Citations

AbstractBackgroundCALGB 30610 trial demonstrated that once daily thoracic radiotherapy (TRT) was not superior compared to standard twice daily TRT, in patients with limited stage small cell lung cancer. Quality of life outcomes may help oncologists decide the best treatment approach.MethodsA total of 417 patients on CALGB 30610 participated in the quality‐of‐life substudy (CALGB 70702), which included the FACT Trial Outcome Index‐Lung Cancer (FACT‐L TOI), FACT‐Esophageal Cancer (FACT‐E) Eating and Swallowing Indices, ECOG Acute Esophagitis Scale, Hospital Anxiety and Depression Scale (HADS), difficulty swallowing, EQ‐5D, and treatment convenience assessment at baseline, 3, 5, 7, 12, 26, and 52 weeks after starting TRT. Primary end points included FACT‐L TOI and FACT‐E at 12 weeks. Mean changes from baseline were compared between arms using general linear mixed models.ResultsFACT‐L worsening was more in the twice daily arm at week 3 (–1.0 vs. –7.0). FACT‐L TOI worsening was less at week 3 (–2.9 vs. –7.6) and greater at week 12 (–7.6 vs. –2.8) in the once daily arm. The once daily arm had a lower EQ‐5D index worsening at 3 weeks (0.01 vs. –0.02). Increase in acute esophagitis score (1.06 vs. 2.89; p < .001) and difficulty swallowing (0.39 vs. 1.14) were greater in the twice daily arm at week 3. A total of 74.5% of patients on the once daily arm felt that treatment was convenient, compared to 67% of patients in the twice daily arm (p = .03).ConclusionsThe once daily arm had better quality‐of‐life scores earlier during treatment and was perceived to be more convenient.

Abstract The A1 domain in Von Willebrand Factor (VWF) initiates coagulation through binding to platelet glycoprotein GPIbα receptors. Von Willebrand Disease (VWD)-Mutations in A1 that either impair (type 2M) or enhance (type 2B) platelet adhesion to VWF can locally destabilize and even misfold the domain. We leveraged misfolding in the gain-of-function type 2B VWD phenotype as a target, distinct from the normal conformation. Two nuclease-resistant 2′-fluoropyrimidine RNA aptamers were selected to discriminate normal A1 domains from a type 2B V1314D A1 variant in a glycosylated A1A2A3 tri-domain VWF-fragment. Two aptamers, W9 and V1, were isolated that selectively recognize, bind, and inhibit the A1–GPIbα interaction with WT A1A2A3 and V1314D A1A2A3, respectively. These aptamers were tested against their respective recombinant targets, plasma VWF, VWF concentrates, and patient plasma with the heterozygous type 2B VWD R1306W variant using clinical assays, surface plasmon resonance and inhibition assays of platelet adhesion to recombinant A1 and A1A2A3 domains under shear stress. The specificity of W9 and V1 aptamers confirms that pathological conformations of VWD Type 2B proteins are different from normal VWF. The availability of aptamers that distinguish normal plasma-derived VWF from VWD suggests potential applicability in clinical diagnosis of severe gain-of-function phenotypes.

Abstract The aims of this review are to appraise the role of the stomach in satiation, the effects of incretin and other hormone agonists on weight loss and the role of altered gastric functions in their effects on obesity or glycaemic control. In addition to the gut in its role in enzymatic digestion and hormonal responses to nutrient ingestion, gastric motor functions include accommodation, trituration and emptying [gastric emptying (GE)] of food and elicitation of postprandial satiation and satiety. The postprandially released hormones most extensively studied and utilized therapeutically are glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP). Their mechanisms of action include stimulation of pancreatic β cells to produce insulin. However, GLP‐1 reduces glucagon and slows GE, whereas GIP increases glucagon and does not alter GE. Molecular modifications of GLP‐1 (which has a T 1/2 of 3 min) led to the development of long‐acting subcutaneous or oral pharmacological agents that have been approved for the treatment of obesity, and their effects on gastric function are documented. Other medications in development target other molecular mechanisms, including glucagon and amylin. Small‐molecule GLP‐1 receptor agonists are promising for the treatment of obesity and may also slow GE. Bariatric surgery and endoscopy increase satiation by restricting gastric size; in addition Roux‐en‐Y gastric bypass and to a lesser extent sleeve gastrectomy (but not endoscopic gastroplasty) increase postprandial circulating incretins, reducing appetite. In conclusion the stomach's function is integral to the impact of the most effective pharmacological and procedural reversal of obesity related to the incretin revolution. image

