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Abstract 3072 Thromboembolic disease (TE) is a major cause of morbidity and mortality in Essential Thrombocythemia (ET). Recently JAK2V617 mutational status and allele burden seem to add prognostic significance to standard risk factors; furthermore it was reported an interesting but not confirmed association between baseline leukocytosis and thrombosis. The aim of the study was to evaluate such factors in a series of patients with ET. Study subjects were recruited from the Ancona Hematology Clinic database of ET patients; clinical and laboratory data were collected at time of diagnosis and correlated with the occurrence of TE. In addition, qualitative and quantitative PCR for JAK2V617F was performed on stored samples of peripheral blood or bone marrow in a subset of study patients. Qualitative JAK2V617F analysis was done according to standard PCR-based methods and quantitative JAK2V617F was determined with a commercially available Taqman assay. Standard statistical methods were applied to test significance of associations between thrombosis and other variables. A total of 218 ET patients were included in the study (median age 59, range 18–90; 71 males and 147 females). At diagnosis the median of platelets, hemoglobin and leukocytes were 776×109/L, 13.9g/dL, and 8.4 ×109/L respectively. At diagnosis a history of remote thrombosis was recorded in 27 patients (12,4%). Of the 122 patients analysed for JAK2 mutational status, 70 (57.4%) were JAK2 wild-type and 52 (42.6%) were JAK2V617F positive. Quantitative analysis was carried out in 48 cases: 6 patients (11.5%) were homozygotic and 42 (80.8%) were heterozygotic. At diagnosis, a total of 17 patients (7.8%) had TE: 8 (3.7%) arterial thrombosis (AT) and 9 (4.1%) venous thrombosis (VT). the AT included acute coronary syndromes (ACS; n=4), transient ischemic attack/cerebrovascular accidents (TIA/CVA; n=3), and peripheral arterial thrombosis (PAT; n=1). The VT included deep vein thrombosis/pulmonary embolism (DVT/PE; n= 4), abdominal vein thrombosis (AVT; n=4) and dural sinus thrombosis (n=1). During follow-up 25 patients experienced TE: 13 VT (6%) and 12 AT (5.5%). Post diagnosis VT included.: DVT/PE (n= 4), AVT (n=4), superficial vein thrombosis (TVS; n=3), retinal vein thrombosis (n=1) and dural sinus thrombosis (n=1). Post diagnosis AT included TIA/CVA (n=6), ACS (n=3) and PAT (n=3). Gender, age, hemoglobin, platelets, leucocyte count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and common vascular risk factors did not affect the probability of thrombotic events at diagnosis and during follow-up. On univariate analysis a significant increase of thrombosis as presenting manifestations, was registered in patients with a history of remote thrombosis (OR= 10.0, 95% CI 4,1-24,5; p Subjects with both JAK2 mutation and a history of remote thrombosis have a OR of 24.44 (95% CI 3.07–194.66; p=0.01) in comparison with wild-type patients without a history of thrombosis. During follow-up, the probability of vascular events was predicted only by a history of remote thrombosis (OR=2.3, 95% CI 1.01–5.35; p=0.05), and neither by JAK2V617F mutational status (OR=1.24, 95% CI 0.43–3.62; p=0.76). The present analysis suggests that the thrombotic risk is higher in JAK2V617F positive patients and is further increased by a past history of thrombosis. The opportunity of combine such criteria must be defined in prospective trials. Disclosures: Leoni: Celgene: Honoraria.

