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1.
Leuk Lymphoma ; : 1-12, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686083

RESUMO

Standard-of-care for newly-diagnosed, autologous hematopoietic stem cell transplantation (auto-HCT)-eligible, multiple myeloma (MM) patients includes bortezomib, lenalidomide, and dexamethasone (VRD) induction followed by melphalan 200 mg/m2 (Mel200)-conditioned auto-HCT and lenalidomide maintenance. We completed a retrospective case series assessing outcomes of 187 MM patients who received this regimen at our institution. The 100-day non-relapse mortality incidence was zero. Before auto-HCT, 9.6 and 52.9% of patients achieved a complete response (CR) or ≥ very good partial response (VGPR), respectively. At day-100 post-transplant, 29.4 and 74.9% had achieved a CR/stringent-CR (sCR) or ≥ VGPR, respectively. At the last evaluation, 57.2% of patients had CR/sCR and 87.1% had ≥ VGPR. Median follow-up, progression-free survival (PFS), and overall survival (OS) were 63.2, 50, and 101.7 months, respectively. The 5-year PFS and OS were 43.1 and 79%. High-risk cytogenetics was associated with worse outcomes. This study illustrates that VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance are associated with good outcomes in MM.

2.
Australas J Dermatol ; 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34699068

RESUMO

PD-1 inhibitors are immunotherapeutic agents used in the treatment of advanced cutaneous squamous cell carcinoma (cSCC). This study aimed to determine the pooled objective response and disease control rates of patients with advanced cSCC treated with PD-1 inhibitors. Pubmed, Cochrane Library and EMBASE databases were searched up to 1 January 2021 to include eligible articles. Objective response rate (ORR) and disease control rate (DCR) were pooled and analysed. Subgroup analysis of the odds ratio (OR) for ORR for patients by PD-L1 tumour proportion score (TPS) was performed. Seven articles including a total of 453 patients were identified and included. Pooled estimate of ORR was 44% (95% CI: 39-49%, I2 = 23.7%) and of DCR was 66% (95% CI: 57-74%, I2 = 68.2%). Pooled odds ratio of ORR for patients by PD-L1 TPS was 2.81 (95% CI: 1.22-6.51, I2 = 0.0%). These results were derived from single-arm studies, some of which were retrospective. No head-to-head trials comparing PD-1 inhibitors have been reported. We present aggregate estimates of ORR and DCR for patients with advanced cSCC treated with PD-1 inhibitors, as well as subgroup analysis for ORR for patients by PD-L1 TPS.

3.
Acad Radiol ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34538550

RESUMO

RATIONALE AND OBJECTIVES: Synthesized mammography with digital breast tomosynthesis (SM+DBT) and full-field digital mammography with DBT were prospectively evaluated for recall rate (RR), cancer detection rate (CDR), positive predictive value 1 (PPV1), lesion recall differences, and disagreements in recall for additional imaging. MATERIALS AND METHODS: From December 15, 2015 to January 15, 2017, after informed consent was obtained for this Health Insurance Portability and Accountability Act compliant study, each enrolled patient's SM+DBT and FFDM+DBT were interpreted sequentially by one of eight radiologists. RR, CDR, PPV1, and imaging findings (asymmetry, focal asymmetry, mass, architectural distortion, and calcifications) recalled were reviewed. RESULTS: For SM+DBT and FFDM+DBT in 1022 patients, RR was 7.3% and 7.9% (SM+DBT vs. FFDM+DBT: diff= -0.6%; 90% CI= -1.4%, 0.1%); CDR was 6.8 and 7.8 per 1000 (SM+DBT vs. FFDM+DBT: diff= -1.0, 95% CI= -5.5, 2.8, p = 0.317); PPV1 was 9.3% and 9.9% (relative positive predictive value for SM+DBT vs. FFDM+DBT: 0.95, 95% CI: 0.73-1.22, p = 0.669). FFDM+DBT detected eight cancers; SM+DBT detected seven (missed 1 cancer with calcifications). SM+DBT and FFDM+DBT disagreed on patient recall for additional imaging in 19 patients, with majority (68%, 13/19 patients) in the recall of patients for calcifications. For calcifications, SM+DBT recalled six patients that FFDM+DBT did not recall, and FFDM+DBT recalled seven patients that SM+DBT did not recall, even though the total number of calcifications finding recalled was similar overall for both SM+DBT and FFDM+DBT. CONCLUSION: Disagreement in recall of patients for calcifications may impact cancer detection by SM+DBT, warranting further investigation.

