Mutations in gene RASA1 have been historically associated with capillary malformation–arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. ...To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes–Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders.
A number of agents are now approved for the treatment of renal cancer. A comparison of two agents, pazopanib and sunitinib, showed similar levels of antitumor activity but distinct side-effect ...profiles. Symptoms affecting quality of life were somewhat worse with sunitinib.
Renal-cell carcinoma is the most common kidney cancer.
1
Up to 30% of patients have metastases at the time of the initial diagnosis.
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Systemic treatment for patients who have metastatic renal-cell carcinoma with a clear-cell histologic component has shifted from cytokines to drugs targeting angiogenesis. Sunitinib, pazopanib, and five other agents have been approved by the Food and Drug Administration for the treatment of clear-cell, metastatic renal-cell carcinoma.
3
,
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Among the tyrosine kinase inhibitors, pazopanib and sunitinib are first-line treatment options.
Sunitinib has been compared with interferon alfa in patients who had not previously received systemic therapy for renal-cell carcinoma,
5
whereas . . .
The Wound‐QoL is an often used reliable and valid measure, originally developed in Germany. It has been sequentially translated and validated for other languages/countries, for the measurement of ...health‐related quality of life (HRQoL) in patients with chronic wounds. However, a study from the United States postulated its benefits from further adaptations. Furthermore, some patients struggled to provide an answer for some of the items. We aimed to test the cross‐cultural structure and psychometric performance of the questionnaire to suggest necessary revisions. This cross‐sectional analysis of existing data sets included 1185 patients from Germany, the US, the Netherlands, Spain, Sweden, and Israel. Patients in the U.S. Wound Registry completed the Wound‐QoL during routine care. Different studies comprised the data collection in the other countries. Almost half of the patients were women (48.4%). Furthermore, 42.6% were diagnosed with leg ulcers. Their average age was 66 years. We used a confirmatory factor analysis and an unconstrained graded response model. We revised and shortened the Wound‐QoL from 17 to 14 items. In addition, we supported the cross‐cultural metric invariance of the revised Wound‐QoL questionnaire. The new version with 14 items and three dimensions revealed good psychometric properties with Cronbach's alpha (α) of 0.913 for the total score, and 0.709–0.907 for different dimensions. Furthermore, we provided strict invariance for different clinical variables. In conclusion, the revised Wound‐QoL is a reliable and cross‐cultural instrument to measure the HRQoL on patients with chronic wounds. Future studies should analyse the revised Wound‐QoL for convergent validity with generic HRQoL questionnaires as well as for determining its sensitivity to clinical change.
Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, ...lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities.
3D in vitro cancer models are important therapeutic and biological discovery tools, yet formation of matrix-embedded multicellular spheroids prepared in high-throughput (HTP), and in a highly ...controlled manner, remains challenging. This is important to achieve robust and statistically relevant data. Here, we developed an enabling technology consisting of a bespoke drop-on-demand 3D bioprinter capable of HTP printing of 96-well plates of spheroids. 3D multicellular spheroids are embedded inside a hydrogel matrix with precise control over size and cell number, with the intra-experiment variability of embedded spheroid diameter coefficient of variation being between 4.2% and 8.7%. Application of 3D bioprinting HTP drug screening was demonstrated with doxorubicin. Measurements of IC50 values showed sensitivity to spheroid size, embedding, and how spheroids conform to the embedding, revealing parameters shaping biological responses in these models. Our study demonstrates the potential of 3D bioprinting as a robust HTP platform to screen biological and therapeutic parameters.
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•3D bioprinter for the high-throughput production of embedded 3D multicellular spheroids•Bioprinted spheroids are biologically similar to manually produced spheroids•Parameters such as spheroid size and embedding affect the response toward doxorubicin•High-throughput screening applications with high content imaging and viability assay
Biotechnology; Cell Biology; Biomaterials
The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data ...is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK.
This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019.
In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months 95% confidence interval: 17.2, not reached. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months 95% CI: 8.8, 23.2. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%).
This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.
