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For chronic lymphocytic leukaemia (CLL), targeted drugs have become the standard of care, in particular for second-line treatment. In this study, overall survival (OS), treatment-free survival (TFS) and adverse events (AE) were registered retrospectively in a Danish population-based cohort upon second-line treatment for CLL. Data were collected from medical records and the Danish National CLL register. For 286 patients receiving second-line treatment, three-year TFS was higher upon targeted treatment (ibrutinib/venetoclax/idelalisib) [63%, 95% confidence interval (CI) 50%-76%] compared with fludarabine, cyclophosphamide and rituximab or bendamustine and rituximab (FCR/BR) (37%, CI: 26%-48%) and chlorambucil+/-CD20-antibody (CD20Clb/Clb) (22%, CI: 10%-33%). Upon targeted treatment, three-year OS estimates were higher for targeted treatment (79%, CI: 68%-91%) compared with FCR/BR (70%, CI: 60%-81%) or CD20Clb/Clb (60%, CI: 47%-74%). The most common AEs were infections and haematological AEs; 92% of patients treated with targeted drugs had AEs, 53% of which were severe. Upon FCR/BR and CD20Clb/Clb, AEs were present for 75% and 53% respectively, of which 63% and 31% were severe. These real-world data demonstrate higher TFS and a tendency towards higher OS following targeted second-line treatment for CLL compared to chemoimmunotherapy, also for patients who may be frailer and more comorbid.

Some patients with basal cell carcinoma develop a large number of basal cell carcinomas during their lives. The most common underlying genetic disease that causes multiple basal cell carcinomas is basal cell naevus syndrome. Basal cell naevus syndrome is caused by a germline mutation in patched-1 (PTCH1), a tumour suppressor gene of the hedgehog signalling pathway. However, in a significant portion of patients with multiple basal cell carcinomas, no underlying genetic cause is found. Nevertheless, these patients can experience a treatment burden comparable to that of patients with basal cell naevus syndrome. They are referred to as high-frequency basal cell carcinoma patients. Hedgehog pathway inhibitors were the first group of targeted therapy for basal cell carcinomas. This study reviews the literature on hedgehog pathway inhibitor therapy for patients with basal cell naevus syndrome and high-frequency basal cell carcinoma, to provide an overview on efficacy, safety, dosing regimens, tumour resistance and reoccurrence, and health-related quality of life.

Cancers 14(5), 1261 (2022). doi:10.3390/cancers14051261, Published by MDPI, Basel

Dissertation, RWTH Aachen University, 2022; Aachen : RWTH Aachen University 1 Online-Ressource : Illustrationen, Diagramme (2022). = Dissertation, RWTH Aachen University, 2022, Within the scope of the High Luminosity LHC upgrade the CMS experiment will be upgraded because due to radiation damage many components cannot be used any longer and higher particle fluxes will raise the technical requirements. In addition to other detector components, the entire silicon strip tracker will be replaced. The new sub-detector will consist of so-called PS and 2S modules with a stacked pair of sensor layers each. This module design will enable the integration of tracking information into the Level-1 trigger of the CMS detector on hardware level. The Physics Institute IB and the Physics Institute IIIB of RWTH Aachen University committed to assemble and test up to one thousand 2S modules. In the course of this PhD thesis multiple prototype detector modules have been assembled and the assembly procedure has been tested and improved with the focus being placed on the wire bonding step. The bonding quality has been evaluated by analyzing the bond machine data. As a tool for the module series production, a user interface has been developed to identify weak bonds. For the reception test of Kapton strips, which are used as high voltage isolators in the module assembly, a test setup with a dedicated user interface has been created. In addition, the series production was prepared by performing a detailed estimation of the assembly time and the required storage capabilities. Prototype modules were also used to test procedures for identifying and repairing damages. The properties of close-to-final prototype modules have been measured at the Test Beam Facility DESY with an electron beam. The particle tracks of the beam telescope have been aligned to the hits on the tested modules and the data have been analyzed. The analysis includes a study of the detector’s spacial resolution, the assembly precision and a detailed evaluation of the hit and stub efficiency at different locations of the sensors and under different incidence angles. The results of the beam test analysis are furthermore discussed in the context of the detector operation at the High Luminosity LHC., Published by RWTH Aachen University, Aachen

