Increased expression of platelet derived growth factor receptor ß on trephine biopsies correlates with advanced myeloma.

PURPOSE: Multiple myeloma (MM), a major cause of cancer mortality, is considered the second most frequent haematological malignancy in Europe. Angiogenesis is a multifactorial process that drives the tumorigenesis in solid tumors and in MM. The platelet derived growth factor (PDGF) receptors are cell surface tyrosine kinase receptors and play an important role in angiogenesis, cancer cell proliferation and dissemination. Few studies have been conducted regarding the expression of PDGF receptors and the correlation with clinical-pathological parameters and prognosis in MM. The purpose of our study was to evaluate, for the first time, in a large cohort of newly-diagnosed MM (NDMM) patients, the expression of PDGF receptor α and ß (PDGFR α, ß) in bone marrow trephine biopsies and investigate the association of PDGFR α, PDGFR ß with angiogenesis in the bone marrow, assessed by bone marrow microvessel density (MVD), clinical characteristics and prognosis. METHODS: In this retrospective study, we assessed the relation of PDGFR α and PDGFR ß immunohistochemical expression with MVD in formalin-fixed paraffin-embedded bone marrow sections from 120 NDMM patients. The immunoreactivity of PDGFR α and ß was examined on the basis of positive plasma cells (PCs) with specific cut off values. RESULTS: PDGFRα and PDGFRß were frequently expressed on malignant PCs. We found that increased PDGFRß expression was strongly associated with advanced disease and adverse prognosis. The expression of PDGFRα and MDV were not correlated with specific features. CONCLUSION: This analysis showed highly expressed PDGFRα and ß PCs of NDMM patients and indicated that high PDGFRß expression at diagnosis was associated with advanced-stage disease.

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis.

Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogren's syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n = 31), SS patients complicated by lymphoma (n = 13) and healthy controls (HC, n = 30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, 2 IFIGs preferentially induced by IFNγ as well as for IFNα and IFNγ genes. The same analysis was performed in minor salivary gland tissues (MSG) derived from 31 SS patients, 10 SS-lymphoma patients and 17 sicca controls (SC). In PB and MSG tissues, overexpression of both type I and type II IFIGs was observed in SS patients versus HC and SC, respectively, with a predominance of type I IFN signature in PB and a type II IFN signature in MSG tissues. In SS-lymphoma MSG tissues, lower IFNα, but higher IFNγ and type II IFIG transcripts compared to both SS and SC were observed. In receiver operating characteristic curve analysis, IFNγ/IFNα mRNA ratio in MSG tissues showed the best discrimination for lymphoma development. Discrete expression patterns of type I and II IFN signatures might be related to distinct SS clinical phenotypes. Additionally, IFNγ/IFNα mRNA ratio in diagnostic salivary gland biopsies is proposed as a novel histopathological biomarker for the prediction of in situ lymphoma development in the setting of SS.

Polymorphisms and haplotypes in TLR9 and MYD88 are associated with the development of Hodgkin's lymphoma: a candidate-gene association study.

Toll-like receptors (TLRs) and myeloid differentiation primary response protein 88 (MYD88) gene polymorphisms may be involved in the pathogenesis of Hodgkin's lymphoma (HL) through altered immunoregulatory and inflammatory responses. A candidate-gene association study was conducted to investigate the association between TLR9 -1237T>C, TLR9 2848A>G, MYD88 -938C>A and MYD88 1944C>G gene polymorphisms and the risk for HL. The impact of haplotypes was also examined. The study showed that carriership for -1237C and 2848A was associated with an increased risk for HL (odds ratio (OR)=2.53 (1.36-4.71) and OR=6.20 (1.3-28.8)). The MYD88 polymorphisms produced nonsignificant results. The estimated frequencies of the TLR9/1237C-2848A and MYD88/938C-1944G haplotypes were also significantly different between HL and controls (P<0.01). In addition, a significant difference between HL and controls was observed for the TLR9/1237C-TLR9/2848A-MYD88/938C-MYD88/1944C haplotypes (P<0.01). In conclusion, our study showed that TLR polymorphisms, and TLR9 and MYD88 haplotypes are related to the development of HL.

Rituximab-based treatments in Waldenström's macroglobulinemia.

