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1.
Am J Surg Pathol ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32118627

RESUMO

In patients with multiple myeloma, plasmablastic transformation in the bone marrow is rare and associated with poor outcomes. The significance of discordant extramedullary plasmablastic transformation in patients with small, mature clonal plasma cells in the bone marrow has not been well studied. Here, we report the clinicopathologic, cytogenetic, and molecular features of 10 such patients (male/female: 6/4, median age: 65 y, range: 48 to 76 y) with an established diagnosis of multiple myeloma in the bone marrow composed of small, mature plasma cells in parallel with a concurrent or subsequent extramedullary plasmablastic transformation. Eight patients with available survival data showed an overall aggressive clinical course with a median survival of 4.5 months after the diagnosis of extramedullary plasmablastic transformation, despite aggressive treatment and even in patients with low-level bone marrow involvement. Pathologically, the extramedullary plasmablastic myeloma were clonally related to the corresponding bone marrow plasma cells, showed high levels of CMYC and/or P53 expression with a high Ki-67 proliferation index by immunohistochemistry and harbored more complex genomic aberrations including frequent mutations in the RAS pathway and MYC rearrangements compared with their bone marrow counterparts. In summary, although genetic and immunohistochemical studies were not uniformly performed on all cases due to the retrospective nature of this study, our data suggest that discordant extramedullary plasmablastic transformation of multiple myeloma has an aggressive clinical course and is characterized by frequent mutations in the RAS pathway and more complex genomic abnormalities.

3.
Oncogene ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051554

RESUMO

TAFRO syndrome, a clinical subtype of idiopathic multicentric Castleman disease (iMCD), consists of a constellation of symptoms/signs including thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. The etiology of iMCD-TAFRO and the basis for cytokine hypersecretion commonly seen in iMCD-TAFRO patients has not been elucidated. Here, we identified a somatic MEK2P128L mutation and a germline RUNX1G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2P128L mutation, which has been identified previously in solid tumor and histiocytosis patients, caused hyperactivated MAP kinase signaling, conferred IL-3 hypersensitivity and sensitized the cells to various MEK inhibitors. The RUNX1G60C mutation abolished the transcriptional activity of wild-type RUNX1 and functioned as a dominant negative form of RUNX1, resulting in enhanced self-renewal activity in hematopoietic stem/progenitor cells. Interestingly, ERK was heavily activated in both patients, highlighting a potential role for activation of MAPK signaling in iMCD-TAFRO pathogenesis and a rationale for exploring inhibition of the MAPK pathway as a therapy for iMCD-TAFRO. Moreover, these data suggest that iMCD-TAFRO might share pathogenetic features with clonal inflammatory disorders bearing MEK and RUNX1 mutations such as histiocytoses and myeloid neoplasms.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32008941

RESUMO

BACKGROUND: The risk of BIA-ALCL for patients with textured breast implants has been estimated between 1/2832 and 1/30,000 women. Existing studies estimating the numbers exposed and at risk, may have under reported cases, and/or lacked comprehensive follow-up. Our objective is to determine the risk of BIA-ALCL in a defined cohort of patients reconstructed with macro-textured breast implants and consistently followed long-term. METHODS: A prospective cohort study was conducted in patients who underwent breast reconstruction by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) from December 1992 to December 2017. Major events related to implants were prospectively recorded. We identified cases of BIA-ALCL by cross-checking clinical, pathology and external records data. Patients were followed until lymphoma occurrence or last follow-up. The primary outcomes were incidence rate per person-years and cumulative incidence. RESULTS: From 1992 to 2017, 3546 patients underwent 6023 breast reconstructions, mainly after breast cancer removal, or contralateral prophylactic mastectomy, using macro-textured surface expanders and implants. All reconstructions were performed by a single surgeon (PGC). Median follow-up was 8.1 years (range, 3 months - 30.9 years). Ten women, 1/354, developed ALCL after a median exposure of 11.5 years (range, 7.4-15.8 years). Overall risk of BIA-ALCL in our cohort is 1/355 women or 0.311 cases per 1000 person-years (95% CI 0.118 to 0.503). DISCUSSION: This study, the first to evaluate the risk of macro-textured breast implants from a prospective database with long term follow-up, demonstrates that the incidence rate of BIA-ALCL may be higher than previously reported. These results can help inform implant choice for women undergoing breast reconstruction.

