Renal infarction due to polyarteritis nodosa in a patient with angioimmunoblastic T-cell lymphoma: a case report and a brief review of the literature.

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma (15-20% of all cases), accounting for approximately 1-2% of all non-Hodgkin lymphomas. It often presents autoimmune phenomena including hemolytic anemia, thrombocytopenia, glomerulonephrities and circulating immune complexes (CIC). Polyarteritis nodosa (PAN) is an autoimmune disease characterized by necrotizing vasculitis of medium vessels, which rarely develops in association with hematological malignant disorders. Herein we report the case of a male patient with AITL who had a renal infarction secondary to PAN, mimicking a neoplastic lesion. A 40-year-old man underwent lymph node biopsy in the suspicious of sarcoidosis. On the basis of histological and immunohistochemical findings, a diagnosis of AITL was performed. The patient was successfully treated with a cytarabine-based regimen for 6 cycles. Three months after the initial diagnosis of AITL, a whole body CT-scan showed a lesion in the lower pole of the left kidney. A renal cell carcinoma was suspected, thus a nephrectomy was carried out. The histological findings were compatible with polyarteritis nodosa. To the best of our knowledge, the association between PAN and AITL has been described only once. This relation may be secondary to the induction of an autoimmune phenomenon by the lymphoma with the formation of circulating immune complexes, leading to vessel walls injury. A careful evaluation is needed in the management of AITL patients with signs of renal failure in order to avoid delay of treatment and organ damage

Multidimensional geriatric evaluation in acromegaly: a comparative cross-sectional study

Background: Improvement in acromegaly management increased disease survival and prevalence. Evidence regarding acromegaly in older adults are sparse. We aim to explore acromegaly impact on aging process quality. Methods: Multicenter case-control study conducted on 42 older adults (≥ 65 years) acromegaly patients (ACRO) compared to an age- and gender-matched control group (CTR). Each participant underwent a multidimensional geriatric evaluation. Results: Mean age in both groups was 73 ± 6 years and female gender was most represented (69%). All comorbidities were more frequent in ACRO than CTR. Thirteen ACRO were in remission and 29 had active disease controlled by medical therapy except for one patient. ACRO showed worse physical performance and mobility skills worsening with age as compared to CTR. ACRO performed poorly in functional status assessment, and age negatively correlated with instrumental and basic daily activities execution. Cognitive evaluation scores were significantly lower in ACRO vs. CTR, worsening with age. No difference was found concerning nutritional and psychological status. Musculoskeletal and bone diseases were more frequent in ACRO than in CTR (52% vs. 12%; 64% vs. 10%; P < 0.05) and independently associated with geriatric outcomes in ACRO. ACRO reported a less satisfactory quality of life concerning physical activity and pain, general health, vitality, social activities. Conclusions: Our study demonstrates increased frailty of older acromegaly patients as compared to non-acromegaly patients with a consequent negative impact on their quality of life. Therefore, it seems advisable to include physical, functional, cognitive, nutritional, and psychological status assessments in routine clinical practice. Further studies are needed to identify the most appropriate geriatric tools

po 292 breast cancer stem cell reprogramming deciphering the impact of glucose and the contribute of tumour microenvironment

Introduction Diabetes-associated hyperglycemia is linked to poorer prognosis and survival in breast cancer (BC). Indeed, glucose can affect both tumour and tumour-surrounding cells. BC cells are embedded in an adipocyte-rich microenvironment, which, beside adipocytes, contains Stromal-Vascular Fraction Cells (SVFCs). In this scenario, epithelial and stromal compartments communicate through the release of soluble factors and establish an intricate crosstalk. Here, we analysed whether glucose could directly affect the phenotype of ER+ MCF7 BC cells and interfere with their interaction with adipose-derived SVFCs, thereby promoting tumour progression. Material and methods MCF7 cell stemness markers were measured by qReal-Time PCR. Adipose-derived (Ad-)SVFCs were obtained by mammary adipose tissue specimens of women undergoing plastic surgery. The trascriptome of MCF7 exposed to either low (LG-5.5 mM) or high glucose concentration (HG-25 mM) was obtained by RNA-Sequencing (Illumina HiSeq3000). Results and discussions HG exposure of MCF7 determined a significant increase of SOX2 mRNA levels as compared to LG, suggesting the induction of stemness programming. Co-culture with Ad-SVFCs in HG increased SOX2, NANOG and OCT4 mRNA levels in MCF7, as compared to isolated culture, indicating the involvement of SVF-produced soluble factors in BC stem cell reprogramming. Moreover, in presence of Ad-SVFCs and HG, MCF7 produced a higher number of mammospheres, which also displayed larger size. However, both in LG and in HG, conditioned media (CM) obtained from Ad-SVFCs produced no relevant effect on MCF7 stemness. Nevertheless, when Ad-SVFCs were pre-incubated with CM obtained from HG-treated MCF7, their CM very effectively increased OCT4, NANOG and SOX2 mRNA levels in MCF7. Thus, HG likely perturbs MCF7, which produce soluble factors leading Ad-SVFCs to release, in turn, reprogramming factors for BC cell stemness. In this regard, we have observed that HG modification of MCF7 transcriptome includes deregulation of 17 genes (pval=0.05) encoding for secreted proteins involved in cancer progression-related pathways, which may potentially play a role in tumour-stroma interactions. Conclusion Glucose affects BC stem cell reprogramming both directly and through Ad-SVFCs. Deciphering the mechanisms that govern this intricate crosstalk will pave the way to new targeted strategies to improve BC control in conditions of metabolic derangement

Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphoma

peer-reviewedThe Epstein–Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a “hit-and-run” mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged

Granulysin, a novel marker for extranodal NK/T cell lymphoma, nasal type

Granulysin is a cytolytic protein expressed in cytotoxic T and natural killer (NK) cells. Abnormal serum levels of granulysin in lymphomas with NK and cytotoxic phenotype have been shown to correlate with tumour progression. In this study, we investigated the expression pattern of granulysin in routine sections of normal and reactive lymphoid tissues as well as in a large series of lymphomas. In normal tissues, granulysin labelled a small population of cells that double immunostaining revealed to belong to the pool of cytotoxic T/NK cells. Among lymphoid neoplasms, the highest expression of granulysin (71%) was found in extranodal NK/T cell lymphomas of nasal type (ENKTL). To note is that 29% of ENKTLs, which were negative for one or more of classical cytotoxic markers strongly expressed granulysin. Furthermore, expression of granulysin was observed in rare cases of T cell lymphomas with a cytotoxic phenotype (i.e. ALK-negative anaplastic large cell lymphoma (26%), enteropathy-associated T cell lymphoma (12%) and peripheral T cell lymphoma, NOS (4%)). None of the investigated non-Hodgkin B cell lymphomas, Hodgkin lymphoma and plasma cell myeloma were granulysin positive. The results suggest granulysin as a novel marker for a subset of cytotoxic NK cell derived malignancies and its usefulness is highlighted in those ENKTLs that lack expression of other cytotoxic markers but retain granulysin expression

Agonist-Directed Desensitization of the β2-Adrenergic Receptor

The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level