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Switzerland, with an adolescent HPV vaccination coverage at 59%, remains far from reaching the crucial swiss national goal of 80% coverage. Our objective was to implement a new information brochure in schools to increase HPV vaccination uptake. We designed a public health quality project. A new information brochure was produced and was distributed to a test group of 9th grade students from the Canton of Vaud, in Switzerland during the 2019-2020 school year. Vaccine uptake of the test group was compared to those of all other students in 2019-2020 and of students in the same schools in 2017-2018. 12,143 electronic records were analyzed. 713 students were enrolled in 6 schools where the new brochure was distributed. Median age was 13 years (IQR 12-13), and 6,031 (49.7%) were female. Vaccine uptake was 52% (6,299/12,143). The new brochure did not result in increased uptake. Age ≥ 13 years (aOR 1.39, 95% CI 1.22-1.58) was significantly associated with uptake. Uptake increased between 2017-2018 (51%, 3,216/6,307) and 2019-2020 (52.8%, 3,083/5,836, p=0.04) due to increased acceptance among boys. The only determinant of uptake in 2019-2020 was uptake in the same schools in 2017-2018. The introduction of a new information brochure was insufficient to increase HPV vaccination coverage. More innovative strategies are needed.

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

PURPOSE The prognosis of advanced-stage diffuse large-cell lymphoma (DLCL) has improved with the use of the third-generation regimens such as methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). However, different results have been reported. Therefore, we started a cooperative study to confirm the efficacy of MACOP-B. An analysis of prognostic factors was also performed to identify poor-prognosis patients. PATIENTS AND METHODS Between June 1986 and March 1989, 180 patients with advanced-stage DLCL were treated with MACOP-B. MACOP-B was given according to the original scheme. Numerous clinical features possibly predictive for complete response (CR), disease-free survival (DFS), and survival were analyzed in univariate and multivariate analyses. RESULTS One hundred twenty-seven patients (71%) achieved a complete remission, 20 (11%) achieved a partial remission, 24 (13%) had unchanged or progressive disease, and nine (5%) died due to toxicity. With a median follow-up of 28 months, 71% of 127 CRs remain in first remission. Predicted 3-year survival for all 180 patients is 60%, and 3-year DFS for the 127 CRs is 67%. Overall toxicity was acceptable, with mucositis being the most frequent severe side effect. A multivariate regression analysis identified lactate dehydrogenase (LDH) level, bone marrow involvement, and tumor burden as independent risk factors for survival. These factors were also important for achievement of remission and DFS and allowed us to identify three distinct risk groups of patients with good, intermediate, and poor prognosis, with 3-year survival rates of 80%, 59%, and %29, respectively. CONCLUSIONS These results confirm the effectiveness of MACOP-B in advanced-stage DLCL at low or intermediate risk; however, high-risk patients are in urgent need of new therapeutic approaches. A better definition of prognostic features would allow a more reliable comparison of different treatment regimens, as well as an effective tailoring of therapy by prognostic groups.

