Miriam Isola

A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis

OBJECTIVE To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV). METHODS Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. RESULTS Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [P < 0.0001]), 6 months (71.4% versus 3.5% [P < 0.0001]), and 24 months (60.7% versus 3.5% [P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated. CONCLUSION RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients.

Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia

Previous observational studies suggest that rituximab may be useful in the treatment of primary immune thrombocytopenia (ITP). This randomized trial investigated rituximab efficacy in previously untreated adult ITP patients with a platelet count of 20 x 10(9)/L or less. One hundred three patients were randomly assigned to receive 40 mg/d dexamethasone for 4 days with or without 375 mg/m(2) rituximab weekly for 4 weeks. Patients who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab. Sustained response (ie, platelet count > or = 50 x 10(9)/L at month 6 after treatment initiation), evaluable in 101 patients, was greater in patients treated with dexamethasone plus rituximab (n = 49) than in those treated with dexamethasone alone (n = 52; 63% vs 36%, P = .004, 95% confidence interval [95% CI], 0.079-0.455). Patients in the experimental arm showed increased incidences of grade 3 to 4 adverse events (10% vs 2%, P = .082, 95% CI, -0.010 to 0.175), but incidences of serious adverse events were similar in both arms (6% vs 2%, P = .284, 95% CI, -0.035 to 0.119). Dexamethasone plus rituximab was an effective salvage therapy in 56% of patients refractory to dexamethasone. The combination of dexamethasone and rituximab improved platelet counts compared with dexamethasone alone. Thus, combination therapy may represent an effective treatment option before splenectomy. This study is registered at http://clinicaltrials.gov as NCT00770562.

Low-grade glioma surgery in eloquent areas: Volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients - Clinical article

OBJECT A growing number of published studies have recently demonstrated the role of resection in overall survival (OS) for patients with gliomas. In this retrospective study, the authors objectively investigated the role of the extent of resection (EOR) in OS in patients with low-grade gliomas (LGGs). METHODS Between 1998 and 2011, 190 patients underwent surgery for LGGs. All surgical procedures were conducted under corticosubcortical stimulation. The EOR was established by analyzing the pre- and postoperative volumes of the gliomas on T2-weighted MRI studies. The difference between the preoperative tumor volumes was also investigated by measuring the volumetric difference between the T2- and T1-weighted MRI images (ΔVT2T1) to evaluate how the diffusive tumor-growing pattern affected the EOR achieved. RESULTS The median preoperative tumor volume was 55 cm(3), and in almost half of the patients the EOR was greater than 90%. In this study, patients with an EOR of 90% or greater had an estimated 5-year OS rate of 93%, those with EOR between 70% and 89% had a 5-year OS rate of 84%, and those with EOR less than 70% had a 5-year OS rate of 41% (p < 0.001). New postoperative deficits were noted in 43.7% of cases, while permanent deficits occurred in 3.16% of cases. There were 41 deaths (21.6%), and the median follow-up was 4.7 years. A further volumetric analysis was also conducted to compare 2 different intraoperative protocols (Series 1 [intraoperative electrical stimulation alone] vs Series 2 [intraoperative stimulation plus overlap of functional MRI/fiber tracking diffusion tensor imaging data on a neuronavigation system]). Patients in Series 1 had a median EOR of 77%, while those in Series 2 had a median EOR of 90% (p = 0.0001). Multivariate analysis showed that OS is influenced not only by EOR (p = 0.001) but also by age (p = 0.003), histological subtype (p = 0.005), and the ΔVT2T1 value (p < 0.0001). Progression-free survival is similarly influenced by histological subtype (fibrillary astrocytoma, p = 0.003), EOR (p < 0.0001), and ΔVT2T1 value (p < 0.0001), as is malignant progression-free survival (p = 0.003, p < 0.0001, and p < 0.0001, respectively). Finally, the study shows that the higher the ΔVT2T1 value, the less extensive the currently possible resection, highlighting an apparent correlation between the ΔVT2T1 value itself and EOR (p < 0.0001). CONCLUSIONS The EOR and the ΔVT2T1 values are the strongest independent predictors in improving OS as well as in delaying tumor progression and malignant transformation. Furthermore, the ΔVT2T1 value may be useful as a predictive index for EOR. Finally, due to intraoperative corticosubcortical mapping and the overlap of functional data on the neuronavigation system, major resection is possible with an acceptable risk and a significant increase in expected OS.

