Mantlecelllymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that it may be an important element in the development of this tumor, but its potential function is not known. Here, we show that SOX11 promotes tumor growth in a MCL- xenotransplant mouse model. Using chromatin immunoprecipitation microarray analysis combined with gene expression profiling upon SOX11 knockdown, we identify target genes and transcriptional programs regulated by SOX11 including the block of mature B-cell differentiation, modulation of cell cycle, apoptosis, and stem cell development. PAX5 emerges as one of the major SOX11 direct targets. SOX11 silencing downregulates PAX5, induces BLIMP1 expression, and promotes the shift from a mature B cell into the initial plasmacytic differentiation phenotype in both primary tumor cells and an in vitro model. Our results suggest that SOX11 contributes to tumor development by altering the terminal B-cell differentiation program of MCL and provide perspectives that may have clinical implications in the diagnosis and design of new therapeutic strategies.
Bortezomib therapy has shown promising clinical activity in mantlecelllymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efﬁcacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeﬁcient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression proﬁling of the tumors and functional validation of the identiﬁed gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition. Leukemia advance online publication, 11 April 2014; doi:10.1038/leu.2014.106
30. Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-celllymphoma. J Clin Oncol 2010; 28: 4485-4491. 31. O’Connor OA, Masszi T, Kerry JS, Pinter-Brown LC, Foss FM, Pop- plewell L, et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-celllymphoma (R/ R PTCL): Results from the BELIEF trial. J Clin Oncol 2013; 31: abstr 8507. 32. Avivi I, Goy A. Refining the MantleCellLymphoma Paradigm: Impact of Novel Therapies on Current Practice. Clin Cancer Res 2015;21(17):3853- 3861.
Mantlecelllymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation that leads to the juxtaposition of the CCND1 gene to the immunoglobulin heavy chain (IGH@) gene, resulting in cyclin D1 overexpression. 1,2 In recent years there has been an ongoing debate after pathologists and geneticists identified a small subset of lymphomas resembling conventional MCL both morphologically and phenotypically, but with absence of the t(11;14)/CCND1 breakpoint and cyclin D1 expression. This observation prompted discussion regarding whether “true” MCL negative for cyclin D1 exists. A gene expression study shed light on this controversy reporting that six recognized cyclin D1-negative lymphomas with morphologic, pathologic, clinical and molecular features similar to typical MCL also had a similar global gene expression profile (GEP). 3 In the absence of cyclin D1, these cases overexpressed cyclin D2 or D3 but without evidence of chromosomal aberrations involving these loci. Subsequent studies have identified isolated cyclin D1-negative MCL harboring a t(2;12)(p12;p13) fusing the CCND2 gene to the IGK@ locus, 4 t(12;22)(p13;q22) with IGL-CCND2 fusion, 5 cryptic t(12;14)(p13;q32)/IGH-CCND2 6 or CCND2 breaks with unidentified partner. 7 Additionally, a translocation of the CCND3 gene has been detected in a single MCL case, 8 although more frequently in other mature B-cell malignancies. 9 Nevertheless, these reports corresponded to isolated cases and the real incidence of CCND2 or CCND3 translocations has not been well studied in this MCL variant.
Mantlecelllymphoma (MCL) is an incurable B-cell neoplasm harboring the t(11;14)(q13;q32) translocation, which leads to the overexpression of cyclin D1 with the consequent cell cycle deregulation. In addition to this translocation, MCL cells carry a high number of secondary genetic alterations that increase the oncogenic potential of cyclin D1 and frequently inactivate the cellular response to DNA damage (1). Typically, MCL is characterized by relatively short survival and brief responses to conventional chemotherapy (2). Thus, new preclinical studies on innovative therapeutic strategies are warranted. In this context, the constitutive activation of several signaling pathways regulated by kinases has been described in MCL cells (3), opening up a new horizon in the treatment of this entity. Specifically, new targeted agents that interfere with BCR signaling, such as Syk-, Btk- and PI3K-inhibitors, are entering clinical trials. Although the number of MCL patients treated with these agents is still very low, preliminary data seem to indicate that the responses to the Btk inhibitor PCI-32765 and the PI3K inhibitor CAL-101 are very favorable (4;5). In B-lymphocytes, activation of the BCR by antigen engagement induces the phosphorylation of Src family kinases, for instance Lyn, leading to the recruitment of Syk. Once phosphorylated, Lyn and Syk propagate the BCR signal by activating downstream kinases, such as Btk, resulting in the activation of multiple downstream signaling pathways. Recently, it has been reported that MCL cells have constitutive activation of the BCR signal transduction proteins Syk and PKC E II (6;7), as well as high expression of the phosphorylated forms of these and other BCR-associated kinases (8).