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN-α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity. Title in Web of Science: Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study

Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Background: \ud In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (≤35%).\ud \ud Objectives: \ud The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil.\ud \ud Methods: \ud Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF.\ud \ud Results: \ud The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (≤22%) compared with the highest EF (≥33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF ≤22% (n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF ≥33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF ≤22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile.\ud \ud Conclusions: \ud In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug’s mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329)

22 pp. (2021)., The current baseline construction schedule of the Pixel detector of the ATLAS Phase-2 Inner Tracker (ITk) is in tension with its foreseen installation date during Long Shutdown (LS) 3. Different staged-installation scenarios are being discussed that could help advancing the construction schedule. This would provide enough time contingency to ensure completion of the detector before the start of the run period. In the considered scenarios, only part of the nominal ITk Pixel detector would be installed during LS3 and be present for the Run-4 data-taking, while the rest of the detector would be installed during LS4. This note presents a study of the implications of the proposed staging scenarios on track reconstruction, physics and technical performance. Tracking and flavour-tagging performance are more severely impacted when taking into account detector defects, while a significant increase in computing power is needed to guarantee reasonable tracking performance even in the absence of defects, with major implications for the tracking reconstruction in trigger.

Der CMS Outer Tracker wird f��r den Betrieb des HL-LHC vollst��ndig ausgetauscht. Diese Arbeit besch��ftigt sich mit den Bestrahlungstests im Zuge der Produktion neuer Siliziumstreifensensoren. Im zweiten Hauptteil wird die Streifenisolation von n-on-p Siliziumstreifensensoren n��her beleuchtet. Hierbei wurde ebenfalls ein starker Fokus auf das Verhalten nach Bestrahlungen gesetzt. Zudem wurde ein TCAD Defektmodell entwickelt, um die Messungen reproduzieren und vorhersagen machen zu k��nnen.

34 pp. (2021)., As part of the ATLAS Phase-II upgrade, the current Inner Detector of the experiment will be replaced with a new all-silicon Inner Tracker (ITk) designed to face the challenging environment associated with the high number of collisions per bunch crossing. Recently, the decision was taken to update the layout of the ITk pixel detector, in particular, to reduce the radius of the innermost pixel layer. This document presents the recent evolution of the ITk design and its impact on the tracking performance, as well as on some representative high- level object reconstruction and identification, including primary vertices, jet flavour-tagging, electrons and converted photons.

Aims The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and results Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N‐terminal pro‐B‐type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC‐HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure, Graphical representation of the GALACTIC‐HF trial design, enrolment and baseline characteristics. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; CRT, cardiac resynchronization therapy (biventricular pacemaker); CV, cardiovascular; EF, ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, Hew York Heart Association; SBP, systolic blood pressure.

