Transforming growth factor ß-mediated micromechanics modulates disease progression in primary myelofibrosis.

Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor-ß (TGF-ß) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF-ß signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF-derived fibroblast cell lines and transforming growth factor-ß receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2.

Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome.

Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.

Progress in Hematopoietic Stem Cell Transplantation and Cellular Therapies.

Hematological malignancies are considered to be one of the most important causes of mortality and morbidity in the modern world [...].

SERS-based DNA methylation profiling allows the differential diagnosis of malignant lymphadenopathy.

This study highlights the potential of surface-enhanced Raman scattering (SERS) to differentiate between B-cell lymphoma (BCL), T-cell lymphoma (TCL), lymph node metastasis of melanoma (Met) and control (Ctr) samples based on the specific SERS signal of DNA extracted from lymph node tissue biopsy. Differences in the methylation profiles as well as the specific interaction of malignant and non-malignant DNA with the metal nanostructure are captured in specific variations of the band at 1005 cm-1, attributed to 5-methylcytosine and the band at 730 cm-1, attributed to adenine. Thus, using the area ratio of these two SERS marker bands as input for univariate classification, an area under the curve (AUC) of 0.70 was achieved in differentiating between malignant and non-malignant DNA. In addition, DNA from the BCL and TCL groups exhibited differences in the area of the SERS band at 730 cm-1, yielding an AUC of 0.84 in differentiating between these two lymphadenopathies. Lastly, using multivariate data analysis techniques, an overall accuracy of 94.7% was achieved in the differential diagnosis between the BCL, TCL, Met and Ctr groups. These results pave the way towards the implementation of SERS as a novel tool in the clinical setting for improving the diagnosis of malignant lymphadenopathy.

Correlation between the prevalence of T-cell lymphomas and alcohol consumption.

BACKGROUND AND AIMS: Alcohol is a psychoactive substance that causes dependence, with many thousands of years in the history of mankind, being widely used in different cultures. According to the International Agency for Research on Cancer, alcohol is involved in the development of cancer, being directly associated with it. Considering that alcohol is involved in the initiation and dissemination of gastrointestinal malignancies, the objective of the study was to assess its role in the pathogenesis of T-cell lymphomas, as well as its possible correlation with chronic consumption. METHODS: The patient cohort was compiled from the Sixth Medical Center of the People's Liberation Army Navy General Hospital in Beijing, China. A total of 30 patients matched the criteria and were enrolled in the study. Statistical analysis of the raw data was performed using R Statistics version R 3.5.1. released on the 29.08.2018. RESULTS: Our data demonstrate that the most common extranodal involvment of T-cell lymphoma patients is represented in decreasing order by bone marrow, peritoneum, rhino-oropharynx and the liver-biliary system. Nodal involvement is mainly represented in decreasing order by the laterocervical, axillary, mediastinal and inguinal regions. CONCLUSIONS: These findings may be of value in further research and practical/clinical settings. Fever is the most common clinical feature and was present in most studied patients.

Differential Diagnosis of Malignant Lymphadenopathy Using Flow Cytometry on Fine Needle Aspirate: Report on 269 Cases.

INTRODUCTION: Fine needle aspiration (FNA) is frequently the first noninvasive test used for the diagnostic workup of lymphadenopathy. There have been many studies showing its usefulness, especially in conjunction with other techniques for the diagnosis of lymphoma, but it remains inferior to histological examination. The data regarding this subject have mostly been reported mostly from first-world countries, but are scarce for emerging economies. Thus, the current study assesses the agreement between fine needle aspiration flow cytometry (FNA FC) and histology in the aforementioned region. MATERIAL AND METHODS: We conducted a retrospective study including the FNA FC adenopathy diagnoses made between January 2011 and December 2016 at the Tygerberg Hospital, Cape Town, South Africa. Additional variables included were the histological diagnosis, sex and age of the included patients. RESULTS: In the descriptive part of the current study, 269 FNA FC samples were included. The most frequent diagnoses made on these were represented by B-cell lymphoma, reactive adenopathy, no abnormality detected (NAD), and non-hematological malignancy. In the analytical part of the current study, there were 115 cases included that had both valid FNA FC and histological diagnoses. It could be observed that FNA FC can correctly diagnose B-cell lymphoma in most cases, but it is a poor diagnostic tool especially for Hodgkin lymphoma in this setting as only a four-color flow cytometer was available for diagnosis. Moreover, FNA FC diagnosis of reactive adenopathy and of no abnormalities detected was shown to frequently hide a malignant disease. CONCLUSION: In countries with scarce resources, FNA FC represents a useful diagnostic tool in the case of B-cell lymphoma, but may misdiagnose reactive adenopathy. Thus, FNA FC should be used in a case-specific manner, in addition to as a screening tool, with the knowledge that in cases with a high clinical suspicion of lymphoma, histological diagnosis is a necessity.