Background: Rituximab is a monoclonal antibody that increases the disease-free and overall survival of patients with non- Hodgkin lymphoma (NHL) CD20+. The objective of this study is to describe the prevalence and spectrum of infections in patients with NHL receiving rituximab-containing chemotherapy and the impact on survival. Materials and Methods: From January 2011 to December 2012, all patients diagnosed with NHL who received at least one dose of rituximab were included. Results: During the study period, 265 patients received rituximab; 108 (40.8%) males; the mean age was 60 ± 15 years. There were 177 infec- tions in 85 patients, being the most common febrile neutropenia (n = 38; 21.5%) and mucosal barrier injury-related infections (n = 28; 15.8%). In 88 events (49%), there was a microbiologic diagnosis, being bacterial infection the most frequent (39.6%), but tuberculosis (TB) was developed in 4 cases (1.5%; incidence rate 721/100,000 person-year). During follow-up, 71 patients died (27%); in 35 cases, it was related to infection. There were no differences in follow-up between those who died due to in- fection versus those who died from another cause (p = 0.188). Multivariate analysis for mortality showed that age >60 years, failure to achieve a complete response, and development of an infectious complication increased the risk of death. Conclusions: It is important to perform a screening test for TB in all patients who will receive rituximab and maintain a constant monitoring to detect an infectious process and begin treatment as soon as possible. (REV INVEST CLIN. 2019;71:275-82)
Some of the drugs that form part of the chemotherapy to treat the DLBCL come from natural sources as plants i.e. alkaloids of the vinca or from microorganisms like the estreptomyces peucetycus where Doxorrubicine is obtained. Doxorubicin is an anthracycline and its effect is a direct damage in the DNA helix without possibilities of restoring, Doxorubicin is considered as cornerstone in treatment of lymphoma patients .The chemotherapy without anthracyclines has obtained poor results in the survival . Thus, it is necessary to look for new options that could increase the rates of response and the survival of the patients besides doxorubicin. There are several compounds in plants and fruits of our flora, which have the property of being anticancerous such as flavonoids. Flavonoids are a series of secondary metabolites of plants with antimicrobial, antiinflammatory, anticancerous properties and effects in the immunological system . They are synthesized from a molecule of fenilalanine and 3 of malonil coenzyme A, from what is known as the route of the flavonoids; whose products are cycled across the isomerase enzyme . The actions of the flavonoids, as mentioned previously, produce different effects; but one of the most important is the antineoplasic, having action against colon cancer, hepatic carcinoma and breast cancer [7-9].
All patients were hospitalized from the beginning of the conditioning regimen and during the period of pancytopenia and received transfusions, prophylactic antiviral, antifungal and antibiotics agents as per institutional guidelines. High doses of morphine were de ﬁ ned as the need of > 10 mg/day of morphine or opioid equivalent in the context of severe oropharyngeal or gastrointestinal mucositis, de ﬁ ned by grades 3 – 4 of the WHO scale . Total parenteral nutri- tion (TPN) was initiated when caloric requirements were under 1000 calories/day by oral nutrition or in those patients with severe mucositis and pain-induced ingestion impair- ment. Febrile neutropenia was de ﬁ ned as the combination of granulocyte counts below 500 cell/ μ L and temperature over 38 o C. Patients were discharged when they reached > 500 neutrophils/ μ L for three consecutive days and 25,000 pla- telets/ μ L without the need of transfusions, with satisfactory oral intake and no active infections.
The most frequent types of cutaneous T-cell lymphomas (CTCL) in the practice of dermatology are mycosis fungoides and Sézary syndrome. It is important for the clinician to be acquainted with the initial management in a patient with the diagnosis of cutaneous T-celllymphoma in order to make a proper staging and begin the correct treatment. We review the different laboratory and imaging studies to be done. We also review the different therapeutic options such as topic and systematic treatments, their indications, side-effects and doses. At present, modifiers of biological response offer an alternative in the management of these patients.
clinical trial from our group for patients with relapsed and refractory hematological malignancies is the only study to include HL patients 23 . Patients were treated with the NK- 92 line with established cytotoxicity against a variety of tumor types and was derived from a patient with aggressive NK cell non-HL 24 . Two of the 12 patients enrolled had HL, and 1 achieved an unmaintained remission of >10 years 23 . A genetically engineered version of the NK-92 cell line (haNK) was developed recently to express the high-af ﬁ nity polymorphism (158V) of the IgG Fc-receptor (Fc γ RIIIa, CD16), with additional capacity for self-production of interleukin-2 (IL-2) 25 . In combination with the selected mAbs, the haNK cells demonstrated an ability to undergo ADCC in contrast to the parental CD16-negative NK-92 line and kill tumor cells 24 . The safety and feasibility of haNK cells to treat cancer patients is currently being studied in a phase 1 clinical trial (NCT03027128; NantKwest, Inc.).
