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1.
Blood ; 139(25): 3605-3616, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35316328

RESUMO

This phase 2 trial evaluated PET-adapted nivolumab alone or in combination with ifosfamide, carboplatin, and etoposide (NICE) as first salvage therapy and bridge to autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory (RR) classical Hodgkin lymphoma (cHL). Patients with RR cHL received 240 mg nivolumab every 2 weeks for up to 6 cycles (C). Patients in complete response (CR) after C6 proceeded to AHCT, whereas patients with progressive disease at any point or not in CR after C6 received NICE for 2 cycles. The primary endpoint was CR rate per the 2014 Lugano classification at completion of protocol therapy. Forty-three patients were evaluable for toxicity; 42 were evaluable for response. Thirty-four patients received nivolumab alone, and 9 patients received nivolumab+NICE. No unexpected toxicities were observed after nivolumab or NICE. After nivolumab, the overall response rate (ORR) was 81%, and the CR rate was 71%. Among 9 patients who received NICE, all responded, with 8 (89%) achieving CR. At the end of protocol therapy, the ORR and CR rates were 93% and 91%. Thirty-three patients were bridged directly to AHCT, including 26 after Nivo alone. The 2-year progression-free survival (PFS) and overall survival in all treated patients (n = 43) were 72% and 95%, respectively. Among 33 patients who bridged directly to AHCT, the 2-year PFS was 94% (95% CI: 78-98). PET-adapted sequential salvage therapy with nivolumab/nivolumab+NICE was well tolerated and effective, resulting in a high CR rate and bridging most patients to AHCT without chemotherapy. This trial was registered at www.clinicaltrials.gov #NCT03016871.


Assuntos
Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/uso terapêutico , Terapia de Salvação , Resultado do Tratamento
2.
Int J Mol Sci ; 21(17)2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32825639

RESUMO

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS) which can lead to severe disability. Several diseases can mimic the clinical manifestations of MS. This can often lead to a prolonged period that involves numerous tests and investigations before a definitive diagnosis is reached. As well as the possibility of misdiagnosis. Molecular biomarkers can play a unique role in this regard. Molecular biomarkers offer a unique view into the CNS disorders. They help us understand the pathophysiology of disease as well as guiding our diagnostic, therapeutic, and prognostic approaches in CNS disorders. This review highlights the most prominent molecular biomarkers found in the literature with respect to MS and its related disorders. Based on numerous recent clinical and experimental studies, we demonstrate that several molecular biomarkers could very well aid us in differentiating MS from its related disorders. The implications of this work will hopefully serve clinicians and researchers alike, who regularly deal with MS and its related disorders.


Assuntos
Biomarcadores/análise , Esclerose Múltipla/diagnóstico , Animais , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/fisiopatologia , Síndrome de Behçet/metabolismo , Síndrome de Behçet/terapia , Biomarcadores/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/fisiopatologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/terapia , Prognóstico
3.
AJR Am J Roentgenol ; 211(1): 176-184, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29792727

RESUMO

OBJECTIVE: FDG PET/MRI examination of the body is routinely performed from the skull base to the mid thigh. Many types of brain abnormalities potentially could be detected on PET/MRI if the head was included. The objective of this study was therefore to identify and characterize brain findings incidentally detected on PET/MRI of the body with the head included. MATERIALS AND METHODS: We retrospectively identified 269 patients with FDG PET/MRI whole-body scans that included the head. PET/MR images of the brain were reviewed by a nuclear medicine physician and neuroradiologist, first individually and then concurrently. Both PET and MRI findings were identified, including abnormal FDG uptake, standardized uptake value, lesion size, and MRI signal characteristics. For each patient, relevant medical history and prior imaging were reviewed. RESULTS: Of the 269 subjects, 173 were women and 96 were men (mean age, 57.4 years). Only the initial PET/MR image of each patient was reviewed. A total of 37 of the 269 patients (13.8%) had abnormal brain findings noted on the PET/MRI whole-body scan. Sixteen patients (5.9%) had vascular disease, nine patients (3.3%) had posttherapy changes, and two (0.7%) had benign cystic lesions in the brain. Twelve patients (4.5%) had serious nonvascular brain abnormalities, including cerebral metastasis in five patients and pituitary adenomas in two patients. Only nine subjects (3.3%) had a new neurologic or cognitive symptom suggestive of a brain abnormality. CONCLUSION: Routine body imaging with FDG PET/MRI of the area from the skull base to the mid thigh may miss important brain abnormalities when the head is not included. The additional brain abnormalities identified on whole-body imaging may provide added clinical value to the management of oncology patients.