Purpose/Objective(s): The current study reports long-term overall survival (OS) and biochemical freedom from recurrence (BFFR) after stereotactic body radiation therapy (SBRT) for men with intermediate and high-risk prostate cancer in a single community hospital setting with early adoption. Materials/Methods: Ninety-seven consecutive men with intermediate and high-risk prostate cancer treated with SBRT between 2007 and 2015 were retrospectively studied. Categorical variables for analysis included National Comprehensive Cancer Network risk group, race, Gleason grade group, T stage, use of androgen deprivation therapy, and planning target volume dose. Continuous variables for analysis included pretreatment prostate-specific antigen (PSA), percent cores positive, age at diagnosis, PSA nadir, prostate volume, percent prostate that received 40 Gy, and minimum dose to 0.03 cc of prostate (Dmin). BFFR was assessed using the Phoenix nadir +2 definition. OS and BFFR were estimated using Kaplan–Meier (KM) methodology with comparisons accomplished using log-rank statistics. Multivariable analysis (MVA) was accomplished with a backwards selection Cox proportional-hazards model with statistical significance taken at the p < 0.05 level. Results: Median FU is 78.4 months. Five- and ten-year OS KM estimates are 90.9 and 73.2%, respectively, with 19 deaths recorded. MVA reveals pretreatment PSA (p = 0.032), percent prostate 40 Gy (p = 0.003), and race (p = 0.031) were predictive of OS. Five- and nine-year BFFR KM estimates are 92.1 and 87.5%, respectively, with 10 biochemical failures recorded. MVA revealed PSA nadir (p < 0.001) was the only factor predictive of BFFR. Specifically, for every one-unit increase in PSA nadir, there was a 4.2-fold increased odds of biochemical failure (HR = 4.248). No significant differences in BFFR were found between favorable intermediate, unfavorable intermediate, and high-risk prostate cancer (p = 0.054) with 7-year KM estimates of 96.6, 81.0, and 85.7%, respectively. Conclusions: Favorable OS and BFFR can be expected after SBRT for intermediate and high-risk prostate cancer with non-significant differences seen for BFFR between favorable intermediate, unfavorable intermediate, and high-risk groups. Our 5-year BFFR compares favorably with the HYPO-RT-PC trial of 84%. PSA nadir was predictive of biochemical failure. This study is ultimately limited by the small absolute number of high-risk patients included. Published version

Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression–based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography–guided response assessment and the evolving cHL treatment landscape.

The “false‐negatives” of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to “false‐negatives” are larger than those leading to “false‐positives,” especially in typically underpowered early‐phase trials. In addition, “false‐negatives” are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early‐phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures.

During the COVID-19 pandemics, balneotherapic establishments were closed in Italy like in the rest of Europe. The Italian Foundation for Research in balneotherapy (FoRST) was asked to prepare a safety protocol to be proposed to the National Health Authorities to allow the establishments to restart their activity when possible, under safe conditions (the so-called Phase-2). The group of experts proposed the following hygienic and sanitary protocols of risk management for the initial reopening of the balneology settings in Italy. The plan aims to define the operating procedures to be implemented at the balneology establishments for the beginning of Phase-2 and to keep them constantly updated in the different periods that will characterize Phase-2 in relation to the trends of the disease. To this end the procedures, defined on the basis of the scientific state-of-the-art available today, will be updated and revised from time to time whenever further scientific evidence and directives from the Health Authorities make it necessary and/or useful. (www.actabiomedica.it)

BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients. ispartof: Journal of Cystic Fibrosis vol:19 issue:1 pages:99-107 ispartof: location:Netherlands status: published

Background: Medications targeting the calcitonin gene-related peptide (CGRP) pathway are exciting and novel therapeutic options in the treatment of migraine. Objective: In this article, we have reviewed the role of these CGRP monoclonal antibodies in patients with episodic migraine. Materials and Methods: We did an extensive literature search for all phase 2 and 3 studies involving CGRP monoclonal antibodies in episodic migraine. Results: Erenumab, fremanezumab, galcanezumab, and eptinezumab have all undergone phase 3 trials and have been found to be effective for episodic and chronic migraine. They have the advantage of being targeted therapies for migraine with very favorable adverse effect profiles comparable to placebo. Importantly, they are effective in subgroups of patients who have failed previous preventive therapies. Conclusion: Increasing use of these medications will certainly revolutionize the treatment and outlook for patients with migraine all over the world.