The use of combined modality therapy in early-stage Hodgkin's disease can spare staging laparotomy and reduces the risk of relapse compared to radiation alone. This paper reports on the efficacy and long-term events of a combined modality approach consisting of a brief course of chemotherapy followed by adjuvant radiotherapy, without laparotomy, in early-stage Hodgkin's disease.This study included 78 patients with Hodgkin's disease (20 in stage I and 58 in stage II); 60% had mediastinal enlargement (12% had bulky disease) and 5% had subdiaphragmatic disease. Their median age was 33 years (range: 15-64) and median follow-up 60 months. The treatment program consisted of four cycles of ABVD followed by adjuvant radiation to involved sites (43 patients) or involved and contiguous sites of disease (35 patients); radiation doses ranged from 30 to 36 Gy to uninvolved and involved sites, respectively; bulky disease received up to 44 Gy. Gonadal function in women was assessed by hormonal tests and evaluation of menses; young men were given the opportunity to have their semen cryopreserved.The treatment program was completed in a median of 6.2 months (range: 5-10). The complete remission rate was 88% after 4 courses of ABVD and 98.7% after adjunctive RT. The 5-year relapse-free survival was 97% and overall survival 98%; three patients died, one of disease progression and two of small cell lung carcinoma. Long-term events included three cases of pulmonary fibrosis with symptomatic interstitial disease, one case of dilated cardiomyopathy with cardiac failure (all had received mediastinal radiation) and four cases of dysthyroidism. Fertility was preserved in young women, with three subsequent normal pregnancies. Second neoplasms included two small cell lung carcinomas and one breast carcinoma.In early-stage Hodgkin's disease, four cycles of ABVD followed by adjuvant radiotherapy produced a 5-year overall survival of 98%. Prolonged monitoring for therapy-related long term complications is mandatory in these potentially curable patients.

Acute graft-versus-host disease (GVHD) results from reactivity of donor immunocompetent cells versus host tissues. Its pathogenesis involves co-stimulatory molecules, cytokines, free radicals, and oxidative stress products. N-Acetylcysteine (NAC) is an antioxidant that inhibits the B7-1/CD28 expression in vitro, and it may contrabalance the effects of free radicals and oxidative stress; it has been tested in eight patients with steroid-resistant acute GVHD.NAC was given at the dose of 150 mg/kg bolus intravenously, followed by 50 mg/kg intravenous continuous infusion over 3 weeks or less up, to clinical GVHD resolution. In four patients, flow cytometric analysis of co-stimulatory molecules was performed on peripheral mononuclear cells before and after NAC therapy.We achieved prompt response in six patients: four had complete response, two partial response. Two patients died of acute GVHD, and four of intercurrent disease. We noticed significant decrease in CD80, CD25, and CD8+ cells after NAC therapy.NAC therapy is feasible; it may give response in steroid-resistant acute GVHD. More extensive studies are needed to confirm these data.

To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

An international collaborative project for the evaluation of clinical competence at the end of the Medical School curriculum using the ECFMG-CSA (Educational Commission for Foreign Medical Graduates--Clinical Skills Assessment) prototype was started in Italy in April 1996. Faculty representatives from Italian Medical Schools and experts from the ECFMG in Philadelphia participated in the Project. The CSA consists of integrated clinical encounters with 10 standardized patients during which the examinee is asked to obtain a focused history, perform a relevant physical examination and communicate initial diagnoses and management plan to the Standardized Patient (SP). The SP then completes checklists that are scored by Faculty members. The project was concluded in Spring 1998 and a total of 173 new graduates were examined. The data elaborated by the primary site in Chieti University will be available in the Fall 1998 by the ECFMG in Philadelphia. This preliminary communication reports the opinions of the examinees on the ECFMG-CSA, contained in the questionnaires administered after the test. Most of the examinees considered this new methodology as a valid tool for the assessment of clinical competence, especially history-taking and interpersonal skills and stated that the SP simulations were realistic. The 72% of examinees indicated that the Medical School curriculum does not adequately prepare for the CSA examination. Lastly, 68% was in favour of including the SP in the Medical Licensing Examination.