Combination therapy is commonly used in the treatment of advanced and aggressive cutaneous T-cell lymphomas (CTCL), like Mycosis Fungoides (MF) and Sézary Syndrome (SS). Alemtuzumab, the humanized anti-CD52 antibody primarily developed for the treatment of B-CLL, has been also administered effectively in patients with CTCL as monotherapy, but it might be an ideal candidate for combination therapy either with a biological immune response modifier like interferon (IFN)-α, or with a drug known to be particularly active in CTCL like gemcitabine. No data on the activity of combination schemes including alemtuzumab in CTCL seem to be available. The aim of this study was to explore the clinical activity of alemtuzumab in two combination modalities, including either IFN-α or gemcitabine. We enrolled 5 patients, 4 males and 1 female, affected by SS/erythrodermic MF, with a median age of 57 yrs (43–74) and a median disease history of 21 mo.s (9–95). Two patients were treated with both combination schemes. Before starting therapy, all patients except one had a rapidly progressive disease, relapsed or refractory to previous treatments, and had previously received three or more systemic chemotherapy regimens. Most patients had reduced performance status and all had severe itching. Four patients received alemtuzumab in combination with IFN-α: subcutaneous alemtuzumab was administered at 3 mg on day 1, 10 mg on day 3, followed by 15 mg on alternating days for 7 total doses; after a further 3 months of treatment with IFN-α (3 MU three times weekly) the patients received reinduction with alemtuzumab (10 mg weekly for another month). Three patients received alemtuzumab in combination with gemcitabine: subcutaneous alemtuzumab was given at 10 mg on days 1, 8 and 15 of a 28-day schedule in combination with gemcitabine at a dose of 1200 mg/m2 intravenously (median number of cycles=4). Trimethoprim/sulphamethoxazole (twice daily 2 times per week) and valacyclovir (500 mg twice daily) were administered from day 2 until at least 2 months after alemtuzumab discontinuation. The response (complete/CR, partial/PR, stable disease/SD) was assessed in skin, lymph nodes and peripheral blood, by using the SWAT criteria and by comparing the absolute number of circulating Sezary cells (SC) detected by flow-cytometry before and after treatment. The overall response (OR) was determined as the worse result obtained in the different sites. The OR rate was 57.1% (4 PR vs 3 SD), higher in the group treated with alemtuzumab and gemcitabine (66.7%: 2 PR vs 1 SD) than in the group treated with alemtuzumab and IFN-α(50%, 2 PR and 2 SD). The better response rate obtained in the group treated with gemcitabine was due to the higher activity in the skin (2 CR, 1 SD vs 2 PR, 2 SD) and in the lymph nodes (3 PR vs 3 PR, 1 SD). The circulating SC count was low at the end of therapy (median, 164, range, 24–530), with a lower median value in the group treated with gemcitabine (131), than in the group treated with IFN-α (303). Itching, self-assessed on a 0 to 10 visual analog scale, was significantly reduced from a median score of 9 before treatment, to 1 at the end of therapy. Both combination treatments were well tolerated. Infusion-related adverse events were not reported. Grade 3–4 hematologic toxicity was observed only in one case treated by alemtuzumab and gemcitabine (grade 3 leukopenia). One patient from the group treated with alemtuzumab and IFN-α had infectious complications (CMV pneumonitis and pulmonary aspergillosis). Two patients treated with gemcitabine showed CMV detectable viral load in peripheral blood without any occurrence of complications. All patients treated with alemtuzumab and IFN-α experienced a progressive disease, respectively at 5, 9, 11, 12 months, whereas the 3 patients treated with alemtuzumab and gemcitabine are still in PR at 4, 10, 12 months (median overall PFS: 9 mo.s). At last follow-up, 3 patients are still alive with disease, while two had died, one for unrelated causes and the other for progressive disease. Although the present series is small, our observations point towards a potential role of alemtuzumab in combination schemes in heavily pretreated CTCL patients, as the response rate (57%) appears better than that reported in the literature for alemtuzumab alone (OR 33%), and the toxicity profile of both combination seems to be fairly acceptable. Moreover, gemcitabine might be a better candidate than IFN-α for combination therapy with alemtuzumab, since the progression-free survival seems to be prolonged.

