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Mechanisms of resistance to FGFR1 inhibitors in FGFR1-driven leukemias and lymphomas:implications for optimized treatment

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Cancer Drug Resistance 2021年第3期4卷 607-619页

作者： John K.Cowell Tianxiang Hu Georgia Cancer Center 1410 Laney Walker BlvdAugustaGA 30912USA

Myeloid and lymphoid neoplasms with eosinophilia and FGFR1 rearrangements(MLN-eo FGFR1)disease is derived from a pluripotent hematopoietic stem cell and has a complex presentation with a myeloproliferative disorder with or without eosinophilia and frequently presents with mixed lineage T-or B-lymphomas.The myeloproliferative disease frequently progresses to AML and lymphoid neoplasms can develop into acute lymphomas.No matter the cell type involved,or clinical presentation,chromosome translocations involving the FGFR1 kinase and various partner genes,which leads to constitutive activation of downstream oncogenic signaling cascades.These patients are not responsive to treatment regimens developed for other acute leukemias and survival is poor.Recent development of specific FGFR1 inhibitors has suggested an alternative therapeutic approach but resistance is likely to evolve over time.Mouse models of this disease syndrome have been developed and are being used for preclinical evaluation of FGFR1 inhibitors.Cell lines from these models have now been developed and have been used to investigate the mechanisms of resistance that might be expected in clinical cases.So far,a V561M mutation in the kinases domain and deletion of PTEN have been recognized as leading to resistance and both operate through the PI3K/AKT signaling axis.One of the important consequences is the suppression of PUMA,a potent enforcer of apoptosis,which operates through BCL2.Targeting BCL2 in the resistant cells leads to suppression of leukemia development in mouse models,which potentially provides an opportunity to treat patients that become resistant to FGFR1 inhibitors.In addition,elucidation of molecular mechanisms underlying FGFR1-driven leukemias and lymphomas also provides new targets for combined treatment as another option to bypass the FGFR1 inhibitor resistance and improve patient outcome.

关键词： MLN-eo FGFR1 lymphomas FGFR1 mutations PTEN PUMA mouse models

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Relationships between lymphomas linked to hepatitis C virus infection and their microenvironment

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World Journal of Gastroenterology 2013年第44期19卷 7874-7879页

作者： Antonino Carbone Annunziata Gloghini Department of Pathology Centro di Riferimento Oncologico Aviano Istituto Nazionale Tumori IRCCSAviano and Pordenone Hospital 33081 Aviano Italy Member of WHO IARC Monograph Working Group on Biological Agents 2009 Lyon France Department of Diagnostic Pathology and Laboratory Medicine Fondazione IRCCS Istituto Nazionale dei Tumori 20133 Milano Italy

The relationships between lymphomas and their microenvironment appear to follow 3 major patterns:(1)an independent pattern;(2)a dependent pattern on deregulated interactions;and(3)a dependent pattern on regulated coexistence.Typical examples of the third pattern are hepatitis C virus(HCV)-associated marginal zone lymphomas(MZLs)and mucosa-associated lymphoid tissue lymphomas.In these lymphomas,a regulated coexistence of the malignant cells and the microenvironmental factors usually occurs.At least initially,however,tumor development and cell growth largely depend on external signals from the microenvironment,such as viral antigens,cytokines,and cell-cell interactions.The association between HCV infection and B-cell lymphomas is not completely defined,although this association has been demonstrated by epidemiological studies.MZL and diffuse large B-cell lymphoma are the histotypes most frequently associated with HCV infection.Many mechanisms have been proposed for explaining HCV-induced lymphomagenesis;antigenic stimulation by HCV seems to be fundamental in establishing B-cell expansion as observed in mixed cryoglobulinemia and in B-cell lymphomas.Recently,antiviral treatment has been proved to be effective in the treatment of HCV-associated indolent lymphomas.Importantly,clinically responses were linked to the eradication of the HCV-RNA,providing a strong argument in favor of a causative link between HCV and lymphoproliferation.