Fifty untreated adult patients with advanced Hodgkin's disease (HD) were given alternating MOPP-ABVD chemotherapy in a prospective eight-cycle program. This series included 33 patients with stage II-III disease and bulky lymphoma and/or B symptoms, and 17 patients with stage IV disease. Nodular sclerosis amounted to 52%, and systemic symptoms were present in 70% of patients. The median follow-up was 50 months from the initiation of therapy (range: 36-78 months). The complete remission rate was 80%, with no differences according to the main patient characteristics before therapy, except for bulky (65%) versus non bulky (88%) disease (p = 0.05). The actuarial 4-year overall (OS) and relapse-free survival were 78% and 71%, respectively. No clear-cut pretreatment characteristics showed an influence on survival, although there was a trend favoring non bulky versus bulky disease (p = 0.08). The actuarial 4-year OS of complete responders was 92%; all 13 patients who died had evidence of HD; the cause of death was disease progression and organ failure in 11 cases, acute myelomonocytic and opportunistic infections with AIDS in the other two cases, respectively. No severe pancytopenia episodes or life-threatening complications occurred during therapy; gastrointestinal and neurological toxicity were mild and no patient refused to complete the treatment. Menstruating women were given estrogen-progesterone combinations, and all continued to have regular menses throughout chemotherapy and afterwards; a young woman had a normal pregnancy resulting in a normal live birth. Only one case of stable amenorrhea was observed. Oligospermia after chemotherapy was seen in seven of 10 tested males, and azoospermia in one case.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors treated a total of 82 patients with Ph′-positive chronic myelogenous leukemia (CML) with recombinant interferon alpha-2b (IFN alpha-2b). Sixty-five patients in chronic phase (CP), 28 of whom were untreated and 37 pretreated, and nine patients in accelerated phase (AP), were started on IFN three times a week. Patients in CP were randomized to receive 2 or 5 X 10(6) IU/m2, while patients in AP were all given the dose of 5 X 10(6) IU/m2, in addition to concomitant chemotherapy. Patients in CP who were unresponsive to the lower dose were crossed to the higher dose. Of 63 evaluable patients in CP, 43 (68%) responded, 29 (46%) achieved complete hematologic response (CHR), and 14 (22%) achieved partial hematologic response (PHR). The response rate appeared to be significantly influenced by the IFN dose in pretreated patients. Of the nine patients in AP, two attained PHR and one CHR. More recently, eight previously untreated CP cases were submitted to daily IFN administration at doses from 2 to 5 X 10(6) IU/m2. This daily schedule was also applied to patients who had obtained, with the intermittent treatment, a PHR persisting unmodified for six months (nine patients) or an unstable CHR (five patients). Seven of the eight previously untreated patients, and five of the nine PHR patients crossed to daily IFN reached CHR. In the total series of previously untreated patients, the response rate proved to be significantly influenced by the initial risk status. Cytogenetic improvement was seen in 37 of 53 responders (70%) treated for more than 3 months, the median of Ph′-positive cells declining from 100% to 65% (range 0% to 95%). Complete suppression of Ph′ chromosome was observed in one case. The cytogenetic response was persistent for over 6 months in 21 patients, but the lowest value of Ph′ positivity was usually unstable. At a median follow-up of 56 weeks, 23 of 36 (64%) CHR patients remain in continued disease control with IFN. A blastic transformation (BT) occurred in seven of 21 unresponsive patients and in one of the 36 CHR patients. The authors' data confirm that IFN alpha- 2b, especially at daily doses, is effective in inducing clinical and cytogenetic response in a good proportion of patients with CML in the benign phase. Longer follow-ups will define the exact influence of this agent on the natural course of the disease.

Of 349 consecutive patients with Philadelphia-positive chronic myelogenous leukemia (Ph' + CML), 14 (4%) developed extramedullary disease (EMD) during their illness. The sites of EMD were: bone (57%), lymph nodes (29%), skin and soft tissues (21%), central nervous system (14%). The median time from diagnosis of CML to the occurrence of EMD was 48 months. At the time of diagnosis of EMD, 7 patients were hematologically in chronic phase, while 7 showed features of accelerated or blastic CML. For patients lacking medullary blastic transformation criteria, the median time from diagnosis of EMD to blast crisis was 4 months. The overall median survival from development of EMD was 5 months. In conclusion, EMD may occur during the course of CML either in the context of a frank blastic transformation, or as an isolated tumoral infiltrate which heralds an impending blast crisis. Its recognition requires a prompt change to acute-phase chemotherapy.