Background In the primary 48-week analysis of a hepatic safety trial in patients with HIV-1 coinfected with HBV and/or HCV, maraviroc-containing treatment regimens were not associated with increased hepatotoxicity. Methods In this randomized, double-blind, placebo-controlled, multicentre study, patients received maraviroc twice daily ( n=70) or placebo ( n=67) with concomitant antiretroviral therapy for 144 weeks (Clinicaltrials.gov identifer, NCT01327547). The primary end point was the proportion of patients with protocol-defined Grade 3/4 alanine aminotransferase (ALT) abnormalities through week 48. Key secondary end points included 144-week analysis of Grade 3/4 ALT abnormalities and liver fibrosis by enhanced liver fibrosis (ELF) testing, hepatic elastography and an optional biopsy substudy. Results Through 144 weeks of treatment, two (maraviroc) and three (placebo) patients met the protocol-defined Grade 3/4 ALT end point. Similar to the 48-week results, there were no statistically significant differences between groups in change from baseline in ELF or hepatic elastography. However, decreased elastography scores were noted in the maraviroc group. Blinded pathologist review suggested that 2 of 11 paired biopsies (both on maraviroc) showed signs of decreased fibrosis. One (maraviroc) and two (placebo) patients experienced treatment-related hepatobiliary adverse events (AEs). Five patients in the maraviroc group discontinued because of treatment-related AEs versus three in the placebo group. One death in the maraviroc group and two deaths in the placebo group were reported. Conclusions Use of maraviroc did not increase hepatotoxicity in this population through 144 weeks. Further investigation regarding possible beneficial effects of maraviroc on liver fibrosis may be warranted.

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.

BACKGROUND Effective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia‐positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with ponatinib versus allogeneic stem cell transplantation (allo‐SCT). METHODS A post hoc, retrospective, indirect comparison of OS among patients who received single‐agent ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo‐SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted. Kaplan‐Meier survival curves and multivariate Cox proportional‐hazards models were used to compare OS between intervention groups, adjusting for time from diagnosis to intervention, age, sex, and geographic region; 24‐month and 48‐month OS rates and median OS were reported. RESULTS After adjustment for potential confounders, 24‐month and 48‐month OS rates were significantly higher in patients with chronic‐phase CML (CP‐CML) who received ponatinib compared with those who underwent allo‐SCT (24 months: 84% vs 60.5%, respectively; P = .004; 48 months: 72.7% vs 55.8%, respectively; P = .013), with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.16‐0.84; P = .017). In patients who had accelerated‐phase CML, OS rates were not significantly different between the groups (HR, 0.90; 95% CI, 0.20‐4.10; P = .889). In patients who had blast‐crisis CML and those with Ph+ ALL, ponatinib was associated with shorter OS compared with allo‐SCT (blast‐crisis CML: HR, 2.29 [95% CI, 1.08‐4.82; P = .030]; Ph+ ALL: HR, 2.77 [95% CI, 0.73‐10.56; P = .146]). CONCLUSIONS Although allo‐SCT remains an important treatment option for patients with T315I‐positive advanced CML and Ph+ ALL, ponatinib represents a valuable alternative for patients with T315I‐positive CP‐CML. Cancer 2017;123:2875–80. © 2017 American Cancer Society., In patients who have chronic‐phase chronic myeloid leukemia (CML) with the Philadelphia chromosome threonine to isoleucine mutation at codon 315, single‐agent ponatinib is associated with significantly longer overall survival compared with allogenic stem cell transplantation. In those who have accelerated‐phase CML, blast‐crisis CML, and Philadelphia chromosome‐positive acute lymphoblastic leukemia with the T315I mutation, single‐agent ponatinib is associated with similar or shorter overall survival compared with stem cell transplantation.

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.

The NEMO Phase-2 tower is the first detector which was operated underwater for more than one year at the "record" depth of 3500 m. It was designed and built within the framework of the NEMO (NEutrino Mediterranean Observatory) project. The 380 m high tower was successfully installed in March 2013 80 km offshore Capo Passero (Italy). This is the first prototype operated on the site where the italian node of the KM3NeT neutrino telescope will be built. The installation and operation of the NEMO Phase-2 tower has proven the functionality of the infrastructure and the operability at 3500 m depth. A more than one year long monitoring of the deep water characteristics of the site has been also provided. In this paper the infrastructure and the tower structure and instrumentation are described. The results of long term optical background measurements are presented. The rates show stable and low baseline values, compatible with the contribution of 40K light emission, with a small percentage of light bursts due to bioluminescence. All these features confirm the stability and good optical properties of the site., Comment: 12 pages, 17 figures

