Anna Maria Nosari

Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

PURPOSE To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression. PATIENTS AND METHODS A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution. RESULTS Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenströms macroglobulinemia (n = 12), non-Hodgkins lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P <.0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression. CONCLUSION Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.

Outcome of hyperleukocytic adult acute myeloid leukaemia: A single-center retrospective study and review of literature

Hyperleukocytic acute myeloid leukaemia is considered to have a poor prognosis due to high early death rate secondary to leukostasis. Supportive treatments do not seem to have reduced early exitus in this subset of patients. Prognostic impact of hyperleukocytosis on outcome has been the object of few studies. Clinical characteristics and outcome of 45 consecutive adult patients with newly diagnosed acute myeloid leukaemia presenting to our institution with a white cell count (WBC) above 100 x 10(9)L(-1) were reviewed. The outcome of this subset of patients was compared with 200 patients with a leukocyte count lower than 100 x 10(9)L(-1) similarly treated in the same period. Eight hyperleukocytic patients (17%) died of intracranial haemorrhage or pulmonary failure due to leukostasis within the first 7 days of treatment. A significant association was found between complete response (CR) and absence of hyperleukocytosis, but if early deaths were removed from analysis the difference was no longer significant. Hyperleukocytosis also significantly reduces the overall survival (OS) but does not significantly influence the disease-free survival (DFS). We reviewed in literature studies in which the outcome of series of at least 10 patients with hyperleukocytosis were compared with that of patients with a leukocyte count lower than 100 x 10(9)L(-1). Our data were consistent with those of the literature regarding the rate of early mortality and causes of death. In most of the reviewed series hyperleukocytosis does not seem to influence the outcome of patients. Avoiding early death seems to be an important step in this subset of patients. New data about pathophysiology of leukostasis are needed.

Utility of computed tomography (CT) and of fine needle aspiration biopsy (FNAB) in early diagnosis of fungal pulmonary infections : study of infections from filamentous fungi in haematologically immunodeficient patients = Utilità della tomografia computerizzata (TC) e dell'agobiopsia (FNAB) nella diagnosi precoce delle flogosi fungine polmonari : studio delle infezioni da funghi filamentosi in pazienti ematologici immunodepressi

Purpose.The purpose of this study was to evaluate the sensitivity of percutaneous computed tomography (CT)-guided lung biopsy in the early diagnosis of fungal pulmonary infections.Materials and methods.Between 1997 and 2003, 18 haematologically immunodeficient patients with suspected filamentous fungi infection and negative bronchoalveolar lavage (BAL) underwent percutaneous pulmonary biopsy to diagnose the nature of the infection. In all cases, infection developed during the post-chemotherapy bone marrow aplasia period.Results.Thirteen out of 18 patients had histologic findings positive for fungal infection: 8 Aspergillus and 5 Mucor. In 3 cases, biopsy was not specific, and in one case, the tissue sample was inadequate for a diagnosis; however, clinical course and response to drugs were compatible with fungal infection. In one patient, biopsy was positive for bronchoalveolar carcinoma. The sensitivity of percutaneous CT-guided biopsy was 80% and its positive predictive value was 100%. We only had one pneumothorax as a complication.Conclusions.Percutaneous CT-guided lung biopsy is an easy, safe and reliable procedure to obtain diagnostic material. Histological discrimination between Aspergillus and Mucor is important in order to plan the correct therapeutic protocols, as Mucor is usually resistant to azoles.

