Repeat or single-dose lentiviral vector administration to mouse lungs? It's all about the timing.

Lentiviral vectors are attractive delivery vehicles for cystic fibrosis gene therapy owing to their low immunogenicity and ability to integrate into the host cell genome, thereby producing long-term, stable gene expression. Nonetheless, repeat dosing may be required to increase initial expression levels, and/or boost levels when they wane. The primary aim of this study was to determine if repeat dosing of a VSV-G pseudotyped LV vector delivered into mouse lungs is more effective than a single dose.

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.

Background: We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells.

Regional control after precision lymph node dissection for clinically evident melanoma metastasis.

Introduction: Completion lymph node dissection (CLND) for microscopic lymph node metastases has been replaced by observation; however, CLND is standard for clinically detectable nodal metastases (cLN). CLND has high morbidity, which may be reduced by excision of only the cLN (precision lymph node dissection [PLND]). We hypothesized that same-basin recurrence risk would be low after PLND.

Immobilization of Wnt Fragment Peptides on Magnetic Nanoparticles or Synthetic Surfaces Regulate Wnt Signaling Kinetics.

Wnt signaling plays an important role in embryogenesis and adult stem cell homeostasis. Its diminished activation is implicated in osteoporosis and degenerative neural diseases. However, systematic administration of Wnt-signaling agonists carries risk, as aberrantly activated Wnt/β-catenin signaling is linked to cancer.

Spatial biology analysis reveals B cell follicles in secondary lymphoid structures may regulate anti-tumor responses at initial melanoma diagnosis.

Introduction: B cells are key regulators of immune responses in melanoma. We aimed to explore differences in the histologic location and activation status of B cell follicles in sentinel lymph nodes (SLN) of melanoma patients.

Methods: Flow cytometry was performed on fresh tumor draining lymph nodes (LN).

Alert-Triggered Patient Education Versus Nurse Feedback for Nonadministered Venous Thromboembolism Prophylaxis Doses: A Cluster-Randomized Controlled Trial.

Background Many hospitalized patients are not administered prescribed doses of pharmacologic venous thromboembolism prophylaxis. Methods and Results In this cluster-randomized controlled trial, all adult non-intensive care units (10 medical, 6 surgical) in 1 academic hospital were randomized to either a real-time, electronic alert-triggered, patient-centered education bundle intervention or nurse feedback intervention to evaluate their effectiveness for reducing nonadministration of venous thromboembolism prophylaxis. Primary outcome was the proportion of nonadministered doses of prescribed pharmacologic prophylaxis.

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers.

Examining the role of wide excision margins in pediatric melanoma: A National Cancer Database analysis.

Background: Although adult guidelines are often applied to children, age-specific surgical margins have not been defined for pediatric melanoma.

Procedure: Patients <20 years of age with invasive, cutaneous melanoma were identified using the 2004-2016 National Cancer Database and categorized as undergoing wide (>1 cm) or narrow (≤1 cm) excision. Unadjusted overall survival (OS) was compared using the Kaplan-Meier method and log-rank test.

Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies.

SETD2, a lysine -methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation.

Cost-effectiveness of Pulmonary Rehabilitation Among US Adults With Chronic Obstructive Pulmonary Disease.

Importance: Pulmonary rehabilitation (PR) after exacerbation of chronic obstructive pulmonary disease (COPD) is effective in reducing COPD hospitalizations and mortality while improving health-related quality of life, yet use of PR remains low. Estimates of the cost-effectiveness of PR in this setting could inform policies to improve uptake.

Objective: To estimate the cost-effectiveness of participation in PR after hospitalization for COPD.

Surgical Evaluation in Patients Undergoing Radiation Therapy for Early-Stage Lung Cancer.

Background: Stereotactic body radiation therapy (SBRT) is used to treat stage I non-small cell lung cancer (NSCLC) in nonsurgical candidates, although guidelines specify that inoperability be determined in multidisciplinary fashion. We characterized NSCLC patients treated with SBRT undergoing thoracic surgical evaluation (TSUe) and quantified TSUe's impact on time to treatment, receipt of diagnostic staging procedures, and health care costs.