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman.

Paraneoplastic hypereosinophilia in a patient with peripheral T cell lymphoma, not otherwise specified.

Under normal physiological conditions, the bone marrow (BM) will have between 1% and 6% eosinophils, translating into a peripheral count of 0.05 - 0.5 ×109/L eosinophils in the blood smear. This process is coordinated by transcription factors with specific roles in differentiation and activation. Secondary eosinophilia may be a paraneoplastic syndrome, related to the presence of a subsequent malignancy, as presented in this case report. Such paraneoplastic manifestations should be addressed properly in order for the patient to receive the best treatment of choice. Even if eosinophilia was associated with B-cell malignancies before, this is a report associating this symptom to a peripheral T-cell lymphoma, not other specified, thus emphasizing the importance of a complex approach for the management of the oncological patient.

Next-generation sequencing-based characterization of the invasion by anatomical contiguity in a primary osseous diffuse large B-cell lymphoma. Correlation between the genetic profile of the malignancy and the clinical outcome of the patient.

Primary bone lymphoma is now a well-described entity in the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone as a malignancy of the lymphoid tissue, with at least one mass within bone, without involvement of supraregional lymph nodes or other extranodal sites. In the current paper, we describe the complete characterization of the mutational landscape of a diffuse large B cell non-Hodgkin's lymphoma (DLBLCL) of the tibial plateau. Currently, there is very little data about the genetic landscape of primary osseous lymphomas and about the genetic background of this type of malignancy, resistant to chemotherapy and invading the surrounding tissues. In the current paper, we describe the complete characterization of the mutational landscape of a DLBCL of the tibial plateau. Our data is consistent with already published data, that have shown that MKI67 activation is correlated with lymphoma progression. Along with a high Ki67 index, resistance to chemotherapy occurs with neurogenic locus notch homolog protein 1 (Notch) and KRAS activation. This is the first molecular characterization for the invasion by anatomical contiguity for a primary bone lymphoma and while we only characterized one case and further deep sequencing analyses are required, we can explain the clinical dismal evolution of the patient by correlating them with the genetic landscape of this type of lymphoma.

Castleman's disease in the HIV-endemic setting.

INTRODUCTION: Castleman's disease (CD), first described by Benjamin Castleman in 1954, is a giant or angiofollicular lymph node hyperplasia, described as a rare monotypic polyclonal B-cell lymphoproliferative disorder with an incompletely understood pathogenesis and variable clinical behavior. This study aimed to determine the incidence of CD diagnosis over an 11-year period. Additionally, the study aimed to describe the demographic, laboratory, and pathological features of CD. METHODS: This is a retrospective study where the demographic and laboratory data were retrieved from the Tygerberg Academic Hospital (TAH) patient electronic records and Tygerberg Lymphoma Study Group (TLSG) and statistical analysis performed on the patients diagnosed with CD. RESULTS: Fifty-four patients were diagnosed with CD during this period. The median age at presentation was 39 years (range: 9-58). HIV serology was available in 53 patients, of which 51 were HIV-positive and two were HIV-negative. The history of initiation of antiretroviral therapy at diagnosis was available in 43 patients (38 on treatment, four were not on treatment, and one defaulted treatment). The median CD4 count was 232.50 cells/µL (range: 2-883). The HIV viral load was performed in 43 patients at diagnosis, which was <49 HIV-1 RNA copies/µL in more than half of the patients (58%). Diagnosis was made on lymph node biopsies in 53 patients, with one case diagnosed on a spleen biopsy. Kaposi sarcoma was found on the same tissue biopsy in 13 cases. A bone marrow biopsy was performed in 31 patients. The predominant features noted were a disorganized hypercellular marrow with plasmocytosis. CONCLUSION: CD is a rare polyclonal B-cell lymphoproliferative disorder. However, we demonstrated a significant increase in the incidence of HIV-associated multicentric CD over the last decade in our area in South Africa.