Moreno Tresoldi

Microvessel density, a surrogate marker of angiogenesis, is significantly related to survival in multiple myeloma patients

Summary. We evaluated microvessel density (MVD) in bone marrow biopsies (BM) from multiple myeloma (MM) patients after staining with anti‐CD34 and anti‐CD105 antibodies (mAbs). The anti‐CD105 mAb was significantly more sensitive than the anti‐CD34 mAb in visualizing blood vessels both in controls and MM samples. MVD was significantly higher in MM than in controls with both anti‐CD34 and anti‐CD105 mAbs. Patients with low CD34+ MVD survived longer than patients with higher MVD (P = 0·01), whereas there was no difference in survival between patients with low and high CD105+ MVD. Multivariate analysis confirmed the independent significant association between CD34+ MVD and survival (P = 0·001).

MICA Expressed by Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance Plasma Cells Costimulates Pamidronate-Activated γδ Lymphocytes

Amino-biphosphonates (like pamidronate) activate human Vgamma9/Vdelta2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)-mediated effector functions of gammadelta cells are enhanced upon triggering of the activating receptor NKG2D by MICA, a stress-inducible antigen expressed by epithelial and some hematopoietic tumors, including multiple myeloma. Here we show that MICA was expressed not only by myeloma cell lines and by 6 of 10 primary multiple myeloma cells from patients but also by bone marrow plasma cells from all (six of six) patients with preneoplastic gammopathy (monoclonal gammopathy of undetermined significance, MGUS), a direct precursor of multiple myeloma. Moreover, compared with multiple myeloma plasma cells, MICA was expressed by MGUS plasma cells at significantly (P < 0.05) higher levels. MICA expressed by myeloma cell lines contributed to killing and IFN-gamma production by Vgamma9/Vdelta2 cells only upon pamidronate treatment, suggesting a dual interaction between Vgamma9/Vdelta2 lymphocytes and multiple myeloma plasma cells involving both TCR triggering and NKG2D-mediated signals. Finally, MICA enhanced killing of freshly derived, pamidronate-treated multiple myeloma cells from patients by gammadelta cells, as indicated by the significantly (P < 0.05) higher gammadelta cytotoxicity against MICA-positive rather than MICA-negative multiple myeloma cells. Our results indicate that MICA expressed by monoclonal plasma cells is functional and correlates with disease stages, suggesting a role for the molecule in the immune surveillance against multiple myeloma. Moreover, pamidronate-activated Vgamma9/Vdelta2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease.

IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients

Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre. Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as ‘definite’ or ‘possible’ according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with ‘definite’ IgG4-RD and 15 with ‘possible’ IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24–51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking. Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Treating life-threatening myocarditis by blocking interleukin-1

Objective:Treatment of viral fulminant myocarditis relies on life support measures. Based on studies pointing to a role for the proinflammatory cytokine interleukin-1 in myocardial inflammation and contractile dysfunction, we treated a patient with fulminant viral myocarditis with the interleukin-1 receptor blocking agent anakinra. We report the response and discuss the biologic rationale of this novel treatment approach. Design:Case report. Setting:ICU. Patient:A 36-year-old woman who was hospitalized for fulminant myocarditis with biventricular failure and cardiogenic shock, acutely manifested with hypotension and dyspnea. Interventions:Following the progressive, life-threatening collapse of the cardiac function in spite of treatment with venous-arterial extracorporeal membrane oxygenation and mechanical circulatory support with a left ventricular assist device, treatment with the interleukin-1 receptor blocking agent anakinra 100 mg/d was started. Measurements and Main Results:The severe depression of cardiac function responded promptly to interleukin-1 inhibition. Within 4 days of treatment initiation, progressive clinical improvement allowed weaning from extracorporeal membrane oxygenation and removal of the percutaneous left ventricular assist device. The patient was discharged home and remains in excellent health at 12 months. Conclusions:Clinical and experimental evidence suggests that interleukin-1 blockade is effective against myocardial inflammation and contractile dysfunction, thus representing a promising candidate for the treatment of inflammatory heart failure. Although further confirmation is needed, these encouraging results indicate that anakinra may be a suitable treatment for fulminant myocarditis.

