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1.
Hum Pathol ; 117: 51-59, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34363799

RESUMO

Human epidermal growth factor receptor 2 (HER2)-positive classic invasive lobular carcinoma (ILC) is a rare entity, and its specific pathological characteristics and clinical behavior are unclear. Therefore, we retrospectively investigated the clinicopathological features of HER2-positive classic ILC and described HER2-targeted neoadjuvant chemotherapy outcome. Fourteen HER2-positive classic ILC cases were identified, their clinicopathological data were collected, and their clinical management was investigated. In general, HER2 positivity is associated with higher grade carcinoma in ductal lesions; however, our 14 cases had typical morphologic features of classic ILC. We did not identify unique morphologic features in HER2-positive classic ILC with the clinicopathological parameters examined, including age, menopausal status, histological grade, and hormone receptor status. Four of six patients who received HER2-targeted neoadjuvant chemotherapy had a pathological complete or partial response. Based on our findings, clinicopathological features of classic ILC may not predict HER2 overexpression or amplification. HER2-targeted neoadjuvant chemotherapy was effective against some HER2-positive classic ILCs. Taken together, these results demonstrate that HER2 immunohistochemistry and fluorescence in situ hybridization should be considered for all ILC patients regardless of subtype.

2.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34244308

RESUMO

BACKGROUND: Neoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination. METHODS: We report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone. RESULTS: Out of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3-4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV. CONCLUSIONS: These results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.

3.
Acad Radiol ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34272161

RESUMO

PURPOSE: Increased levels of stromal tumor-infiltrating lymphocytes (sTILs) have recently been considered a favorable independent prognostic and predictive biomarker in triple-negative breast cancer (TNBC). The purpose of this study was to determine the relationship between BI-RADS (Breast Imaging Reporting and Data System) ultrasound lexicon descriptors and sTILs in TNBC. MATERIALS AND METHODS: Patients with stage I-III TNBC were evaluated within a single-institution neoadjuvant clinical trial. Two fellowship-trained breast radiologists used the BI-RADS ultrasound lexicon to assess pretreatment tumor shape, margin, echo pattern, orientation, posterior features, and vascularity. sTILs were defined as low <20 or high ≥20 on the pretreatment biopsy. Fisher's exact tests were used to assess the association between lexicon descriptors and sTIL levels. RESULTS: The 284 patients (mean age 52 years, range 24-79 years) were comprised of 68% (193/284) with low-sTIL tumors and 32% (91/284) with high-sTIL tumors. TNBC tumors with high sTILs were more likely to have the following features: (1) oval/round shape than irregular shape (p = 0.003), (2) circumscribed or microlobulated margins than spiculated, indistinct, or angular margins (p = 0.0005); (3) complex cystic and solid pattern than heterogeneous pattern (p = 0.006); and (4) posterior enhancement than shadowing (p = 0.002). There was no significant association between sTILs and descriptors for orientation and vascularity (p = 0.06 and p = 0.49, respectively). CONCLUSION: BI-RADS ultrasound descriptors of the pretreatment appearance of a TNBC tumor can be useful in discriminating between tumors with low and high sTIL levels. Therefore, there is a potential use of ultrasound tumor characteristics to complement sTILs when used as stratification factors in treatment algorithms for TNBC.

4.
Clin Cancer Res ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253579

RESUMO

PURPOSE: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. EXPERIMENTAL DESIGN: We obtained pretreatment core-needle biopsies from 105 patients with stage I-III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. RESULTS: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 µm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. CONCLUSIONS: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.

5.
Transplant Cell Ther ; 27(11): 913.e1-913.e12, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34329753

RESUMO

Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m2 busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m2 and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% µmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

6.
Leukemia ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312462

RESUMO

In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105-1 × 108 cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).

7.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34021033

RESUMO

BACKGROUND: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen-loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses. DESIGN: We tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival. RESULTS: Ten patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8+ TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated. CONCLUSIONS: The combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups. TRIAL REGISTRATION NUMBER: NCT00338377.

