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We studied the effects of liming on soils and forest songbirds as well as vegetation and calcium-rich invertebrate prey variables that were predicted to link birds to changes in soil conditions. We observed increases in soil pH, calcium, and magnesium, as well as in songbird abundances in response to lime application, with continuing increases through five years after liming. We observed an overall increase in snail abundance on limed sites, but an initial peak of a 23 fold increase three years after liming was reduced to an 11 fold increase five years after liming. We observed an increase in forb ground cover on limed sites, but liming had no effect on millipede abundance or other vegetation measures. Of the variables we measured, snail abundance was the most likely mechanism for the response in bird abundances. Because we observed continued benefits of liming up to five years post treatment, we concluded that liming is a very promising technique for restoring forest ecosystems impacted by acidic deposition.

Background: Children with medical complexity (CMC) account for high health care utilization. Telemedicine holds significant potential in CMC, as it allows a provider to engage with CMC in their home environment and can alleviate both financial and transportation burdens. Remote exam devices that enable the performance of a physical exam could expand the ability of providers to clinically assess CMC during a telemedicine visit. In this pilot study, our goal was to develop a process for integrating an in-home remote exam device into a complex care clinic during the COVID-19 pandemic and evaluate the usability and feasibility of this device. Methods: The remote exam device was distributed to caregivers of CMC cared for at a complex care outpatient center. Using deliberate practice framework, our onboarding process provided opportunities for caregivers and providers to learn how to utilize the device. Surveys examining usability and feasibility were administered to both caregivers and providers after each telemedicine encounter. Results: A total of 43 caregivers participated in the onboarding process, which included a total of 83 practice visits. The remote exam device was rated as having excellent usability by caregivers; however, providers rated the device as having lower usability. Feasibility was notable for technology issues contributing to 15% of encounters being cancelled or ending early. Conclusions: The remote exam device was successfully integrated into a complex care clinic. Data from this pilot study supports the usability and feasibility of deploying a remote exam device across a telemedicine platform in a busy and complex outpatient academic practice.

Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 10 6 to 200 × 10 6 CART/m 2 . In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504., (© 2024. The Author(s).)

The short-term scaling exponent of detrended fluctuation analysis (DFAα1) applied to interbeat intervals may provide a method to identify ventilatory thresholds and indicate systemic perturbation during prolonged exercise. The purposes of this study were to (i) identify the gas exchange threshold (GET) and respiratory compensation point (RCP) using DFAα1 values of 0.75 and 0.5 from incremental exercise, (ii) compare DFAα1 thresholds with DFAα1 measures during constant-speed running near the maximal lactate steady state (MLSS), and (iii) assess the repeatability of DFAα1 between MLSS trials. Twelve runners performed an incremental running test and constant-speed running 5% below, at, and 5% above the MLSS, plus a repeat trial at MLSS. During 30-min running trials near MLSS, DFAα1 responses were variable (i.e., 0.27-1.24) and affected by intensity (p = 0.031) and duration (p = 0.003). No difference in DFAα1 was detected between MLSS trials (p = 0.597). In the early phase (~ 8 min), DFAα1 measures at MLSS (0.71 [0.13]) remained higher than the DFAα1 identified at RCP from the incremental test (0.57 [0.13]; p = 0.024). In addition, following ~ 18 min of constant speed running at MLSS, DFAα1 measures (0.64 [0.14]) remained higher than 0.5 (p = 0.011)-the value thought to demarcate the boundaries between heavy and severe exercise intensities. Accordingly, using fixed DFAα1 values associated with the RCP from incremental exercise to guide constant-speed exercise training may produce a greater than expected exercise intensity, however; the dependency of DFAα1 on intensity and duration suggest its potential utility to quantify systemic perturbations imposed by continuous exercise., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The short-term scaling exponent alpha1 of detrended fluctuation analysis (DFA-a1) of heart rate variability (HRV) has been shown to be a sensitive marker for assessing global organismic demands. The wide dynamic range within the exercise intensity spectrum and the relationship to established physiologic threshold boundaries potentially allow in-field use and also open opportunities to provide real-time feedback. The present study expands the idea of using everyday workout data from the AI Endurance app to obtain the relationship between cycling power and DFA-a1. Collected data were imported between September 2021 and August 2023 with an initial pool of 3123 workouts across 21 male users. The aim of this analysis was to further apply a new method of implementing workout group data considering representative values of DFA-a1 segmentation compared to single workout data and including all data points to enhance the validity of the internal-to-external load relationship. The present data demonstrate a universal relationship between cycling power and DFA-a1 from everyday workout data that potentially allows accessible and regular tracking of intensity zone demarcation information. The analysis highlights the superior efficacy of the representative-based approach of included data in most cases. Validation data of the performance level and the up-to-date relationship are still pending.