The oral anticoagulant therapy (OAT) in oncologic patient is often problematic because both the haemorragic risk and the thrombotic risk, i.e. the recurrence of venous thromboembolism, are increased. Many studies have been conducted in patient with solid neoplasms; it remains still unclear whether these results could be entirely extrapolated to patients with haematological malignancies. Our aim was to analyse the clinical outcomes and the control of anticoagulation, measured as % time in target INR range, in the patients with cancer compared to patients without cancer; moreover we focused on patients with haematological neoplasms. A total of 500 patients were recruited in 6 years, regardless of the indication for OAT; 146 (29%) of them were affected by cancer (47 haematological and 99 solid neoplasms); those being treated with warfarin for less than 1 month were excluded from this analysis. It resulted that patients affected with cancer had a worse anticoagulation control, compared to those without cancer (55% vs 60%; p

Pegylated liposomal doxorubicin (PLD) is approved in breast cancer, ovarian cancer, Kaposi’s sarcoma. Its skin-tropism suggests a role in the therapy of primary cutaneous lymphomas (PCLs). Among the cutaneous toxicities of PLD, the palmar-plantar erythrodysesthesia (PPE) is characterized by tingling, dysesthesia, erythema, swelling and, in severe cases desquamation, crusting, ulceration and necrosis. PPE is dose- and schedule-dependent and is usually reversible. Different pathophysiologic mechanisms are suggested: PLD, excreted from sweat glands, penetrates into the corneum stratum with local oxidative and inflammatory reactions; direct cytotoxic effect; extravasation of PLD from the deep microvessels through the local pressure. At our knowledge no specific reports on PPE in patients (pts) with PCLs treated with PLD were presented. We report 31 PCL pts treated with PLD: 26 affected by primary cutaneous T-cell lymphomas (PCTCL) and 5 by primary cutaneous B-cell lymphomas (PCBLC). Among PCTLC, 21 pts (16 M, 5 W, median age 67 yrs) received PLD in monotherapy at the dosage of 20 mg/m2 every 3–4 weeks. They were affected by relapsed or refractory PCTCLs: Mycosis Fungoides (MF) (52%), transformed MF in large cell lymphoma (20%), Sèzary Syndrome (SS) (14%), peripheral T-cell lymphoma unspecified (PTCL–U) (14%). After 6 courses, 47% achieved a CR, with ORR of 81%. The median time to the max response was 3 mo.s. After a median follow-up of 36 months 5 pts had progression of disease (PD) and 5 relapsed. To date 9 pts are alive and 12 dead, 4 for PD and 8 for non-related causes. Median OS, EFS and PFS are 36, 17 and 19 mo.s respectively; OS, EFS and PFS rates at 66 mo.s are 33%, 16% and 37%, respectively. Among the remaining 5 PCTLC pts one with transformed MF in large cell lymphoma was treated with PLD in monotherapy and then intensified with bortezomib and dexamethasone obtaining a VGPR. Another pt with PTCL-U received PLD plus rituximab with a CR and the last 3 pts (MF, MF transformed and SS) underwent CBVD scheme obtaining a PR. Among the 5 PCBCLs a woman was affected by marginal zone lymphoma (PCMZL) and 4 men by large B-cell lymphoma (PCLBCL) (all in stage: T3,N0,M0). All pts showed a CR with PLD monotherapy, in a short period (median 2,5 mo.s), even when heavily pretreated. One of them experienced a relapse. One died for PD; to date the others are still in CR after 5, 52, 63 and 69 mo.s. PLD was well tolerated. In PCTLC adverse effects were observed in 6 pts (23%) and grade III–IV toxicity occurred in 2 (8%): capillary leakage syndrome and neutropenia. Nobody required dose modifications or delays. Grade II gastrointestinal toxicity was present in 2 pts. Only two showed a grade I PPE. In these cases we delayed the dose up to 1 week, obtaining a complete resolution, thus returning to the original interval. Even in the five pts affected by PCBCL, PLD was well tolerated and no one decreased or delayed the dose. A pt showed a reversibile grade I neurotoxicity; the hematological toxicity was mild with one case of grade III neutropenia treated with G-CSF. Nobody experienced PPE. PPE is frequently reported in pts with cancer treated with PLD: about 50% off all pts who received the currently approved dose of 50 mg/m2 every 4 weeks experienced PPE and about 20% grade III PPE. When PPE develops, PLD dose reduction, schedule modification, ultimately drug withdrawal are considered. In our pts affected by PCLs, PPE occurred rarely, with mild grade (2 case of grade I). It is probably due to low dosages of Peg-Doxo, compared to the commonly used in other solid neoplasms. Besides oral prophylaxis with pyridoxine 300 mg daily was administered from the beginning of the treatment until 1 month after its discontinuation in all pts, as suggested by some authors. This is the first report of PLD in PCBCL; as regarding the other few studies (Wollina, Cantonetti, Di Lorenzo, Lybaek, Quereux) concerning PLD in PCTLC the incidence of PPE resulted always low. In conclusion, it emerges that PLD shows a significantly high clinical activity and a good safety profile in PCLs. Our data seem to confirm the dose dependent toxicity effect of PLD, since three-four weekly schedule of PLD at the dose of 20 mg/m2 has less PPE compared to the classical schedule of 50 mg/m2 every 4 weeks. Some studies in ovarian and breast cancer demonstrated that PLD dose intensity reduction can prevent PPE. The administration of prophylactic pyridoxine seems to be useful in the reduction of the incidence and severity of PPE.

