Development of ultralow-background cryogenic calorimeters for the measurement of surface α contamination.

Next-generation experiments searching for rare events must satisfy increasingly stringent requirements on the bulk and surface radioactive contamination of their active and structural materials. The measurement of surface contamination is particularly challenging, as no existing technology is capable of separately measuring parts of the 232Th and 238U decay chains that are commonly found to be out of secular equilibrium. We will present the results obtained with a detector prototype consisting of 8 silicon wafers of 150 mm diameter instrumented as bolometers and operated in a low-background dilution refrigerator at the Gran Sasso Underground Laboratory of INFN, Italy. The prototype was characterized by a baseline energy resolution of few keV and a background <100 nBq/cm2 in the full range of  α energies, obtained with simple procedures for cleaning of all employed materials and no specific measures to prevent recontamination. Such performance, together with the modularity of the detector design, demonstrate the possibility to realize an alpha detector capable of separately measuring all alpha emitters of the 232Th and 238U chains, possibly reaching a sensitivity of few nBq/cm2.

Erratum: Measurement of the 2νßß Decay Half-Life of

This corrects the article DOI: 10.1103/PhysRevLett.126.171801.

New Direct Limit on Neutrinoless Double Beta Decay Half-Life of

The Cryogenic Underground Observatory for Rare Events (CUORE) at Laboratori Nazionali del Gran Sasso of INFN in Italy is an experiment searching for neutrinoless double beta (0νßß) decay. Its main goal is to investigate this decay in ^{130}Te, but its ton-scale mass and low background make CUORE sensitive to other rare processes as well. In this Letter, we present our first results on the search for 0νßß decay of ^{128}Te, the Te isotope with the second highest natural isotopic abundance. We find no evidence for this decay, and using a Bayesian analysis we set a lower limit on the ^{128}Te 0νßß decay half-life of T_{1/2}>3.6×10^{24} yr (90% CI). This represents the most stringent limit on the half-life of this isotope, improving by over a factor of 30 the previous direct search results, and exceeding those from geochemical experiments for the first time.

Measurement of the 2νßß Decay Half-Life of

We measured two-neutrino double beta decay of ^{130}Te using an exposure of 300.7 kg yr accumulated with the CUORE detector. Using a Bayesian analysis to fit simulated spectra to experimental data, it was possible to disentangle all the major background sources and precisely measure the two-neutrino contribution. The half-life is in agreement with past measurements with a strongly reduced uncertainty: T_{1/2}^{2ν}=7.71_{-0.06}^{+0.08}(stat)_{-0.15}^{+0.12}(syst)×10^{20} yr. This measurement is the most precise determination of the ^{130}Te 2νßß decay half-life to date.

[The use of RCGO triggers in the obstetric - gynecological procedures: the impact on the reduction of adeverse events. The experience of the Lombardia Region]. / L'utilizzo dei RCOG trigger in area ostetrica - ginecologica e la riduzione degli eventi avversi. L'esperienza della regione Lombardia.

The last few weeks of pregnancy are critical to a baby's health because important organs, including the brain and lungs, are not completely developed until the end of pregnancy. The adverse events during labor and childbirth can have very serious physical, psychological and financial consequences for the child, the family, health professionals and the whole community. These events can be reduced through interventions aimed at improving the safety and quality of care, based on evidence-based knowledge, guidelines and practices that must be widely and effectively applied. This work reports the experience of the Lombardy Region on improvement actions in the obstetric and gynecological procedures for the reduction of adverse events and sentinel events through the monitoring and management of the RCGS trigger tool.

Improved Limit on Neutrinoless Double-Beta Decay in

We report new results from the search for neutrinoless double-beta decay in ^{130} Te with the CUORE detector. This search benefits from a fourfold increase in exposure, lower trigger thresholds, and analysis improvements relative to our previous results. We observe a background of (1.38±0.07)×10^{-2} counts/(keV kg yr)) in the 0νßß decay region of interest and, with a total exposure of 372.5 kg yr, we attain a median exclusion sensitivity of 1.7×10^{25} yr. We find no evidence for 0νßß decay and set a 90% credibility interval Bayesian lower limit of 3.2×10^{25} yr on the ^{130} Te half-life for this process. In the hypothesis that 0νßß decay is mediated by light Majorana neutrinos, this results in an upper limit on the effective Majorana mass of 75-350 meV, depending on the nuclear matrix elements used.

Search for Neutrinoless Double-Beta Decay of (130)Te with CUORE-0.

