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1.
J Oncol Pract ; 15(9): e825-e834, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386608

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described. METHODS: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined. RESULTS: Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2). CONCLUSION: A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.

2.
Neuro Oncol ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31271213
3.
Am Soc Clin Oncol Educ Book ; 39: 454-466, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099614

RESUMO

Primary central nervous system (CNS) lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis during its natural history of disease and is therefore considered stage IE disease. PCNSL is diffuse large B-cell lymphoma (DLBCL) morphology in more than 95% of patients and is designated primary diffuse large B-cell lymphoma of the CNS on the basis of the 2017 World Health Organization classification of hematopoietic and lymphoid tumors. Rapidly evolving therapeutic paradigms have been linked to evidence of progress in PCNSL, a disease long considered to be incurable. Increasing evidence supports the need for efficient diagnosis, staging, and initiation of therapy, ideally at centers with experience with this type of brain cancer. High-dose methotrexate (MTX) remains a cornerstone of induction regimens, and most data support the use of rituximab. However, clinical research challenges must address key questions, including the development of ever more effective and less toxic induction regimens and the selection of the most appropriate and effective consolidation approaches, as well as the fact that, increasingly, PCNSL affects older patients who do not tolerate strong genotoxic irradiation or high-dose chemotherapy (HDC)-based strategies. Maintenance therapy, immunotherapy, and the implementation of targeted agents on the basis of the molecular and biologic properties of the disease create opportunities for precision medicine and the potential for long-term disease-free survival and cure, with minimal treatment-related neurotoxicity, for a greater fraction of patients.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30952612

RESUMO

BACKGROUND: The Coronary Artery Calcium Data and Reporting System (CAC-DRS), which takes into account the Agatston score category (A) and the number of calcified vessels (N) has not yet been validated in terms of its prognostic significance. METHODS: We included 54,678 patients from the CAC Consortium, a large retrospective clinical cohort of asymptomatic individuals free of baseline cardiovascular disease (CVD). CAC-DRS groups were derived from routine, cardiac-gated CAC scans. Cox proportional hazards regression models, adjusted for traditional CVD risk factors, were used to assess the association between CAC-DRS groups and CHD, CVD, and all-cause mortality. CAC-DRS was then compared to CAC score groups and regional CAC distribution using area under the curve (AUC) analysis. RESULTS: The study population had a mean age of 54.2 ±â€¯10.7, 34.4% female, and mean ASCVD score 7.3% ±â€¯9.0. Over a mean follow-up of 12 ±â€¯4 years, a total of 2,469 deaths (including 398 CHD deaths and 762 CVD deaths) were recorded. There was a graded risk for CHD, CVD and all-cause mortality with increasing CAC-DRS groups ranging from an all-cause mortality rate of 1.2 per 1,000 person-years for A0 to 15.4 per 1,000 person-years for A3/N4. In multivariable-adjusted models, those with CAC-DRS A3/N4 had significantly higher risk for CHD mortality (HR 5.9 (95% CI 3.6-9.9), CVD mortality (HR4.0 (95% CI 2.8-5.7), and all-cause mortality a (HR 2.5 (95% CI 2.1-3.0) compared to CAC-DRS A0. CAC-DRS had higher AUC than CAC score groups (0.762 vs 0.754, P < 0.001) and CAC distribution (0.762 vs 0.748, P < 0.001). CONCLUSION: The CAC-DRS system, combining the Agatston score and the number of vessels with CAC provides better stratification of risk for CHD, CVD, and all-cause death than the Agatston score alone. These prognostic data strongly support new SCCT guidelines recommending the use CAC-DRS scoring.

5.
Cancer Invest ; 37(2): 67-72, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873889

RESUMO

There has been controversy about the presence and potential role of aquaporin-4 (AQP4) in glioblastoma (GBM). We analyzed tissue from 22 patients with newly-diagnosed GBM as well as matching tissue from 17 of these cases who underwent repeat resection for suspected recurrence and performed immunohistochemical analysis for AQP-4 expression. While some degree of AQP4 expression was detected in all 22 cases (39 samples), there was no clear relationship between staining pattern and disease status (active versus inactive GBM) between baseline and time of repeat biopsy. In addition, there was no clear relationship between AQP4 expression and degree of edema.


Assuntos
Aquaporina 4/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Adulto , Idoso , Biópsia , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Progressão da Doença , Edema/metabolismo , Edema/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos
6.
World Neurosurg ; 126: e1436-e1448, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30904794

