Carla Minoia

Rheumatic disorders as paraneoplastic syndromes

The long-established observation that some rheumatologic disorders (RDs) are associated with--or precede--the clinical manifestations of a variety of solid and hematological tumors represents an important clue for the early diagnosis and effective treatment of the cancers. Inflammatory myopathies, seronegative rheumatoid arthritis and some atypical vasculitides are the most frequently reported paraneoplastic RDs, although paraneoplastic scleroderma- and lupus-like syndromes, erythema nodosum, and Raynauds syndrome have also been observed. Generally, the clinical course of a paraneoplastic RD parallels that of the cancer, and surgical removal of the tumor or its medical treatment usually results in a marked regression of the clinical manifestations of the RD. Most paraneoplastic RDs are difficultly distinguishable from idiopathic RDs. Even so, some atypical features of the clinical presentation raise the suspicion of an underlying tumor. This review summarizes current hypotheses for the pathogenesis that leads a tumor to present as an RD and discusses the clinical features that help distinguish paraneoplastic from idiopathic RDs.

HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target

Purpose: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. Experimental Design: HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed. Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis–related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival. Conclusions: The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance. Clin Cancer Res; 20(4); 847–58. ©2013 AACR.

The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a “real life” retrospective multicenter experience of the Rete Ematologica Pugliese (REP)

Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3xa0%) were treated by romiplostim and 69 (55.6xa0%) by eltrombopag. Mean age, number of young patients (<60xa0years), time from primary diagnosis of ITP to TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80xa0% (44/55) for romiplostim and 94.2xa0% (65/69) for eltrombopag; the duration of response and the time to response were similar (pu2009=u2009NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients (pu2009<u20090.05). The mean duration of response was 30xa0months for romiplostim and 15xa0months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3xa0% of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted.

Challenges and Opportunities of MicroRNAs in Lymphomas

MicroRNAs (miRNAs) are small non-coding RNAs that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Consequently their aberrant expression and/or functions are related to pathogenesis of many human diseases including cancers. Haematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate commitment, differentiation, proliferation, and apoptosis of hematopoietic stem cells (HSC). Alterations on this network could affect the normal haematopoiesis, leading to the development of haematological malignancies such as lymphomas. The incidence of lymphomas is rising and a significant proportion of patients are refractory to standard therapies. Accurate diagnosis, prognosis and therapy still require additional markers to be used for diagnostic and prognostic purpose and evaluation of clinical outcome. The dysregulated expression or function of miRNAs in various types of lymphomas has been associated with lymphoma pathogenesis. Indeed, many recent findings suggest that almost all lymphomas seem to have a distinct and specific miRNA profile and some miRNAs are related to therapy resistance or have a distinct kinetics during therapy. MiRNAs are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum where they are highly stable and quantifiable within the diagnostic laboratory at each consultation. Accordingly they could be specific biomarkers for lymphoma diagnosis, as well as useful for evaluating prognosis or disease response to the therapy, especially for evaluation of early relapse detection and for greatly assisting clinical decisions making. Here we summarize the current knowledge on the role of miRNAs in normal and aberrant lymphopoiesis in order to highlight their clinical value as specific diagnosis and prognosis markers of lymphoid malignancies or for prediction of therapy response. Finally, we discuss their controversial therapeutic role and future applications in therapy by modulating miRNA.

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: A retrospective analysis

For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1-37.4 months), the median PFS was 8 months for all patients (95% CI 5.5-26.6). The median DOR was 24.7 months (95% CI 3.2-24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.

Changes in angiogenesis and hypoxia-inducible factor-1α protein expression in relapsed/refractory indolent non-Hodgkin lymphomas.

Angiogenesis is involved in the pathogenesis and progression of non‐Hodgkin lymphomas (NHL), and hypoxia‐inducible factor‐1α (HIF‐1α, also termed HIF1A) might contribute to this process. Currently, there is no direct evidence that the clinical progression of indolent NHL is associated with angiogenesis, and the expression of HIF‐1α at recurrence is unknown. Matched lymph node biopsies at diagnosis and recurrence of relapsed/refractory indolent NHL patients were analysed by immunohistochemical and morphometric analysis. We observed an increased vascular network and HIF‐1α protein expression in the second biopsy, providing direct evidence that angiogenesis is an essential process for disease progression.