Management of melanoma Corrie, Pippa; Hategan, Mirela; Fife, Kate ...
British medical bulletin
111, Issue:
1
Journal Article
Peer reviewed
Open access
Melanoma is a potentially curable cancer, but around 20% of patients will develop disease which is beyond surgical clearance. Rising incidence alongside breakthroughs in understanding the molecular ...biology of this disease identifying systemic therapies offering survival gains now demand a more proactive, integrated approach to melanoma management.
PubMed references relating to aspects of melanoma research and treatment.
Rapidly rising incidence throughout the world. Effective surgery as well as new molecular targeted systemic biological agents and immunotherapies necessitating early diagnosis and multidisciplinary therapeutic interventions.
Role of screening and prevention. Benefit of interventions for locoregional melanoma, including role of sentinel lymph node biopsy. Integration and sequencing of treatments for unresectable melanoma.
Molecular determinants of melanoma influencing disease outcome and treatment decisions.
Education and training of patient and healthcare professionals. Role of screening, surveillance and follow-up strategies. Biology of melanoma guiding treatment decisions.
Background. Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. ...Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 57%), compared with the TDF arm (1 of 19 5.3%; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.
Couple therapists have the unique and challenging opportunity of helping people find deeper connection in their intimate relationships. These clinicians apply therapeutic models and interventions ...designed to help couples. However, many of these models are derived from theoretical, scientific, and sociocultural traditions that conceptualize human phenomena as individualistic and reductionistic, and the language in these theories may not match clients' experiences, which include deeply relational phenomena such as love and loss. We review how Western scientific and sociocultural traditions have shaped conceptualization of problems and clinical intervention in couple therapy. In contrast, we provide an alternative, strongly relational framework for couple therapy that draws upon philosophical perspectives asserting that relational, rather than individual, experience is fundamental in human interaction. These ideas provide relational language which can influence how couple therapy is viewed and enacted. Specifically, we discuss how a strongly relational approach changes how therapists understand and intervene with conflict, abuse, love, and deception. This relational framework can help couples in their own goals to become more unified. Implications for the therapeutic relationship, interventions, and scholarship are provided.
Evidence suggests lymphatic function mediates local rheumatoid arthritis (RA) flares. Yet biologics that target the immune system are dosed systemically via the subcutaneous (SC) administration ...route, thereby inefficiently reaching local lymphatic compartments. Nanotopography has previously been shown to disrupt tight cellular junctions, potentially enhancing local lymphatic delivery and potentially improving overall therapeutic efficacy.
We first characterized nanotopography (SOFUSA™) delivery of an anti-TNF drug, etanercept, by comparing pharmacokinetic profiles to those obtained by conventional SC, intravenous (IV), and intradermal (ID) routes of administration, and assessed uptake of radiolabeled etanercept in draining lymph nodes (LNs) in single dosing studies. We then compared etanercept efficacy in a progressive rat model of collagen-induced arthritis (CIA), administered systemically via SC route of administration; via the regional lymphatics through ID delivery; or through a nanotopography (SOFUSA™) device at 10, 12, and 14 days post CIA induction. Measurements of hind limb swelling and near-infrared fluorescence (NIRF) imaging of afferent lymph pumping function and reflux were conducted on days 11, 13, and 18 post CIA induction and compared to untreated CIA animals. Univariate and multivariate analysis of variance were used to compare the group differences for percentage swelling and lymphatic contractile activity.
Even though all three modes of administration delivered an equal amount of etanercept, SOFUSA™ delivery resulted in increased lymphatic pumping and significantly reduced swelling as compared to untreated, ID, and SC groups. Pharmacokinetic profiles in serum and LN uptake studies showed that using the nanotopography device resulted in the greatest uptake and retention in draining LNs.
Locoregional lymphatic delivery of biologics that target the immune system may have more favorable pharmacodynamics than SC or IV administration. Nanotopography may provide a more efficient method for delivery of anti-TNF drugs to reverse impairment of lymphatic function and reduce swelling associated with RA flares.
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