MULTIPLE MYELOMA ASSOCIATED TO HIV INFECTION : REPORT OF TWO PATIENTS

A 52-yr-old heterosexual man, affected by cerebral stroke with transitory left syndrome. Neurologic symptoms disappeared rapidly, but the patient had to be transfused due to associated stress gastric ulcers and melena. A few months later, tests revealed a moderate thrombocytopenia (50 x 109/1) and the patient was found to be HIV-positive, probably due to blood transfusions. He was observed during the following 5 yr: immunodeficiency worsened despite Zidovudine treatment. He had Herpes zoster, Cryptococcus and Candida albicans infections, with a serious decrease of CD4 levels and positivity of p24 antigenemia. Platelets increased during Zidovudine therapy. A monoclonal gammopathy (IgG/lambda) was found and evaluated as MGUS (bone marrow biopsy; plasma cells < 5 %). 2 years later the patient suffered a rapid worsening of clinical conditions: a relevant loss of weight ( 6 Kg), fever, astenia and neurologic symptoms (parestesias and atassic gait, with loss of memory) were observed. No significant skeletal pain was present. On physical examination a generalized lymphadenopathy was found. Cerebral CAT revealed a malacic area in the temporal region with other smaller “spots”. Hematologic tests showed a relevant monoclonal gammopathy IgG/ lambda (IgG 47.0 g/l; IgA 5.7 g/l; IgM 2.1 g/l); LDH was 932 U/1 and beta-2-microglobulin 5.70 mg/l; calcium was normal; anemia was also associated (Hb 8.5 g/dl). A bone marrow biopsy showed an increase of plasma cells (15%) with clusters and atypical binucleated forms. Slight proteinuria was present, but renal tests were normal. Bone scan showed a relevant ipercaptation of iliac bone; Rx scan confirmed a typical focal lysis. Multiple myeloma was diagnosed, stage I11 according to Durie and Salmon. Zidovudine was stopped but no other therapy was started due to severe immunodeficiency (CD4’ 0.021 x 109/1) and very poor general condition. The patient died soon thereafter due to associated infections and worsening of neurologic status. Autopsy was not performed.

DCEP chemotherapy followed by a single, fixed dose of pegylated filgrastim allows adequate stem cell mobilization in multiple myeloma patients

BACKGROUND: Pegylated filgrastim (PEG‐f), a long‐lasting granulocyte–colony‐stimulating factor, has been used in different hematologic conditions to shorten chemotherapy‐induced neutropenia and to mobilize peripheral blood stem cells. Data on mobilization efficacy in patients with multiple myeloma are, however, still limited.

Total serum tryptase: a predictive marker for KIT mutation in acute myeloid leukemia.

Human tryptase is a serine protease expressed in mast-cells. We previously observed that AML blast cells, cultured in vitro from a KIT D816Y patient, give rise to adherent cells with mast-cell like phenotype and tryptase was released in the serum-free medium. To correlate total serum tryptase (ts-try) levels with cytogenetic features and KIT mutational status, we analyzed serum samples from AML patients at diagnosis. In 70 out of 155 patients (45%) we detected elevated ts-try (>15 ng/mL), significantly linked to t(8;21) (P < .001) and inv(16) (P = .007). In patients that achieved complete remission the ts-try decreased to normal values. In 75 patients screened for KIT mutation, we found a clear relationship between elevated ts-try and mutated patients with t(8;21) (P < .001). In conclusion, we propose that checking for ts-try at diagnosis of AML may be a simple tool to select patients to be addressed to KIT mutation screening.

Prospective monocentric study of non-tunnelled central venous catheter-related complications in hematological patients

Indwelling central venous catheters (CVCs) are used in the management of hematologic patients. However, insertion and maintenance of CVCs are susceptible to complications. Study design and methods data concerning 388 consecutive catheterisations, performed in oncohematologic patients between April 2003 and December 2004, were prospectively collected. At insertion thrombocytopenia was present in 109 cases (28.1%) and neutropenia in 67 (17.3%). Hemorrhage after CVC insertion occurred in five thrombocytopenic patients (1.3%). The median duration of catheterisation was 18.8 days (range 1–89), longer in the 7-French CVCs utilised in leukemic patients (24.3 days) and shorter in 12-French CVCs (11 days), used for PBSC harvesting. Deep venous thrombosis was diagnosed in 13 cases (3.3%). Ninety-two catheterisations (12.6/1000 days-catheter) were complicated by infections: 19 local infections (4.8%) and 73 (18.8%) bacteraemias of which 45 (11.6%) were catheter-related, mainly due to Gram positive germs (32/45, 71.1%). The frequency of catheter-related bacteraemia was 7.2 events/1000 days-catheter. Thirteen CVCs were removed due to thrombosis, 15 due to infections, 20 due to malfunction, the remaining 333 at patients discharge. At univariate analysis high-dose chemotherapy (p = 0.013), 7-Fr lumen (p = 0.023), acute myeloid leukemia (AML) (p = 0.001), duration of neutropenia >10 days and length of catheterisation were significantly correlated to infection. Multivariate analysis confirmed the duration of catheterisation, AML and high-dose chemotherapy as risk factors. Even though hematological in-patients are at increased risk for bleeding and infections, non-tunnelled CVCs offer a safe venous access also in patients affected by severe thrombocytopenia and prolonged neutropenia.

Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience

Abstract Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.

A hematology consensus agreement on antifungal strategies for neutropenic patients with hematological malignancies and stem cell transplant recipients: Antifungal therapy in neutropenic patients

In the attempt to establish key therapy definitions and provide shared approaches to invasive fungal diseases in neutropenic patients, trials of empiric, preeemptive and targeted antifungal therapy (EAT, PAT and TAT) were reviewed, and a Consensus Development Conference Project was convened. The Expert‐Panel concurred that all antifungal treatments, including EAT, should always follow an adequate diagnostic strategy and that the standard definition of PAT may be misleading: being PAT guided by the results of a diagnostic work‐up, it should better be termed diagnostic‐driven antifungal therapy (DDAT). The Expert‐Panel agreed that radiological findings alone are insufficient for the choice of a TAT and that the identification of the etiologic pathogen is needed. The Consensus Agreement proceeded identifying which clinical and microbiological findings were sufficient to start a DDAT and which were not. Finally, an algorithm to rationalize the choice of antifungal drugs on the basis of clinical manifestations, antifungal prophylaxis, instrumental and laboratory findings was drawn up. Copyright

Radiofrequency ablation of hepatic Hodgkin lymphoma

Image-guided percutaneous radiofrequency ablation (RFA) is widely accepted in the local treatment of primary and secondary hepatic tumors [1,2]; valid results of this procedure, together with low side effects, encouraged its use in other settings [3]. During RFA a needle electrode is placed under image-guide into the tumor and delivers an alternating current which causes localised ionic agitation, frictional heating and finally tissue destruction [4]. RFA has been described in a few cases of refractory non-Hodgkin lymphoma (NHL) of different subtypes with interesting results [5,6]. No data are available regarding this modality of treatment in Hodgkin lymphoma (HL). In this report, we describe RFA of a residual hepatic localisation of HL in a young female patient after multiple lines of systemic chemotherapy. In October 2003, a 33-year-old woman presented with enlarged cervical lymphnodes, fever, fatigue and abdominal pain. Classical HL, nodular sclerosis subtype, was diagnosed by cervical lymphnode biopsy. Epstein-Barr assay on bioptic sample was negative. CT scan showed multiple cervical, thoracic and abdominal non bulky lymphadenophaties and a lesion in the left liver with a 23617 mm size suggestive for lymphoma localisation. Bone marrow biopsy was negative for lymphoma. Hepatitis C and B virus antibodies were absent. Clinical stage IVB was confirmed and patient started ABVD chemotherapy. After four courses, restaging by CT showed a complete regression of nodal disease whereas the hepatic lesion was unmodified. After the sixth cycle, CT was negative for nodal localisation, whereas the hepatic lesion was still present even if with a minimal size reduction (maximum diameter of 20 mm). PET scan showed a solitary metabolically active lesion in the left liver. Patient underwent two additional ABVD courses. At the end of chemotherapy, restaging showed persistence of the hepatic lesion, again with a further minimal size reduction (maximum diameter of 16 mm). Two DHAP courses were administered, and PBSC harvest after first cycle was successful (CD34þ cells 20.3610/ kg). At restaging 4 weeks after the second DHAP course, the hepatic lesion further reduced but was still appreciable with a maximum diameter of 14 mm (Figure 1, PET1-CT1), being the only residual site of disease. No biopsy was performed, because shrinkage on treatment and PET positivity were considered indirect evidence of residual hepatic localisation of HL. In January 2005, patient underwent percutaneous ultrasound-guided RFA of the hepatic localisation. Before RFA blood count, liver function (including serum alkaline phospathase) and coagulation profile were normal. The intervention was performed in the angiographic suite in local anaesthesia with mild sedation (midazolam 2 mg IV). A multihooks needle (Leveen Radiotherapeutics) with a 3 cm diameter was deployed into the nodule using ultrasound guidance. A progressive amount of energy was delivered (from 20 to 120 W) avoiding the charring of the