TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature.

Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma (ALK+ LBCL) is an aggressive and rare subtype of B-cell lymphoma. Patients typically present with advanced clinical stage disease and do not respond to conventional chemotherapy; the median overall survival is 1.8 years. The genetic landscape of this entity remains poorly understood. Here we report a unique case of ALK+ LBCL harbouring a rare TFG::ALK fusion. Targeted next-generation sequencing showed no significant single nucleotide variants, insertions/deletions, or other structural variants beyond the TFG::ALK fusion; deep deletions of FOXO1, PRKCA, and the MYB locus were also detected. Our case report draws attention to this rare disease, highlights a need for larger genetic profiling studies, and focuses on the pathogenesis and potential therapeutic targets of this aggressive disease. To our knowledge, this is the first report of a TFG::ALK fusion in ALK+ LBCL.

A comprehensive analysis of RHOA mutation positive and negative angioimmunoblastic T-cell lymphomas by targeted deep sequencing, expression profiling and single cell digital image analysis.

Angioimmunoblastic T­cell lymphoma (AITL) is a uniquely aggressive mature T­cell neoplasm. In recent years, recurrent genetic mutations in ras homolog family member A (RHOA), tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3 alpha (DNMT3A) and isocitrate dehydrogenase [NADP(+)] 2 (IDH2) have been identified as associated with AITL. However, a deep molecular study assessing both DNA mutations and RNA expression profile combined with digital image analysis is lacking. The present study aimed to evaluate the significance of molecular and morphologic features by high resolution digital image analysis in several cases of AITL. To do so, a total of 18 separate tissues from 10 patients with AITL were collected and analyzed. The results identified recurrent mutations in RHOA, TET2, DNMT3A, and IDH2, and demonstrated increased DNA mutations in coding, promoter and CCCTC binding factor (CTCF) binding sites in RHOA mutated AITLs vs. RHOA non­mutated cases, as well as increased overall survival in RHOA mutated patients. In addition, single cell computational digital image analysis morphologically characterized RHOA mutated AITL cells as distinct from cells from RHOA mutation negative patients. Computational analysis of single cell morphological parameters revealed that RHOA mutated cells have decreased eccentricity (more circular) compared with RHOA non­mutated AITL cells. In conclusion, the results from the present study expand our understanding of AITL and demonstrate that there are specific cell biological and morphological manifestations of RHOA mutations in cases of AITL.

Revisiting diagnostic criteria for myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis: Borderline cases without anemia exist.

INTRODUCTION: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease in the 2016 revised World Health Organization (WHO) classification. Diagnostic criteria include the following: persistent thrombocytosis (>450 × 109 /L) with clustering of atypical megakaryocytes, refractory anemia, dyserythropoiesis with ring sideroblasts, and the presence of the spliceosome factor 3b subunit (SF3B1) mutation. It is unclear if anemia should be a required criterion for this diagnosis as cases which show all other features of MDS/MPN-RS-T but without anemia exist. METHODS: We searched for borderline cases of MDS/MPN-RS-T in which refractory anemia was absent at diagnosis in two major academic institutes. RESULTS: Three cases without anemia were identified. These cases all showed other classic morphologic and clinical features of MDS/MPN-RS-T, including thrombocytosis, atypical megakaryocytes with clustering, and characteristic SF3B1 and JAK2 V617F mutations. CONCLUSION: Given these findings, the requirement of refractory anemia as a diagnostic criterion for MDS/MPN-RS-T should be re-evaluated. Removal of refractory anemia as a diagnostic criterion would incorporate current borderline cases and extend the spectrum of this disorder.

Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas.

Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8-/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1, PTPN6, and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins.

Mutations in the signal transducer and activator of transcription family of genes in cancer.

In recent years, it has become clear that members of the signal transducer and activator of transcription (STAT) family of genes play an important role in cancer. The STAT family consists of seven genes, STAT1-4, STAT5A, STAT5B and STAT6, that are involved in regulating cellular proliferation, apoptosis, angiogenesis and the immune system response. Constitutive activation of STAT3, via mutational changes, is important in oncogenesis in both solid and hematopoietic cancers. In the case of hematopoietic neoplasms, STAT3 driver mutations have been described in T-cell large granular lymphocytic (T-LGL) leukemia and chronic natural killer lymphoproliferative disorders (CLPD-NK) and are seen in 30%-40% of T-LGL leukemia patients. STAT5B is also mutated in T-LGL leukemia and CLPD-NK, but in a much smaller proportion. Here we review past and current research on STAT genes in hematopoietic and solid cancers with emphasis on STAT3 and STAT5B and their roles in the pathogenesis of hematopoietic malignancies, particularly T-LGL leukemia and CLPD-NK.

Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer.

OBJECTIVES: Case reports of capecitabine cardiotoxicity resemble those seen with intravenous 5-fluorouracil (5-FU) with chest pain as the predominant manifestation, but few studies of capecitabine cardiotoxicity are available. We aimed to determine the incidence of symptomatic cardiotoxicity from capecitabine in patients with breast cancer and to identify risk factors. METHODS: We reviewed medical records of consecutive women with breast cancer treated with capecitabine (1000 mg/m2 two times per day) from 2002 to 2012 at one institution. RESULTS: 22 of 452 patients (4.9%) (95% CI 2.9% to 6.9%) had symptoms of cardiotoxicity (chest pain: n=13, dyspnoea: n=9, palpitations: n=2). 11 patients had changes on ECG (atrial fibrillation: n=5, ST deviations: n=3, T-wave abnormalities: n=2 and QTc prolongation: n=1). 2 patients (0.4%) sustained acute myocardial infarction. 1 patient (0.2%) developed cardiac arrest with lethal outcome. 4 of 6 patients (66%) retreated with capecitabine had recurrent symptoms at retreatment. Cardiac comorbidity (p=0.001), hypercholesterolaemia (p=0.005) and current smoking (p=0.023) were risk factors for cardiotoxicity in univariate analyses and remained significant when adjusted for age. Patients with cardiac comorbidity were 5.5 times (95% CI 2.0 to 14.8) more likely to develop cardiotoxicity. In the subgroup of patients with apparently no cardiac comorbidity, the incidence of cardiotoxicity was lower (3.7%) and hypercholesterolaemia (p=0.035) and current smoking (p=0.020) were risk factors of cardiotoxicity. CONCLUSIONS: The incidence of cardiotoxicity from capecitabine resembles that of intravenous 5-FU (≈5%). Cardiac comorbidity, hypercholesterolaemia and current smoking were associated with development of cardiotoxicity.