Interleukin-1 Receptor Blockade Rescues Myocarditis-Associated End-Stage Heart Failure

Support measures currently represent the mainstay of treatment for fulminant myocarditis, while effective and safe anti-inflammatory therapies remain an unmet clinical need. However, clinical and experimental evidence indicates that inhibition of the pro-inflammatory cytokine interleukin 1 (IL-1) is effective against both myocardial inflammation and contractile dysfunction. We thus evaluated treatment with the IL-1 receptor antagonist anakinra in a case of heart failure secondary to fulminant myocarditis. A 65-year-old man with T cell lymphoma developed fulminant myocarditis presenting with severe biventricular failure and cardiogenic shock requiring admittance to the intensive care unit and mechanical circulatory and respiratory support. Specifically, acute heart failure and cardiogenic shock were initially treated with non-invasive ventilation and mechanical circulatory support with an intra-aortic balloon pump. Nevertheless, cardiac function deteriorated further, and there were no signs of improvement. Treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, was started at a standard subcutaneous dose of 100 mg/day. We observed a dramatic clinical improvement within 24 h of initiating anakinra. Prompt, progressive amelioration of cardiac function allowed weaning from mechanical circulatory and respiratory support within 72 h of anakinra administration. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for both myocardial inflammation and contractile dysfunction. Furthermore, IL-1 receptor blockade with anakinra is characterized by an extremely rapid onset of action and remarkable safety and may thus be suitable for the treatment of patients critically ill with myocarditis.

Megakaryoblastic differentiation of myeloid sarcoma in a patient with essential thrombocythemia

Myeloid sarcoma (MS) is a neoplastic growth of myeloblasts or immature myeloid cells arising in an extra-medullary site or in the bone. MS may precede, occur simultaneously or follow acute or chronic myeloid leukemia, as well as other types of myeloproliferative disorders or myelodysplastic syndromes [1]. The WHO classification scheme recognizes three types of MS based on degree of myeloid maturation: blastic, immature and differentiated [1]. Additionally, sporadic cases differing from myeloid lineage, such as megakaryoblastic or erythroid differentiation, have been described. A 68 year-old man was referred to our Institution for a sudden worsening buttock pain extended to left thigh, that arose a month earlier in association with fever up to 398C. Infectious causes were ruled out and fever was treated with cortisone, taking into account a 7 year-history of symmetric polyarthritis. Five years prior to admission a diagnosis of Essential Thrombocythaemia (ET) based on clinical, laboratory and morphological criteria had been made. In particular, morphologic examination of bone marrow aspirate showed increased cellularity, normal-looking myeloid and erythroid lineages and a marked increase of megakaryocytes, which displayed a range of morphological abnormalities, including giant forms, albeit in the absence of bizarre nuclei. Blasts cell count was less than 2%. Therapy with hydroxyurea has been initiated. Physical examination disclosed left buttock enlargement and swelling. Laboratory tests revealed: hemoglobin 11.3 g L, white blood cell count 28.7610 L (N 77%, L 5%, M 3%, E 1%, B 2%), without any evidence of blasts, platelets count 862610 L, LDH 1235 U L and elevated acute phase reagents (ESR/1 h 120, Reactive C-protein 90 mg dl). Total body CT-scan revealed a left iliac bone osteolysis measuring 11 cm in diameter and locally infiltrating the posterior muscles, multiple iliac and inguinal lymphadenopathies and a mediastinal lesion measuring 4 cm. Bone scintigraphy showed increased uptake of Tc-99 m in the previously described areas, as well as in femurs and tibias. A 2.5 cm diameter inguinal lymph node was excised, formalin-fixed and paraffin-embedded. Histopathological analysis revealed almost complete effacement of lymph node architecture by a diffuse proliferation of large sized, immature-looking elements; these cells exhibited a high nuclear/cytoplasmic ratio with coarse chromatin and quite regular nuclear outline (Figure 1(a)). Within this population, scattered larger cells were readily visible: these cells showed irregular, polylobated nuclei and were similar to immature megakaryocytes (Figure 1(b)). These two types of neoplastic cells were both immunoreactive for CD43, CD45, CD34, focally for factor VIII (Figure 1(c)), CD61, vimentin and EMA (Figure 1(d)), with also a focal positivity for CD117 and CD68. The same elements did not stain for CD20, CD30, CD16, CD138, cytokeratin-pool, actin, desmin, S-100 protein, HMB45, ALK-1, myeloperoxydase and lysozyme. Fluorescence in-situ

Unusual bleeding manifestations in a case of primary amyloidosis with factor X deficiency but elevations of in vivo markers of thrombin formation and activity