关键词： Hepatitis C virus-infection B-cell lymphomas Marginal zone lymphoma Mucosa-associated lymphoid tissue lymphomas Diffuse large B-cell lymphomas Microenvironment

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Endoscopic features of gastro-intestinal lymphomas: From diagnosis to follow-up

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World Journal of Gastroenterology 2014年第36期20卷 12993-13005页

作者： Calogero Vetro Alessandra Romano Irene Amico Concetta Conticello Giovanna Motta Amalia Figuera Annalisa Chiarenza Cosimo Di Raimondo Giorgio Giulietti Giacomo Bonanno Giuseppe Alberto Palumbo Francesco Di Raimondo Division of Hematology AOU Policlinico-OVE University of Catania 95124 Catania Italy Department of Diagnostic and Interventional Radiology A.O. "Policlinico-Vittorio Emanuele" 95124 Catania Italy Division of Gastroenterology A.O. Policlinico-Vittorio Emanuele 95124 Catania Italy

Many progresses have been done in the management of gastrointestinal(GI) lymphomas during last decades, especially after the discovery of Helicobacter pylori-dependent lymphoma development. The stepwise implementation of new endoscopic techniques, by means of echoendoscopy or double-balloon enteroscopy, enabled us to more precisely describe the endoscopic features of GI lymphomas with substantial contribution in patient management and in tailoring the treatment strategy with organ preserving approaches. In this review, we describe the recent progresses in GI lymphoma management from disease diagnosis to follow-up with a specific focus on the endoscopic presentation according to the involved site and the lymphoma subtype. Additionally, new or emerging endoscopic technologies that have an impact on the management of gastrointestinal lymphomas are reported. We here discuss the two most common subtypes of GI lymphomas: the mucosaassociated lymphoid tissue and the diffuse large B cell lymphoma. A general outline on the state-of-the-art of the disease and on the role of endoscopy in both diagnosis and follow-up will be performed.

关键词： Non-Hodgkin lymphomas Endoscopy Gastrointestinal t

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Gastrointestinal B-cell lymphomas:From understanding B-cell physiology to classification and molecular pathology

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World Journal of Gastrointestinal Oncology 2012年第12期4卷 238-249页

作者： Xavier Sagaert Thomas Tousseyn Rhonda K Yantiss Department of Pathology University Hospitals Leuven Department of Pathology and Laboratory Medicine Weill Cornell Medical College

The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.

关键词： B-cell Non-Hodgkin’s lymphomas Gut Molecular pathology

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Contribution of Immunohistochemistry in the Diagnosis of lymphomas

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Open Journal of Blood Diseases 2018年第1期8卷 17-25页

作者： Daouda Kone Yao Nicaise Atimere Zana Ismael Coulibaly Ulrich Acko Sogbety Eric Diomande Maimouna Toure Pr Aissata Tolo Hematology Ward of University and Teaching Hospital of Treichville Abidjan C&ocirc te d’Ivoire Pathologist Ward of University and Teaching Hospital of Treichville Abidjan C&ocirc te d’Ivoire Internal Medecine Ward of University and Teaching Hospital of Treichville Abidjan C&ocirc te d’Ivoire Internal Hospital Abidjan C&ocirc te d’Ivoire Department of Biology Abidjan Cote d’ivoire Department of Hematology Abidjan C&ocirc te d’ivoire

Objective: Making the interest of using immunohistochemistry clear in addition to histological test in the diagnosis of lymphomas. Methods: This is a retrospective study from January 2011 to June 2013 involving 18 cases of lymphomas collected in the teaching hospitals of Treichville and Yopougon. Results: 1) 38.88% diagnosis of LMNH B large-cell in histology against 38.88% LDGCB with IHC. 2) 11.11% diagnosis of LMNH small cell in histology against 11.11% with IHC. 3) 5.55% diagnosis of T lymphoma in histology against 27.77% diagnosis of T lymphoma with IHC. 4) 5.55% diagnosis of follicular lymphoma in histology against 11.11% diagnosis of LF with IHC. 5) 11.11% diagnosis of Burkitt lymphoma in histology against 5.55% diagnosis of LB with IHC. 6) 5.55% diagnosis of medullary hypoplasia in histology against 5.55% diagnosis of Hodgkin’s disease. Our results confirm the contribution of immunohistochemistry in the diagnosis of lymphomas in addition to histological test. This is striking, especially as there is 27.77% of T lymphoma with immunohistochemistry against only 5.55% with histology.

关键词： lymphomas Immunohistochemistry Histology WHO Classification

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AIDS and associated malignancies

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Cell Research 2005年第Z1期15卷 947-952页

作者： Charles WOOD William HARRINGTON Jr Nebraska Center for Virology & School of Biological Sciences University of Nebraska Lincoln NE 68588 USA Sylvester Cancer Center University of Miami Miami FL 33136 USA