Assuntos
Encefalopatias/diagnóstico por imagem , Imagem Multimodal , Imagem Corporal Total , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18 , Humanos , Achados Incidentais , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Estudos Retrospectivos
4.
Radiology ; 282(2): 602-608, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28099107

RESUMO

History A 54-year-old white woman with a history of rheumatoid arthritis who was taking glucocorticoids and methotrexate presented to the emergency department in December with worsening shortness of breath and chest heaviness for 1 week. She reported additional symptoms of weakness, headache, and arthralgia primarily involving her bilateral hands, wrist, ankles, and feet. She denied experiencing fevers, syncope or presyncope, focal neurologic deficits, chest pain, nausea, vomiting, unintentional weight loss, or recent trauma. Additional medical history included hypertension, asthma, degenerative disk disease, and migraine, all of which were reportedly controlled with medications. This patient had a smoking history of 80 pack-years, but she had quit smoking 2 months prior to presentation. She denied abuse of alcohol or recreational drugs and reported she was up-to-date on her immunizations, including those for pneumonia and flu. Family history was pertinent for breast cancer in her mother, sister, and maternal aunt. The patient reported normal findings at screening mammography and colonoscopy. A physical examination was remarkable for slightly asymmetric breath sounds, which appeared to be diminished on the right side. This patient had multiple joint deformities, most notably in the bilateral metacarpophalangeal joints. Initial electrocardiography findings and cardiac biomarkers were negative. Her complete blood count and basic metabolic profile were unremarkable. Posteroanterior and lateral chest radiographs were obtained in the emergency department. Subsequently, computed tomography (CT) of the chest was performed.


Assuntos
Pneumotórax/diagnóstico por imagem , Pneumotórax/etiologia , Nódulo Reumatoide/complicações , Nódulo Reumatoide/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Necrose , Radiografia Torácica , Tomografia Computadorizada por Raios X
5.
J Vasc Interv Radiol ; 27(2): 239-43, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26710969

RESUMO

PURPOSE: To evaluate the safety and efficacy of cryoneurolysis in patients with refractory peripheral neuropathic pain. MATERIALS AND METHODS: Twenty-two patients referred for cryoneurolysis of refractory peripheral neuropathy were recruited prospectively from July 2011 to July 2013. The mean patient age was 49.5 years, and 41% of patients were female. Ultrasound imaging of the involved nerves was used for guidance. Percutaneous ablations were performed with a PerCryo 17R device. Pain levels were recorded on a visual analog scale (scores 0-10) before and at 1, 3, 6, 9, and 12 months after the procedure, and complications were documented. RESULTS: Mean pain levels were 8.3 ± 1.9 before intervention and 2.3 ± 2.5 at 1 month, 3.2 ± 2.5 at 3 months, 4.7 ± 2.7 at 6 months, and 5.1 ± 3.7 at 12 months afterward. A Wilcoxon rank-sum test was performed and showed a statically significant decrease between pre- and postprocedural pain scores. There were no complications from the procedures. DISCUSSION: Cryoneurolysis caused a significant decrease in self-reported pain scores in patients with chronic refractory neuropathic pain, with moderately long-term relief. Cryoneurolysis is an additional therapy that can alleviate severe chronic neuropathic pain.


Assuntos
Dor Crônica/cirurgia , Criocirurgia/métodos , Neuralgia/cirurgia , Manejo da Dor/métodos , Criocirurgia/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Prospectivos , Resultado do Tratamento , Ultrassonografia de Intervenção
6.
J Comput Assist Tomogr ; 40(1): 61-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26599963