After the results of our survey, Antarctic Chordata represent a much more important potential source for pharmacological purposes than previously. In fact, this is the group with the highest percentage of activity in our tests (Figure 1). Among these interesting results there is one that stands out from the rest: aplicyanins A–F (Figure 6), new compounds from the ascidian Aplidium cyaneum yielding strong antitumoural activity (Reyes et al. 2008). Other examples with a similar relevance such as didemnin B (Rinehart et al. 1981) or Ecteinascidin (Rinehart et al. 1990), both derived from tropical ascidians, highlight the importance of these animals in the context of the marine drug discovery field. In our study, two of the tunicates found to be active against tumour cell lines, belong to the genus Aplidium (A. cyaneum and A. falklandicum). This genus has been widely recognized as a source of antitumoural compounds in different areas of the world (McKee et al. 1998, Le Tourneau et al. 2007). Another species to highlight is Polysyncraton trivolutum, from the family Didemnidae. This family is also recognized as a source of chemical products with potent biological properties (e.g. Rinehart et al. 1981) and a congeneric species from the Fiji Islands, P. lithostrotum, also displays relevant antitumoural effects (McDonald et al. 1996). On the other hand, this is the first time that the ascidian Tylobrachion speciosum is reported as a source for antitumoural activity. Tunicates, together with bryozoans and the above-mentioned sponges and cnidarians, all of them being sessile suspension feeders, conform the basis of the Antarctic benthic ecosystems (Orejas et al. 2000). Nevertheless, little chemical work has been conducted to date in tunicates from the Southern Ocean (Avila et al. 2008). It is also worth mentioning the antitumoural activity described in the Antarctic ascidian Synoicum adareanum (Diyabalanage et al. 2006).
Clinical data and experimental studies have suggested a relationship between psycho- social factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progres- sion taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response.
hood, celiac disease is now recognized as a common condition that may be diag- nosed at any age and that affects many organ systems. The therapy for the disease is a gluten-free diet; however, the response to therapy is poor in up to 30% of patients, and dietary nonadherence is the chief cause of persistent or recurrent symptoms. Small intestinal adenocarcinoma, refractory sprue, and enteropathy-associated T-celllymphoma are complications of celiac disease that must be ruled out when alarm- ing symptoms such as abdominal pain, diarrhea, and weight loss develop despite a strict gluten-free diet.
Background: Available prognosis scores for patients with diffuse large B-celllymphoma (DLBCL) included a limited number of patients ≥ 65 years of age, and most of them did not include comorbidities. Here, we propose a prognos- tic score for overall survival (OS) for this group of patients. Materials and Methods: Patients ≥ 65 years with DLBCL treated at a single national reference center were included. Clinical features including comorbidities and biochemical parameters were analyzed. Results: We included 141 patients. Response rate in the whole group was 77%. Based on multivariate analysis, the presence of the European Cooperative Oncology Group (ECOG) > 2, elevated levels of beta-2 microglobulin, bulky disease, and anemia (hemoglobin < 10 g/dL) had a significant effect on OS. These parameters were considered when computing the prognostic score, which identified three groups with differential survival: Low, intermediate, and high risk of death, with a probability of survival at 60 months of 80.05%, 55.5%, and 29.84%, respectively. Discussion: This score may select patients to optimize treatment. The presence of high levels of beta-2 microglobulin, bulky disease, and hemoglobin < 10 g/dL, and ECOG > 2 was associated with poor OS in elderly patients with DLBCL.
EL4 cell inoculation, all animals developed solid tumors. Hyperthyroid mice showed a significant increase in EL4 lymphoma growth, while the hypothyroid mice showed no statistically significant differences when compared with the euthyroid controls (Fig. 1B, C, and D). Addition- ally, Kaplan–Meier survival curves (Fig. 1E) showed a significant reduction in the survival of hyperthyroid mice compared with hypothyroid and euthyroid mice, indi- cating a worse prognosis. Hyperthyroid mice showed a survival of 50% at 17.2G1.4* days, while hypothyroid and euthyroid mice showed a survival of 50% at 22.1G 1.5 and 21.3G1.7 days respectively (*P ! 0.05 vs the euthyroid or hypothyroid mice). As the hyperthyroid animals showed increased tumor development compared with control and hypothyroid mice, the kinetics of EL4 cell division were evaluated. For this analysis, EL4 cells were stained with CFSE before inoculation, and the MFI of the CFSE-labeled cells in the tumors was evaluated by flow cytometry, ten days post-inoculation. The EL4 cells growing in hyperthyroid mice exhibited a lower MFI than the tumor cells in control or hypothyroid animals (Fig. 2A and B). Consistent with these findings, hyperthyroid mice showed an increased rate of cell proliferation when compared with euthyroid and hypothyroid mice (Fig. 2C). No significant differences were observed between the hypothyroid and euthyroid groups. The increase in the cell division rate that was observed in hyperthyroid mice could contribute to the rapid tumor growth and the lower survival of these animals.