8.
Transplant Cell Ther ; 27(5): 430.e1-430.e7, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33965187

RESUMO

Prolonged thrombocytopenia occurs in up to 37% of patients after hematopoietic stem cell transplantation (HSCT) and is associated with adverse prognosis and increased risk of bleeding. Eltrombopag, a thrombopoietin receptor agonist, can increase platelet counts in thrombocytopenic patients. We conducted a phase II study, adaptively randomizing patients at ≥35 days post-HSCT to receive placebo or eltrombopag at a platelet count ≤20,000/µL for 7 days or platelet transfusion-dependent and a neutrophil count ≥1500/µL. Sixty patients were randomized to eltrombopag (n = 42) or placebo (n = 18) and received at least 1 dose. Fifteen patients (36%) in the eltrombopag arm achieved a platelet count of ≥30,000/µL, compared with 5 patients (28%) in the placebo arm, with a posterior probability of 0.75. (The protocol required this probability to be >0.975 to declare a winner; thus, the results are inconclusive.) However, 9 patients (21%) in the eltrombopag arm achieved a platelet count of ≥50,000/µL, compared with no patients in the placebo arm (P = .046). The overall survival, progression-free survival, relapse rate, and nonrelapse mortality were similar in the 2 arms. In conclusion, compared with placebo, treatment with eltrombopag led to a higher percentage of patients achieving a platelet count of ≥50,000/µL in patients with persistent thrombocytopenia after HSCT.


Assuntos
Recidiva Local de Neoplasia , Trombocitopenia , Benzoatos/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Pirazóis , Trombocitopenia/tratamento farmacológico
9.
J Clin Pathol ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952592

RESUMO

AIMS: In advanced-stage non-small-cell lung cancer (NSCLC), incomplete genotyping for guideline-recommended genomic biomarkers poses a significant challenge to making informed and timely clinical decisions. We report our institution's experience in assessing the adequacy of small specimens for comprehensive genomic profiling for guideline-recommended lung cancer biomarker testing. METHODS: We performed a retrospective evaluation of all image-guided procedures for NSCLC performed in our institution between October 2016 and July 2018, including core needle biopsy (CNB) and fine-needle aspiration (FNA) in patients who had undergone genomic profiling for lung cancer. Lung cancer biomarker adequacy, defined as successful testing of guideline-recommended biomarkers including, epidermal growth factor receptor (EGFR); serine/threonine protein kinase B-Raf (BRAF); anaplastic lymphoma kinase (ALK); proto-oncogene tyrosine protein kinase ROS (ROS1); Rearranged during Transfection (RET); Tyrosine protein kinase Met (MET); and programmed cell death ligand 1 (PD-L1), was evaluated. RESULTS: A total of 865 cases were evaluated in this study, 785 of which included testing of all lung cancer biomarkers. Lung tissue was adequate for biomarker testing in 84% of cases; this rate increased to 87% when biomarker testing was combined with concurrently acquired FNA or CNB specimens. Biomarker testing success correlated strongly with DNA concentration (p<0.0001) and the use of 22G needles in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) procedures (p=0.0035). Biomarker testing of CNB specimens showed a significantly higher success rate than did biomarker testing of cytology FNA specimens (p=0.0005). The adequacy of EBUS-TBNA samples was not significantly different from that of the transthoracic needle aspiration samples (p=0.40). Variables such as age, gender, lesion size, site, diagnosis and number of needle passes showed no significant correlation with success rates in lung cancer biomarker testing. CONCLUSION: The growing numbers of therapeutic biomarkers in NSCLC requires judicious triage of limited-volume tissue from small specimens. Our study showed that thoracic small tissue specimens can be used successfully to provide prognostic and predictive information for the current guideline-recommended biomarkers for NSCLC in most cases.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34006396

RESUMO

OBJECTIVE: Historically, wire localization was the most widely utilized procedure for preoperative breast lesion localization. Occasionally a portion of the wire is retained in the breast. When recognized intraoperatively, the fragment can be removed immediately, but some cases are identified during post-surgical mammographic follow-up. There is little research detailing long-term stability of retained wire fragments, associated complications, or management options for cases requiring removal. We aimed to determine how often retained wire fragments remained stable, the frequency with which intervention was required, and methods available for fragment removal. METHODS: Following IRB approval, we conducted a retrospective review of patients with a retained wire localization fragment identified by EMR search seen at our institution between January 1990 and July 2019. Mammograms, localization images, specimen radiographs, and relevant clinical notes were reviewed. Information collected included breast tissue density, patient age, associated pathology, length of time the fragment was retained, presence and/or absence of fragment migration or other complications, and management of removed fragments. RESULTS: Eighteen eligible patients were identified with 19 retained wire fragments. Fragments ranged in length from 1 mm -33 mm. Twelve wire fragments had mammograms available to evaluate stability. All twelve fragments were stable mammographically for an average of 96.9 months. Seven wire fragments had no follow-up mammograms available. Eight wire fragments were surgically excised. None were excised due to migration. CONCLUSION: Localization wire fragments retained in the breast are at low risk for clinically significant migration and can be safely followed mammographically rather than undergoing immediate surgical excision or imaging-guided percutaneous removal.