Real world outcome of lenalidomide plus dexamethasone in the setting of recurrent and refractory multiple myeloma: Extended follow-up of a retrospective multicenter study by the "rete ematologica pugliese"

This current retrospective multicenter analysis represents, to our knowledge, the first Italian study evaluating the efficacy and toxicity profile of lenalidomide plus dexamethasone as salvage therapy in patients with recurrent-refractory MM in the real life contest. Our study included patients who are usually excluded from clinical trials because of unfavorable baseline characteristics. Median OS was significantly longer in patients receiving lenalidomide plus dexamethasone for more than 12 months compared with those who had received lenalidomide plus dexamethasone for a shorter interval (P<0.0001). Median OS was not affected by best response achieved (P 0.4) and age (P 0.3). Quality of response did not correlate with number of previous lines of therapy (P 0.77) and age. Higher ORRs were recorded in the patients group with relapsed MM compared to those with refractory disease, but this difference was not statistically significant (P 0.38).

Staging multiple myeloma patients with active disease using serum levels of β2m-free HLA class I heavy chain together with IgM or platelet count

PURPOSEnIn multiple myeloma (MM), serum beta-2-microglobulin (beta2m)-free heavy chains (FHC) of HLA class I has been shown to reflect disease activity. We investigated the possibility of stratifying patients with active disease according to FHC and other clinical parameters.nnnEXPERIMENTAL DESIGNnWe studied 146 patients with MM, including 100 at diagnosis, 31 in relapse and 15 unresponsive to therapy. Univariate and multivariate analyses were used to assess the prognostic significance of FHC together with continuous variables (age, albumin, creatinine, hemoglobin, erythrocyte sedimentation rate, beta2m, calcium, IgM, platelet count) and categorical variables (Durie-Salmon disease stage, gender, bone lesion burden, heavy and light chain isotypes of M-component, clinical status). Survival tree analysis on significant variables was used to develop an MM staging system.nnnRESULTSnFHC, IgM, platelet count and hemoglobin were independent predictors of prognosis. Survival tree analysis of these variables defined 2 three-risk-group staging systems involving FHC and either IgM or platelet count. Median survival for FHC/IgM stages II and III was 41.5 and 27.8 months, whereas it was not reached for stage I patients (p<0.0001). In the FHC/platelets system, median survival was 93.2 (stage I), 44.1 (stage II) or 27.8 (stage III) months (p<0.0001). Similar results were obtained for the 117 MM patients without renal insufficiency (FHC/IgM p<0.0001; FHC/platelets p=0.001). For the 100 patients at diagnosis, FHC/IgM (p=0.001) was more effective than FHC/platelets (p=0.04).nnnCONCLUSIONSnThe independent prognostic markers FHC, IgM and platelets provide two staging systems unaffected by renal insufficiency. Both are effective in evaluating MM patients with active disease.

Role of WB-MR/DWIBS compared to (18)F-FDG PET/CT in the therapy response assessment of lymphoma.

IntroductionThis study prospectively evaluated whole-body magnetic resonance/diffusion-weighted imaging with body signal suppression (WB-MR/DWIBS) reliability compared to 18F-FDG PET/CT in the treatment response assessment of classic Hodgkin lymphomas (HL) and aggressive non-Hodgkin lymphomas (aNHL).Materials and methodsTwenty-seven consecutive patients were prospectively enrolled at the time of diagnosis. Eighteen (11 HL and seven aNHL) were considered for the analysis. They received chemo/radiotherapy as induction and completed post-treatment evaluation performing both 18F-FDG PET/CT and WB-MR/DWIBS. The revised response criteria for malignant lymphomas were used to assess the response to treatment. We evaluated the agreement between the two methods by Cohen’s K test. Post-therapy WB-MR/DWIBS sensitivity, specificity, PPV, NPV and accuracy were then calculated, considering the 12xa0months of follow-up period as the gold standard.ResultsBy using an evaluation on a lesion-by-lesion basis, WB-MR/DWIBS and 18F-FDG PET/CT showed an overall good agreement (Kxa0=xa00.796, 95xa0% ICxa0=xa00.651–0.941), especially in the evaluation of the nodal basins in aNHL (Kxa0=xa00.937, 95xa0% ICxa0=xa00.814–1). In reference to the revised response criteria for malignant lymphomas, the two methods showed a good agreement (Kxa0=xa00.824, 95xa0% ICxa0=xa00.493–1). Post-therapy sensitivity, specificity, PPV, NPV and accuracy of WB-MR/DWIBS were 43, 91, 75, 71 and 72xa0%, respectively.ConclusionWB-MR/DWIBS seems to be an appropriate method for the post-treatment assessment of patients affected by HL and aNHL. The small discrepancies between the two methods found within HL could be due to the biological and metabolic behavior of this group of diseases. Larger prospective studies are necessary to better define the role of WB-MR/DWIBS in this setting of patients.

mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma.

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.