Idarubicin, an anthracycline analogue, is active in non-Hodgkin's lymphoma. This study evaluates the efficacy and toxicity of a combination of idarubicin, etoposide and intermediate-dose cytarabine (IVA) in unfavorable lymphoma in relapse or resistant to prior doxorubicin- or novantrone-based regimens.Thirty patients with relapsing or resistant unfavorable lymphoma received a combination of idarubicin 12 mg/m2 i.v. on day 1, etoposide 60 mg/m2 i.v. every 12 hours for 3 days, and Ara-C 1 g/m2 i.v. every 12 hours for 3 days (3-hour infusion). Median age was 39 years (range: 22-60). All patients had been given prior doxorubicin or novantrone; 54% of them had received 2 or more chemotherapy regimens; 67% of total were in clinical relapse (30% in their second relapse), and 23% had resistant disease.The overall response rate to IVA was 60% (18 of 30 patients). Complete remission rate was 20% (6 of 30) in the whole group, 45% (5 of 11) among patients in their first relapse. Remission median duration was 9 months (range: 1-18), with a 3-year relapse-free and overall survival of 20% and 15%, respectively. Severe neutropenia occurred in 13 patients (43%) and severe thrombocytopenia in 11 patients (37%), with a median duration of 9 and 13 days, respectively. No cardiac toxicity developed; sepsis during neutropenia was documented in four instances and two patients (7%) died of therapy-related events (septic shock).Idarubicin combined with etoposide and intermediate-dose cytarabine proved to be an active salvage therapy in unfavorable lymphoma given prior doxorubicin or novantrone; the best results were obtained among patients in their first relapse, with low tumor burden.

Pipobroman (PB) was tested in a prospective efficacy trial in 24 previously untreated patients with essential thrombocythemia and followed up for a median of 47 months (range, 12-120). Plateletpheresis was not done. Hematologic complete response (platelet count less than 450 X 10(9)/L for 3 consecutive months) was achieved in 92% of the cases, in a median time of 12 weeks (range, 2-22). However, continuous low-dose maintenance therapy with PB was necessary to avoid recurrences of the disease. Major thrombocythemia-related complications were observed in 20% of the cases; the 5-year overall and complication-free survival rates were 92% and 75%, respectively. No acute or chronic toxicity was observed; no drug-induced amenorrhea and subsequent acute leukemia occurred. PB does appear to be efficacious in essential thrombocythemia; however, the evaluation of its leukemogenic risk will await further experience.

The aim of this study was to determine the oxigen affinity actually present in vivo in blood from patients with acute myocardial infarction. Patients with uncomplicated acute myocardial infarction had normal value of P50 in vivo (partial pressure of oxygen at which 50 percent of the hemoglobin is saturated with oxygen at fixed levels of pHand PC02 present in vivo). Also the values of P50 in vivo of blood from patients with low cardiac output with mild or severe heart failured did not differ from the normal mean. This was the consequence of an increase of 2, 3-diphosphoglycerate levels (which reduces the oxygen affinity of hemoglobin) and of the immediate effect of alkalosis (Bohr effect). By contrast, the values of P50 in vivo were significantly increased in patients with cardiogenic shock. This could be ascribed to the state of acute acidiosis present in these patients. In these conditions the changes in the values of P50 in vivo play an important role in the oxygen delivery to the tissues. However, high values of P50 do not enhance oxygen delivery when a severe arterial hypoxemia (P02 smaller than 40-45 mm Hg) is also present.