6.
Cancer Discov ; 10(3): 440-459, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31915197

RESUMO

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.This article is highlighted in the In This Issue feature, p. 327.

8.
Neuro Oncol ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950179

RESUMO

BACKGROUND: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the mitogen-activating protein kinase (MAPK) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. METHODS: We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. RESULTS: Median age was 52 (range: 7-77) years and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%) patients. Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and two fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppresants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%) and complete metabolic response in 1/16 (6%) by FDG-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. CONCLUSIONS: These data highlight underrecognized symptomatology, heterogenous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

10.
Biol Blood Marrow Transplant ; 26(1): 204-208, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31446197

RESUMO

Treatment for AL amyloidosis aims to eradicate clonal plasma cells, thereby disrupting the amyloid deposition causing organ damage. Risk-adapted high-dose melphalan plus autologous stem cell transplantation (RA-ASCT) is an effective therapy. We conducted a prospective pilot analysis of a comprehensive approach using bortezomib and dexamethasone (BD) before and after RA-ASCT in 19 patients. BD induction (up to 3 cycles of bortezomib 1.3 mg/m2 i.v. and dexamethasone 40 mg orally [p.o.] or i.v. on days 1, 4, 8, and 11) was followed by RA-ASCT and then BD consolidation (6 cycles of bortezomib 1.3 mg/m2i.v. and dexamethasone 20 mg p.o. or i.v. weekly for 4 weeks, every 12 weeks). The overall hematologic response rate (partial response or better) was 95%, including 37% minimal residual disease negative [MRD(-)] complete response (CR) by flow cytometry (sensitivity up to 1/106 cells). At 2 years, progression-free survival (PFS) and overall survival were 68% (95% confidence interval [CI], 50% to 93%) and 84% (95% CI, 69% to 99%), respectively, with median duration of follow-up in survivors of 61 months (range, 42 to 84 months). In a landmark analysis, patients achieving MRD(-) CR had superior PFS (P= .008). This approach is safe and yields deep and durable remissions promoting organ recovery. Each treatment phase deepened the response. Future aims include improving the efficacy and toxicity of each phase.

12.
Blood Cancer J ; 9(12): 101, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827071

RESUMO

Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (>99%) and specificity (>99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53. In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era.

13.
Blood ; 134(Supplement_1): 22, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31724028

RESUMO

DISCLOSURES: Kumar: Seattle Genetics: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Forty-Seven: Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Astex: Consultancy; Trillium: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Forty-Seven: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Portola: Consultancy; Trillium: Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moskowitz:miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria,Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. von Keudell:Genentech: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding. Younes:Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; Biopath: Consultancy. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees.

14.
Cancer Med ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31568670

RESUMO

BACKGROUND: To assess the incidence of benign and malignant peri-implant fluid collections and/or masses on magnetic resonance imaging (MRI) in women with silicone implants who are being screened for silent implant rupture. METHODS: The institutional review board approved this HIPAA-compliant retrospective study and waived informed consent. Women who underwent silicone implant oncoplastic and/or cosmetic surgery and postoperative implant-protocol MRI from 2000 to 2014 were included. Peri-implant fluid collections and/or masses were measured volumetrically. A benign peri-implant fluid collection and/or mass was pathologically proven or defined as showing 2 years of imaging and/or clinical stability. A malignant peri-implant fluid collection was pathologically proven. Incidence of peri-implant fluid collections and/or masses and positive predictive value (PPV) were calculated on a per-patient level using proportions and exact 95% confidence intervals (CIs). Fisher's exact test was used in the analysis to test statistical significance pre-defined as P-value < 0.05. RESULTS: A total of 1070 women with silicone implants were included (mean age, 50.7 years; range, 40.4-53.8). Median time between reconstructive surgery and first MRI was 88.9 months (range, 0.8-1363.3). Eighteen women (1.7%) had a peri-implant fluid collection and/or mass: 15/18 (83.3%) had adequate follow-up; and only 1/15 was malignant implant associated anaplastic large cell lymphoma, with a PPV of 6.7% (95% CI: 0.003-0.0005). The median peri-implant fluid collection size was 89 mL (range, 18-450 mL). CONCLUSION: Peri-implant fluid collections and/or masses identified at silicone implant protocol breast MR imaging are rarely seen 24 months after reconstructive surgery. Image-guided fine-needle aspiration with flow cytometry may be warranted to evaluate for implant-associated lymphoma.