Human papillomavirus (HPV) primary screening is an effective approach to assessing cervical cancer risk. Self-collected vaginal swabs can expand testing access, but the data defining analytical performance criteria necessary for adoption of self-collected specimens are limited, especially for those occurring outside the clinic, where the swab remains dry during transport. Here, we evaluated the performance of self-collected vaginal swabs for HPV detection using the Cobas 6800. There was insignificant variability between swabs self-collected by the same individual (n = 15 participants collecting 5 swabs per participant), measured by amplification of HPV and human β-globin control DNA. Comparison of self-collected vaginal swab and provider-collected cervical samples (n = 144 pairs) proved highly concordant for HPV detection (total agreement = 90.3%; positive percentage agreement = 84.2%). There was no relationship between the number of dry storage days and amplification of HPV (n = 68; range, 4 to 41 days). Exposure of self-collected dry swabs to extreme summer and winter temperatures did not affect testing outcomes. A second internal control (RNase P) demonstrated that lack of amplification for β-globin from self-collected specimens was consistent with poor, but not absent, cellularity. These data suggest that self-collected vaginal samples enable accurate clinical HPV testing, and that extended ambient dry storage or exposure to extreme temperatures does not influence HPV detection. Furthermore, lack of β-globin amplification in HPV-negative samples accurately identified participants who required recollection., Competing Interests: Disclosure Statement At the time of experimentation and/or writing, M.Q., A.R.N., M.R., and D.N.G. were salaried employees at LetsGetChecked., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)

Background: Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce., Methods: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP)., Results: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented., Conclusions: In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: This quality improvement project was a collaborative effort with Penn Medicine's emergency department (ED) and oncology nurse navigators (ONNs). The goal of the project was to streamline patient transitions from the ED to the outpatient oncology clinic by developing a standardized referral process. The main objectives were to simplify and automate the referral process using the electronic medical record, improve multidisciplinary communication across the care continuum, ensure timely follow-up, and address barriers to oncology care., Methods: The ED providers placed a consult to ONNs. The ONNs reached out to the patient within 48 hours of the consult. They maintained a database of patient referrals and collected information such as patient demographics, reason for referral, insurance, and patient outcomes., Results: The ED providers referred 204 patients to the ONNs from April 2022 to September 2023. The development of a standardized referral process from the ED to the outpatient oncology clinic proved successful. Of the patients referred, the ONNs facilitated 98 cancer diagnoses and 80 of those patients are receiving oncology care at Penn Medicine. The median time to the patient's first appointments was seven days, diagnosis was 15 days, and treatment initiation occurred within 32 days., Conclusion: The project team achieved their goal of facilitating timely access to oncology care, ensuring continuity, and addressing patient-specific barriers., Implications for Nursing Practice: This quality improvement initiative highlights the ONNs' role in enhancing access and equity in cancer care delivery. The success of the project underscores the ONN's expertise and leadership in addressing healthcare disparities in oncology care. Collaboratively, the teams created a new referral workflow improving care transitions from the ED to the outpatient oncology clinic. The project sets a precedent for optimizing patient care transitions, demonstrating the positive impact of ONNs as key members of the multidisciplinary healthcare team., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katie Fanslau reports a relationship with Oncology Nursing Society that includes: writer. Margaret Rummel reports a relationship with Academy of Oncology Nurse & Patient Navigators: various committees. Megan Roy reports a relationship with AstraZeneca: speakers bureau. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Direct access testing (DAT) is an emerging care model that provides on-demand laboratory services for certain preventative, diagnostic, and monitoring indications. Unlike conventional testing models where health care providers order tests and where sample collection is performed onsite at the clinic or laboratory, most interactions between DAT consumers and the laboratory are virtual. Tests are ordered and results delivered online, and specimens are frequently self-collected at home with virtual support. Thus, DAT depends on high-quality information technology (IT) tools and optimized data utilization to a greater degree than conventional laboratory testing. This review critically discusses the United States DAT landscape in relation to IT to highlight digital challenges and opportunities for consumers, health care systems, providers, and laboratories. DAT offers consumers increased autonomy over the testing experience, cost, and data sharing, but the current capacity to integrate DAT as a care option into the conventional patient-provider model is lacking and will require innovative approaches to accommodate. Likewise, both consumers and health care providers need transparent information about the quality of DAT laboratories and clinical decision support to optimize appropriate use of DAT as a part of comprehensive care. Interoperability barriers will require intentional approaches to integrating DAT-derived data into the electronic health records of health systems nationally. This includes ensuring the laboratory results are appropriately captured for downstream data analytic pipelines that are used to satisfy population health and research needs. Despite the data- and IT-related challenges for widespread incorporation of DAT into routine health care, DAT has the potential to improve health equity by providing versatile, discreet, and affordable testing options for patients who have been marginalized by the current limitations of health care delivery in the United States.

While the incidence of infections with the human immunodeficiency virus largely remained unchanged in Germany, an increase of other sexually transmitted infections (STIs) was observed. The aim was to analyse the effectiveness of our sexual education lecture for students in improving the awareness, knowledge and prevention of STIs. We conducted a cross-sectional survey after students had attended our extra-curricular lecture at the Department of Dermatology of the Ludwig-Maximilians-University of Munich, Germany (LMU). We compared the data with a previously performed study in which the same survey was carried out before the lecture had started. A total of 5866 questionnaires were included in the analysis. After attending the lecture significantly more students were aware of STIs (syphilis: 36.8% (before) vs. 63.5% (after); chlamydia: 30.5% vs. 49.3%; gonorrhoea: 22.4% vs. 38.2%; human papillomaviruses (HPV): 17.7% vs. 30.2%), the transmission pathways of STIs (oral: 36.6% vs. 82.6%; vaginal: 81.8% vs. 97.3%; anal: 42.8% vs. 94.0%; penile: 68.7% vs. 92.1%), knew that the HPV vaccination is directed against a virus (36.8% vs. 56.9%) and were interested in receiving a vaccination (57.7% vs. 78.8%). This study demonstrates the positive educative effects of our lecture for awareness and improved knowledge of STIs. To satisfy the need for a comprehensive sexual education, a combination of school and health facility-based programmes should be implemented as one single lecture cannot convey the entire information about STIs.