RESUMO

BACKGROUND AND PURPOSE: Myeloid sarcoma is a rare form of extramedullary leukemia, which can present with or without systemic leukemia. The purpose of this study was to evaluate characteristic computed tomography (CT) and magnetic resonance imaging (MRI) findings (including diffusion weighted imaging and susceptibility weighted imaging) of myeloid sarcoma involving the brain. MATERIALS AND METHODS: One hundred nine patients with pathologically proven myeloid sarcoma underwent pretreatment CT and MRI, which were retrospectively reviewed. Computed tomography and MRI characteristics reviewed include lesion location, shape, size, architecture, margins, ± multiplicity, ± bone destruction, pattern and degree of enhancement, ± restricted diffusion, and ± susceptibility artifact. RESULTS: Twenty-five patients (14 men, 11 women; mean age, 55 years; range, 9-80 years) met the inclusion criteria. Acute myeloid leukemia with subtypes M3 (44.4%) and M5 (22.2%) were the most common. On unenhanced CT, mean lesion size was 1.9 ± 0.4 cm; 60% were intra-axial hyperdense masses, 8% were intraventricular hyperdense masses, 12% were isodense intra-axial masses, and 20% of cases were extra-axial hyperdense nodular masses. There was no observable intralesional or perilesional calcium. On MRI, mean lesion size was 2.1 ± 0.6 cm. The lesions were isointense (80%) or hypointense (20%) on T1-weighted images with homogeneous (88%) or heterogeneous (12%) enhancement. On fluid-attenuated inversion recovery and T2-weighted images, lesions were hyperintense (96%) or isointense (4%) with mild vasogenic edema. Majority (96%) of cases demonstrated restricted diffusion, whereas only a few (16%) demonstrated susceptibility artifact. CONCLUSIONS: In patients with history of leukemia or myeloproliferative disorder, identification of homogenous mass hyperdense on unenhanced CT, T1 isointense, and T2/fluid-attenuated inversion recovery hyperintense with restricted diffusion and homogenous postcontrast enhancement without significant susceptibility artifact is suggestive of myeloid sarcoma.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética , Sarcoma Mieloide/diagnóstico por imagem , Sarcoma Mieloide/patologia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
7.
AJR Am J Roentgenol ; 204(1): 128-39, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25539248

RESUMO

OBJECTIVE: The purpose of this article is to review the imaging features of necrotizing fasciitis and its potential mimics. Key imaging features are emphasized to enable accurate and efficient interpretation of variables that are essential in appropriate management. CONCLUSION: Necrotizing fasciitis is a medical emergency with potential lethal outcome. Dissecting gas along fascial planes in the absence of penetrating trauma (including iatrogenic) is essentially pathognomonic. However, the lack of soft-tissue emphysema does not exclude the diagnosis. Mimics of necrotizing fasciitis include nonnecrotizing fasciitis (eosinophilic, paraneoplastic, inflammatory (lupus myofasciitis, Churg-Strauss, nodular, or proliferative), myositis, neoplasm, myonecrosis, inflammatory myopathy, and compartment syndrome. Necrotizing fasciitis is a clinical diagnosis, and imaging can reveal nonspecific or negative findings (particularly during the early course of disease). One should be familiar with salient clinical and imaging findings of necrotizing fasciitis to facilitate a more rapid and accurate diagnosis and be aware that its diagnosis necessitates immediate discussion with the referring physician.


Assuntos
Fasciite Necrosante/diagnóstico , Inflamação/diagnóstico , Doenças Musculares/diagnóstico , Neoplasias/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Adulto Jovem
8.
J Comput Assist Tomogr ; 39(6): 842-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26359582

RESUMO

BACKGROUND AND PURPOSE: Anemia is an underdiagnosed clinical entity with significant mortality and morbidity. We aimed to assess whether attenuation of dural venous sinuses correlates with hemoglobin/hematocrit and to determine if the degree of anemia can be predicted by quantitative analysis of unenhanced computed tomography (CT) of the head. MATERIALS AND METHODS: This is an institutional review board-approved retrospective study including 500 patients who underwent emergency department investigation for potential central nervous system etiology of their symptoms with unenhanced CT head at a tertiary care center. Computed tomographic attenuation values were obtained by 2 independent readers, whereas 2 separate investigators collected clinical data. Regression analyses were performed to evaluate the strength of correlation and the predictability of anemia and its severity on unenhanced CT. Receiver operating characteristic curve analyses were performed to evaluate sensitivity, specificity, as well as positive and negative predictive values. RESULTS: A total of 243 met the inclusion criteria, and attenuation values for all the dural venous sinuses were averaged and categorized according to hemoglobin values of less than 8, 8 to 10, 10 to 14, and greater than 14. Mean CT attenuation values for both readers were 36.30, 42.35, 47.99, and 53.25 Hounsfield units. Regression analysis revealed the highest positive correlation of hemoglobin/hematocrit with attenuation at the confluence of sinuses with R value of 0.63 and 0.60. The sensitivity, specificity, and negative predictive value of detecting hemoglobin of less than 10 at confluence of sinuses were 91.2%, 88.5%, and 98.6%, respectively. Interobserver agreement was found to be good (0.64) using the κ statistic. CONCLUSIONS: Our study substantiates direct positive correlation between CT attenuation of dural venous sinuses and hemoglobin/hematocrit, with strongest correlation at the confluence of sinuses with good sensitivity, specificity, and negative predictive value.