Contrast-Enhanced Breast MRI in Patients with Suspicious Microcalcifications on Mammography: Results of a Multicenter Trial

OBJECTIVE The objective of our study was to test dynamic MRI in evaluating mammographically detected suspicious microcalcifications. MATERIALS AND METHODS One hundred twelve patients with mammographically detected microcalcifications with BI-RADS category 5 (n = 78) or 4 (n = 34) lesions were studied at 17 centers a using 3D gradient-echo dynamic coronal technique (< or = 3 mm thickness) and 0.1 mmol/kg of gadoteridol. A pathologic sample was obtained in all cases. Agreement between the major diameter measured on mammography, MRI, or both and the major diameter measured at pathologic examination was calculated in 62 cases. RESULTS Of the 112 lesions, pathologic examination revealed 37 benign lesions, 33 ductal carcinoma in situ (DCIS), and 42 invasive carcinomas. The specificity of MRI for benign lesions was 68%. Considering the subgroups of calcifications alone and calcifications associated with masses, the specificity values became 79% and 33%, respectively. The sensitivity of MRI for DCIS was 79%. Analysis of the two subgroups showed sensitivity values of 68% for calcifications alone and of 1% for calcifications associated with masses. The sensitivity for invasive carcinomas was 93%. Analysis of the two subgroups showed sensitivity values to be 92% for calcifications alone and 94% for calcifications associated with masses. Considering the overall results, the sensitivity of MRI was 87%; specificity, 68%; positive predictive value, 84%; negative predictive value, 71%; and accuracy, 80%. Considering the subgroups of calcifications alone and calcifications associated with masses, the sensitivity values became 80% and 97%; the positive predictive values, 86% and 82%; the negative predictive values, 71% and 75% (95% confidence interval [CI], 0.19-0.99); and the accuracy values, 80% and 82% (95% CI, 0.66-0.92), respectively. An odds ratio (OR) of 13.54 (95% CI, 5.20-35.28) showed a raised risk of malignant breast tumor in subjects with positive MR examination of mammographically detected suspicious clusters of microcalcifications. The statistical analysis on each subgroup showed an OR of 15.07 (95% CI, 4.73-48.08) for calcifications alone and an OR of 14.00 (95% CI, 1.23-158.84) for calcifications associated with masses. Any significant improvement in the predictive ability of dynamic MRI depending on the extent of calcifications on mammography was not proved. Considering the 62 cases of proved malignancy with measured maximal diameter at pathologic examination, both mammography and MR examination seem to overestimate tumor extent. CONCLUSION The not-perfect sensitivity of MRI (87%), when applying our interpretation criteria and imaging sequences, is a crucial point that prevents us from clinical use of MRI in the diagnosis of mammographically detected microcalcifications.

Relevance of b‐values in evaluating liver fibrosis: A study in healthy and cirrhotic subjects using two single‐shot spin‐echo echo‐planar diffusion‐weighted sequences

To investigate the relevance of increasing b‐values in evaluating liver fibrosis through the agreement of two diffusion‐weighted (DW) sequences.

Diffusion-weighted MRI in evaluating liver fibrosis: a feasibility study in cirrhotic patients.

AbstractPurpose.This study was designed to establish whether the measurement of apparent diffusion coefficients (ADCs) is clinically accurate in diagnosing liver fibrosis in a selected series of cirrhotic patients.Materials and methods.Twenty-eight cirrhotic patients (mean age 58.1 years) with histologically proven liver fibrosis and 29 healthy controls (mean age 43.8 yeas) underwent liver diffusion-weighted magnetic resonance (MR) using a 1.5-Tesla (T) magnet equipped with a phased-array coil. Diffusion studies with parallel imaging [generalized autocalibrating partially parallel acquisitions (GRAPPA)] were performed within a single breath-hold using a single-shot spin-echo echo-planar sequence (TE 74 ms) using four b values: b=0, 150, 250 and 400 s/mm2. A unidirectional diffusion gradient was applied. ADCs were measured on ADC maps.Results.Mean ADC was significantly lower in cirrhotic livers than in controls (1.11±0.16 vs. 1.54±0.12.10-3mm2/s) (p<0.0001). Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.96 [confidence interval (CI) 95%:(0.87; 0.94)], demonstrating higher sensitivity and specificity (92.9% and 100%, respectively) for an ADC cutoff of 1.31.10-3mm2/s. Positive predictive value (PPV), negative predictive value (NPV) and overall accuracy were 100%, 99.9% and 96.4%, respectively.Conclusions.Diffusion-weighted MRI is an accurate tool in evaluating advanced liver fibrosis if an optimised single-shot spinecho echo-planar sequence with maximum intermediate b value is used. The ADC threshold for liver fibrosis was 1.31.10-3mm2/s.

Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura

Rituximab 375 mg/m2 weekly for four weeks has significant activity in patients with immune thrombocytopenia. We evaluated the activity of lower dose rituximab (100 mg iv weekly for 4 weeks) in 28 adults with idiopathic thrombocytopenic purpura. Overall (platelet count > 50×109/L) and complete responses (platelet count > 100×109/L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively. The median time to response and time to complete response were 31 and 44 days respectively. After a median follow-up of 11 months (range 3–18), 7/21 (33%) patients relapsed and 3 needed further treatments. In patients with idiopathic thrombocytopenic purpura, lower dose rituximab seems to show similar activity to standard dose.

Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

In this GITMO study, Patriarca and coworkers evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. They conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. See related perspective article on page 1449. Background Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. Design and Methods One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients’ characteristics and the clnical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. Results The median age of the patients at the time of stem cell transplantation was 49 years (range, 21–68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87–0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. Conclusions We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.

Preliminary classification criteria for the cryoglobulinaemic vasculitis

Background To develop preliminary classification criteria for the cryoglobulinaemic syndrome or cryoglobulinaemic vasculitis (CV). Methods Study part I developed a questionnaire for CV to be included in the formal, second part (study part II). Positivity of serum cryoglobulins was defined by experts as an essential condition for CV classification. In study part II, a core set of classification items (questionnaire, clinical and laboratory items, as agreed) was tested in three groups of patients and controls—that is, group A (new patients with the CV), group B (controls with serum cryoglobulins but lacking CV) and group C (controls without serum cryoglobulins but with features which can be observed in CV). Results In study part I (188 cases, 284 controls), a positive response to at least two of three selected questions showed a sensitivity of 81.9% and a specificity of 83.5% for CV. This questionnaire was employed and validated in study part II, which included 272 patients in group A and 228 controls in group B. The final classification criteria for CV, by pooling data from group A and group B, required the positivity of questionnaire plus clinical, questionnaire plus laboratory, or clinical plus laboratory items, or all the three, providing a sensitivity of 88.5% and a specificity of 93.6% for CV. By comparing data in group A versus group C (425 controls), the same classification criteria showed a sensitivity 88.5% and a specificity 97.0% for CV. Conclusion Classification criteria for CV were developed, and now need validation.

BLyS upregulation in Sjögren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands

OBJECTIVE Primary SS is characterized by an increased risk of lymphoma in patients with prelymphomatous manifestations (i.e. myoepithelial sialadenitis or mixed cryoglobulinaemia). Serum B-lymphocyte stimulator (s-BLyS) levels in SS-related B-cell lymphoproliferative disorders were studied by integrating the results with the disease activity score and with molecular analyses of B-cell expansion in the salivary glands. METHODS Seventy-six primary SS patients (with or without lymphoma or prelymphomatous manifestations), 56 HCV-related cryoglobulinaemic vasculitis patients and 55 controls were studied. s-BLyS and molecular analyses of B-cell expansion in the salivary gland tissues were performed. Patients with SS and persistent parotid swelling underwent parotid biopsy. RESULTS s-BLyS differed between SS subgroups, higher levels being documented in patients with lymphoma or prelymphomatous manifestations vs SS without [1.85 (0.45-4.12) ng/ml vs 1.12 (0.56-1.98) ng/ml; P < 0.0001]. s-BLyS levels significantly correlated with the European League Against Rheumatism (EULAR) SS disease activity index (r = 0.62, P < 0.0001, Spearmans test). Clonal B-cell expansion in the salivary glands, but not polyclonal B-cell expansion, was associated with higher s-BLyS levels [1.98 (0.45-4.12) ng/ml vs 1.15 (0.56-3.25) ng/ml; P = 0.013)]. CONCLUSION Higher s-BLyS levels and tissue clonal B-cell expansion characterize SS with B-cell lymphoproliferative disorders, even at prelymphomatous stages. This subgroup of SS patients showed the highest EULAR SS disease activity index scores. This represents a biologic rationale for targeting both clonal B-cell expansion and s-BLyS overproduction in SS.