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Targeted therapies have revolutionized the frontline treatment landscape for patients with chronic lymphocytic leukemia (CLL) and have largely displaced a reliance on chemoimmunotherapy when treating this disease. Multiple randomized trials have documented the efficacy of oral therapy with the Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib (and zanubrutinib, pending a supplemental new drug application in CLL), as well as BCL2 inhibition using venetoclax. In this review, the authors highlight novel therapeutic strategies for using these agents in combination, either as doublet therapy or as triplet therapy, with anti‐CD20 antibodies. First, the current treatment landscape is outlined, and the data are reviewed for continuous and time‐limited therapeutic approaches, which constitute the current standard of care. Then, more recent reports are described from phase 2 and 3 studies exploring different combination strategies of Bruton tyrosine kinase and BCL2 inhibition for treatment‐naive patients. In addition, relevant differences are emphasized between patient characteristics (e.g., patient fitness and the presence of high‐risk disease features) and study methodology (e.g., dosing schedule, randomization, and assessment of measurable residual disease) across trials. Finally, the authors revisit the currently available data for these approaches in the context of ongoing studies and future planned trials, evaluating their potential impact on the frontline treatment landscape for CLL in the years to come. This review highlights novel therapeutic strategies of using targeted therapeutic agents, including Bruton tyrosine kinase and BCL2 inhibitors as either doublet or triplet therapy, in combination with anti‐CD20 antibodies for patients with chronic lymphocytic leukemia. Recent reports are reviewed from phase 2 and 3 studies exploring different combination strategies of Bruton tyrosine kinase and BCL2 inhibition for treatment‐naive patients. [ABSTRACT FROM AUTHOR]

Dermatologic presentations of orthopedic diseases are commonly encountered in the dermatology clinic. These disorders often necessitate prompt recognition in order to properly refer for definitive treatment as well as to avoid unnecessary diagnostic procedures. As such, the presentations of these diseases as well as the treatments available deserve special attention. This review aims so identify orthopedic diseases with dermatologic presentations and discuss the diagnosis and treatment of these pathologies. In conducting this review, a comprehensive literature search was conducted. Our inquiry was limited to conditions with a unitary orthopedic etiology. By excluding syndromic dysfunctions with both orthopedic and dermatologic manifestations, we were able to create a consistent approach to the review. At the same time, such exclusions created an omission of many important disease processes that require the cooperation of orthopedists and dermatologists. In all, 19 orthopedic disorders and disorder classes with dermatologic findings were identified and carefully examined. The orthopedic pathologies identified require varying diagnostic and therapeutic approaches. While some do not warrant further work-up or referral, the disease course of certain pathologies is drastically altered by timely recognition, cautious diagnostic interrogation, and prompt referral. [ABSTRACT FROM AUTHOR]

Changes to fisheries that result from offshore wind farm (OWF) installations may be considered good or bad depending on various stakeholders' perspectives. OWFs can act as artificial reefs that may benefit secondary fish production, but such effects may also have ecological consequences. The fisheries exclusion effect that turns some OWFs into no-go areas, hence effectively no-take zones, could provide resource enhancements or redistribution. However, the displacement of fishing effort may have consequences to fisheries elsewhere. Changes in the sensory environment related to sound, as well as electromagnetic fields and physical alterations of current and wind wakes, may have as yet unknown impacts on fisheries resources. Understanding the interactions among effect type, OWF development phase, and spatiotemporal population dynamics of commercial and recreational species remains challenging, exemplified by the commercial fishery lobster genus Homarus in European and North American waters. While knowledge of the interactions between resource species and OWFs is improving, there remain questions on the wider interaction between and consequences of OWFs and fisheries. Studies of this wider relevance should aim to improve understanding of the economic and societal impacts of OWFs linked to ecosystem services that support fisheries. Furthermore, assisting fisheries management and providing advice requires monitoring and survey data collection at appropriate spatiotemporal scales. This information will help to determine whether OWFs have any meaningful impact on regional fisheries, and increased investments will be needed to target scientifically appropriate monitoring of OWFs and fisheries, which is supported by better integrated policy and regulation. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing). [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330. [ABSTRACT FROM AUTHOR]

Efforts are in motion globally to address coastal and marine management needs through spatial planning and concomitant seabed habitat mapping. Contrasting strategies are often evident in these processes among local, regional, national and international scientific approaches and policy needs. In answer to such contrasts among its member states, the United States Northeast Regional Ocean Council formed a Habitat Working Group to conduct a regional inventory and comparative evaluation of seabed characterization, classification, and modeling activities in New England. The goals of this effort were to advance regional understanding of ocean habitats and identify opportunities for collaboration. Working closely with the Habitat Working Group, we organized and led the inventory and comparative analysis with a focus on providing processes and tools that can be used by scientists and managers, updated and adapted for future use, and applied in other ocean management regions throughout the world. Visual schematics were a critical component of the comparative analysis and aided discussion among scientists and managers. Regional consensus was reached on a common habitat classification scheme (U.S. Coastal and Marine Ecological Classification Standard) for regional seabed maps. Results and schematics were presented at a region-wide workshop where further steps were taken to initiate collaboration among projects. The workshop culminated in an agreement on a set of future seabed mapping goals for the region. The work presented here may serve as an example to other ocean planning regions in the U.S., Europe or elsewhere seeking to integrate a variety of seabed characterization, classification and modeling activities. [ABSTRACT FROM AUTHOR]

Summary Background Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations. Methods In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov , number NCT01500733 , and is fully enrolled. Findings Between Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12·9–27·0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86–100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0·4 months. 12 (80%; 95% CI 52–96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient. Interpretation The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings. Funding Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc. [ABSTRACT FROM AUTHOR]