Preliminary independent reports of the Italian GIMEMA and the Spanish PETHEMA trials for newly diagnosed acute promyelocytic leukemia (APL) indicated a similarly high antileukemic efficacy in terms of complete remission and disease-free survival rates. To better investigate these studies and the prognostic factors influencing relapse risk, this study analyzed the updated results of 217 patients with PML/RAR alpha-positive APL enrolled in GIMEMA (n = 108) and PETHEMA (n = 109). All patients received identical induction (AIDA schedule) and maintenance. For consolidation, GIMEMA patients received 3 courses including idarubicin/cytarabine, mitoxantrone/etoposide, and idarubicin/cytarabine/thioguanine, whereas PETHEMA patients received the same drugs and dose schedule of idarubicin and mitoxantrone with the omission of nonintercalating agents. Depending on whether molecular relapses were classified as censored or uncensored events, the 3-year Kaplan-Meier estimates of relapse-free survival (RFS) for the combined series were 90 +/- 2% and 86 +/- 2%, respectively. Minor differences observed between the 2 patient cohorts were negligible. Multivariate regression analysis of RFS showed that initial leukocyte (WBC) and platelet counts were the only variables with independent prognostic value. The resulting predictive model for RFS demonstrated its capability of segregating patients into low-risk (WBC count/= 10 x 10(9)/L, platelet count40 x 10(9)/L), intermediate-risk (WBC count/= 10 x 10(9)/L, platelets/= 40 x 10(9)/L), and high-risk (WBC count10 x 10(9)/L) groups, with distinctive RFS curves (P.0001). The conclusions are that omission of nonanthracycline drugs from the AIDA regimen is not associated with reduced antileukemic efficacy and a simple predictive model may be used for risk-adapted therapy in this disease. (Blood. 2000;96:1247-1253)

In multiple myeloma (MM) patients treated with conventional chemotherapy, the attainment and duration of a plateau phase seems to affect survival more than the degree of response to initial treatment. The aims of this study are: 1) to analyze within a cohort of previously untreated MM patients the incidence and the duration of the plateau phase; 2) to correlate it with the presenting features; 3) to assess its impact on survival.A series of 146 consecutive MM patients treated with conventional chemotherapy were evaluated for this study. Of 146 patients, 102 responded (13 achieving complete response, 21 partial response, and 68 minimal response), and 44 showed less than minimal response or a progression. A plateau phase was documented in 115 patients (comprising all responders and 13 non responders. The median plateau phase duration was 21.6 months. The majority of patients received intermittent cycles of chemotherapy (melphalan or interferon) during the plateau phase. In multivariate analysis, lytic lesions, response, and time to the best response (TBR) correlated with the attainment of a plateau, while stage, response as a whole, and TBR showed a significant correlation with the duration. In contrast, the type of response did not correlate with either the attainment or the duration of plateau. To analyze the prognostic impact of presenting features, response to therapy and plateau we used a hierarchical model for survival. The analysis showed that the response to therapy and the duration of plateau significantly affect the survival.In multiple myeloma a plateau phase of at least 6 months' duration has a higher impact on survival than the degree of response to conventional chemotherapy so plateau duration could be used as target of therapeutic trials. The best way to maintain the plateau phase remains, however, undefined.

The protective activity of a DNA plasmid encoding the immunodominant capsid protein VP1 of coxsackievirus B4 (CBV-4) was studied in BALB/c mice. The plasmid pCI-B4-1-c - which gave the highest expression level of VP1 in cultured monkey and human cells - was chosen for immunization. Two injections of pCI-B4-1-c (1 month apart) into the regenerating mouse muscle tissue induced a specific antibody response to CBV-4, as shown by immunoenzyme and neutralization assays. Upon challenge with live CBV-4, the mortality rate of mice vaccinated with the recombinant plasmid was significantly reduced (21% versus58%) as compared with that of mice that had been either nontreated or injected with a control plasmid devoid of the insert. The VP1-based vaccine, however, did not provide complete protection as - after virus challenge - moderate viraemia occurred together with modest plasma elevations of pathogenesis-related enzymes (amylase and creatine kinase). Yet, immunofluorescence of the small intestine and heart did confirm the protective effect of the VP1-encoding vaccine. In order to obtain a more complete protection against CBV-4, it may be beneficial to immunize mice with combinations of separate DNA plasmids encoding not only VP1 but also the VP2 and VP3 capsid proteins.