Background: Recruitment of neoplastic T-cells in skin is a critical step in the pathogenesis of Mycosis Fungoides (MF) lesions. The chemokine CCL27 attracts memory CCR10-positive T cells to the skin. Increased CCL27 serum levels and skin epidermal expression have been observed in MF patients compared to normal controls, but the interactions between neoplastic cells and the skin immune system needs to be further elucidated. Aims: We investigated whether CCL27 expression in MF is related to the density of dendritic cells (DC), CD8+ lymphocytes and CD4+ neoplastic lymphocytes; moreover, whether it influences the clinical response to therapy, it is modifiable by therapy itself and if the changes eventually observed can predict the frequency of recurrences and event-free survival. Material and methods: CCL27 epidermal immunohistochemical staining was performed in 52 early stage-MF patients, 34 M/18 F, treated by PUVA plus interferon a for 14 months, with a complete follow-up data. Specimens were obtained at diagnosis and at the end of treatment. Formalin-fixed/paraffin-embedded tissue sections were immunostained with anti-CCL27, CD1a, CD8, CD4 antibodies. CCL27 immunoreactivity was graded as + (faint/moderate staining, limited to epidermal basal layer, as in normal skin); ++ (faint/moderate staining in the suprabasal layers; strong staining up to the lower two-thirds of epidermis); +++ (strong staining of full-thickness epidermis). Density of CD1a-positive DC and CD8+ lymphocytes was graded as + (few/isolated cells), ++ (small, ≤5 cell clusters), +++ (larger, >5 cell clusters). Density of CD4+ lymphocytes was graded as + (perivascular infiltrate), ++ (discontinuous subepidermal band), +++ (continuous band). Statistical analysis was also performed (c2 test for tables of contingency; event-free survival curves (EFS) by Kaplan-Meier method). Results: At diagnosis, CCL27 expression was similar to normal skin in 16 cases and abnormal/suprabasal in 36, with 12 +++ cases. A normal/basal CCL27 expression tended to be correlated with a high DC density and with a low neoplastic infiltrate density (although P=NS). CCL27 at diagnosis was not correlated with clinical response (50 complete remission/CR, 2 partial remission). Treatment induced a significant CCL27 increase (suprabasal in 42 cases with 24 +++ cases; c2 test: P=0.004). Skin CCL27 expression at the end of treatment, but not at diagnosis, was related to recurrence and influenced EFS. During follow-up (median, 92.5 mo.s; range, 43–165), 33 patients relapsed (median EFS, 46 mo.s). A normal/basal CCL27 expression at the end of treatment, was correlated with a lower incidence of disease recurrence (3/9 compared to 30/41 with suprabasal expression; c2 test: P=0.022) and a longer median EFS (111 mo.s vs 39 mo.s with suprabasal expression; log rank test: P=0.031). Conclusions: Increased CCL27 expression in early-stage MF lesions might be related to a balance between neoplastic cells and immunomodulant dendritic cells. CR induction in almost all patients by treatment is not correlated with a CCL27 reduction, but a normal CCL27 expression after treatment designates a subset of patients (about 20%) with a favourable behaviour. The mechanisms involved in the increased CCL27 expression after therapy in the remaining 80% patients, which have a higher probability to recur, need to be further investigated.