Background: Urine albumin-to-creatinine ratio (uACR) is a screening assay for chronic kidney disease (CKD). A value of >30 mg/g is flagged abnormal, but lower ratios have prognostic implications. Thus, to maximize diagnostic utility, urine albumin (uAlb) should be measurable to 3 mg/L to match the lowest creatinine concentration generally utilized (10 mg/dL). Most uAlb assays have lower limits of quantitation (LLOQs) 2- to 4-fold higher. We sought to determine the performance characteristics of a commonly used uAlb assay at 3 mg/L and to evaluate the clinical screening impact of reducing the LLOQ., Methods: Urine was serially diluted to assess uAlb linearity and precision for concentrations near the claimed LLOQ (12 mg/L). Samples (n = 30) with uAlb <12 mg/L were compared between laboratories. Sequential samples (n = 1239) were evaluated for clinical impact of reducing the measuring range to 3 mg/L., Results: The assay was linear to 1.6 mg/L. Interday precision at 3.7 mg/L and 4.3 mg/L was 7.7% and 8.6%, respectively. Minimal bias was observed between labs (y = 1.091x - 0.75; average bias = -0.13 mg/L). Clinical validation demonstrated 501 of 1239 samples (40.4%) had uAlb <12 mg/L. Using 11.9 mg/L as the numerator for samples with uAlb <12 mg/dL and urine creatinine >10 mg/L, 107 of 499 (21.4%) would have a ratio flagged abnormal at >30 mg/g. Using the numeric value for these samples to 3 mg/L reduced alarm to <1%., Conclusions: A uAlb LLOQ of 3 mg/L improves screening utility of uACR by simplifying reporting and clinical interpretation when uAlb is low and provides clinical information for prognostic tools developed for people at risk of CKD., Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: D.N. Greene, The Journal of Applied Laboratory Medicine, AACC, committee appointments in AACC and CAP; M.A Marzinke, committees for AACC, CoMACC, and American Board for Clinical Chemistry. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: D.N. Greene, Mayo Clinic, ASCP; M.A Marzinke, AACC; M.P. Hoenig, PriMED. Research Funding: M.A Marzinke, NIH, ViiV Healthcare, Gilead, and Merck. Expert Testimony: None declared. Patents: None declared. Other Remuneration: D.N. Greene, travel support from AACC, ASCP, and CAP; M.A Marzinke, royalties from Elsevier, travel funding from AACC, MSACL, and University of Utah; M.P. Hoenig, travel funding from AACC., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany., Patients: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020., Results: A total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue., Conclusion: This real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies., (Copyright © 2022. Published by Elsevier Inc.)

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objectives: Despite numerous information sources and campaigns on sexually transmitted infections (STIs), there has been an increase in STIs in Germany in recent years. The aim was to evaluate the awareness and knowledge level among young students in Bavaria/Germany for STIs with a focus on human papilloma viruses (HPV)., Methods: In a cross-sectional survey rendered completely and irreversibly anonymous, a total of 4,100 students from Bavaria between the ages of 12 and 17 were interviewed using a multiple choice questionnaire about their knowledge and awareness of STI, on the basis of gender, school education and preventive youth health examinations that had taken place., Results: A total of 3,834 questionnaires were included in the data analysis. Interestingly, the awareness level for HPV is remarkably lower compared to other STIs. Girls and adolescents who had already taken preventive youth health examinations showed a higher knowledge of STIs on average. Additionally, we could show that adolescents of lower educational levels, such as secondary school students, had the least knowledge., Conclusions: The cross-sectional study shows that many young people are still insufficiently informed about STIs. The gaps in information and lack of knowledge underline the necessity of intensive and long-term educational work., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Phage display technology (PD) is a powerful technique for the generation of tumor‑targeting antibodies. However, there are a number of different selection methods established in different laboratories around the world. Cell‑based PD panning methods using primary tumor cells are particularly heterogeneous between laboratories, which can lead to inconsistent results. Therefore, the present study evaluated different cell‑based PD selection methods regarding their potential to generate acute myeloid leukemia (AML) blast‑binding antibodies. In addition to this evaluation, the present study improved the PD procedure by optimizing selection as well as depletion strategies. To the best of our knowledge, the current study demonstrated for the first time that antigen diversity during the depletion step is of importance for the enrichment of tumor‑targeting phage antibodies. It is demonstrated that medium levels of depletion antigen diversity led to the most promising antibody candidates. In addition, it was determined that purification of blast cells from patients with AML by immunomagnetic separation ameliorated the selection of AML‑binding phages during panning. Furthermore, suggesting a common design‑related mechanism using a 'single‑pot' PD library, such as the well‑known Tomlinson single‑chain fragment variable (scFv) library, the present study identified specific binding consensus phage particles in independent panning procedures. By means of these optimized strategies, four promising AML blast‑binding phage particles were isolated and soluble scFv‑Fc (scFv cloned to a fragment crystallizable of an IgG2a mouse antibody) fusion proteins were produced. These scFv‑Fc antibodies bound the surface of AML blasts and were successfully internalized into their cytoplasm, indicating that they are potential immunoconjugate candidates for AML immunotherapy.