RESUMO

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) account for 1%-2% of primary central nervous system tumors. Until recently, treatment has centered on biopsy, radiotherapy, and high-dose methotrexate, without a clear role for cytoreductive surgery. The objective of this article is to compare the impact of biopsy versus cytoreductive surgery in outcomes of patients with PCNSL, including postoperative complications and survival. METHODS: We performed a systematic review of literature published from January 1, 1968 to May 2, 2018 related to PCNSL treatment in patients undergoing biopsy or resection. Data on morbidity, progression-free survival, and overall survival were extracted and analyzed. RESULTS: A total of 1291 nonduplicate citations were identified, with 244 articles selected for full-text review. Twenty-four articles were included for data abstraction including 2 level IIb studies, 4 level IIIb studies, and the remaining 18 articles representing level IVb studies. Of these articles, 15 failed to show benefit with cytoreductive surgery; most of these articles included relatively small sample sizes and predated standardization of high-dose systemic methotrexate treatment. Larger, more recent series included 9 articles providing evidence in support of cytoreductive surgery. Patient age, functional status, and treatment with chemotherapy and/or radiation were associated with improved survival across studies. CONCLUSIONS: The treatment of PCNSL is challenging and ever-evolving. Earlier, smaller studies failed to show the benefit of cytoreductive surgery over biopsy in patients with PCNSL. Larger, more recent series seem to show the possible benefit of cytoreductive surgery in PCNSL. Future well-designed prospective studies may help further elucidate the role of resection in the modern treatment of PCNSL.

7.
J Neurooncol ; 143(1): 87-93, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864101

RESUMO

PURPOSE: H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation. METHODS: Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX. RESULTS: Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03). CONCLUSIONS: H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.


Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Glioma/epidemiologia , Glioma/patologia , Histonas/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Estudos de Coortes , Feminino , Glioma/genética , Glioma/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sobrevida , Adulto Jovem
8.
Blood Adv ; 3(3): 375-383, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30723112

RESUMO

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.

9.
Diagn Pathol ; 14(1): 16, 2019 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-30738431

RESUMO

BACKGROUND: Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy. CASE PRESENTATION: We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease. Biopsy of a liver lesion confirmed metastasis of the patient's known brain primary and chemotherapy with temozolomide was initiated. The patient's rapidly growing tumor burden with fulminant liver failure and tumor lysis led to multisystem failure of which the patient died. Further molecular testing illustrated features more consistent with glioblastoma: multiple large chromosomal aberrations including loss of whole chromosome 1 and 2q; gain/amplification of MYCN, MET, and CDK4; loss of CDKN2A/B; and an ATRX mutation. CONCLUSION: This case illustrates the importance of higher level molecular diagnostic testing for patients with particularly aggressive disease progression that is not concordant with standard prognoses. Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Isocitrato Desidrogenase/genética , Adulto , Aberrações Cromossômicas , Evolução Fatal , Humanos , Masculino , Mutação
10.
J Neurooncol ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30414096

RESUMO

PURPOSE: Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor progression from pseudo-progression. As a result, surgery is commonly recommended to establish a final diagnosis. However, studies evaluating the pathologists' agreement on pathologic diagnoses in this setting have not been previously evaluated. METHODS: A hypothetical clinical history coupled with images of histological sections from 13 patients with glioblastoma who underwent diagnostic surgery for suspected early recurrence were sent to 101 pathologists from 50 NCI-designated Cancer Centers. Pathologists were asked to provide a final diagnosis (active tumor, treatment effect, or unable to classify) and to report on percent active tumor, treatment effect, and degree of cellularity and degree of mitotic activity. RESULTS: Forty-eight pathologists (48%) from 30 centers responded. In three cases > 75% of pathologists diagnosed active tumor. In two cases > 75% diagnosed treatment effect. However, in the remaining eight cases the disparity in diagnoses was striking (maximum agreement on final diagnosis ranged from 36 to 68%). Overall, only marginal agreement was observed in the overall assessment of disease status [kappa score 0.228 (95% CI 0.22-0.24)]. CONCLUSIONS: Confidence in any clinical diagnostic assay requires that very similar results are obtained from identical specimens evaluated by sophisticated clinicians and institutions. The findings of this study illustrate that the diagnostic agreement between different cases of repeat resection for suspected recurrent glioblastoma can be variable. This raises concerns as pathological diagnoses are critical in directing standard and experimental care in this setting.

11.
Clin Cancer Res ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30366937

RESUMO

PURPOSE: To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma post-treatment via radiographically guided stereotactic tissue validation. EXPERIMENTAL DESIGN: Twenty-one patients referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent pre-operative APTw imaging. Stereotactic biopsies were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology as well as the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform receiver-operating-characteristic (ROC) analysis. RESULTS: Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations (R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from non-active tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff. CONCLUSIONS: APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomical brain MRI with high sensitivity and specificity.