11.
Breast Cancer Res Treat ; 187(1): 95-104, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33813685

RESUMO

PURPOSE: HER2 overexpression and gene amplification are routinely tested by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. In addition, HER2 mRNA expression is also tested by the Oncotype DX assay. Discordance between laboratories among the different assays remains a problem. To improve the routine HER2 reporting, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) updated their guidelines in 2018. Our study will compare concordance of HER2 status by IHC and FISH using ASCO/CAP 2013 and 2018 guidelines with Oncotype DX. METHODS: We retrospectively reviewed 657 estrogen receptor positive primary breast cancer cases with available Oncotype DX tests between 2011 and 2018. Medical records were reviewed for HER2 results by IHC, FISH, and Oncotype DX. The HER2 results by different assays and between 2013 and 2018 guidelines were compared. RESULTS: Of the 657 cases, 280 were tested by IHC, FISH, and Oncotype DX. HER2-equivocal cases by IHC 2013 guidelines were all negative (67/67, 100%) by FISH 2018 guidelines and by Oncotype DX. HER2-equivocal cases by FISH 2013 guidelines were all negative (16/16, 100%) by FISH 2018 guidelines, while 15/16 (93.8%) negative and 1/16 (6.2%) equivocal by Oncotype DX. The HER2-equivocal and HER2-negative groups were similar in age, gender, histology, grade, and Ki67 score. CONCLUSIONS: HER2 concordance was highest between Oncotype DX (99.6%) and FISH per 2018 guidelines. This suggests that the ASCO/CAP 2018 guidelines improved the accurate stratification of HER2-equivocal cases.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética , Estudos Retrospectivos
12.
Endocr Relat Cancer ; 28(7): 419-431, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-33890870

RESUMO

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6-3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

13.
Breast J ; 27(3): 242-247, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33393706

RESUMO

Pseudoangiomatous stromal hyperplasia (PASH), a rare, noncancerous lesion, is often an incidental finding on magnetic resonance imaging (MRI)-guided biopsy analysis of other breast lesions. We sought to describe the characteristics of PASH on MRI and identify the extent to which these characteristics are correlated with the amount of PASH in the pathology specimens. We identified 69 patients who underwent MRI-guided biopsies yielding a final pathological diagnosis of PASH between 2008 and 2015. We analyzed pre-biopsy MRI scans to document the appearance of the lesions of interest. All biopsy samples were classified as having ≤50% PASH or ≥51% PASH present on the pathological specimen. On MRI, 9 lesions (13%) appeared as foci, 19 (28%) appeared as masses with either washout or persistent kinetics, and 41 (59%) appeared as regions of nonmass enhancement. Of this latter group, 33 lesions (80%) showed persistent kinetic features. Masses, foci, and regions of nonmass enhancement did not significantly correlate with the percentage of PASH present in the biopsy specimens (P ≥ .05). Our findings suggest that PASH has a wide-ranging appearance on MRI but most commonly appears as a region of nonmass enhancement with persistent kinetic features. Our finding that most specimens had ≤50% PASH supports the notion that PASH is usually an incidental finding. We did not identify a definitive imaging characteristic that reliably identifies PASH.


Assuntos
Angiomatose , Doenças Mamárias , Neoplasias da Mama , Angiomatose/diagnóstico por imagem , Angiomatose/patologia , Mama/diagnóstico por imagem , Mama/patologia , Doenças Mamárias/diagnóstico por imagem , Doenças Mamárias/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Hiperplasia/diagnóstico por imagem , Hiperplasia/patologia , Imageamento por Ressonância Magnética
14.
Bone Marrow Transplant ; 56(6): 1316-1324, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33398094

RESUMO

Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1 mg/kg at day 28 and <0.5 mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n = 51) or steroids alone (n = 30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.