Objective: We evaluated the outcomes and complications of transcarotid artery revascularization (TCAR) outside of academic vascular surgery programs., Methods: An institutional review board-approved retrospective study was performed. Data from all cases of TCAR performed at a community hospital from May 2017 to February 2020 were collected and analyzed. Seven vascular surgeons performed the procedures after receiving appropriate training. The primary outcomes included technical success, the need for further revascularization, and major adverse events (death, cerebrovascular accident [CVA], myocardial infarction). The secondary outcomes included other adverse events and complications. The outcomes were assessed in the perioperative and 30-day follow-up periods., Results: During a 33-month period, TCAR was completed in 147 of 149 attempted cases (98.7%). No patients required further revascularization. The perioperative and 30-day major adverse event rates were 0.7% (n = 1) and 3.4% (n = 5), respectively. One case of a minor perioperative CVA occurred. At 30 days, one patient had died. The 30-day complications included CVA (n = 1) and myocardial infarction (n = 3). The combined perioperative and 30-day minor complication rates were 2.7% and 1.4%, respectively., Conclusions: TCAR is a safe and effective method of carotid artery revascularization in a community hospital setting. This technology might help improve revascularization in patients without access to larger academic centers., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs., (© 2021 by The American Society of Hematology.)

Purpose: For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10-15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated., Patients and Methods: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS)., Results: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high- and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44-0.97; P = 0.032), 36% and 23% of patients had stringent CR as best response ( P = 0.08), and 4-year OS was 79% and 67% ( P = 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-of-life (QoL) scores in both arms were similar., Conclusions: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up- and down-titration for each patient to the current maximum tolerated dose is prudent., (©2020 American Association for Cancer Research.)

Background: The Food and Drug Administration recommends that retrievable inferior vena cava filters (IVCFs) be removed 29-54 days postinsertion. Nationally, the retrieval rate is around 23-25%. The objectives of this study are to assess the effect of a plan for IVCF retrieval and access to an office endovascular center (OEC) on filter removal rates and to assess the safety of the procedure in an OEC., Methods: In this institutional review board-exempt retrospective study, the medical records of all patients who had an IVCF placed or removed in the hospital and OEC setting by one group of vascular surgeons between January 2011 and February 2017 were analyzed. Informed consent was not required for this retrospective chart review. The following data were abstracted: filter model, procedure site, retrieval plan, number of removal attempts, complications attributed to removal, success of removal, and the duration that the filter was in place. Anticoagulation was not discontinued before filter retrieval. Filters were removed under local anesthesia with or without mild conscious sedation., Results: IVCF removal was attempted in all eligible patients, 120 of 191 with IVCFs, whereas 71 patients were lost to follow-up (46), died (19), or the indication changed (6). Of the patients who had filters placed in the hospital (n = 161), 62% were removed (n = 101), of which 86% had a removal attempt in the OEC, whereas 14% had the filter removed in the hospital. Sixty-three percent of patients who had filters placed in the OEC (n = 30) had the filter removed in the OEC (n = 19). All patients with a newly placed filter were given an office appointment with a vascular surgeon for evaluation and removal planning. Of patients who had their filter removed at the OEC, all were removed via the jugular approach, resulting in 103 of 106 (97%) successful removals in the OEC. Visipaque (GE Healthcare, Chicago, IL) contrast was used during filter removal. Intravascular ultrasound was not used because the study predates the insurance coverage of this technology in the office laboratory. There was no mortality related to filter removal. In addition, there were no bleeding complications, despite patients remaining on anticoagulant therapy during the removal. In 4% of patients, the filter was removed in less than 3 weeks, 30% of patients between 3 and 6 weeks, 26% of patients between 6 weeks and 3 months, and 40% of patients after 3 months., Conclusions: Having access to both an OEC and a documented retrieval plan increases the frequency of IVCF removal in a community compared with national rates. Retrievable filters can be safely removed in an OEC with extremely high success and safety. Anticoagulation therapy can be continued during retrieval attempt without increased risk of bleeding., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the safety and effectiveness of infrainguinal artery revascularization via atherectomy supplemented with other endovascular techniques in an office endovascular center (OEC) setting., Methods: A retrospective study was conducted examining 352 lower extremity atherectomy revascularization procedures between 2011 and 2016 at an OEC by five board-certified vascular surgeons. Patients received laser atherectomy or orbital atherectomy followed by angioplasty or angioplasty and stent placement as needed. Reintervention was indicated based on evidence of clinical symptoms and imaging studies. Demographics, vessel-specific data, treatment information, and outcome of procedures were recorded. Data analysis was carried out using Kaplan-Meier survival curves., Results: Lower extremity atherectomy was carried out in 282 patients in 352 limbs with average age of 69 ± 11 years. Technical success of <30% residual stenosis by angiogram was achieved in 571/594 vessels treated. Within 30 days of procedure, 23/352 limbs required major amputation resulting from pre-existing disease, ranging from 3 Rutherford class 4, 17 Rutherford class 5, to 3 Rutherford class 6 limbs. No 30-day mortality was noted. The primary patency of the 571 treated vessels at 12 months was 90%, and 84% at 29 months. The patency of treated vessels that reached >50% stenosis on follow-up and required reintervention (51/571 vessels) or did not require reintervention (79/571) was 72% and 87% at 23 months' follow-up, respectively, with no difference in risk of occlusion identified (P = .181). There was a significantly increased risk of occlusion for vessels treated with laser atherectomy as compared with orbital atherectomy (odds ratio, 2.552; 95% confidence interval, 1.375-4.735; P = .003). No significant difference in risk of occlusion was found between treatment with atherectomy and angioplasty (466/571 vessels) compared with atherectomy, angioplasty, and stenting (102/571) with secondary patency of 90% and 85% at 6 months' follow-up, respectively. There was no difference in patency between claudicants and patients with critical limb ischemia., Conclusions: Atherectomy in conjunction with angioplasty and/or stenting has satisfactory patency with minimal complications when the procedure is carried out in an OEC. Asymptomatic >50% restenosis of treated vessels does not warrant reintervention unless the patient presents with clinical symptoms. Various atherectomy devices may result in different outcomes., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