AIDS associated malignancies (ARL) is a major complication associated with AIDS patients upon immunosuppression. Chronically immunocompromised patients have a markedly increased risk of developing lymphoproliferative disease. In the era of potent antiretrovirals therapy (ARV), the malignant complications due to HIV-1 infection have decreased in developed nations where ARV is administered, but still poses a major problem in developing countries where HIV-1 incidence is high and ARV is still not yet widely available. Even in ARV treated individuals there is a concern that the prolonged survival of many HIV-1 carriers is likely to eventually result in an increased number of malignancies diagnosed. Malignancies that were found to have high incidence in HIV-infected individuals are Kaposi’s sarcoma (KS), Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL). The incidence of NHL has increased nearly 200 fold in HIV-positive patients, and accounts for a greater percentage of AIDS defining illness in the US and Europe since the advent of HAART therapy. These AIDS related lymphomas are distinct from their counterparts seen in HIV-1 seronegative patients. For example nearly half of all cases of ARL are associated with the presence of a gamma herpesvirus, Epstein Barr virus (EBV) or human herpesvirus-8 (HHV-8)/ Kaposi’s sarcoma associated herpesvirus (KSHV). The pathogenesis of ARLs is complex. B-cell proliferation driven by chronic antigenemia resulting in the induction of polyclonal and ultimately monoclonal lymphoproliferation may occur in the setting of severe immunosuppression.

关键词： Kaposi’s sarcoma lymphomas Epstein-Barr virus KS-associated herpesvirus human herpesvirus 8.

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Antiviral therapy of hepatitis C as curative treatment of indolent B-cell lymphoma

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World Journal of Gastroenterology 2016年第38期22卷 8447-8458页

作者： Michele Merli Giuseppe Carli Luca Arcaini Carlo Visco Division of Hematology University Hospital Ospedale di Circolo & Fondazione MacchiUniversity of Insubria Department of Cell Therapy and Hematology San Bortolo Hospital Department of Molecular Medicine University of Pavia

The association of hepatitis C virus(HCV) and B-cell non-Hodgkin lymphomas(NHL) has been highlighted by several epidemiological and biological insights; however the most convincing evidence is represented by interventional studies demonstrating the capability of antiviral treatment(AT) with interferon(IFN) with or without ribavirin to induce the regression of indolent lymphomas, especially of marginal-zone origin. In the largest published retrospective study(100 patients) the overall response rate(ORR) after first-line IFN-based AT was 77%(44% complete responses) and responses were sustainable(median duration of response 33 mo). These results were confirmed by a recent metaanalysis on 254 patients, demonstrating an ORR of 73%. Moreover this analysis confirmed the highly significant correlation between the achievement of viral eradication sustained virological response(SVR) and hematological responses. Two large prospective studies demonstrated that AT is associated with improved survival and argue in favor of current guidelines' recommendation of AT as preferential first-line option in asymptomatic patients with HCV-associated indolent NHL. The recently approved direct-acting antiviral agents(DAAs) revolutionized the treatment of HCV infection, leading to SVR approaching 100% in all genotypes. Very preliminary data of IFN-free DAAs therapy in indolent HCV-positive NHL seem to confirm their activity in inducing lymphoma regression.

关键词： Non-hodgkin lymphomas Hepatitis C virus Antiviral therapy Interferon Ribavirin Sofosbuvir Direct-acting antiviral agents Marginal zone lymphomas

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HCV infection, B-cell non-Hodgkin's lymphoma and immunochemotherapy: Evidence and open questions

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World Journal of Gastrointestinal Oncology 2012年第3期4卷 46-53页

作者： Maria Christina Cox Maria Antonietta Aloe-Spiriti Elena Cavalieri Eleonora Alma Elia Gigante Paola Begini Caterina Rebecchini Gianfranco Delle Fave Massimo Marignani Department of Haematology Sant'Andrea Hospital La Sapienza University Department of Gastroenterology and Liver Disease Sant'Andrea Hospital La Sapienza University

There is plenty of data confirming that hepatitis C virus (HCV) infection is a predisposing factor for a B-cell non-Hodgkin's lymphoma (B-NHL) outbreak, while relatively few reports have addressed the role of HCV in affecting B-NHL patients' outcome. HCV infection may influence the short-term outcome of B-NHL because of the emergence of severe hepatic toxicity (HT) during immunochemotherapy. Furthermore, the long term outcome of HCV-related liver disease and patients' quality of life will possibly be affected by Rituximab maintenance, multiple-lines of toxicity during chemotherapy and hematopoietic stem cell transplantation. In this review, data dealing with aggressive and low-grade B-NHL were separately analyzed. The few retrospective papers reporting on aggressive B-NHL patients showed that HCV infection is a risk factor for the outbreak of severe HT during treatment. This adverse event not infrequently leads to the reduction of treatment density and intensity. Existing papers report that low-grade B-NHL patients with HCV infection may have a more widespread disease, more frequent relapses or a lower ORR compared to HCV-negative patients. Notwithstanding, there is no statistical evidence that the prognosis of HCV-positive patients is inferior to that of HCV-negative subjects. HCV-positive prospective studies and longer follow-up are necessary to ascertain if HCV-positive B-NHL patients have inferior outcomes and if there are long term sequels of immunochemotherapies on the progression of liver disease.