We report the results of a search for neutrinoless double-beta decay in a 9.8 kg yr exposure of (130)Te using a bolometric detector array, CUORE-0. The characteristic detector energy resolution and background level in the region of interest are 5.1±0.3 keV FWHM and 0.058±0.004(stat)±0.002(syst)counts/(keV kg yr), respectively. The median 90% C.L. lower-limit half-life sensitivity of the experiment is 2.9×10(24) yr and surpasses the sensitivity of previous searches. We find no evidence for neutrinoless double-beta decay of (130)Te and place a Bayesian lower bound on the decay half-life, T(1/2)(0ν)>2.7×10(24) yr at 90% C.L. Combining CUORE-0 data with the 19.75 kg yr exposure of (130)Te from the Cuoricino experiment we obtain T(1/2)(0ν)>4.0×10(24) yr at 90% C.L. (Bayesian), the most stringent limit to date on this half-life. Using a range of nuclear matrix element estimates we interpret this as a limit on the effective Majorana neutrino mass, m(ßß)<270-760 meV.

Reactive perivascular T-cell infiltrate predicts survival in primary central nervous system B-cell lymphomas.

Well-established histopathological prognostic factors are lacking in primary central nervous system (CNS) lymphomas (PCNSL). The present study investigated the presence and prognostic role of tumour necrosis (TN) and reactive perivascular T-cell infiltrate (RPVI), defined as a rim of small reactive T-lymphocytes occurring alone or located between the vascular wall and large neoplastic cells, in tumour samples from 100 immunocompetent patients with PCNSL. World Health Organization histotypes of the patients were: 96 diffuse large B-cell lymphomas, two Burkitt-like lymphomas, one anaplastic large T-cell lymphoma and one unclassified B-cell lymphoma. TN was observed in 24 (24%) cases and RPVI in 26 (36%) of 73 assessable cases. Patients with RPVI-positive lesions exhibited a significantly better overall survival (OS) than patients with RPVI-negative lymphoma, particularly among patients treated with high-dose methotrexate-based chemotherapy (3-year OS: 59 +/- 14% vs. 42 +/- 9%, P = 0.02). By contrast, the presence of TN did not demonstrate prognostic significance. Multivariate analysis confirmed an independent association between RPVI and survival. In conclusion, the presence of RPVI is independently associated with survival in PCNSL. This parameter can be easily and routinely assessed at diagnosis on histopathological specimens.

MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas.

The authors assessed MATILDE chemotherapy followed by response-tailored radiation therapy in 41 patients aged 70 years or younger with primary CNS lymphoma in a Phase II trial. With response rates of 76% after MATILDE and 83% after chemotherapy with or without radiation therapy, this was an active strategy, particularly in low- to intermediate-risk patients (International Extranodal Lymphoma Study Group [IELSG] score). Myelosuppression was the dose-limiting toxicity, with 9.5% of lethal complications. After a median follow-up of 49 months, a plateau in the survival curve (5-year overall survival: 41 +/- 7%) was obtained.

Raltitrexed-eloxatin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer.

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status (PS) and are candidate for further treatment. Patients >18 years, PS >or=50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-containing chemotherapy, and progression-free survival (PFS) <12 months received a combination of raltitrexed (3 mg m(-2)) and oxaliplatin (130 mg m(-2)) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade >2 toxicity was: neutropenia in five patients (12%), thrombocytopenia, liver and vomiting in three (7%), fatigue in two (5%). In total, 10 patients (24%) yielded a partial response, 11 a stable disease. Progression-free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS >6 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed-oxaliplatin regimen may constitute a treatment opportunity in gemcitabine-resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment.

Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma.