Assuntos
Anemia/diagnóstico , Cavidades Cranianas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
9.
J Comput Assist Tomogr ; 39(5): 804-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25974720

RESUMO

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) offers a curative treatment for lung cancer in patients who are marginal surgical candidates. However, unlike traditional surgery the lung cancer remains in place after treatment. Thus, imaging follow-up for evaluation of recurrence is of paramount importance. MATERIALS AND METHODS: In this retrospective designed Institutional Review Board-approved study, follow-up contrast-enhanced computed tomography (CT) exams were performed on sixty one patients to evaluate enhancement pattern in the ablation zone at 1, 3, 6, and 12 months after SABR. RESULTS: Eleven patients had recurrence within the ablation zone after SABR. The postcontrast enhancement in the recurrence group showed a washin and washout phenomenon, whereas the radiation-induced lung injury group showed continuous enhancement suggesting an inflammatory process. CONCLUSIONS: The textural feature of the ablation zone of enhancement and perfusion as demonstrated in computed tomography nodule enhancement may allow early differentiation of recurrence from radiation-induced lung injury in patients' status after SABR or primary lung cancer.


Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/diagnóstico por imagem , Radiocirurgia/métodos , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Seguimentos , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Intensificação de Imagem Radiográfica , Estudos Retrospectivos , Resultado do Tratamento
10.
J Clin Rheumatol ; 21(3): 144-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25807094

RESUMO

Numerous autoimmune diseases can affect the central nervous system (CNS), and variable clinical presentations confound the differential diagnosis. The challenging task of properly characterizing various CNS autoimmune diseases enables patients to be rapidly triaged and appropriately treated. In this review article, we aim to explore different CNS manifestations of rheumatologic diseases with emphasis on the utility of imaging and cerebrospinal fluid findings. We review the classic physical examination findings, characteristic imaging features, cerebrospinal fluid results, and serum biomarkers. In addition, we also present a unique case of newly described autoimmune entity CLIPPERS syndrome. Our case is unique in that this is the first case which demonstrates involvement of the supratentorial perivascular spaces in addition to the classic infratentorial involvement as initially described by Pittock et al (Brain. 2010;133:2626-2634).


Assuntos
Ataxia/diagnóstico , Doenças Autoimunes/diagnóstico , Doenças do Sistema Nervoso Central/diagnóstico , Diplopia/diagnóstico , Paraparesia Espástica/diagnóstico , Doenças Reumáticas/diagnóstico , Idoso , Ataxia/tratamento farmacológico , Comorbidade , Diagnóstico Diferencial , Diplopia/tratamento farmacológico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Paraparesia Espástica/tratamento farmacológico , Prednisolona/uso terapêutico , Medula Espinal/patologia , Síndrome , Resultado do Tratamento
11.
J Clin Oncol ; 42(7): 808-820, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38042525

RESUMO

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.


Assuntos
Acrilamidas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Sistema Nervoso Central , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Pemetrexede/uso terapêutico , Platina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico
12.
Nat Med ; 30(6): 1636-1644, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38867077

RESUMO

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .


Assuntos
Antígenos de Neoplasias , Proteínas Ligadas por GPI , Imunoterapia Adotiva , Proteínas de Neoplasias , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Pessoa de Meia-Idade , Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Proteínas Ligadas por GPI/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Metástase Neoplásica , Linfócitos T/imunologia , Linfócitos T/transplante , Antígeno Prostático Específico/sangue
13.
Nat Med ; 30(4): 1001-1012, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38454126

RESUMO

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .


Assuntos
Glioblastoma , Glioma , Receptores de Antígenos Quiméricos , Humanos , Recidiva Local de Neoplasia , Glioma/terapia , Linfócitos T , Glioblastoma/terapia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos
14.
Cancers (Basel) ; 15(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36765610

RESUMO

BACKGROUND: Cancer patients infected with COVID-19 were shown in a multitude of studies to have poor outcomes on the basis of older age and weak immune systems from cancer as well as chemotherapy. In this study, the CT examinations of 22 confirmed COVID-19 cancer patients were analyzed. METHODOLOGY: A retrospective analysis was conducted on 28 cancer patients, of which 22 patients were COVID positive. The CT scan changes before and after treatment and the extent of structural damage to the lungs after COVID-19 infection was analyzed. Structural damage to a lung was indicated by a change in density measured in Hounsfield units (HUs) and by lung volume reduction. A 3D radiometric analysis was also performed and lung and lesion histograms were compared. RESULTS: A total of 22 cancer patients were diagnosed with COVID-19 infection. A repeat CT scan were performed in 15 patients after they recovered from infection. Most of the study patients were diagnosed with leukemia. A secondary clinical analysis was performed to show the associations of COVID treatment on the study subjects, lab data, and outcome on mortality. It was found that post COVID there was a decrease of >50% in lung volume and a higher density in the form of HUs due to scar tissue formation post infection. CONCLUSION: It was concluded that COVID-19 infection may have further detrimental effects on the lungs of cancer patients, thereby, decreasing their lung volume and increasing their lung density due to scar formation.

15.
Neuro Oncol ; 25(5): 886-898, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-36394567

RESUMO

BACKGROUND: Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.


Assuntos
Galectina 3 , Glioma , Camundongos , Humanos , Animais , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Galectina 3/genética , Ligantes , Linhagem Celular Tumoral , Glioma/patologia , Imunidade , Microambiente Tumoral/genética
16.
Ocul Immunol Inflamm ; 30(1): 95-103, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-32812810

RESUMO

Purpose: To describe a case of panuveitis with occlusive vasculitis leading to the diagnosis of neuro-Behcet disease (NBD) and discuss the relationship between uveitis and NBD.Methods: Case report with a literature review of ocular inflammation in NBD.Results: A 26-year-old woman with a seven-month history of recurrent cerebral venous sinus thromboses (CVST) and right-sided hemiparalysis secondary to rhombencephalitis presented with bilateral panuveitis and occlusive retinal vasculitis. Systemic evaluations were negative for hypercoagulability and infection. Although HLA-51 negative, the diagnosis was consistent with NBD.Conclusion: NBD is a rare subset of BD with a limited number of studies and patients. However, uveitis is more common in adults with parenchymal disease; may predate the development of neurological symptoms. The most common locations of ocular inflammation were posterior and panuveitis. MRI/V of the brain can identify enhancing lesions in the rhombencephalon or CVST in patients with uveitis with neurological findings.


Assuntos
Síndrome de Behçet , Vasculite Retiniana , Uveíte , Adulto , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Feminino , Humanos , Inflamação/complicações , Vasculite Retiniana/complicações , Vasculite Retiniana/etiologia , Uveíte/complicações , Uveíte/etiologia , Transtornos da Visão
17.
Eur J Radiol ; 146: 110062, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34890935

RESUMO

Immunotherapy has revolutionized clinical outcomes in both early-stage and advanced-stage malignancies. Immunotherapy has improved patient survival in both solid and hematologic disorders with the potential added benefit of less toxicity compared to conventional cytotoxic chemotherapy. Imaging plays a fundamental role in monitoring treatment response and assessment of immune-related adverse events, e.g. pneumonitis, colitis, etc. Familiarity with the current strategies of immune-related response evaluation and their limitations is essential for radiologists to guide clinicians with their treatment decisions. Radiologists should be aware of the wide spectrum of immune-related adverse events and their various radiological features as well as the patterns of treatment response associated with immunotherapies.


Assuntos
Imunoterapia , Neoplasias , Diagnóstico por Imagem , Humanos , Imunoterapia/efeitos adversos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Critérios de Avaliação de Resposta em Tumores Sólidos
18.
Leuk Lymphoma ; 63(12): 2912-2917, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35938581

RESUMO

Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Humanos , Transplante Autólogo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Doença de Hodgkin/patologia , Prognóstico , Neoplasia Residual/diagnóstico , Leucócitos Mononucleares/patologia , Recidiva Local de Neoplasia , Transplante de Células-Tronco
19.
Radiology ; 281(1): 311-3, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27643770
20.
Neuroimaging Clin N Am ; 31(1): 93-102, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33220831

RESUMO

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms.


Assuntos
Mapeamento Encefálico/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Cuidados Pré-Operatórios/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Neoplasias Encefálicas/cirurgia , Humanos
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