Patients who develop severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (alloSCT) have a higher risk for invasive fungal infection (IFI). At our center, fluconazole prophylaxis is standard and upfront mold-effective prophylaxis performed only in patients with specific risk constellations. A total of 290 patients undergoing alloSCT between May 2002 and August 2011 were analyzed. Patients were regarded as high-risk if they suffered from acute GvHD II-IV° or extensive chronic GvHD. The 2-year incidence of an IFI after alloSCT was 8.97% (26/290) in the entire cohort and 7.78% (7/90) in the high-risk group. Mortality due to IFI was 3.85% (1/26) without including a high-risk patient. In the multivariate analysis a pre-transplant fungal infection was the only significant risk factor for developing an IFI after alloSCT (HR = 5.298; p  = .001). A fluconazole prophylaxis in patients with GvHD after alloSCT is feasible in facilities with HEPA filtration and high awareness of clinical signs for IFI.

Objective: The objective of this study was to evaluate the safety and efficacy of a retrograde tibial approach in revascularization of lower extremities for treatment of ischemia in anatomically challenging patients., Methods: This is a retrospective study of 57 procedures performed between 2012 and 2016 using the retrograde approach to treat patients with flush occlusion, inability to cross the lesion, failed bypass, or hostile groin. Demographic data, Rutherford classes, vessels treated, and approach were noted. Type of procedure, complications, amputations, deaths, and patency of access tibial vessels and treated vessels were recorded. Ultrasound-guided tibial access was achieved through the anterior tibial artery, posterior tibial artery, or peroneal artery. Technical success was defined as residual stenosis of <30%. Restenosis was defined as two times increase in velocity at the site of treatment. In follow-up, access vessel patency and treated vessel patency were evaluated by physical examination and ultrasound. Kaplan-Meier survival curves were used to assess proportional hazards before using the marginal Cox model to determine statistical significance in risk of postintervention occlusion., Results: In 53 patients (32 men) with an average age of 67 ± 10.6 years, Rutherford categories were as follows: class 2, n = 1; class 3, n = 37; class 4, n = 5; class 5, n = 12; and class 6, n = 2. Tibial arteries were successfully accessed in all limbs. Lesions were crossed in 56 of 57 limbs. One procedure was terminated because of local arterial dissection. Revascularization was achieved in 55 of 57 limbs. Within 30 days of the procedure, 2 of 2 Rutherford class 6 patients and 1 of 12 class 5 patients needed major amputation because of pre-existing disease. There was no 30-day mortality. Of 103 vessels treated, technical success was achieved in 97 (94%). Secondary patency for 103 vessels was 79% with mean follow-up of 6.66 ± 5.4 months. The primary patency was 90% compared with a primary assisted patency of 51%. There was no statistically significant difference in access vessel primary patency in follow-up: 86% (30/35) for anterior tibial artery, 80% (16/20) for posterior tibial artery, and 100% (2/2) for peroneal artery. In addition, in follow-up, there was no significant difference in incidence of occlusion of target vessels based on choice of access vessel used (P = .109)., Conclusions: In this group of anatomically challenging patients, a retrograde tibial approach was safely used. Accessing the tibial artery does not usually cause access vessel occlusion and resulted in no adverse outcomes. The majority of access vessels remained patent for future bypass if necessary., (Copyright © 2018 Society for Vascular Surgery. All rights reserved.)