BACKGROUND: Optimal therapeutic management of intravascular lymphoma (IVL) lacks precise guidelines. PATIENTS AND METHODS: The clinico-pathological features of 38 HIV-negative patients with IVL were reviewed to define efficacy of chemotherapy in these malignancies. Clinical characteristics of 22 patients treated with chemotherapy and of 16 untreated patients were compared in order to understand better the impact and causes of potential patient selection. RESULTS: Median age was 70 years (range 34-90), with a male/female ratio of 0.9; 23 (61%) patients had Eastern Cooperative Oncology Group performance status (ECOG-PS) > 1; 21 (55%) had systemic symptoms. Cutaneous lesions and anemia were significantly more common among patients treated with chemotherapy; central nervous system (CNS) and renal involvement were significantly more common among untreated patients. Chemotherapy was associated with a response rate of 59% and a 3-year overall survival of 33 +/- 11%. Five of six patients with CNS involvement received chemotherapy: four of them died early; only one patient, treated with adriamycin, cyclophosphamide, vincristine, methotrexate, bleomycin and prednisolone (MACOP-B) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), was alive at 19 months. High-dose chemotherapy supported by ASCT was indicated at diagnosis in another patient (43 years of age, stage I), who was alive at 71 months, and at relapse after cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in two patients who died early after transplantation. PS < or = 1, disease limited to the skin, stage I, and use of chemotherapy were independently associated with better outcome. CONCLUSIONS: Anthracycline-based chemotherapy is the standard treatment for IVL. However, survival is disappointing, with a relevant impact of diagnostic delay and lethal complications. More intensive combinations, containing drugs with higher CNS bioavailability, are needed in cases with brain involvement, and the role of high-dose chemotherapy supported by ASCT should be further investigated in younger patients with unfavorable features.

Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas.

Although high-dose methotrexate (HD-MTX) is the most effective drug against primary CNS lymphomas (PCNSL), outcome-determining variables related to its administration schedule have not been defined. The impact on toxicity and outcome of the area under the curve (AUC(MTX)), dose intensity (DI(MTX)) and infusion rate (IR(MTX)) of MTX and plasmatic creatinine clearance (CL(crea)) was investigated in a retrospective series of 45 PCNSL patients treated with three different HD-MTX-based combinations. Anticonvulsants were administered in 31 pts (69%). Age >60 years, anticonvulsant therapy, slow IR(MTX) (1100 micromol hl(-1) were independently associated with a better survival. Slow CL(crea) and high AUC(MTX) are favourable outcome-determining factors in PCNSL, while slow CL(crea) is significantly related to higher toxicity. AUC(MTX) significantly correlates with age, anticonvulsant therapy, IR(MTX), and DI(MTX). These findings, which seem to support the choice of an MTX dose >/=3 gm(-2) in a 4-6-h infusion, every 3-4 weeks, deserve to be assessed prospectively in future trials. MTX dose adjustments in patients with fast CL(crea) should be investigated.

Guidelines for the treatment of primary central nervous system lymphomas in immunocompetent patients.

The best therapeutic management in primary central nervous system lymphomas remains to be defined because of current knowledge on these malignancies results from small retrospective series with a short follow-up, a limited number of prospective studies with some methodological pitfalls and a single published randomised trial. This review focuses on the current therapeutic approaches, most commonly used drugs, role of intrathecal chemotherapy, and indications for consolidation radiotherapy, providing recommendations for ordinary clinical practice. Some important therapeutic issues, such as the management of meningeal and intraocular lymphomas, as well as the relevance of salvage therapy as a playground for evaluation of new drugs are also analysed. Finally, the main open questions, as well as current and expected investigation trends are discussed.

Immunoreactivity for p27(KIP1) and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin's lymphoma.

Our aim was to assess the prognostic implications of the expression of p27(KIP1) and cyclin E in gastric lymphoma. We investigated the prognostic value of the immunoreactivity of these molecules in 92 cases of primary gastric lymphoma: 34 LGMLs, 24 DLCLMLs and 34 DLCLs. p27 was positive in 88% of LGMLs, 71% of DLCLMLs and 32% of DLCLs (p = 0.004); cyclin E was positive in 9%, 33% and 59% of cases, respectively (p < 0.00001). p27/cyclin E immunoreactivity significantly correlated with histologic category, stage and LDH serum level. p27 immunoreactivity was significantly associated with better survival, whereas cyclin E reactivity was significantly related to worse outcome. Five-year CSS was 94% for patients with p27(+)/cyclin E(-) phenotype (n = 42), 79% for p27(+)/cyclin E(+) (n = 14) or p27(-)/cyclin E(-) (n = 16) phenotype and 60% for p27(-)/cyclin E(+) phenotype (n = 16) (p = 0.02). The prognostic role of p27/cyclin E expression was confirmed when analyzed separately within LGMLs and large-cell lymphomas. Immunoreactivity for p27 and cyclin E is an independent predictor of survival in PGLs that may be an adjunctive tool in identifying high-risk patients. It correlates with histologic category, stage and LDH serum level. p27(-)/cyclin E(+) phenotype is associated with worse survival, probably due to a synergistic effect of both cell-cycle defects. The predictive role of these molecules within each histologic group of PGLs deserves to be confirmed in larger series.

Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate.

PURPOSE: To evaluate the optimal dose of methotrexate (MTX) and the efficacy of other drugs, intrathecal chemotherapy (CHT), and radiotherapy (RT) in primary brain lymphomas. METHODS AND MATERIALS: Two hundred eighty-eight immunocompetent patients with histologically documented, previously untreated primary brain lymphomas, receiving CHT containing high-dose MTX (> or =1 g/m(2)) with or without RT were selected from 19 prospective series. The impact on survival of the MTX dose (<3 g/m(2) vs.> or =3 g/m(2)), the main drugs, intrathecal CHT, and combination CHT (mono-CHT vs. poly-CHT) was assessed, according to the intention-to-treat principle. The role of post-CHT irradiation (immediate vs. delayed RT) was evaluated in 119 patients with a complete response to CHT. The whole brain and tumor bed dose (<40 Gy vs. > or =40 Gy) was assessed in 70 irradiated complete responders. RESULTS: No difference in overall survival (OS) was detected between mono-CHT and combination CHT (p = 0.38). MTX > or =3 g/m(2) (p = 0.04), thiotepa (p = 0.03), and intrathecal CHT (p = 0.03) improved the OS, and nitrosoureas (p = 0.01) correlated with a worse survival. In multivariate analysis, limited to patients receiving MTX > or =3 g/m(2), only the addition of cytarabine improved the OS; nitrosoureas reduced MTX efficacy. Of the 119 complete responders, 70 received immediate RT. A RT dose of > or =40 Gy to the whole brain or tumor bed did not improve OS. The 3-year OS was similar between the immediate and delayed RT groups. In multivariate analysis, RT delay had no negative impact on survival. CONCLUSIONS: MTX > or =3 g/m(2) seems to improve survival in primary brain lymphoma patients. The efficacy of additional drugs, except for cytarabine, remains unproved. Randomized trials are needed to confirm that RT withdrawal yields no detrimental effect in complete responders.

Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients.

OBJECTIVES: To assess the feasibility and the activity, as well as the efficacy to treat meninges, of chemotherapy (CHT) containing high-dose methotrexate (HD-MTX) followed by radiation therapy (RT), without intrathecal CHT, in patients with primary central nervous system lymphoma. METHODS: Eligibility criteria were histologically proven diagnosis, disease limited to the CNS, age < or = 70, ECOG performance status < or = 3, HIV-negative and no prior treatment. Thirteen patients (1996-1999; median age 54 years) received two courses of vincristine 1.4 mg/m2 day 1, MTX 3 g/m2 days 3 and 10 and procarbazine 100 mg/m2 days 1-14 every 4 weeks. Patients who achieved a complete remission were referred to RT, those with progressive disease were excluded from further study; all the remaining patients received a third course of CHT followed by RT. RESULTS: Twelve patients responded to CHT (overall response rate = 92%, complete response rate = 77%): 9 underwent consolidation RT, 3 did not. Two patients experienced severe acute toxicity; lethal pulmonary thromboembolism and transient renal failure. Five patients relapsed: 2 after CHT and 3 after RT. Relapse was local in all cases, with a case of concomitant hepatic involvement. No cases of ocular or meningeal relapse were observed. In contrast to high-dose cytarabine-containing CHT, salvage therapy with temozolomide produced good results. Two patients died of treatment-related neurotoxicity. Six patients are alive with a median follow-up of 17 months, and a 2-year overall survival (OS) of 61%. The median survival of the 9 patients who completed the planned treatment is 25+ months with a 2-year OS of 80%. CONCLUSIONS: HD-MTX, procarbazine and vincristine followed by RT, without intrathecal therapy, produce similar results with respect to other HD-MTX-containing regimens. These results seem to suggest that adequate meningeal treatment is possible without intrathecal drug delivery, even in CSF-positive patients. Corroborating data from a larger series are, however, necessary. Temozolomide should be tested in relapsed patients in a phase II prospective trial.

Prognostic significance of the histopathologic recognition of low- and high-grade components in stage I-II B-cell gastric lymphomas.

