Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials.

Background: Patients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall survival (OS) stratified by progression-free survival (PFS) at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration. Patients and methods: PFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient's age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs). Results: A total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18-92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8-8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0-34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09-1.37). The observed OS versus expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively. Conclusion: Patients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24.

The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL).

BACKGROUND: [18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. PATIENTS AND METHODS: In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. RESULTS: A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. CONCLUSIONS: In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.

Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi.

BACKGROUND: Tumor regression after antiviral therapy (AT) is in favor of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL). PATIENTS AND METHODS: We carried out a cohort study of 704 consecutive HIV-negative, HCV-positive patients with indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the Fondazione Italiana Linfomi; 134 patients were managed with AT for lymphoma control. RESULTS: For entire cohort, 5-year overall survival (OS) was 78% [95% confidence interval (CI): 74%-82%] and 5-year progression-free survival (PFS) was 48% (95% CI: 44%-53%). In multivariate analysis, the use of AT during the patients' life had positive impact on OS. Forty-four of the 100 patients treated with first-line AT achieved a complete remission (CR) and 33 a partial response (PR). HCV-RNA clearance was achieved in 80 patients and was related to lymphoma response. At a median follow-up of 3.6 years, 5-year PFS was 63% (95% CI: 50%-73%). CR + PR rate was 85% with AT as second-line treatment. CONCLUSION: AT produces HCV-RNA clearance and consequent tumor regression in most patients with HCV-related indolent NHL. AT used at any time is associated with improved OS. Consequently, AT can be considered an option for patients with indolent lymphomas who do not need immediate cytoreductive treatment.

The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi.

BACKGROUND: The role of [¹8F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool.

Long term results of a randomized study performed by Intergruppo Italiano Linfomi comparing Mini-CEOP vs P-VEBEC in elderly patients with diffuse large B-cell lymphoma.

The Intergruppo Italiano Linfomi started, in 1996, a randomized trial for the initial treatment of elderly patients (older than 65 years) with Diffuse Large B-Cell Lymphoma (B-DLCL) comparing 6 courses of Mini-CEOP vs 8 weeks of P-VEBEC chemotherapy. Study objectives were survival, response and Quality of Life (QoL). Two hundred and thirty-two patients were evaluable for final analysis. Complete Response (CR) and Overall Response Rates (ORR) were 54% vs 66% (p = 0.107) and 90% vs 78% (p = 0.021) for P-VEBEC and Mini-CEOP, respectively. With a median follow-up of 72 months, the 5-year Overall Survival (OS), Relapse Free Survival (RFS), and Failure Free Survival (FFS) were 32%, 52%, and 21%, respectively. Subjects achieving a CR showed improvement of QoL regardless of treatment arm. Both Mini-CEOP and P-VEBEC determined a similar outcome for elderly patients with B-DLCL, with a third of patients alive after more than 6 years of follow-up. Both regimens can be considered equally for combination treatment with anti-CD20 monoclonal antibody.

The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL).

GISL recently conducted an exhaustive survey of 1078 patients with Hodgkin's Lymphoma (HL) enrolled between 1988 and 2002 in different prospective trials. Treatment failure was observed in 82 out of 1078 patients; of these 82 patients with refractory HL, complete information was available for 72, who form the evaluable population of the present study. After the initial therapy failure, 51 patients were treated with conventional salvage chemotherapy (CC) (n = 24) or high-dose chemotherapy (HDC) (n = 27); 4-year overall survival (OS) was 81% in the HDC group versus 38% in the CC group (P = 0.019). The remaining 21 patients had rapidly progressive disease and died. After a median follow-up of 2.8 years, the projected OS for all 72 patients is 58 and 49% at 3 and 5 years, respectively. Age <45 years, the absence of systemic symptoms and a PS <1 predicted a significantly longer OS. Interestingly, the majority of patients with two or three negative prognostic factors did not receive potentially curative therapy. In conclusion, HDC seems to be a reasonable option for selected patients with refractory HL, although the majority of them did not receive a transplant. Finally, patients with a high-risk score had little chance of receiving potentially curative treatment.

Image-aided estimate of tumor burden in Hodgkin's disease: evidence of its primary prognostic importance.