5.
Clin Lung Cancer ; 2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34419375

RESUMO

INTRODUCTION: The historical standard of care for brain metastases (BMs) from small cell lung cancer (SCLC) has been whole-brain radiotherapy (WBRT). However, there is growing interest in upfront stereotactic radiosurgery (SRS) for select SCLC patients. MATERIALS AND METHODS: We invited United State-based Radiation Oncologists (ROs) via email to answer an anonymous survey using a branching logic system addressing their use of SRS and WBRT for SCLC BMs. Wilcoxon rank-sum test and Fisher's exact test were used to compare differences in continuous and categorical variables, respectively. Multivariable logistic regression analyses were fitted for outcome variables including covariates with P < .10 obtained on univariable analysis. RESULTS: In total, 309 ROs completed the survey and 290 (95.7%) reported that they would consider SRS for SCLC BMs under certain clinical circumstances. Across patient characteristics, the number of BMs was the most heavily weighted factor (mean 4.3/5 in importance), followed by performance status, cognitive function, and response to prior therapy. Fewer BMs were correlated with increased SRS use (55.8% offered SRS "very frequently" [>75% of cases] or "often" [51%-75% of cases] for 1 BM vs. 1.1% for >10 BM, P < .001). In situations where WBRT was preferred, concern for rapid intracranial progression (45.3%) and lack of high-level data (36.9%) were the most important factors. The majority (60.6%) were aware of a large recent international retrospective analysis (the FIRE-SCLC study) reporting similar OS between upfront SRS and WBRT; awareness of this study was the only respondent variable predictive of SRS use for limited BMs (19.2% of those aware of the study preferring SRS for limited [≤4] BMs before vs. 61% preferring SRS after the publication, P < .001). The majority of respondents (88.2%) expressed a willingness to enroll patients on a recently opened recently opened randomized trial, NRG-CC009, comparing SRS versus hippocampal-avoidance WBRT. CONCLUSIONS: In the first survey of SRS for SCLC BMs, we observed a high level of physician openness to upfront SRS in SCLC, particularly for patients with limited numbers of BMs, as well as significant interest in generating prospective randomized data to clarify the role of SRS in this population.

6.
Haematologica ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435482

RESUMO

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (aGVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and Predicted Indirectly Recognizable HLA Epitopes score (PS) in a cohort of 1,514 patients receiving HSCT from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci. HLA-DPB1 alloimmunity in the GVH direction determined by high GVH ME/PS was associated with a reduced risk of relapse (HR 0.83, P= .05 for ME) and increased risk of grade 2-4 aGVHD (HR 1.44, P< .001 for ME), whereas high HVG ME/PS was only associated with an increased risk of grade 2-4 aGVHD (HR 1.26, P= .004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high HVG ME/PS was associated with an increased risk of relapse (HR 1.36, P= .026 for ME) and grade 2-4 aGVHD (HR 1.43, P= .003 for PS-II). Decision curve analysis showed GVH ME outperformed other models and provided the best clinical net benefit for the modification of aGVHD prophylaxis regimen in patients with high risk of developing clinically significant aGVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of HVG or GVH alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.