The prognostic value of histopathologic features was assessed in 83 patients with stage I-II gastric B-cell lymphomas (PGL). The following histotypes were considered: low-grade mucosa-associated lymphoid tissue (MALT)-type lymphoma (LGML; n = 35), diffuse large B-cell lymphoma with areas of MALT-type lymphoma (DLCLML; n = 20) and diffuse large B-cell lymphoma without areas of MALT-type lymphoma (DLCL; n = 28). Low-grade (LG) and high-grade (HG) components, lymphoepithelial lesions (LEL), size of cells giving rise to LEL, and amount and growth pattern of large cells (LC) were analyzed. Five-year cause-specific survival (CSS) for patients with LGML, DLCLML, and DLCL were 94%, 84%, and 64%, respectively (p = 0.05). LG component or LEL were associated with a significantly longer 5-year CSS, whereas the presence of an HG component, defined as clustered LC greater than 10% of neoplastic population, was significantly related to a shorter survival. Lymphomas with LC disposed in clusters were associated with a worse survival in comparison with cases with scattered LC. The presence of scattered LC 5%-10% appeared irrelevant in LGML. When analysis was limited to DLCLML/ DLCL patients, the presence of LG component or LEL was associated with a significantly longer 5-year CSS, whereas the existence of LEL formed by LC (HG LEL) did not modify survival. Multivariate analysis, adjusted by the main prognostic factors, confirmed the independent and significant association between histopathologic categorization and survival. Age, stage, lactate dehydrogenase (LDH) ratio, thrombocytopenia, and use of chemotherapy had independent prognostic value. In conclusion, histopathologic categorization is an independent prognosticator in PGL. The formation of compact clusters by LC, rather than their amount, is a true prognostic variable. The presence of scattered LC 5%-10% appears irrelevant in LGML. LG component and LEL are favorable predictors in HG lymphomas, helping to identify two subsets of DLCL with different prognosis.

Phase II study of paclitaxel and epirubicin as first-line treatment in patients with metastatic nonsmall cell lung carcinoma.

BACKGROUND: The combination of paclitaxel and epirubicin has shown a favorable interaction in patients with advanced breast carcinoma. Therefore the efficacy and toxicity of this regimen was evaluated in a Phase II study of patients with metastatic nonsmall cell lung carcinoma (NSCLC). METHODS: Thirty-two chemotherapy-naive patients with AJCC Stage IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1 were entered into the study. Patients received epirubicin, 90 mg/m(2), followed by paclitaxel, 175 mg/m(2) by 3-hour infusion, on Day 1. The treatment was repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) was not used routinely. RESULTS: A total of 116 treatment cycles was delivered. All patients could be assessed for response, toxicity, and survival. There were 16 partial responses and no complete responses, giving rise to an overall response rate of 50% (95% confidence interval, 31. 9-68.1%). The median time to progression in responders was 7 months. The median survival was 8 months, and the 1-year survival rate was 37%. World Health Organization Grade 4 neutropenia occurred in 69% of patients, but could be managed easily with G-CSF, which was used in 35% of cycles. Cumulative peripheral neuropathy was the main nonhematologic toxicity and was observed in 7 of 8 patients who received 6 treatment courses (Grade 2-3 in 3 cases) and in 6 of 11 patients who received 4 cycles (Grade 2 in 2 patients). One patient died shortly after the first course of chemotherapy from a ventricular arrhythmia. CONCLUSIONS: The combination of paclitaxel and epirubicin was found to be effective and well tolerated in chemotherapy-naive patients with metastatic NSCLC and warrants further evaluation in a multicenter trial of a larger number of patients. Careful cardiac evaluation before treatment is indicated.

Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas.

BACKGROUND: To assess the impact on survival of consolidation radiotherapy to bulky or semibulky lesions in patients with advanced diffuse large B cell lymphoma (DLCL) in complete remission after primary chemotherapy. PATIENTS AND METHODS: Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty-eight patients were irradiated to the involved field and 12 to the extended field with a dose of 30-46 Gy. RESULTS: In patients with bulky disease, consolidation radiotherapy prevented relapses involving exclusively the bulky area, prolonged time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p = 0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with semibulky lesions. Multivariate analyses confirmed the independent association between consolidation radiotherapy and survival, and showed that a dose > or =36 Gy was related to a longer OS, while the extension of the radiotherapy field did not modify outcome. No treatment-related deaths were observed. Four patients developed a second malignancy, none of whom had undergone consolidation radiotherapy. CONCLUSIONS: Consolidation radiotherapy to bulky or semibulky lesions significantly improved the outcome in patients with advanced DLCL in complete remission after primary chemotherapy. Involved-field irradiation with 36-45 Gy made a prolonged disease control possible without either lethal toxicity or a higher incidence of second malignancies.