PURPOSE: To explore a more direct method for evaluating tumor burden (TB) in Hodgkin's disease (HD) and to verify its prognostic importance. PATIENTS AND METHODS: The volume of TB at diagnosis was directly and retrospectively measured in 121 HD patients through images of the lesions recorded by computed tomographic (CT) scan of the thorax, abdomen, and pelvis for all deep sites of involvement and many superficial ones, and by ultrasonography (US) for the remaining superficial lesions. RESULTS: The TB, which was obtained from the sum of the volumes of all the lesions measured on CT scans and US and normalized to body-surface area (relative TB [rTB]), showed a median value of 102.6 cm(3)/m(2) (range, 2.2 to 582.8). At multivariate analysis for prognostic value, rTB was the parameter that statistically correlated best with time to treatment failure (P = 2.2 x 10(-6)), followed by erythrocyte sedimentation rate (ESR) (P =.0003), and serum fibrinogen (P =.0112). The prognostic discrimination allowed by rTB alone proved to be clearly superior to that obtained with the score of the International Prognostic Factor Project. The rTB was found to be correlated with many clinical staging parameters (bulky disease, number of involved lymph node regions, serum lactate dehydrogenase, ESR, hemoglobin, Karnofsky index), but its predictability from these variables was low (R(2) =.668). CONCLUSION: Relative TB is emerging as a strong prognostic factor in HD, more powerful than and largely independent of those hitherto known and used. Further studies are needed to confirm these results and exploit their clinical value, particularly the relationship among rTB, drug doses, and response.

Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis.

We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽ 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients.

Heavy metals: sources and environmental presence.

The Istituto Superiore di Sanità has for many years been involved in the problem of environmental pollution caused by heavy metals. A brief review of the sources of this pollution is first presented which also includes the presence in nature of some heavy metals which are among the most dangerous. Data gathered by the authors is then presented from sampling of the emissions of urban solid waste (USW) incinerators and from environmental monitoring programs in different areas in Italy according to four categories: urban, industrial, rural and mixed.

The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL).

BACKGROUND: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. METHODS: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. RESULTS: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. CONCLUSIONS: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS--at least within the limits clinically attainable without stem cell rescue--does not improve results.

Analytical procedures to detect 2,3,7,8-TCDD at Seveso after the industrial accident of July 10, 1976.

The analytical procedures used at Seveso (Milan, Italy) for the determination of 2,3,7,8-TCDD, and some isomers, in biological and environmental samples are reviewed in this paper. During the emergency period, up until the first 10 days of August, the extracts, mostly from soil or vegetation samples, were evaporated to dryness and then mixed with less than or equal to 10-ml solvent. Of these solutions, aliquots up to 10 microliter were injected into a low-resolution gas chromatograph (GC) combined with a low-resolution mass spectrometer (MS). Analytical sensitivity for vegetation and soil was less than 10 ppb and approximately 100 ppt, respectively--sufficient for the early mapping of the most heavily contaminated territory. After the emergency period, the greatest improvement in environmental sample analysis was the introduction of cleanup procedure which greatly reduced the presence of unwanted material in samples. Cleanup was followed by the complete removal of the solvent. Dry samples could be taken up with rather small volumes (greater than or equal to 0.1 ml) of solvent, of which an aliquot was used for GC-MS analysis. The instrumental setup was kept as above. For animal samples, extraction entailed preliminary alkaline digestion followed by a number of cleanup steps. The final dry sample was taken to desired volume by adding solvent (greater than or equal to 0.1 ml), of which a few microliters were injected in GC-MS apparatuses. Detection thresholds improved markedly and were less than 10 ppt for agricultural soil and sediment, less than or equal to 0.05 ppt for water, in the range of 60 to 200 ppt for air dust, less than 10 ng/m2 and 10 ppt for wipe and scrape tests, respectively, less than 50 ppt for vegetation, and 250 ppt for biological substrata. Major later improvements in TCDD assay were the use of high-resolution gas chromatography (hrGC-MS), in some cases combined with high-resolution mass spectrometry (hrGC-hrMS). This provided greater specificity, sometimes accompanied by a very marked increase in detection sensitivity.

