-DNA methyltransferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29-78) and median KPS score was 90 (range, 70-100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2-8.0) and 4-month PFS was 63% (95% CI: 46%-75%). Median OS was 12.6 months (95% CI: 8.5-16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p=0.07) and PFS (p=0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Neoplasias Encefálicas/sangue , Celecoxib , Metilação de DNA/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Endostatinas/sangue , Endostatinas/efeitos dos fármacos , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Glioblastoma/sangue , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , O(6)-Metilguanina-DNA Metiltransferase/genética , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Temozolomida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Trombospondinas/sangue , Trombospondinas/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacosRESUMO
PURPOSE: One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases. PATIENTS AND METHODS: Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity. RESULTS: Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). CONCLUSION: The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.