Background: Although intensified chemotherapy regimens have improved tumour control and survival in advanced-stage Hodgkin's lymphoma, data on the long-term sequelae are scarce. We did preplanned follow-up analyses of the German Hodgkin Study Group (GHSG) trials HD9 and HD12 to assess whether the primary results of these trials-which had shown that intensive initial therapy in advanced-stage Hodgkin's lymphoma has a beneficial effect on treatment outcomes-would continue with longer follow-up., Methods: In HD9 (Feb 1, 1993, to March 10, 1998), 1282 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight alternating cycles of COPP and ABVD (COPP/ABVD), eight cycles of bBEACOPP, or eight cycles of eBEACOPP. In HD12 (Jan 4, 1999, to Jan 13, 2003; registered with ClinicalTrials.gov [NCT00265031]), 1670 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy, to analyse two non-inferiority objectives. In both trials, randomisation was done centrally in the GHSG trial coordination centre using the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease. Patients and investigators were not masked to treatment allocation. All analyses were done on the intention-to-treat principle. The primary endpoint of this follow-up analysis was progression-free survival (time from first diagnosis to progressive disease, relapse, or death from any cause or censoring at the date of last information on disease status). To assess whether long-term outcome might be impaired by long-term sequelae, we analysed overall survival and second primary malignant neoplasm incidence as key secondary endpoints., Findings: Median observation time was 141 months (IQR 101-204) in HD9 and 97 months (69-143) in HD12. For HD9 trial patients, 15-year progression-free survival was 57·0% (95% CI 50·0-64·0) for COPP/ABVD, 66·8% (61·9-71·8) for bBEACOPP, and 74·0% (69·0-79·0) for eBEACOPP, 15-year overall survival was 72·3% (95% CI 66·5-78·1), 74·5% (70·1-78·9), and 80·9% (76·7-85·0), respectively. Progression-free survival and overall survival in the eBEACOPP group remained significantly better than in the COPP/ABVD group (hazard ratio [HR] 0·53, 95% CI 0·41-0·69, p<0·0001, and 0·68, 0·50-0·93, p=0·015, respectively). The 15-year cumulative incidence of second primary malignant neoplasms was 7·2% (95% CI 3·7-10·7) after COPP/ABVD, 13·0% (9·1-16·9) after bBEACOPP, and 11·4% (7·6-15·1) after eBEACOPP. For HD12 trial patients, non-inferiority of 4 + 4 was shown, with 10-year progression-free survival of 82·6% (95% CI 79·6-85·6) for eBEACOPP and 80·6% (77·4-83·7) for 4 + 4 (HR 1·13 [0·89-1·43], within non-inferiority margin of 1·50), and 10-year overall survival of 87·3% (95% CI 84·7-89·9) and 86·8% (84·2-89·4), respectively (HR 1·02 [95% CI 0·77-1·36]). Among 555 (37%) patients with residual disease after chemotherapy, omission of radiotherapy was associated with significantly worse 10-year progression-free survival (89·7% [95% CI 85·8-93·6] radiotherapy vs 83·4% [78·2-88·5] for no radiotherapy; p=0·027) and 10-year overall survival (94·4% [91·4-97·3] vs 88·4% [83·8-93·0]; p=0·025). 10-year cumulative second primary malignant neoplasms incidence was 6·4% (95% CI 3·3-9·5) for 4 + 4 and 8·8% (5·2-12·4) for eBEACOPP., Interpretation: Long-term follow-up of HD9 and HD12 shows an ongoing benefit of intensive first-line treatment and consolidation radiotherapy to residual disease in terms of progression-free survival and overall survival. Our results support the use of eBEACOPP in advanced-stage Hodgkin's lymphoma. However, because late toxicities such as second primary malignant neoplasms contribute to mortality, less toxic but equally effective treatments need to be developed to further improve overall survival., Funding: Deutsche Krebshilfe e.V., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Current treatment of patient with mantle cell lymphoma (MCL) is insufficient and does not result in cure. To assess the efficacy and safety of maintenance therapy for patients with MCL, we performed a systematic review and meta-analysis of randomized controlled trials. Six trials randomizing 858 patients were included in the meta-analysis. In 5 trials, maintenance therapy consisted of rituximab. The pooled hazard ratio (HR) of death with rituximab maintenance compared to observation was 0.79, 95% CI 0.58 to 1.06 (4 trials, 737 patients). Progression free survival was longer with rituximab maintenance in each of the trials and in the pooled analysis (HR 0.58, 95% CI 0.45-0.73). The risk of neutropenia was higher with maintenance compared to observation risk ratio (RR) 1.31, 95% CI 1.03 to 1.66. None of the trials reported on quality of life outcomes. The grade 3 to 4 infection rate was 7% in each of the treatment groups. The risk of grade 3 to 4 infection was not affected by allocation to maintenance. Rituximab maintenance is recommended after R-CHOP or R-cytarabine-containing induction in the frontline setting for transplant eligible and ineligible patients, and after R-CHOP in the relapse setting. It is unclear if maintenance is of benefit after different induction chemotherapy such as bendamustine or fludarabine. It is too early to conclude on other type of maintenance for MCL patients., (Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Myelodysplastic syndromes are hematological neoplasias in which immunohistologic examination of bone marrow trephines is important for a definite diagnosis. Unequivocal distinction from reactive bone marrow changes is, however, sometimes difficult. Because neoplastic clones in myelodysplastic syndrome carry mutations in recurrent genes, mutation detection by targeted next-generation sequencing may be a useful support for differential diagnosis. To elucidate the accuracy of this approach in the clinical diagnostic setting, we analyzed single and consecutive bone marrow trephines processed for immunohistologic examination from 145 patients by targeted next-generation sequencing of 12 genes recurrently mutated in myelodysplastic syndromes. Of 110 patients with immunohistologic unequivocal diagnosis, 41 of 47 with myelodysplastic syndrome carried mutations. In 14 consecutive samples available from these patients, remissions were accompanied by loss of mutations and ongoing disease with persisting mutations. Of 35 samples with indefinite immunohistologic appearance, 22 developed clinical unequivocal myelodysplastic syndrome in the further course, and 19 carried mutations already in the initial biopsy, which persisted in consecutive samples available from 13 patients. No mutation was detected in any initial and consecutive sample of 13 patients with indefinite immunohistologic appearance without clinical unequivocal myelodysplastic syndrome in the further course. We conclude that targeted next-generation sequencing is an accurate tool for differential diagnosis of myelodysplastic syndrome in the clinical diagnostic setting., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy., Methods: HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m 2 on day 1 plus cytarabine 2 g/m 2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m 2 on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m 2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m 2 on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920., Findings: Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT., Interpretation: WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision., Funding: Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rituximab (MabThera ® /Rituxan ® ), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies. A subcutaneous (SC) formulation of rituximab has been developed, comprising the same monoclonal antibody as the originally marketed formulation [rituximab concentrate for solution for intravenous (IV) infusion], and has undergone a detailed, sequential clinical development program. This program demonstrated that, at fixed doses, rituximab SC achieves non-inferior serum trough concentrations in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia, with comparable efficacy and safety relative to the IV formulation. The added benefit of rituximab SC was demonstrated in dedicated studies showing that rituximab SC allows for simplified and shortened drug preparation and administration times resulting in a reduced treatment burden for patients as well as improved resource utilization (efficiency) at the treatment facility. The improved efficiency of delivering rituximab's benefit to patients may broaden patient access to rituximab therapy in areas with low levels of healthcare resources, including IV-chair capacity constraints. This article is a companion paper to G. Salles, et al., which is also published in this issue., Funding: F. Hoffmann-La Roche Ltd.