We describe a case of primary amyloidosis (AL) with severe factor X (FX) deficiency in an amateur cyclist presenting with muscular pain at rest and ecchymoses in his legs. No circulating inhibitor of FX was found by mixing studies and there was no deficiency of other vitamin K-dependent coagulation factors and inhibitors or of alpha 2-antiplasmin. Thrombin-time and reptilase time were abnormally prolonged and were not corrected by mixing with normal plasma. Administration of plasma or prothrombin complex concentrate (PCC) were unsuccessful in controlling bleeding: the apparent half-life of transfused FX was 6 minutes. Resting resulted in cessation of muscular pain and bleeding. Renal and cardiac deterioration led the patient to death 3 years after presentation. No further bleeding manifestations did occur during this period. FX levels remained consistently below 3%, but prothrombin fragment 1.2 and thrombin-antithrombin complex--measured at distance from PCC administration and prior to deterioration of renal and cardiac function--were markedly elevated. At autopsy, disseminated amyloidosis was found with sparing of the skeletal muscles and of the skin. This is the first report of increased in vivo prothrombin activation and activity in AL-associated FX deficiency.

Serum CXCL12 levels on hospital admission predict mortality in patients with severe sepsis/septic shock.

OBJECTIVES We evaluated serum levels of CXCL12 in patients with severe sepsis/septic shock and controls. METHODS We enrolled 27 patients admitted to our emergency department with severe sepsis/septic shock and 20 healthy controls. Complete blood count, serum levels of CXCL12, C-reactive protein, lactate, Charlson comorbidity index, sequential organ failure score on hospital admission, and inhospital mortality were evaluated at baseline (T0) and after 24 hours (T24). RESULTS Mean serum levels of CXCL12 were higher in patients with severe sepsis/septic shock than in healthy subjects (3121 vs 1991 pg/mL; P < .001). We also found that patient who survived had lower serum levels of CXCL12 than those who died (2630 vs 3957 pg/mL; P < .001) but still higher than controls (2630 vs 1991 pg/mL; P = .001) on admission. CXCL12 serum levels were higher in patients with serum lactate greater than 4 mmol/L. CONCLUSIONS Our data suggest a possible role for CXCL12 as a prognostic marker in severe sepsis/septic shock and give background evidence for larger trials to evaluate the pathophysiologic and clinical role of CXCL12 in sepsis, with respect to other markers of inflammation and hypoxia.

Primary granulocytic sarcoma presenting with bone pain and hypergammaglobulinemia.

Granulocytic sarcoma (GS), is an extramedullary tumorous aggregate of neoplastic myeloid precursor cells, most often associated with acute myeloid leukemia (AML). Primary GS occurs in patients with normal bone marrow and no history of hematological disorders. It is a rare disease, which can involve any organ and mimic other tumors. A correct initial diagnosis, which can be difficult, and early treatment with chemotherapy as for AML patients results in a higher rate of complete remission. We report a case of multifocal primary GS of the bone associated with oligoclonal hypergammaglobulinemia, successfully treated with AML-like induction chemotherapy followed by post-induction therapy with autologous peripheral stem cells transplantation. The possible significance of the associated hypergammaglobulinemia is discussed.

Kaposi's Sarcoma in a Patient with Eosinophilic Granulomatosis with Polyangiitis While Taking Mycophenolate Mofetil

A 67-year-old man with an 11-month history of ANCAnegative eosinophilic granulomatosis with polyangiitis (EPGA) was evaluated in our department for weight loss of 5 kg over 2 months and progressive fatigue. He had a 20-year history of asthma, for which he was taking maintenance therapy with an inhaled corticosteroid twice daily. He later developed glomerulonephritis, peripheral eosinophilia, and sinusitis, and a histological sample of a nasal polyp confirmed the diagnosis of EPGA (small-sized vessel inflammatory arteriopathy with fibrinoid necrosis, granulomata, and perivascular eosinophilic infiltration). The patient achieved clinical remission after high doses of glucocorticoids and started daily oral prednisone 5 mg and mycophenolate mofetil (MMF) 2 g as a maintenance regimen. MMF was chosen because of its low renal toxicity, given the patient’s renal failure secondary to glomerulonephritis (creatinine clearance 17.6 mL/min). At clinical examination, multiple cutaneous lesions on the neck and limbs’ extremities were observed. He reported that a sore and purplish skin lesion on the right leg appeared 6 weeks before admission (Figure 1, A) and then a few of similar, fast-growing lesions came up (Figure 1, B). He was afebrile, hemodynamically stable, and maintained a room air oxygen saturation of 94%. Superficial lymph nodes were not palpable. Blood tests revealed normal complete blood count, inflammatory indexes, and biochemistry. Percutaneous tissue biopsy was performed, and histologic analysis revealed spindle cell proliferation suggestive of Kaposi’s sarcoma (KS)