Discontinuation of alpha-interferon treatment in patients with chronic myeloid leukemia in long-lasting complete molecular response

To evaluate follow-up after α-interferon (IFN) discontinuation, 23 patients with chronic myeloid leukemia (CML) in stable complete molecular response (CMolR) with IFN were revisited. After a median IFN treatment of 105.8 months (IR 56.1 - 127.3), all patients discontinued IFN for prolonged CMolR (12), intolerance (8) or planned ABMT (3). After 12.5 months, one patient developed an extramedullar blast crisis. Four patients needed to start imatinib, all achieving again molecular response. Eighteen patients are still off-therapy (median time from IFN discontinuation 125.5 months, IR 86.9-205.3); among these, five are BCR-ABL negative, six present with a sporadic positivity (BCR-ABL ratio < 0.1) and seven show a stable and long-lasting mild positivity (BCR-ABL ratio < 0.5). Patients in prolonged CMolR with IFN have low risk of recurrence after discontinuation; the reappearance of a BCR-ABL positivity < 0.5 did not always precede a relapse, suggesting mechanisms of immunological control induced by IFN

Posterior reversible encephalopathy syndrome (PRES) as complication in a patient with relapsed/refractory multiple myeloma

Background: Multiple myeloma (MM) is a common hematologic malignancy. Immunomodulants, inhibitors of proteasome and monoclonal antibodies represent the standard of care regimens. Neurologic complications could occur in MM patients, both related to the disease or to the therapy. Posterior reversible encephalopathy syndrome (PRES) is a rare disease occurring with a several neurologic symptoms (seizures, headaches, visual loss and confusions) and characterized by typical imaging. It has been described in patients affected by malignancies but only few cases have been reported in MM patients on treatment. Case Report: We herein report the case of a 71 year-old woman with relapsed-refractory micro-molecular MM on treatment with immunomodulants who developed a clonic-tonic seizure during hospitalization for acute kidney failure. The brain computed-tomography (CT) scan and the magnetic resonance imaging (MRI), performed after the event, showed pathologic variations of cortical and subcortical signal of posterior cerebral regions. These findings were considered to be consistent with PRES. The cerebral lesions gradually disappeared, due to supportive therapy. The patient died to hematologic disease progression few months later. Conclusion: The pathophysiology of PRES is still unclear. Further studies are warranted to better understand its relation with multiple myeloma on treatment

The Ultimate State of Thermal Convection in Rayleigh-Taylor Turbulence

Abstract This paper discusses the so-called ultimate state of thermal convection, first proposed by Kraichnan almost 50 years ago and recently observed in numerical simulations of turbulent convection in the absence of boundaries. We focus on numerical simulations of turbulence generated by the Rayleigh–Taylor instability in a wide range of Rayleigh and Prandtl numbers. Our results point out to the conclusion that RT turbulence provides a natural realization of the ultimate state of thermal convection thus highlighting the relationship between the absence of boundaries and the emergence of the ultimate state scaling for global statistical quantities

Monoclonal antibodies in multiple myeloma.

Treatment of multiple myeloma (MM) patients has radically changed over the last years following the introduction of next generation proteasome inhibitors (PI) and immunomodulatory derivative (IMiDs). In the last years, one further therapeutic option for MM patients is represented by monoclonal antibodies (MoAbs), that seem to change the paradigm of MM treatment, particularly for heavily pretreated or double refractory to a PI and IMiDs patients. Antibodies have an immune-based mechanism, induce durable responses with limited toxicity and combine well with existing therapies. The therapeutic effects are prevalently obtained by means of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) and concurrently by the induction of signals on cell effectors. Immunotherapeutic strategies offer a new and exciting approach to target key molecular pathways that continue to be implicated in the survival of malignant plasma cells. These targets include cell surface proteins (CD38, CD138 [SDC1], B cell maturation antigen [BCMA, TNFRSF17]), cytokines that play a role in plasma cell survival and proliferation (interleukin 6 [IL6] and B cell activating factor), signal regulators of bone metabolism (RANKL [TNFSF11], DKK1) and regulators of the immune system (PD-1[PDCD1], PD-L1[CD274]). This article focuses on new MoAbs and related innovative immunotherapeutic modalities currently under investigation in the treatment landscape of MM