Obesity is a well-known risk factor for the development of cancer, but its influence on the course of disease is still controversial. We investigated the influence of body mass index (BMI) on overall survival (OS) in 502 patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma in a subgroup analysis of the StiL (Study Group Indolent Lymphomas) NHL1 trial. We defined a cut-off of 22.55 kg/m 2 by ROC calculation and Youden Index analysis and stratified patients into "low BMI" and "high BMI". Five-year OS was significantly longer in the high BMI group (82.2%) when compared to that of the low BMI group (66.2%) (HR 0.597; 95%CI 0.370-0.963; p = 0.034). BMI was also an independent prognostic factor for OS in multivariate analysis (HR 0.541; 95%CI 0.332-0.883; p = 0.014). Of note, patients had a significantly lower BMI in the presence than patients in the absence of B-symptoms (p = 0.025). BMI significantly impacts on OS in indolent non-Hodgkin's lymphoma and mantle cell lymphoma, which may be influenced by the effect of B-symptoms on BMI.

Background: The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL)., Patients and Methods: Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8., Results: At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected., Conclusion: Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration., Registered Clinical Trial Number: NCT01724021 (ClinicalTrials.gov)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM., (© 2016 by The American Society of Hematology.)

Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975)., (Copyright© Ferrata Storti Foundation.)

Background: Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma., Methods: For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m(2), day 1) plus either bendamustine (90 mg/m(2), days 1 and 2) or fludarabine (25 mg/m(2), days 1-3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0-2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m(2) every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing)., Findings: Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0·76 (95% CI 0·68-0·84) and 0·48 (0·39-0·58) with fludarabine plus rituximab (non-inferiority p<0·0001). At a median follow-up of 96 months (IQR 73·2-112·9), median progression-free survival with bendamustine plus rituximab was 34·2 months (95% CI 23·5-52·7) and 11·7 months (8·0-16·1) with fludarabine plus rituximab (hazard ratio [HR] 0·54 [95% CI 0·38-0·72], log-rank test p<0·0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections., Interpretation: In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas., Funding: Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Many patients with autoimmune hemolytic anemia (AIHA) do not respond to standard therapy and/or may develop severe complications which can be of fatal outcome. There is some evidence that erythropoiesis-stimulating agents (ESAs) may be helpful in the management of such patients., Methods: We describe the effect of ESAs in 12 new patients with therapy-refractory AIHA (7 of warm type and 5 of cold type) and review 5 previously reported cases. Serological testing was performed using standard methods., Results: All patients responded well to treatment with ESAs. At least 5 of the 17 patients demonstrated complete recovery, and none of the patients developed significant adverse reactions due to treatment with ESAs., Conclusion: The mechanism by which ESAs improves hemolysis in AIHA is not completely clear. In addition to increased production and prolonged RBC survival, it may inhibit eryptosis (programmed cell death). ESAs represent a new option in the treatment of decompensated and/or refractory AIHA of warm and cold type. However, more information is required to assess which patients can be treated with ESAs.