7.
Am J Cancer Res ; 11(6): 3227-3239, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249457

RESUMO

Activating transcription factor 4 (ATF4) is a crucial mediator of the integrated stress response and a negative regulator of RET tyrosine kinase receptor in medullary thyroid carcinoma (MTC). However, the impact of genomic abnormalities in the ATF4 locus on MTC pathogenesis and response to tyrosine kinase inhibitor therapy remains unknown. Here, we evaluated ATF4 copy number variation and protein levels, with overall survival and response to TKIs in a clinical cohort of fifty-nine sporadic primary MTC. We assessed the somatic RETM918T mutation by sequencing, ATF4 copy number by a real-time polymerase chain reaction, and ATF4 protein levels using immunohistochemistry. This MTC cohort comprised 45 (76%) stage IV patients with a median follow-up of 100 months (interquartile range: 58-134 months). Somatic RETM918T was present in 23/57 (40%) tumors. Mono-allelic (36%; 21/59) and bi-allelic (5%; 3/59) loss of ATF4 was identified and was associated with low ATF4 protein expression (0-20%). Kaplan-Meier curves highlight low ATF4 protein or ATF4 loss alone had a significant negative impact on median survival compared to high protein expression (P<0.001) or diploid ATF4 (P=0.011), respectively. The combination of somatic RETM918T and low ATF4 protein levels further decreased overall survival. Both allelic loss and protein reduction were associated with worse overall survival (HR=3.79, 4.06 +RETM918T , and HR=10.64, 11.66 +RETM918T , respectively). Additionally, all 4 of the 11 patients treated with TKIs with a progressive disease by RECIST had low tumor ATF4 protein, with the two partial responder's tumors having high ATF4 protein. These findings suggest that ATF4 may predict response to tyrosine kinase inhibitors, serve as a prognostic marker for personalized care, and a therapeutic target in MTC.

8.
Am J Surg Pathol ; 45(9): 1155-1165, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34280940

RESUMO

Pheochromocytomas are rare neuroendocrine tumors arising from chromaffin cells in the adrenal medulla. They may occur sporadically or in the context of hereditary syndromes. All pheochromocytomas are considered to have malignant potential (defined as risk of metastasis, not local invasion). The use of grading systems with incorporated clinical and histopathologic parameters can help but not definitively predict the metastatic potential of pheochromocytomas. The recent discovery of susceptibility genes provided new insights into the pathogenesis and introduced additional approaches to estimate the metastatic risk of pheochromocytoma. However, the prevalence of these genetic signatures in pheochromocytomas has yet to be fully addressed. Therefore, in the present study, we retrospectively reviewed cases of pheochromocytoma from 1980 to 2018 in the archives of our institution. Three hundred ninety cases were identified, and their clinicopathologic characteristics and genetic statuses were analyzed. About 25% of the cases had metastases, which were more common in older patients (median, 49 y) than in younger ones. Univariate and multivariate analyses revealed that older age, Hispanic ethnicity, metastasis, and large primary tumor size were markedly associated with poor overall survival. In contrast, family history of pheochromocytoma, lack of symptoms, and bilateral adrenal involvement were associated with better survival. About 37% of the pheochromocytomas were associated with inherited syndromes. About 52% of tested patients had pathogenic mutations of pheochromocytoma susceptibility genes. Of these, succinate dehydrogenase B gene mutation had the strongest association with metastasis. These data support that genetic testing should be offered to all patients with pheochromocytoma.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Feocromocitoma/patologia , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/genética , Estudos Retrospectivos , Adulto Jovem
9.
Stat Med ; 40(21): 4629-4639, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34101217

RESUMO

We propose a Bayesian hierarchical monitoring design for single-arm phase II clinical trials of cancer treatments that incorporates the information on the duration of response (DOR) into the monitoring rules. To screen a new treatment by evaluating its preliminary therapeutic effect, futility monitoring rules are commonly used in phase II clinical trials to make "go/no-go" decisions timely and efficiently. These futility monitoring rules are usually focused on a single outcome (eg, response rate), although a single outcome may not adequately determine the efficacy of the experimental treatment. For example, targeted agents with a long response duration but a similar response rate may be worth further evaluation in cancer research. To address this issue, we propose Bayesian hierarchical futility monitoring rules to consider both the response rate and duration. The first level of monitoring evaluates whether the response rate provides evidence that the experimental treatment is worthy of further evaluation. If the evidence from the response rate does not support continuing the trial, the second level monitoring rule, which is based on the DOR, will be triggered. If both stopping rules are satisfied, the trial will be stopped for futility. We conducted simulation studies to evaluate the operating characteristics of the proposed monitoring rules and compared them to those of standard method. We illustrated the proposed design with a single-arm phase II cancer clinical trial to assess the safety and efficacy of combined treatment of nivolumab and azacitidine in patients with relapsed/refractory acute myeloid leukemia. The proposed design avoids an aggressive early termination for futility when the experimental treatment substantially prolongs the DOR but fails to improve the response rate.