Gas-liquid-chromatography of trimethylsilyl derivatives from whole cell methanolysates of Leptospira : preliminary evaluation of its applicability to the taxonomy of the genus.

Gas-liquid-chromatography of trimethylsilyl derivatives from whole cell methanolysates was investigated as a supplmentary means for taxonomical classification within the genus Leptospira. Reproducibility of this technique was assessed through the peak height variations occurring in chromatograms of strain Patoc 1, serotype patoc, when samples either from the same or different batches of culture were used. From each chromatogram seven peaks were selected. Their heights were measured and calculated as percent values of the seven peaks total height. The values of relative standard deviation reported show that the reproducibility of this technique lies within the usual limits of biological methods. Four out of seven different serotypes analyzed gave elution patterns dissimilar enough to allow a clear distinction among them by the simple visual examination. Differentiation of the other three had to be done comparing the relative heights of the seven selected peaks. One not yet classified new strain was submitted to this technique; results seemed to confirm available serological information about it. Data reported encourage further research in order to evaluate the potential of GLC as an useful aid in the taxonomy of genus Leptospira.

Polycyclic aromatic hydrocarbons in olive oils on the Italian market.

The six olive oils and seven virgin olive oils which are most consumed in Italy were analysed for 28 polycyclic aromatic hydrocarbons (PAHs). The aim was to evaluate whether a carcinogenic hazard for the general population can derive from the dietary intake of this food, which is consumed particularly highly in the Mediterranean area. The analytical method involved extraction by liquid-liquid partition, filtration on silica gel, clean-up by thin-layer chromatography on silica gel, and analysis by high-resolution gas chromatography with a flame ionization detector. The 3- and 4-ring PAHs which are most abundant in the environment were found in all samples, at individual levels up to ca. 40 micrograms/kg (for phenanthrene); no important difference was observed between olive oils and virgin olive oils. PAHs which are most suspected of being carcinogenic for humans were not detected (limit of detection, ca. 3 micrograms/kg). The average yearly intake of the detected PAHs through this food was estimated at ca. 0.56 mg per capita.

Erythema nodosum and Hodgkin's disease.

A 27-year-old woman with a 5-month history of recurrent erythema nodosum was found to have Hodgkin's disease. A temporal relationship between the two disorders suggested a causative role of the lymphoma. A review of the literature yielded 15 cases of this association, suggesting that the diagnosis of Hodgkin's disease should be considered in patients with unexplained erythema nodosum.

[Ovarian hyperstimulation syndrome with bilateral hydrothorax and ascites]. / Sindrome da iperstimolazione ovarica con idrotorace bilaterale ed ascite.

Ovarian hyperstimulation syndrome (OHSS) is an unusual complication of ovarian stimulation with exogenous gonadotrophins. We describe a case of severe OHSS with bilateral hydrothorax and ascites. We discuss the different pathogenetic hypothesis and the differential diagnostic possibility.

Autoimmune thyroid dysfunctions in hematologic malignancies treated with alpha-interferon.

The widespread use of alpha-interferon (IFN-alpha) therapy in different diseases draws attention to its side effects, such as autoimmune-related diseases, especially thyroid autoimmune dysfunctions. Data about hepatitis and nonhematologic neoplasia are available, while data about hematologic malignancies are fragmentary. We studied the incidence of autoimmune-related disturbances and thyroid dysfunctions in 54 consecutive patients suffering from hematologic malignancies, treated with recombinant human IFN-alpha for a mean time of 15.9 +/- 8.9 months. Our results minimize the incidence of autoimmune dysfunctions in hematologic malignancies as side effects of IFN-alpha therapy. We registered the appearance of autoantibodies in only 3 females (5% of total): 2 patients (1 affected with essential thrombocythemia and one with multiple myeloma) presented antithyroglobulin antibodies with no clinical symptoms; 1 patient, affected with essential thrombocythemia, developed antinuclear antibodies with arthralgia and myalgia. ARA criteria for systemic lupus erythematosus were not fulfilled but the therapy had to be interrupted. No patient developed thyroid dysfunction. In patients with hematologic malignancies, the dosage and the duration of IFN-alpha treatment do not seem to influence the appearance of autoantibodies, while female sex appears to be a risk factor.