Pregnancy in patients with myelodysplastic syndromes (MDS)

We report 6 pregnancies in 5 females with low-risk myelodysplastic syndromes (MDS) (median age at diagnosis 28 years, range 26-29) observed in the last 15 years. In 2 cases pregnancy was concomitant to the diagnosis of MDS, in the remaining 4 cases the intervals from diagnosis were 2, 3, 4 and 9 years, respectively. One patient had a foetal growth retardation corrected with steroid treatment while the remaining 5 pregnancies were uneventful. After a median time from delivery of 104 months (range 18-187) none of the patients developed acute myeloid leukemia (AML) and all are alive in stable disease. In conclusion, selected females with low-risk MDS could not be discouraged to have full term pregnancies. © 2008 Elsevier Ltd. All rights reserved

PICC-related upper deep venous thrombosis in patients with hematological malignancies. Management of anticoagulant therapy according to the platelet count

Peripherally inserted central catheters (PICCs) for central venous access are frequently used in patients with hematological malignancies. Their use may be complicated by upper extremity deep venous thrombosis (UEDVT). Additionally, hematological patients are frequently thrombocytopenic and the optimal management of UEDVT in patients with thrombocytopenia is challenging and poorly standardized. We retrospectively analyzed 50 adult patients affected by hematological malignancies who presented a PICC-associated UEDVT. UEDVT treatment was compared in 3 groups: patients with a platelet count ≥ 50 × 109/l (group1) who underwent a therapeutic dose of low molecular weight heparin (LMWH) or fondaparinux 7.5 mg; patients with a platelet count < 50 × 109/l and ≥ 30 × 109/l (group 2) who were treated with a 50% reduced dose of LMWH or fondaparinux 5 mg; patients with platelets < 30 × 109/l (group 3) were observed and treated with anticoagulants when the count was > 30 × 109//l. At the onset of thrombosis, 36 patients were in group 1, 8 in group 2 and 6 in group 3. We observed no hemorrhagic or thrombotic complications related to the anticoagulant therapy; length of treatment was comparable between groups 1 and 2 (51 days group 1 vs 50 days group 2). Reduced doses of LMWH or fondaparinux may represent a safe and effective therapeutic approach in patients with moderate thrombocytopenia (< 50 × 109/l and ≥ 30 × 109/l) and a PICC-associated UEDVT

Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear

The endocannabinoid system is a key regulator of the response to psychological stress. Inhibitors of monoacylglycerol lipase (MGL), the enzyme that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), exert anxiolytic-like effects in rodent models via 2-AG-dependent activation of CB1 cannabinoid receptors. In the present study, we examined whether the MGL inhibitor JZL184 might modulate persistent predator-induced fear in rats, a model that captures features of human post-traumatic stress disorder. Exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile chemical that is innately aversive to some rodent species, produced in male rats a long-lasting anxiety-like state that was measured 7 days later in the elevated plus maze test. Systemic administration of JZL184 [4, 8 and 16 mg/kg, intraperitoneal (IP)] 4 h before testing caused dose-dependent inhibition of MGL activity and elevation of 2-AG content in brain tissue. Concomitantly, the inhibitor suppressed TMT-induced fear behaviors with a median effective dose (ED50) of 4 mg/kg. A similar behavioral response was observed with another MGL inhibitor, KML29 (4 and 16 mg/kg, IP). Surprisingly, the effect of JZL184 was prevented by co-administration of the CB2 inverse agonist AM630 (5 mg/kg, IP), but not the CB1 inverse agonist rimonabant (1 mg/kg, IP). Supporting mediation of the response by CB2 receptors, the CB2 agonist JWH133 (0.3, 1 and 3 mg/kg, IP) also produced anxiolytic-like effects in TMT-stressed rats, which were suppressed by AM630. Notably, (i) JWH133 was behaviorally ineffective in animals that had no prior experience with TMT; and (ii) CB2 mRNA levels in rat prefrontal cortex were elevated 7 days after exposure to the aversive odorant. The results suggest that JZL184 attenuates the behavioral consequences of predator stress through a mechanism that requires 2-AG-mediated activation of CB2 receptors, whose transcription may be induced by the stress itself