The anti-CD20 monoclonal antibody rituximab has shown activity in approximately one third of patients with Waldenström's Macroglobulinemia (WM). Because this agents is nonmyelosuppressive, several studies have assessed its combination with chemotherapeutic agents such as fludarabine, cladribine, cyclophosphamide, and doxorubicin. These regimens induce at least partial response in > 70% of previously untreated patients. Recent data suggest that prolonged exposure to nucleoside-containing regimens should be avoided because of concerns of myelodysplasia and disease transformation. Rituximab has also been combined with thalidomide, which is an active and nonmyelosuppressive regimen. The rituximab-based combination represents today the most commonly used primary treatment for WM.

Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone.

BACKGROUND AND OBJECTIVES: High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis. DESIGN AND METHODS: Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD. RESULTS: Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients. INTERPRETATION AND CONCLUSIONS: The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment.

Extranodal non-Hodgkin's lymphoma presenting as an abdominal wall mass. A case report and review of the literature.

Soft tissue lymphoma is a very rare clinical entity with varying presentation characteristics and atypical clinical and imaging features. The present report describes a patient who presented with a painless soft tissue mass on the posterolateral surface of the abdominal wall, simulating a neoplasm of mesenchymal origin. After complete surgical excision, the tumor was diagnosed as a diffuse large B-cell lymphoma. No B-symptoms were present and clinical staging did not reveal other sites of disease (stage I EA). The International Prognostic Index score was equal to 1 and classified the patient to the good risk group. Post-operatively the patient was treated with immuno-chemotherapy consisting of rituximab plus cyclophosphamide, epirubicin, vincristine and prednisolone and is currently free of disease for 10 months. The case is discussed with a brief review of the literature on the diagnosis, treatment and outcome of soft tissue lymphomas.

Non-Hodgkin's lymphoma of the renal pelvis.

Primary lymphoma of the upper urinary tract is an extremely rare entity without specific clinical or laboratory findings. Thus, this particular diagnosis is rarely anticipated and might well be reached only after nephroureterectomy. We describe a patient with primary follicular and diffuse follicle center lymphoma arising in the renal pelvis that was treated with surgery and postoperative immunochemotherapy. Furthermore, we review the literature regarding the treatment and outcome of this rare disease.

Treatment of relapsed/refractory multiple myeloma with thalidomide-based regimens: identification of prognostic factors.

We evaluated the predictive value of several parameters, including the International Staging System (ISS) for myeloma, in patients with advanced disease treated with thalidomide-based regimens (TBR). We analyzed 119 patients, from 3 phase II studies. Patients with pretreatment beta2 microglobulin<3.5 mg/l and albumin 3.5 g/dl were scored ISS stage 1, patients with beta2 microglobulin<3.5 mg/l and albumin<3.5 g/dl or beta2 microglobulin 3.5-5.5 mg/l regardless of albumin levels were scored ISS stage 2, patients with beta2 microglobulin>5.5 mg/l ISS stage 3. ISS stage was 1, 2 and 3 in 45, 32 and 23% of patients respectively. Seventy-four patients (62%) achieved at least partial response. Median progression-free and overall survival were 8 months and 19.5 months respectively. ISS stage, serum LDH and performance status were independent predictive factors for survival. Based on these 3 variables a scoring system was developed with survival times of 38.1, 28.8 and 5.8 months for scores 0, 1 and 2 respectively. The ISS staging system was highly predictive for overall survival of patients with advanced myeloma treated with TBR. With the addition of performance status and serum LDH, a simple scoring system was developed which may help select patients likely to benefit from TBR.

Minor salivary gland inflammatory lesions in Sjögren syndrome: do they evolve?

OBJECTIVE: The lymphocytic infiltrates of minor salivary gland (MSG) lesions of Sjögren syndrome (SS) vary in grade and composition and are generally thought to develop in stepwise manner. Their progression over time is not well defined. METHODS: We studied repetitive MSG biopsy specimens from 28 patients with primary SS. RESULTS: The infiltration grade and prevalence of the major infiltrating cell types (T and B cells, macrophages, dendritic cells, natural killer cells) remained largely unchanged during a median 55 month biopsy time interval followup (quartiles 42-81). CONCLUSION: We found significant disease progression involving the development of mucosa-associated lymphoid tissue lymphoma in patients expressing adverse serologic prognostic factors, such as low serum C4 complement levels and cryoglobulinemia.