Assuntos
Leucemia Mieloide Aguda , Projetos de Pesquisa , Teorema de Bayes , Ensaios Clínicos Fase II como Assunto , Simulação por Computador , Humanos , Futilidade Médica
10.
Transplant Cell Ther ; 27(5): 404.e1-404.e5, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33965178

RESUMO

The cell of origin (COO) classification into germinal center B cell (GCB) and non-GCB types has been shown to predict survival outcomes in newly diagnosed diffuse large B cell lymphoma (DLBCL). In the relapsed/refractory (R/R) setting, there is building evidence that COO does not predict prognosis after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT). The present analysis aimed to compare survival outcomes based on COO classification in R/R DLBCL patients who underwent auto-SCT. This retrospective study included adult patients with R/R DLBCL who underwent auto-SCT at MD Anderson Cancer Center between January 2007 and December 2016. The Hans algorithm using CD10, BCL6, and MUM1 markers was used to classify patients by COO. A total of 122 patients with DLBCL (71 GCB, 51 non-GCB) were included in the analysis. There were no significant differences in patient characteristics between the 2 groups, except for older median age in the GCB cohort (64 years versus 58 years; P < .004). The median overall survival (OS) time was 68.5 (95% confidence interval [CI], 51.3 to not reached) months for the total population, 68.5 (95% CI, 44.8 to not reached) for GCB, and not reached for non-GCB. The 3-year OS rate was 0.659 (95% CI, 0.575 to 0.755) for the total population, 0.653 (95% CI, 0.547 to 0.779) for GCB, and 0.666 (95% CI, 0.537 to 0.824) for non-GCB. When adjusted for age and other factors of interest, no statistically significant associations for OS or progression-free survival were observed between the 2 cohorts. Our results confirm that COO loses its prognostic potential in patients with R/R DLBCL who receive high-dose chemotherapy followed by auto-SCT and both GCB and non-GCB types of DLBCL derive similar benefit from auto-SCT. Younger age, female sex, and pretransplantation disease status were associated with better OS.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Adulto , Feminino , Centro Germinativo , Humanos , Linfoma Difuso de Grandes Células B/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Autólogo
11.
Chest ; 160(3): 1108-1120, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33932466

RESUMO

BACKGROUND: Two models, the Help with the Assessment of Adenopathy in Lung cancer (HAL) and Help with Oncologic Mediastinal Evaluation for Radiation (HOMER), were recently developed to estimate the probability of nodal disease in patients with non-small cell lung cancer (NSCLC) as determined by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to prospectively externally validate both models at multiple centers. RESEARCH QUESTION: Are the HAL and HOMER models valid across multiple centers? STUDY DESIGN AND METHODS: This multicenter prospective observational cohort study enrolled consecutive patients with PET-CT clinical-radiographic stages T1-3, N0-3, M0 NSCLC undergoing EBUS-TBNA staging. HOMER was used to predict the probability of N0 vs N1 vs N2 or N3 (N2|3) disease, and HAL was used to predict the probability of N2|3 (vs N0 or N1) disease. Model discrimination was assessed using the area under the receiver operating characteristics curve (ROC-AUC), and calibration was assessed using the Brier score, calibration plots, and the Hosmer-Lemeshow test. RESULTS: Thirteen centers enrolled 1,799 patients. HAL and HOMER demonstrated good discrimination: HAL ROC-AUC = 0.873 (95%CI, 0.856-0.891) and HOMER ROC-AUC = 0.837 (95%CI, 0.814-0.859) for predicting N1 disease or higher (N1|2|3) and 0.876 (95%CI, 0.855-0.897) for predicting N2|3 disease. Brier scores were 0.117 and 0.349, respectively. Calibration plots demonstrated good calibration for both models. For HAL, the difference between forecast and observed probability of N2|3 disease was +0.012; for HOMER, the difference for N1|2|3 was -0.018 and for N2|3 was +0.002. The Hosmer-Lemeshow test was significant for both models (P = .034 and .002), indicating a small but statistically significant calibration error. INTERPRETATION: HAL and HOMER demonstrated good discrimination and calibration in multiple centers. Although calibration error was present, the magnitude of the error is small, such that the models are informative.

12.
Mol Cancer Ther ; 20(4): 665-675, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33536187

RESUMO

Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogenesis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2 Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Imidazóis/uso terapêutico , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Estudos Retrospectivos
13.
Cancers (Basel) ; 12(8)2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32824391

RESUMO

Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12-74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0-41%). The clinical benefit rate was 73% (95% CI: 39-94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37-not reached). The median survival duration was 19 months (95% CI: 9.9-not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients' hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor.