Patients with primary cutaneous lymphomas (PCLs) are treated with multiple therapeutic regimens, which may increase the risk of subsequent solid and haematological neoplasms. The aim of our study was to assess the incidence of other malignancies in our series of PCLs. From March 1994 to January 2007, 272 patients with PCLs (179 M, 93 F, median age 65 yr, range 14–88) were referred to our center for staging, treatment and follow-up. The clinical charts were reviewed to detect the incidence of malignancies occurred before or after the diagnosis of PCL or concomitantly. The series was composed by 228 patients (150 M, 78 F, median age 66 yrs) with T-cell lymphomas (202 Mycosis Fungoides/MF, 10 Sézary Syndrome/SS, 9 CD30+ PCL, 7 non MF/non CD30+ T cell PCL); 43 patients (28 M, 15 F, median age 60 yrs) with B-cell lymphomas (25 Follicular/FL, 14 marginal/MZL, 3 Leg-type, 1 Lymphoblastic) and one patient with CD4+/CD56+ hematodermic neoplasm. Chemotherapy was administered to 48 patients. During follow-up 12 patients died for the disease and 24 for other causes. A second tumor was observed in 41 patients (15%): 6 of them experienced more than one neoplasms: overall we observed 48 malignancies, 38 solid and 10 haematological. The other neoplasms appeared similarly before (20) and after (21) the diagnosis of PCL; in 7 cases they were diagnosed simultaneously. Solid tumours (17 preceding, 4 concurrent, 17 subsequent) were diagnosed in: skin (11), colon (5), lung (4), breast (3), CNS (3), bladder (2), liver (2), kidney (2), uterus (2), testis (1), prostate (1), stomach (1), thyroid (1). The haematological malignancies (3 preceding, 3 concurrent, 4 subsequent) were: B-cell lymphomas (4), acute myeloid leukemias (3), plasmocytoma (1), T-cell lymphoma (1), Hodgkin’s lymphoma (1). Among the six patients with more than one adjunctive neoplasms one patient had lung and kidney carcinoma preceding PCL; two patients a preceding carcinoma (skin and bladder, respectively) and subsequently a lung carcinoma; other two patients showed both a preceding and a concurrent neoplasm (skin and colon carcinoma, B-cell lymphoma and skin carcinoma, respectively). Finally a patient had a preceding skin carcinoma, a concurrent nodal Hodgkin’s lymphoma and a subsequent nodal B-cell lymphoma. So we have reported 48 other neoplasms in 41 patients within 272 PCLs (15%). The occurrence of the other malignancy was not related to the B/T phenotype of PCLs, as it was observed in 35/228 (15.4%) T-cell lymphomas (32 MF, 2 SS, 1 non MF/non CD30+ T cell lymphoma) and in 6/43 (14%) B-cell lymphomas (3 FL, 3 MZL; χ2 test: P=0.88). The interval of occurrence was longer for tumors preceding (median 60 mo.s, range 8–180) than for tumors following PCL (median 45, range 6–122). The administration of chemotherapy for PCL was not associated with an increased incidence of second neoplasm(χ2 test, P=0.77). Multicentric studies might help in elucidating the role of genetic and immunitary factors in the pathogenesis of multiple neoplasms in patients with PCLs.

Pubblicazione di due dipinti inediti di Francesco de Mura nella sede del Consolato d'Italia a New York, e un contributo sugli indirizzi strategici e operativi della tutela dei beni artistici in consegna alle sedi diplomatiche italiane all'estero.

Il saggio ricostruisce il contesto storico di un dipinto famoso ai suoi tempi, che è rimasto occultato per circa centocinquanta anni e che probabilmente costò al suo autore, Luigi Rocco, la sua stessa carriera artistica ufficiale. Il dipinto era dedicato al ritrovamento del corpo dell'ammiraglio Caracciolo, personaggio di primo piano della Repubblica napoletana del 1799, considerato certamente un personaggio scomodo per i Borbone sia al tempo di Ferdinando IV, ma anche successivamente all'epoca dei moti del '48, quando l'esibizione di quel dipinto avrebbe potuto rinfocolare le ribellioni popolari dei moti appena sedati. Il saggio offre anche l'occasione di ricostruire il percorso di questo artista minore, ma interessante, dell'arte napoletana della prima metà del XIX secolo, precisandone su base documentaria i dati anagrafici fin qui tramandati in modo errato.