Assuntos
Doença Enxerto-Hospedeiro , Fotoferese , Doença Aguda , Adolescente , Adulto , Idoso , Teorema de Bayes , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Esteroides/uso terapêutico , Adulto Jovem
15.
Mod Pathol ; 34(2): 327-335, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32908255

RESUMO

Gains or amplification (amp) of chromosome 1q21/CKS1B are reported to be a high-risk factor in myeloma. In this retrospective study, we analyzed the impact of CKS1B gain/amp on overall survival in the context of other genetic aberrations, such as TP53 deletion, FGFR3-IGH, IGH-MAF, MYEOV/CCND1-IGH, and RB1, as well as karyotype. The cohort included 132 myeloma patients with CKS1B gain/amp detected by fluorescence in-situ hybridization. There were 72 men and 60 women with a median age of 65 years (range 39-88 years). A normal, simple, or complex karyotype was observed in 39.5%, 5.4%, and 55% of patients, respectively. "Double hit," defined as CKS1B gain/amp coexisting with TP53 deletion, or "triple hit," defined as double hit plus t(4;14)FGFR3-IGH or t(14;16)IGH-MAF, were identified in 25 patients (18.9%) and five patients (3.8%), respectively. Double and triple hit were highly associated with a complex karyotype (p = 0.02). Ninety-nine patients (99/128, 77.3%) received stem cell transplantation. The median follow-up time was 48.2 months (range 2-104 months); 68 patients (51.5%) died, with a median overall survival of 58.8 months. Multivariate analysis (Cox model) showed that double hit with TP53 deletion (p = 0.0031), triple hit (p = 0.01), and complex karyotype (p = 0.0009) were each independently associated with poorer overall survival. Stem cell transplantation was associated with better overall survival, mainly in patients with a double or triple hit and complex karyotype (p = 0.003). These findings indicate that the inferior outcome of myeloma patients with CKS1B gain/amp is attributable to the high number of high-risk patients in this group. The prognostic impact of CKS1B gain/amp depends on the background karyotype and TP53 status.

16.
Cancer Cytopathol ; 129(5): 374-382, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33119213

RESUMO

BACKGROUND: The use of RNA-based next-generation sequencing (NGS) assays to detect gene fusions for targeted therapy has rapidly become an essential component of comprehensive molecular profiling. For cytology specimens, the cell block (CB) is most commonly used for fusion testing; however, insufficient cellularity and/or suboptimal RNA quality are often limiting factors. In the current study, the authors evaluated the factors affecting RNA fusion testing in cytology and the added value of smears in cases with a suboptimal or inadequate CB. METHODS: A 12-month retrospective review was performed to identify cytology cases that were evaluated by a targeted RNA-based NGS assay. Samples were sequenced by targeted amplicon-based NGS for 51 clinically relevant genes on a proprietary platform. Preanalytic factors and NGS quality parameters were correlated with the results of RNA fusion testing. RESULTS: The overall success rate of RNA fusion testing was 92%. Of the 146 cases successfully sequenced, 14% had a clinically relevant fusion detected. NGS testing success positively correlated with RNA yield (P = .03) but was independent of the tumor fraction, the tumor size, or the number of slides used for extraction. CB preparations were adequate for testing in 45% cases, but the inclusion of direct smears increased the adequacy rate to 92%. There was no significant difference in testing success rates between smears and CB preparations. CONCLUSIONS: The success of RNA-based NGS fusion testing depends on the quality and quantity of RNA extracted. The use of direct smears significantly improves the adequacy of cytologic samples for RNA fusion testing for predictive biomarkers.


Assuntos
Biomarcadores Tumorais/genética , Citodiagnóstico/métodos , Técnicas Citológicas/métodos , Fusão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Estudos Retrospectivos
17.
J Clin Oncol ; 39(6): 599-607, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33125309

RESUMO

PURPOSE: Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. PATIENTS AND METHODS: We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. RESULTS: Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. CONCLUSION: The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma, with deep and sustained confirmed responses.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias Uveais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Ipilimumab/farmacologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia
18.
J Clin Endocrinol Metab ; 106(4): e1683-e1697, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33382403