14.
BMC Cancer ; 20(1): 83, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005111

RESUMO

BACKGROUND: Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification. METHODS: Mutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma. RESULTS: The proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival. CONCLUSIONS: The mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Medicina de Precisão , Prognóstico , Estudos Retrospectivos , Análise de Sequência de DNA , Análise de Sobrevida
15.
Clin Cancer Res ; 25(22): 6781-6787, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31481508

RESUMO

PURPOSE: Patients with multiple myeloma with t(11;14) have been considered to have standard-risk disease. However, several recent reports have shown contradictory results. We identified 95 patients with multiple myeloma with t(11;14) on FISH studies, who underwent upfront autologous hematopoietic stem cell transplant (auto-HCT) at our center. We compared their outcome with a group of standard-risk patients with multiple myeloma who had diploid cytogenetics by both conventional cytogenetics (CC) and FISH (n = 287). EXPERIMENTAL DESIGN: To reduce the bias between the groups, we performed a 1:1 propensity score matching technique for analysis. A total of 160 patients, 80 in each group, were identified. Patients in the 2 groups were matched for age, International staging system stage at diagnosis, serum creatinine at presentation, disease status at auto-HCT, type of preparative regimens, dose of melphalan used for conditioning, and induction and maintenance regimens. RESULTS: Patients in t(11;14) group had a post auto-HCT overall response rate (ORR) of 97.5% (78/80), compared with 100% (80/80) in the standard-risk control group (P = 0.50). Complete response rate in the t(11;14) group was 35% (28/80), compared with 45% (36/80) in the standard-risk control group (P = 0.26). The 4-year PFS rates were 40.8% (95% CI, 29.6%-56.1%) and 51.1% (95% CI, 39.4%-66.3%) in the t(11;14) and standard-risk control groups, respectively (P = 0.14). The 4-year OS rates were 74.9% (95% CI, 63.3%-88.7%) and 88.3% (95% CI, 80.4%-97.0%) in the t(11;14) and standard-risk control groups, respectively (P = 0.17). Also, patients with t(11;14) with concurrent cytogenetics had significantly poor PFS and OS compared with a propensity matched standard-risk control group. CONCLUSIONS: Our study confirms that t(11;14) multiple myeloma undergoing upfront autologous transplantation had similar outcomes as patients with multiple myeloma with normal cytogenetic and FISH studies. Existence of additional genomic aberrations by CC or FISH was associated with a worse outcome.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Translocação Genética , Idoso , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Indução de Remissão , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento
16.
Cancer ; 125(23): 4193-4202, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398264

RESUMO

BACKGROUND: Melanoma brain metastases (MBM) occur in up to 50% of patients with metastatic melanoma (MM) and represent a frequent site of systemic treatment failure for targeted therapies. However, to the authors' knowledge, little is known regarding the incidence, patterns of disease progression, and outcomes of MBM in patients treated with anti-PD-1 immunotherapy. METHODS: A total of 320 patients with MM who were treated with anti-PD-1 at The University of Texas MD Anderson Cancer Center in Houston were reviewed. Analyses were performed to identify factors associated with brain metastasis-free survival and overall survival (OS) using Cox regression models. RESULTS: The median age of the patients was 63.3 years. OS from the initiation of anti-PD-1 therapy was not significantly different between patients without MBM prior to anti-PD-1 compared with patients with prior MBM (P = .359). Among patients without prior MBM, 21 patients (8.6%) developed MBM during anti-PD-1 therapy, 12 of whom (4.9%) presented with disease progression in the central nervous system (CNS) only. Developing MBM during or after therapy with anti-PD-1 (hazard ratio, 4.70; 95% CI, 3.18-6.93) was associated with shorter OS. Among patients with MBM prior to anti-PD-1 treatment, 15 (20.0%) progressed in the CNS only and 19 (25.3%) progressed both intracranially and extracranially; at the time of the last data cutoff, 27 patients (36.0%) had not developed disease progression. Radiation necrosis occurred in 11.3% of patients (7 of 62 patients) in the group with a prior MBM who received stereotactic radiosurgery. CONCLUSIONS: Anti-PD-1 therapy may change the natural history of patients with preexisting MBM. However, CNS failure during treatment with anti-PD-1 is predictive of a worse prognosis compared with extracranial progression. The results of the current study support the activity of anti-PD-1 in patients with MBM, although routine CNS imaging during therapy is warranted.