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation. Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients. In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients. We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Immune thrombocytopenia (ITP) is a bleeding disorder caused by IgG autoantibodies (AAbs) directed against platelets (PLTs). IgG effector functions depend on their Fc-constant region which undergoes posttranslational glycosylation. We investigated the role of Asn279-linked N-glycan of AAbs in vitro and in vivo. AAbs were purified from ITP patients (n=15) and N-glycans were enzymatically cleaved by endoglycosidase F. The effects of native AAbs and deglycosylated AAbs were compared in vitro on enhancement of phagocytosis of platelets by monocytes and complement fixation and activation applying flow cytometry, laser scanning microscopy, and a complement consumption assay. AAb-induced platelet phagocytosis was inhibited by N-glycan cleavage (median phagocytic activity: 8% vs 0.8%, p=0.004). Seven out of 15 native AAbs bound C1q and activated complement. N-glycan cleavage significantly reduced both effects. In vivo survival of human PLTs was assessed after co-transfusion with native or N-glycan cleaved AAbs in a NOD/SCID mouse model. Injection of AAbs resulted in rapid clearance of human platelets compared to control (platelet clearance after 5h (CL(5h))75% vs 30%, p<0.001). AAbs that were able to activate complement induced more pronounced platelet clearance in the presence of complement compared to the clearance in the absence of complement (CL(5h) 82% vs 62%, p=0.003). AAbs lost their ability to destroy platelets in vivo after deglycosylation (CL(5h) 42%, p<0.001). N-glycosylation of human ITP AAbs appears to be required for platelet phagocytosis and complement activation, reducing platelet survival in vivo. Posttranslational modification of AAbs may constitute an important determinant for the clinical manifestation of ITP.

Our knowledge about the mechanisms of human motor cortex facilitation induced by repetitive transcranial magnetic stimulation (rTMS) is still incomplete. Here we used pharmacological conditioning with carbamazepine, dextrometorphan, lorazepam, and placebo to elucidate the type of plasticity underlying this facilitation, and to probe if mechanisms reminiscent of long-term potentiation are involved. Over the primary motor cortex of 10 healthy subjects, we applied biphasic rTMS pulses of effective posterior current direction in the brain. We used six blocks of 200 pulses at 5-Hz frequency and 90% active motor threshold intensity and controlled for corticospinal excitability changes using motor-evoked potential (MEP) amplitudes and latencies elicited by suprathreshold pulses before, in between, and after rTMS. Target muscle was the dominant abductor digiti minimi muscle; we coregistered the dominant extensor carpi radialis muscle. We found a lasting facilitation induced by this type of rTMS. The GABAergic medication lorazepam and to a lesser extent the ion channel blocker carbamazepine reduced the MEP facilitation after biphasic effective posteriorly oriented rTMS, whereas the N-methyl-d-aspartate receptor-antagonist dextrometorphan had no effect. Our main conclusion is that the mechanism of the facilitation induced by biphasic effective posterior rTMS is more likely posttetanic potentiation than long-term potentiation. Additional findings were prolonged MEP latency under carbamazepine, consistent with sodium channel blockade, and larger MEP amplitudes from extensor carpi radialis under lorazepam, suggesting GABAergic involvement in the center-surround balance of excitability.

Romiplostim was effective, safe, and well-tolerated over 6-12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia (ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long-term, single-arm, open-label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50 × 10(9) per litre), and the proportion of patients requiring rescue treatments. Treatment-related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6.5% of patients and were not associated with platelet count. Median platelet counts of 50-200 × 10(9) per litre were maintained with stable doses of romiplostim (mean 5-8 μg/kg; generally self-administered at home) throughout the study. A platelet response was achieved at least once by 95% of patients, with a platelet response maintained by all patients on a median 92% of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and well-tolerated over 614 patient-years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment., (© 2013 Blackwell Publishing Ltd.)

In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log(10)(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

The treatment of hematologic patients in palliative situations remains a major challenge as there are special clinical needs, e.g., transfusions and the high risk for infectious complications with subsequent use of broad anti-infective treatment. Furthermore, most hematologic patients have a relatively long history of disease and are acquainted with "their" wards; that is why most are treated on these hematologic and not on specialized palliative wards. The standardized approach to the care of hematologic patients with curative treatment intention is probably not fully appropriate for palliative patients. In order to evaluate the current situation of treatment characteristics in a German university hospital, we retrospectively evaluated the medical documentation of all patients who died on a hematologic ward between 2005 and 2008. While we found a high number of chemotherapeutic, anti-infective, analgesic, and sedative treatments, of transfusions, of treatment on the intensive care units, and of invasive nature, non-somatic interventions were rather scarce. Symptom control, e.g., for bleeding events or pain, was frequently not adequately achieved. With regard to the palliative situation, a holistic approach with the maintenance of patients' autonomy and the preference for dying at home, the treatment of hematologic patients in a palliative situation has to be reconsidered.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet destruction and insufficient platelet production. The resulting thrombocytopenia reduces patient health-related quality of life (HRQOL). In a randomized, open-label, 52-week study of non-splenectomized ITP patients treated with romiplostim or medical standard of care (SOC), patients completed the 10-scale ITP-patient assessment questionnaire (PAQ) at the start of the study and after 12, 24, 36, 48,and 52 weeks of treatment. HRQOL changes were examined for all patients in both treatment groups and by responder status, splenectomy status, and after the use of rituximab. Patients in both groups showed marked increases in all HRQOL scales over 52 weeks of treatment.These change scores exceeded the minimally important difference values (a measure of clinical relevance) for most of these scales,especially in responders to treatment. Compared with baseline,patients receiving romiplostim showed statistically significant improvements compared to SOC over 52 weeks for the ITP-PAQ scales of Symptoms, Bother, Activity, Psychological Health, Fear, Overall QOL,and Social QOL. Overall, treatment of ITP was associated with improvement in HRQOL. Patients receiving romiplostim had greater HRQOL improvements than those receiving SOC, but the magnitude ofthe difference is of uncertain clinical benefit.