15.
Arch Esp Urol ; 72(7): 670-676, 2019 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31475678

RESUMO

OBJECTIVES: To investigate the efficacy of tadalafil 5mg in patients with lower urinary tract symptoms who failed alpha blocker treatment. PATIENTS AND METHODS: Twenty-three patients were included. Patient consent was obtained after explaining the efficacy of tadalafil 5mg in lower urinary tract symptoms. Before initiating tadalafil 5mg treatment, prostate cancer and urinary tract infection in the patients were eliminated. IPSS, IIEF-5 and Qmax values were assessed before and one month after tadalafil 5mg treatment. Difference between two assessments was evaluated by the Wilcoxon method. RESULTS: After 1 month of Tadalafil 5mg treatment, IPSS decreased and IIEF-5 and Qmax increased. The difference between two assessments were statistically significant. CONCLUSION: Tadalafil 5mg once daily in the treatment of BPH/LUTS is found to be successful in patients who failed previous alpha blocker treatment.


Assuntos
Sintomas do Trato Urinário Inferior/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Tadalafila/uso terapêutico , Disfunção Erétil , Humanos , Masculino , Hiperplasia Prostática , Resultado do Tratamento
16.
Artigo em Inglês | MEDLINE | ID: mdl-31395597

RESUMO

Clonal heterogeneity and evolution of mantle cell lymphoma (MCL) remain unclear despite the progress in our understanding of its biology. Here, we report a 71-yr-old male patient with an aggressive MCL and depict the clonal evolution from initial diagnosis of typical MCL to relapsed blastoid MCL. During the course of the disease, the patient was diagnosed with classic Hodgkin lymphoma (CHL) and received a CHL therapeutic regimen. Molecular analysis by next-generation sequencing of both MCL and CHL demonstrated clonally related CHL with characteristic immunophenotype and PDL1/2 gains. Moreover, our data illustrate the clonal heterogeneity and acquisition of additional genetic aberrations including a rare fusion of SEC22B-NOTCH2 in the process of clonal evolution. Evidence obtained from our comprehensive immunophenotypic and genetic studies indicates that MCL and CHL can originate from a common precursor by divergent clonal evolution, which may pose a therapeutic challenge.

18.
Expert Rev Proteomics ; 16(9): 783-793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31443619

RESUMO

Introduction: Systemic amyloidosis is a diverse group of diseases that, although rare, pose a serious health issue and can lead to organ failure and death. Amyloid typing is essential in determining the causative protein and initiating proper treatment. Mass spectrometry-based proteomics is currently the most sensitive and accurate means of typing amyloid. Areas covered: Amyloidosis can be systemic or localized, acquired or hereditary, and can affect any organ or tissue. Diagnosis requires biopsy, histological analysis, and typing of the causative protein to determine treatment. The kidneys are the most commonly affected organ in systemic disease. Fibrinogen alpha chain amyloidosis (AFib) is the most prevalent form of hereditary renal amyloidosis. Select mutations in the fibrinogen Aα (FGA) gene lead to AFib. Expert commentary: Mass spectrometry is currently the most specific and sensitive method for amyloid typing. Identification of the mutated fibrinogen alpha chain can be difficult in the case of 'private' frameshift mutations, which dramatically change the sequences of the expressed fibrinogen alpha chain. A combination of expert pathologist review, mass spectrometry, and gene sequencing can allow for confident diagnosis and determination of the fibrinogen alpha chain mutated sequence.

20.
Cancer Discov ; 9(10): 1452-1467, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31285298

RESUMO

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking. SIGNIFICANCE: Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.This article is highlighted in the In This Issue feature, p. 1325.

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