12.
Adv Radiat Oncol ; 3(4): 582-590, 2018 Oct-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30370358

RESUMO

Purpose: Reirradiation for recurrent glioma remains controversial without knowledge of optimal patient selection, dose, fractionation, and normal tissue tolerances. We retrospectively evaluated outcomes and toxicity after conventionally fractionated reirradiation for recurrent high-grade glioma, along with the impact of concurrent chemotherapy. Methods and materials: We conducted a retrospective review of patients reirradiated for high-grade glioma recurrence between 2007 and 2016 (including patients with initial low-grade glioma). Outcome metrics included overall survival (OS), prognostic factors for survival, and treatment-related toxicity. Results: Patients (n = 118; median age 47 years; median Karnofsky performance status score: 80) were re-treated at a median of 28 months (range, 5-214 months) after initial radiation therapy. The median reirradiation dose was 41.4 Gy (range, 12.6-54.0 Gy) to a median lesion volume of 202 cm3 (range, 20-901 cm3). The median cumulative (initial radiation and reirradiation combined) potential maximum brainstem dose was 76.9 Gy (range, 5.0-108.3 Gy) and optic apparatus dose was 56.0 Gy (range, 4.5-90.9 Gy). Of the patients, 56% received concurrent temozolomide, 14%, bevacizumab, and 11%, temozolomide plus bevacizumab; 19% had no chemotherapy. The planned reirradiation was completed by 90% of patients. Median OS from the completion of reirradiation was 9.6 months (95% confidence interval [CI], 7.5-11.7 months) for all patients and 14.0, 11.5, and 6.7 months for patients with initial grade 2, 3, and 4 glioma, respectively. On multivariate analysis, better OS was observed with a >24-month interval between radiation treatments (hazard ratio [HR]: 0.3; 95% CI, 0.2-0.5; P < .001), reirradiation dose >41.4 Gy (HR: 0.6; 95% CI, 0.4-0.9; P = .03), and gross total resection before reirradiation (HR: 0.6, 95% CI, 0.3-0.9; P = .02). Radiation necrosis and grade ≥3 late neurotoxicity were both minimal (<5%). No symptomatic persistent brainstem or optic nerve/chiasm injury was identified. Conclusions: Salvage reirradiation, even at doses >41.4 Gy in conventional fractionation, along with chemotherapy, was safe and well tolerated with meaningful survival duration. These data provide information that may be useful in implementing safe reirradiation treatments for appropriately selected patients and guiding future studies to define optimal reirradiation doses, maximal safe doses to critical structures, and the role of systemic therapy.

13.
Int J Radiat Oncol Biol Phys ; 102(4): 1219-1235, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29966725

RESUMO

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology.

14.
Nature ; 560(7718): 387-391, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29925955

RESUMO

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCß to promote the assembly of the CARD11-BCL10-MALT1 adaptor complex, which recruits and activates IκB kinase4-6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR-Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

15.
J Natl Compr Canc Netw ; 16(5S): 642-645, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29784746

RESUMO

The 2016 WHO Classification of Tumors of the Central Nervous System integrated molecular biomarkers into the classifications of malignant gliomas. Several markers now play a key role in our understanding of these tumors and are integral for clinical decision-making; these include codeletion of 1p and 19q and IDH1 and IDH2 mutations. The presentation by Matthias Holdhoff, MD, PhD, at the NCCN 23rd Annual Conference discussed the current understanding of anaplastic gliomas (WHO grade III) in the context of the new classification and its implications on clinical practice. The 2018 NCCN Guidelines for Central Nervous System Cancers incorporate molecular and histologic characteristics in the staging and treatment of both low- and high-grade gliomas (WHO grades II-IV).

16.
Aging (Albany NY) ; 10(2): 154-155, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29394496
17.
J Natl Compr Canc Netw ; 15(11): 1331-1345, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29118226

RESUMO

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/diagnóstico , Glioma/diagnóstico , Sistema Nervoso/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada/métodos , Terapia Combinada/normas , Glioma/classificação , Glioma/patologia , Glioma/terapia , Humanos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Gradação de Tumores , Prognóstico , Radioterapia/métodos , Radioterapia/normas
18.
Biol Blood Marrow Transplant ; 23(12): 2127-2136, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28807769

RESUMO

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.


Assuntos
Transplante de Medula Óssea/métodos , Ciclofosfamida/uso terapêutico , Neoplasias/terapia , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Sobrevivência de Enxerto , Humanos , Neoplasias/mortalidade , Transplante Haploidêntico/mortalidade , Resultado do Tratamento , Adulto Jovem
19.
Clin Nucl Med ; 42(10): e433-e435, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28737579

RESUMO

High-grade gliomas (World Health Organization grade III-IV) are highly lethal primary brain tumors. Imaging modalities, including MRI and FDG PET, provide a limited ability to differentiate treatment effects (such as radiation necrosis) from recurrent or residual tumor. As the first step in validating the applicability of prostate-specific membrane antigen (PSMA)-targeted imaging in high-grade gliomas, we evaluated the ability of the PSMA-targeted small molecule [F]DCFPyL (2-(3-(1carboxy-5-(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid) to image high-grade gliomas in a series of 3 prospectively recruited patients. We found [F]DCFPyL binds PSMA in the neovasculature of glioblastoma multiforme and tumor cells of anaplastic astrocytoma.


Assuntos
Antígenos de Superfície/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Glioma/diagnóstico por imagem , Glioma/patologia , Glutamato Carboxipeptidase II/metabolismo , Lisina/análogos & derivados , Ureia/análogos & derivados , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Gradação de Tumores , Tomografia por Emissão de Pósitrons
20.
Science ; 357(6349): 409-413, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28596308

RESUMO

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Síndromes Neoplásicas Hereditárias/imunologia , Síndromes Neoplásicas Hereditárias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/mortalidade , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Adulto Jovem
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