OBJECTIVE To report thrombocytopenia in a patient prescribed thalidomide for multiple myeloma (MM). CASE SUMMARY A 70-year-old woman was diagnosed in 2003 with MM. At diagnosis, melphalan 0.25 mg/kg/day and prednisolone 2 mg/kg/day were started; however, the patient became refractory to therapy. Melphalan and prednisolone were discontinued, and monotherapy with dexamethasone 40 mg for 12 days per month was started. The patient's hematologic condition deteriorated again after about one year; dexamethasone was discontinued, and treatment with oral thalidomide 200 mg/day was initiated. About 2 weeks after thalidomide administration, the woman developed disabling adverse effects (flu-like symptoms, swollen fingers, rash and hematoma on her legs, shortness of breath, dry mouth, multiple petechiae). Laboratory testing showed neutropenia (neutrophils 0.4 × 109/L) and thrombocytopenia (platelets 58 × 109/L). Thalidomide was promptly discontinued; within 3 weeks, the laboratory values returned to pretreatment levels (1.3 × 109/L and 267 × 109/L, respectively) and her symptoms disappeared. DISCUSSION Thrombocytopenia is a rarely reported hematologic adverse consequence of thalidomide therapy. A recent report identified 5 patients who developed thrombocytopenia while undergoing monotherapy with thalidomide for MM. According to the Naranjo probability scale, thalidomide was classified as the probable cause of thrombocytopenia in our patient. CONCLUSIONS Unlike other antineoplastic drugs, thalidomide is rarely reported to cause severe hematologic toxicity. We present this case to increase clinicians’ awareness for the potential of thalidomide to adversely affect platelet counts, particularly because its effectiveness in MM will likely result in expansion of its clinical use.

This multicenter, open-label, non-comparative phase II trial evaluated the safety and efficacy of salvage therapy with lenalidomide, melphalan, prednisone and thalidomide (RMPT) in patients with relapsed/refractory multiple myeloma (MM). Oral lenalidomide (10 mg/day) was administered on days 1-21, and oral melphalan (0.18 mg/kg) and oral prednisone (2 mg/kg) on days 1-4 of each 28-day cycle. Thalidomide was administered at 50 mg/day or 100 mg/day on days 1-28; six cycles were administered in total. Maintenance included lenalidomide 10 mg/day on days 1-21, until unacceptable adverse events or disease progression. Aspirin (100 mg/day) was given as thromboprophylaxis. A total of 44 patients with relapsed/refractory MM were enrolled and 75% achieved at least a partial response (PR), including 32% very good PR (VGPR) and 2% complete response (CR). The 1-year progression-free survival (PFS) was 51% and the 1-year overall survival (OS) from study entry was 72%. Grade 4 hematologic adverse events included neutropenia (18%), thrombocytopenia (7%) and anemia (2%). Grade 3 non-hematologic adverse events were infections (14%), neurological toxicity (4.5%) and fatigue (7%). No grade 3/4 thromboembolic events or peripheral neuropathy were reported. In conclusion, RMPT is an active salvage therapy with good efficacy and manageable side effects. This study represents the basis for larger phase III randomized trials.

The clinical data on the efficacy and toxicity of bortezomib as treatment for multiple myeloma patients are restricted to prospective phase II studies in expert myeloma centers. Here we report a multi-institutional analysis of the efficacy and toxicity of bortezomib in patients with relapsed or refractory multiple myeloma who were treated in community centers in a compassionate need program.

The clinical data on the efficacy and toxicity of bortezomib as treatment for multiple myeloma patients are restricted to prospective phase II studies in expert myeloma centers. Here we report a multi-institutional analysis of the efficacy and toxicity of bortezomib in patients with relapsed or refractory multiple myeloma who were treated in community centers in a compassionate need program.