Angioimmunoblastic T-celllymphoma (AITL) accounts for 15–20% of all peripheral T-cell lymphomas. It is a rare subtype of CD4 T-cell peripheral lymphoma that affects aged in- dividuals, causing B symptoms, generalized lymphadenopathy and hepatosplenomegaly. Its pathogenesis is still unclear, but in some cases it has been associated with infection, allergic reaction or drug exposure. The majority of patients are diagnosed in an advanced stage and anthracycline based regimen is considered the first-line therapy. Skin involvement is not well characterized, occurring in up to 50% of patients and presenting as nonspecific rash, mac- ules, papules, petechiae, purpura, nodules and urticaria. We present the illustrative case of a 55-year-old woman with an AITL who presented prominent skin findings, arthritis, lymphade- nopathy and hypereosinophilia. Skin biopsy reported a T-celllymphoma and the diagnosis of AITL was confirmed by an axillary lymph node biopsy, which was also positive for Epstein- Barr virus. Chemotherapy with CHOP-21 and thalidomide was given, accomplishing complete
The case of a 25-year-old male patient, with an apparent history of good health, who began to have retrosternal pain with several months of evolution, fainting and occasional dyspnea, is reported. A chest X- ray, a simple lung computed tomography and a contrasted computed tomography were carried out. They showed the presence of a mediastinal tumor. In a right anterolateral thoracotomy, a thick polylobulated tumor was found, covering the superior and anterior mediastinum and encompassing the great vessels. Surgical resection was decided (cytoreductive surgery), since the tumor exerted a compressive effect on the right atrium and ventricle. The pathologic anatomy report indicates: Classical Hodgkin lymphoma, nodular sclerosis variant in the thymic area. The patient improved.
El linfoma anaplásico de células grandes asociado a implantes mamarios (BIA-ALCL, breast implant associated-anaplastic large celllymphoma) es una enfermedad infrecuente, pero el número de casos ha aumentado en los últimos años. Se pue- de presentar en la consulta del cirujano como un aumento del volumen mamario por derrame periprotésico o como masa capsular. El tratamiento de elección es la cirugía, con explante de las prótesis y exéresis de la cápsula periprotésica. El pronóstico, si el diagnóstico es precoz y el tratamiento es adecuado, es bueno. El objetivo del presente trabajo fue revisar la literatura científica existente hasta la fecha sobre el BIA-ALCL y poner de manifiesto la importancia que este tipo de neo- plasia tiene para el cirujano.
methods. The study selection was based on Medline. Using a peer-review process we identified the following group of publications: cohort studies of pediatric patients with ALL that were analyzed for prognostic factors associated with 5-year survival. In addition, we also included original or review articles in which prognostic factors or scales were related to mortality in ALL pediatric patients. Data collected are presented descriptively. In order to determine the magnitude of the factors identified associated with mortality, different meta-analyses were performed. Results. We selected 29 publications. It was determined that the following patient characteristics at diagnosis are associated with more favorable survival: ages 1 to 9 years, female gender and without CNS infiltration. Favorable characteristics related to leukemic cells are white blood cell count <50,000 cell/µL, B-cell immunophenotype, DNA index 1.16–1.60 and absence of translocations t(9; 22), t(1; 19) and t(4, 11). Conclusions. The study of prognostic factors of pediatric patients with ALL has contributed to reduced mortality; however, further research is required in this area.
served in our patient was a reflection of the failure of immune reconstitution, and it induced intracellu- lar oxidative stress and mitochondrial dysfunction, which in turn were responsible for the cholestatic damage. But we believe that this was not the only mechanism that realized a cholestatic hepatitis in our patient. In the past medical history the patient reported several episodes of sinusitis and bronchitis and two episodes of pneumonia due to Klebsiella pneumoniae. Furthermore this patient had a persist- ence low dosage of circulating IgG immunoglobulin present before the advent of NHL. We cannot clear- ly demonstrate but can only suspect that the patient could have had a common variable immune deficien- cy (CVID). This condition is characterized by sever- al episodes of recurrent infections involving ears, nasal sinuses, bronchi and lungs and is associated to very low levels of immunoglobulins. In CVID ex- tranodal B cell type lymphomas are a frequent com- plication and are more common in subjects in the fourth to seventh decade of life. 20,21 We can speculate