Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Using a General Case Management Tool With Partner-violent Men on Community Supervision in Iowa.

Intimate partner violence (IPV) is among the most common acts of violence against women worldwide, making it a major global threat to women's health and safety. The assessment and management of IPV offenders are therefore vital tasks in criminal justice systems. The current study examined whether the DRAOR, a general case management tool, was useful for supervising 112 male IPV offenders in Iowa, United States. Several risk factors emerged as potentially important treatment targets for partner-violent men, including poor attachment with others, substance abuse, anger/hostility, opportunity/access to victims, and problematic interpersonal relationships. While further research is needed to improve the utility of the DRAOR for predicting IPV recidivism, it assesses several factors that are relevant for supervising IPV cases (e.g., substance abuse, anger/hostility, victim access). This suggests the DRAOR could potentially be used to guide case management in the presence of a validated IPV tool that focuses on static risk factors, such as the ODARA. The use of the DRAOR with IPV offenders may also be warranted if they are found to be generally violent/antisocial rather than as family only offenders.

Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline ß2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

Author Correction: High-dose chemotherapy and autologous stem cell transplantation in enteropathy-associated and other aggressive T-cell lymphomas: a UK NCRI/Cancer Research UK Phase II Study.

In the original version of this article, the mention of 'ifosfamide 1500 mg/m2 days 1-3' should, in fact, read 'ifosfamide 1500 mg/m2 bd days 1-3'. This has now been updated in the original version of the article.

Improving Survival of Patients With Hodgkin Lymphoma Over 4 Decades: Experience of the British National Lymphoma Investigation (BNLI) With 6834 Patients.

BACKGROUND: The management of Hodgkin lymphoma (HL) has changed markedly over the last 50 years. This is due to the expanding understanding about the biology of the disease, the development of increasingly efficacious multimodal treatment, and the recognition of how to reduce late effects. The British National Lymphoma Investigation (BNLI) was formed in the 1970s to coordinate UK research in the diagnosis and treatment of lymphoma. We describe the improvement in trial patient survival over 4 decades. PATIENTS AND METHODS: This analysis is of data on 6834 patients with a de novo diagnosis of HL registered onto studies with BNLI oversight from January 1, 1970, to December 31, 2009. Patients were subdivided in 4 groups according to their decade of registration; 1970s, 1980s, 1990s, and 2000s. Because of the lengthy data collection period, there is a difference in duration of follow-up between decade groups, with median follow-up in the 1970s group of 28.2 years, 18.0 years in the 1980s group, 9.4 years in the 1990s group, and 5.4 years in the 2000s group. Comparison between data in all 4 groups is not possible beyond 13.4 years (maximum duration of follow-up in the 2000s group), and so a cutoff has been applied at 14 years. Data on overall survival, cause of death, primary treatment modality, and incidence of secondary malignancy were collected. RESULTS: Clear and statistically significant improvements in survival curves between the decades were present, with 10-year overall survival increasing from 62.4% in the 1970s to 89.6% in the 2000s. There was a suggestion that second malignancy and cardiac-related deaths have been reducing over time, but longer follow-up is needed for the later decades to confirm this trend. CONCLUSION: Results support existing registry data demonstrating that survival for HL has improved over the 4 decades analyzed. This data set is robust and validated, and it adds valuable understanding to the reasons behind the survival curves, which are a balance between efficacious therapies and decreased death related to cardiac conditions and second malignancies.

Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial.

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R-CHOP-14 versus R-CHOP-21 (two- versus three-weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B-cell lymphoma identified from the trial database. At a median follow-up of 7·2 years the 5-year progression-free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R-CHOP-14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.

Using Dynamic Risk to Enhance Conditional Release Decisions in Prisoners to Improve Their Outcomes.

Advances in criminal risk assessment have increased sufficiently that inclusion of valid risk measures to anchor assessments is considered a best practice in release decision-making and community supervision by many paroling authorities and probation agencies. This article highlights how decision accuracy at several key stages of the offender's release and supervision process could be further enhanced by the inclusion of dynamic factors. In cases where the timing of release is discretionary and not legislated, the utilization of a validated decision framework can improve transparency and potentially reduce decision errors. In cases where release is by statute, there is still merit in using dynamic risk assessment and case analysis to inform the assignment of release conditions, thereby attending to re-entry and public safety considerations. Finally, preliminary results from a recent study are presented to highlight the fact that community supervision outcomes may be improved by incorporating changes in dynamic risk into case planning and risk management, although this work requires replication with larger populations reflecting diverse groups of offenders. Nonetheless, these decision strategies have implications for both resource allocation and client outcomes, as outlined here. Copyright © 2016 John Wiley & Sons, Ltd.

T-lymphoblastic leukemia/lymphoma: a single center retrospective study of outcome.

T-lymphoblastic leukemia/lymphoma (LBL and ALL) is a rare lymphoid malignancy typically presenting in adolescent and young adult males. Patients are traditionally treated with ALL-type protocols, with no consensus on the role of maintenance therapy, or allogeneic or autologous transplant. Outcome results are thus difficult to interpret. The successful use of intensified ALL protocols in patients <25 years with lymphoblastic malignancies without transplant prompted the Haematology Unit at St James's Hospital (SJH) to change practice in 2005 from transplanting in first complete remission (CR1) to treating patients <25 years with chemotherapy alone. We reviewed the outcome of patients treated before 2005 in order to compare the pre- and post-2005 management approaches in the future. This retrospective study included 31 patients with T-LBL treated from 1980 to 2004. The patients were divided into group A (16-25 years) and group B (>25 years). Twenty-one patients had an allograft in CR1 (group A, n = 12 and group B, n = 9). For the allografted patients the 5-year EFS and OS was 57%, with a treatment related mortality of 10%. In conclusion, this series confirms that allograft in CR1 has an acceptable cure rate, and we will use these results to benchmark outcomes using pediatric-type protocols in the future.

Large granular lymphocyte leukemia: natural history and response to treatment.

Large granular lymphocyte leukemia (T-LGL) is an indolent T lymphoproliferative disorder that was difficult to diagnose with certainty until clonality testing of the T cell receptor gene became routinely available. We studied the natural history and response to treatment in 25 consecutive patients with T-LGL diagnosed between 2004 and 2008 in which the diagnosis was confirmed by molecular analysis, to define an effective treatment algorithm. The median age at diagnosis was 61 years (range 27-78), with a male to female ratio of 1:1.8 and presenting features of fatigue (n = 13), recurrent infections (n = 9), and/or abnormal blood counts (n = 5). Thirteen patients with symptomatic disease were treated as follows: pentostatin (nine patients), cyclosporine (six patients), methotrexate (three patients), and alemtuzumab in two patients in whom pentostatin was ineffective. Pentostatin was the single most effective therapy, with a response rate of 75% and minimal toxicity. The overall survival (OS) and progression-free survival (PFS) 37 months from diagnosis were 80% and 52%, respectively. Treatment of T-LGL should be reserved for patients with symptomatic disease, but in this series, pentostatin treatment was less toxic and more effective than cyclosporine or methotrexate.