RESUMO

CONTEXT: Distant metastases (DM) from childhood differentiated thyroid carcinoma (DTC) are uncommon and published studies are limited. OBJECTIVE: This work aimed to describe the outcomes of patients with DM from childhood DTC and to evaluate the molecular landscape of these tumors. METHODS: A retrospective study was conducted at a tertiary cancer center including patients with pediatric DTC (diagnosed at age ≤ 18 years from 1946 to 2019) and DM. RESULTS: We identified 148 patients; 144 (97%) had papillary thyroid carcinoma (PTC) and 104 (70%) were female. Median age at DTC diagnosis was 13.4 years (interquartile range [IQR], 9.9-15.9 years). Evaluable individuals received a median of 2 (IQR, 1-3) radioactive iodine (RAI) treatments at a median cumulative administered activity of 238.0 mCi (IQR, 147.5-351.0 mCi). The oncogenic driver was determined in 64 of 69 PTC samples: RET fusion (38/64; 59%), NTRK1/3 fusions (18/64; 28%), and the BRAF V600E mutation (8/64; 13%). At last evaluation, 93% had persistent disease. The median overall and disease-specific survival after DTC diagnosis were 50.7 and 52.8 years, respectively. Eight (5%) PTC patients died of disease after a median of 30.7 years (IQR, 20.6-37.6 years). CONCLUSION: Childhood DTC with DM persists in most patients despite multiple courses of RAI, but disease-specific death is uncommon, typically occurring decades after diagnosis. Fusion genes are highly prevalent in PTC, and all identified molecular alterations have appropriate targeted therapies. Future studies should focus on expanding genotype-phenotype correlations, determining how to integrate molecularly targeted therapy into treatment paradigms, and relying less on repeated courses of RAI to achieve cure in patients with DM from childhood DTC.


Assuntos
Metástase Neoplásica , Neoplasias da Glândula Tireoide/epidemiologia , Adolescente , Diferenciação Celular , Criança , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Mutação , Metástase Neoplásica/genética , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genética
19.
J Belg Soc Radiol ; 104(1): 69, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33283149

RESUMO

Purpose: To perform a meta-analysis comparing the diagnostic performance of increased signal intensity on T1- and T2-weighted magnetic resonance images and apparent diffusion coefficient (ADC) values in differentiating uterine leiomyosarcoma (LMS) from benign leiomyoma (LM). Methods: A systematic literature search for original studies was performed using PubMed/MEDLINE, the Cochrane Library, Embase, and Web of Science. Data necessary for the meta-analysis was extracted from the selected articles and analyzed. Results: Eight studies with 795 patients met our predefined inclusion criteria and were included in the analysis. Increased signal on T1-weighted imaging had a pooled sensitivity of 56.8% (95% CI: 20%-87.4%) for LMS (n = 60) which was significantly higher than 7.6% (95% CI: 2.2%-22.7%) for LM (n = 1272) (p = 0.0094). Increased signal analysis on T2-weighted imaging had a pooled sensitivities of 93.2% and 93.2% (95% CI: 45.7%-99.6% and 42.9%-99.6%) for LMS (n = 90), which were not significantly different from the 54.5% and 53.9% (95% CI: 33.6%-74%, 32%-74%) for LM (n = 215) (p = 0.102 and 0.112). On ADC value analysis, LMS (n = 43) had a weighted mean and standard deviation of 0.896 ± 0.19 10-3 mm2/s, 0.929 ± 0.182 10-3 mm2/s, which were significantly lower from 1.258 ± 0.303 10-3 mm2/s, 1.304 ± 0.303 10-3 mm2/s for LM (n = 159) (p = < 0.0001, < 0.0001). Conclusion: Our meta-analysis demonstrated that high signal intensity on T1-weighted images and low ADC values can accurately differentiate LMS from LM. Although, LMS had a higher pooled sensitivity for T2-weighted increased signal intensity compared to LM, there was no statistical significance.

20.
Cancers (Basel) ; 12(12)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327409

RESUMO

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, we tested our hypothesis on CD74-regulated inflammatory markers' expression in stage IV melanoma tumors whether the signature is associated with survival outcome and/or risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA), we examined the expression of cells with CD74, its receptor MIF, and downstream inflammatory markers iNOS, nitrotyrosine (NT), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to CNS metastasis using Kaplan-Meier survival analyses. Our data validates CD74 as a useful prognostic tumor cell protein marker associated with favorable OS as in stage III melanomas, while the tumor NT expression strongly predicts an increased risk of developing CNS metastasis (p = 0.0008) in those patients.

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