Methods: Adults with newly diagnosed NSCLC undergoing SBRT were identified in the MarketScan all-payer claims database (2014-2018).

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

Objective: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma.

Summary Background Data: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization.

Surgical resection is associated with improved long-term survival of patients with resectable pancreatic head cancer compared to multiagent chemotherapy.

Background: Standard of care for resectable pancreatic cancer is a combination of surgical resection (SR) and multiagent chemotherapy (MCT). We aim to determine whether SR or MCT is associated with superior survival for patients receiving only single-modality therapy.

Methods: Patients with stage I-IIb pancreatic head adenocarcinoma who received either MCT or SR were identified in the NCDB (2013-2015).

How much time is enough? Sentinel lymph node mapping time depends on the radiotracer agent.

Background: In 2014, technetium-99m tilmanocept (TcTM) replaced technetium-99m sulfur colloid (TcSC) as the standard lymphoscintigraphy (LS) mapping agent in melanoma patients undergoing sentinel lymph node biopsy (SLNB). The aim of this study was to examine differences in mapping time, intra-operative identification of sentinel lymph node (SLN), and false negative rate (FNR) between patients who underwent SLNB with TcTM compared to TcSC.

Methods: Patients who underwent SLNB between 2010 and 2018 were retrospectively identified.

Acral Lentiginous Melanoma: A United States Multi-Center Substage Survival Analysis.

Background: Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care.

Objectives: To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients.

Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies.

SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as a target of interest in certain hematological malignancies, including multiple myeloma. This account details the discovery of , a novel and potent SETD2 inhibitor with a high selectivity over other histone methyltransferases. A screening campaign of the Epizyme proprietary histone methyltransferase-biased library identified potential leads based on a 2-amidoindole core.

Lung Cancer Screening Eligibility and Use: A Population Health Perspective of One Community.

Low-dose chest CT (LDCT) is the only effective screening test for lung cancer. Annual lung cancer screening (LCS) is recommended by the US Preventive Services Task Force (USPSTF) for individuals at high risk for primary lung neoplasm. We retrospectively identified patients receiving LCS from January 2016 through March 2018 whose residential addresses were within our health center's county.

Indole Inhibitors of MMP-13 for Arthritic Disorders.

Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained.

Constraints on Cosmic Strings Using Data from the Third Advanced LIGO-Virgo Observing Run.

We search for gravitational-wave signals produced by cosmic strings in the Advanced LIGO and Virgo full O3 dataset. Search results are presented for gravitational waves produced by cosmic string loop features such as cusps, kinks, and, for the first time, kink-kink collisions. A template-based search for short-duration transient signals does not yield a detection.

The Impact of Adjuvant Hemithoracic Radiation on Outcomes in Patients With Stage I-III Malignant Pleural Mesothelioma: A Dual Registry Analysis.

Background: The outcomes associated with receipt of adjuvant radiation in patients after surgery for MPM are poorly understood.

Objective: The objective of this study was to use 2 registries to compare the outcomes of patients receiving adjuvant radiation or no radiation after definitive surgery for pathologic stage I-III MPM.

Methods: Patients with resected pathologic stage I-III MPM were identified from the Duke University registry (1996-2016) and National Cancer Database (NCDB) (2004-2015).

Breaching the Delivery Barrier: Chemical and Physical Airway Epithelium Disruption Strategies for Enhancing Lentiviral-Mediated Gene Therapy.

The lungs have evolved complex physical, biological and immunological defences to prevent foreign material from entering the airway epithelial cells. These mechanisms can also affect both viral and non-viral gene transfer agents, and significantly diminish the effectiveness of airway gene-addition therapies. One strategy to overcome the physical barrier properties of the airway is to transiently disturb the integrity of the epithelium prior to delivery of the gene transfer vector.

The Effects of Conditioning and Lentiviral Vector Pseudotype on Short- and Long-Term Airway Reporter Gene Expression in Mice.

A gene addition therapy into the conducting airway epithelium is a potential cure for cystic fibrosis lung disease. Achieving sustained lung gene expression has proven difficult due to the natural barriers of the lung. The development of lentiviral (LV) vectors pseudotyped with viral envelopes that have a natural tropism to the airway has enabled persistent gene expression to be achieved .