Assuntos
Neoplasias Encefálicas/secundário , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Incidência , Masculino , Melanoma/complicações , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento
17.
Respirology ; 24(12): 1198-1203, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31209954

RESUMO

BACKGROUND AND OBJECTIVE: Analysis of programmed death ligand-1 (PD-L1) in tumour samples is necessary to identify candidates for anti-PD-L1/PD-L1 therapy. Because PD-L1 is evaluated by immunohistochemistry (IHC), an adequate amount of tumour tissue is a prerequisite for PD-L1 testing. To examine whether pleural fluid might be an alternative to biopsy/resection specimens for IHC evaluation of PD-L1 in patients with non-small cell lung carcinoma (NSCLC), we compared PD-L1 by IHC between histological specimens and matched pleural fluid. METHODS: A retrospective cohort study of patients with NSCLC who underwent core biopsy of a lung mass/surgical resection with PD-L1 IHC and had a pleural fluid cell block (CB) available for PD-L1 staining was conducted. PD-L1 was categorized as negative (PD-L1 in <1% of tumour cells), moderately positive (PD-L1 in ≥1% to <50%), strongly positive (PD-L1 ≥ 50) or inadequate for PD-L1 testing (<100 tumour cells in the CB). Weighted Cohen's kappa was calculated to evaluate the agreement between PD-L1 on biopsy/resection specimen and pleural fluid for variables with more than two categories. RESULTS: Of the 115 patients included in this study, 82 (71.3%) had at least 100 tumour cells and were included in the analysis. Of these, 80 (97.6%) had adenocarcinoma. For PD-L1 of histological specimens versus pleural fluid categorized as negative, moderately positive or strongly positive, the weighted kappa statistic was 0.76 (95% CI: 0.64-0.88), and the concordance was 0.78 (95% CI: 0.68-0.86). CONCLUSION: Correlation and concordance are high between PD-L1 in histological specimens and matched pleural fluid. Evaluation of PD-L1 in pleural fluid should be considered in patients unable to undergo histological biopsies.


Assuntos
Antígeno B7-H1 , Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Derrame Pleural/metabolismo , Adulto , Antígeno B7-H1/análise , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Correlação de Dados , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
Nat Commun ; 10(1): 1398, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30923315

RESUMO

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/ß-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.


Assuntos
Carcinogênese/genética , Código das Histonas/genética , Histonas/metabolismo , Dedos de Zinco PHD/genética , Neoplasias de Mama Triplo Negativas/genética , Ubiquitina-Proteína Ligases/genética , Animais , Caderinas/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/genética , Via de Sinalização Wnt
20.
Biom J ; 61(4): 902-917, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30786040

RESUMO

The evolution of "informatics" technologies has the potential to generate massive databases, but the extent to which personalized medicine may be effectuated depends on the extent to which these rich databases may be utilized to advance understanding of the disease molecular profiles and ultimately integrated for treatment selection, necessitating robust methodology for dimension reduction. Yet, statistical methods proposed to address challenges arising with the high-dimensionality of omics-type data predominately rely on linear models and emphasize associations deriving from prognostic biomarkers. Existing methods are often limited for discovering predictive biomarkers that interact with treatment and fail to elucidate the predictive power of their resultant selection rules. In this article, we present a Bayesian predictive method for personalized treatment selection that is devised to integrate both the treatment predictive and disease prognostic characteristics of a particular patient's disease. The method appropriately characterizes the structural constraints inherent to prognostic and predictive biomarkers, and hence properly utilizes these complementary sources of information for treatment selection. The methodology is illustrated through a case study of lower grade glioma. Theoretical considerations are explored to demonstrate the manner in which treatment selection is impacted by prognostic features. Additionally, simulations based on an actual leukemia study are provided to ascertain the method's performance with respect to selection rules derived from competing methods.


Assuntos
Biometria/métodos , Medicina de Precisão , Teorema de Bayes , Glioma/diagnóstico , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/radioterapia , Humanos , Gradação de Tumores , Probabilidade , Prognóstico
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