关键词： Marginal zone lymphoma Diffuse large B cell lymphoma Hepatitis C virus Non-Hodgkin’s lymphomas Hepatotoxicity Chemotherapy Immunochemotherapy Prognosis Rituximab

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^(18)F-Fluorodeoxyglucose positron emission tomography/computed tomography comparison of gastric lymphoma and gastric carcinoma

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World Journal of Gastroenterology 2016年第34期22卷 7787-7796页

作者： Xiao-Feng Li Qiang Fu You-Wen Dong Jian-Jing Liu Xiu-Yu Song Dong Dai Cong Zuo Wen-Gui Xu Department of Molecular Imaging and Nuclear Medicine Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy

AIM To compare ^(18)F-fluorodeoxyglucose positron emission tomography/computed tomography(^(18)F-FDG PET/CT) features in gastric lymphoma and gastric carcinoma.METHODS Patients with newly diagnosed gastric lymphoma or gastric carcinoma who underwent ^(18)F-FDG PET/CT prior to treatment were included in this study. We reviewed and analyzed the PET/CT features of gastric wall lesions,including FDG avidity,pattern(focal/diffuse),and intensity [maximal standard uptake value:(SUVmax)]. The correlation of SUVmax with gastricclinicopathological variables was investigated by χ~2 test,and receiver-operating characteristic(ROC) curve analysis was performed to determine the differential diagnostic value of SUVmax-associated parameters in gastric lymphoma and gastric carcinoma. RESULTS Fifty-two patients with gastric lymphoma and 73 with gastric carcinoma were included in this study. Abnormal gastric FDG accumulation was found in 49 patients(94.23%) with gastric lymphoma and 65 patients(89.04%) with gastric carcinoma. Gastric lymphoma patients predominantly presented with type Ⅰ and type Ⅱ lesions,whereas gastric carcinoma patients mainly had type Ⅲ lesions. The SUVmax(13.39 ± 9.24 vs 8.35 ± 5.80,P < 0.001) and SUVmax/THKmax(maximal thickness)(7.96 ± 4.02 vs 4.88 ± 3.32,P < 0.001) were both higher in patients with gastric lymphoma compared with gastric carcinoma. ROC curve analysis suggested a better performance of SUVmax/THKmax in the evaluation of gastric lesions between gastric lymphoma and gastric carcinoma in comparison with that of SUVmax alone.CONCLUSION PET/CT features differ between gastric lymphoma and carcinoma,which can improve PET/CT evaluation of gastric wall lesions and help differentiate gastric lymphoma from gastric carcinoma.

关键词： Gastric lymphomas Gastric carcinomas 18F-fluorodeoxyglucose positron emission tomography/ computed tomography Maximal standard uptake value Maximal thickness Differential diagnosis

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Primary cutaneous B cell lymphoma: Clinical features, diagnosis and treatment

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World Journal of Dermatology 2015年第1期4卷 50-56页

作者： Fergun Yilmaz Nur Soyer Filiz Vural Department of Hematology Ege University

Primary cutaneous B cell lymphoma(PCBCL) is defined as B cell lymphomas that presents in the skin without any evidence of extra-cutaneous involvement at diagnosis. They are the second most common type of primary cutaneous lymphomas accounting for 25%-30%. Since the prognosis and treatment differ from systemic lymphomas involving the skin, differential diagnosis is very important. PCBCL is a heterogeneous group of disease comprising different B cell lymphomas with distinct treatment and prognosis. PCBCL is divided into 5 subclasses according to World Health Organization and European Organization of Research and Treatment of Cancer classification. Primary cutaneous marginal zone lymphoma and primary cutaneous follicle centerlymphoma are indolent forms and often confined to skin at presentation and during the course of the disease. But primary cutaneous diffuse large B cell lymphoma, leg type and intravascular large B cell lymphoma are more aggressive forms that may disseminate to extra-cutaneous tissues. There is not a treatment consensus since they are rare entities. Local therapies like radiotherapy, surgery or intralesional steroids are options for localized disease in indolent forms. More disseminated disease may be treated with a systemic therapy like single agent rituximab. However combination chemotherapies which are used in systemic lymphomas are also required for aggressive PCBCL. Although indolent forms have relatively better prognosis, early relapses and disseminated diseases are mostly observed in aggressive form with a consequent poor prognosis.

关键词： Primary cutaneous lymphomas Diagnosis Treatment Bcell lymphoma

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