Polycythemia vera (PV) is a myeloproliferative disorder, characterized by the expansion of the red cell mass. Our purpose was to evaluate the efficacy of pipobroman (PB) in the long-term control of PV and to assess early and late events.From June 1975 to December 1997, 163 untreated patients with PV (median age 57 years, range 30-82) were treated with PB in a single Institute for a median follow-up of 120 months. The diagnosis was made according to the Polycythemia Vera Study Group criteria. PB was given at the dose of 1 mg/kg/day until hematologic response (hematocrit45% and platelets400x109/L) and of 0.3-0.6 mg/kg/day as maintenance therapy.Hematologic remission was achieved in 94% of patients in a median time of 13 weeks (range 6-48). Median overall survival was 215 months, with a standardized mortality ratio of 1.7. The cumulative risk of death was 11%, 22%, and 26% at 7, 10, and 12 years, respectively. The incidence of thrombotic events was 18.4x105 person-year and the cumulative risk was 6%, 11%, 16%, and 20% at 3, 7, 10, and 12 years respectively. Acute leukemia occurred in 11 patients, myelofibrosis in 7, and solid tumors in 11. The 10-year cumulative risk of leukemia, myelofibrosis, and solid tumors was 5%, 4%, and 8%, respectively. In the logistic analysis age over 65 (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher risk of death. Female gender (p = 0.02) and age over 65 (p = 0.01) significantly influenced the occurrence of thrombotic complications. Age was the only significant risk factor for leukemia (p = 0.04) and for solid tumors (p = 0.03), while the duration of PB treatment did not influence these risks. No significant risk factor was demonstrated for myelofibrosis.This study demonstrates in a large series of patients, observed for a long period, that pipobroman is effective in the long-term control of PV. The risk of early thrombotic complications at 3 years is 6% and the 10-year risk of acute leukemia, late myelofibrosis, and solid tumors is 5%, 4%, and 8%, respectively. The duration of pipobroman treatment did not correlate with these events.

Multiple sclerosis Esclerosi múltiple Esclerosis múltiple Objective To validate the smartphone sensor-based Draw a Shape Test – a part of the Floodlight Proof-of-Concept app for remotely assessing multiple sclerosis-related upper extremity impairment by tracing six different shapes. Methods People with multiple sclerosis, classified functionally normal/abnormal via their Nine-Hole Peg Test time, and healthy controls participated in a 24-week, nonrandomized study. Spatial (trace accuracy), temporal (mean and variability in linear, angular, and radial drawing velocities, and dwell time ratio), and spatiotemporal features (trace celerity) were cross-sectionally analyzed for correlation with standard clinical and brain magnetic resonance imaging (normalized brain volume and total lesion volume) disease burden measures, and for capacity to differentiate people with multiple sclerosis from healthy controls. Results Data from 69 people with multiple sclerosis and 18 healthy controls were analyzed. Trace accuracy (all shapes), linear velocity variability (circle, figure-of-8, spiral shapes), and radial velocity variability (spiral shape) had a mostly fair/moderate-to-good correlation (|r| = 0.14–0.66) with all disease burden measures. Trace celerity also had mostly fair/moderate-to-good correlation (|r| = 0.18–0.41) with Nine-Hole Peg Test performance, cerebellar functional system score, and brain magnetic resonance imaging. Furthermore, partial correlation analysis related these results to motor impairment. People with multiple sclerosis showed greater drawing velocity variability, though slower mean velocity, than healthy controls. Linear velocity (spiral shape) and angular velocity (circle shape) potentially differentiate functionally normal people with multiple sclerosis from healthy controls. Interpretation The Draw a Shape Test objectively assesses upper extremity impairment and correlates with all disease burden measures, thus aiding multiple sclerosis-related upper extremity impairment characterization. This research was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m2 intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity ( P