AbstractGastroenteropancreatic neuroendocrine tumours (GEP‐NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non‐secreting (also known as non‐functioning NETs) are associated with severe morbidity and have a median overall survival of 75–124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP‐NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled‐receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP‐NET subtypes. Using RNA‐Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non‐functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP‐NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC‐seq analyses in the pancreatic NET cell line QGP‐1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP‐1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP‐NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.

Abstract BACKGROUND Both radiation and temozolomide (TMZ) have meaningful single-modality anti-tumor activity against low-grade gliomas. ECOG-ACRIN E3F05 tested whether combined therapy with radiation and temozolomide is more effective than radiation alone in patients with grade II gliomas. METHODS Patients with grade II gliomas (central pathology review performed post hoc), no prior radiation/chemotherapy, and either age &gt; 40, uncontrolled symptoms/seizures, or progression after initial observation were randomized 1:1 to radiation 50.4 Gy alone in 28 fractions (Arm A) versus radiation 50.4 Gy with concomitant and 12 four-week cycles of post-radiation TMZ (Arm B). Randomization was stratified by 1p/19q codeletion status, age, KPS, pre-operative tumor diameter, and contrast enhancement. The primary endpoint was progression-free survival (PFS); overall survival (OS), quality of life, cognition, severe toxicities, and impact of codeletion status were secondary objectives. RESULTS The trial opened 1/09. Accrual was stopped in 1/14 after RTOG 9802 reported benefit from the addition of PCV chemotherapy to radiation in grade II gliomas. A total of 172 subjects were enrolled. Median age was 44 (range 19-78) and 54% male. 1p/19q codeletion was present in 44%. NCI CTCAE (version 4) grade 3+ toxicity was more common in participants treated with TMZ: thrombocytopenia (11%) and neutropenia (5%) versus none in the radiation alone arm. With a median follow-up of 117 months, OS was superior in Arm B (HR 0.54, 95% CI 0.31-0.95, stratified log-rank p value 0.03). OS HRs were 0.56 and 0.53 for subjects with and without 1p/19q codeleted tumors, respectively. PFS did not differ between Arms A and B (HR 0.76, 95% CI 0.44-1.28, p = 0.30). Five and ten-year OS were 78% and 70% in Arm B versus 70% and 47% in Arm A. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and non-co-deleted grade II gliomas.

AbstractLymph nodes (LNs) are specialized secondary lymphoid tissues essential to the priming and maintenance of adaptive immune responses, including the B cell germinal center response; thus, they are central to immunity. However, the anatomically restricted and time‐resolved nature of immune priming means that sampling disease‐relevant human LNs requires specialized techniques. This article describes the application of ultrasound‐guided fine‐needle aspiration (FNA) to sample LNs, using cervical LNs of the head and neck as an exemplar. This minimally invasive technique allows collection of both immune cells and cell‐free material that are relevant to both neuroimmune diseases and basic lymphatic functions. Downstream use of cellular material can include multiplexed flow cytometry, single‐cell transcriptome sequencing (RNA‐seq), and B cell cultures. The cell‐free supernatant can be used for proteomics or other similar ‘omics approaches. This unit describes collection of samples by FNA as well as processing and storage of samples for downstream assays. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Sampling of human cervical lymph nodes by ultrasound‐guided fine‐needle aspirationAlternate Protocol: Sampling of human lymph nodes by ultrasound‐guided fine‐needle aspiration with negative pressureBasic Protocol 2: Processing and storage of human lymph node samples

Fetal cardiovascular magnetic resonance imaging (MRI) has emerged as a complementary modality for prenatal imaging in suspected congenital heart disease. Ongoing technical improvements extend the potential clinical value of fetal cardiovascular MRI. Ascertaining equivocal prenatal diagnostics obtained with ultrasonography allows for appropriate parental counseling and planning of postnatal surgery. This work summarizes current acquisition techniques and clinical applications of fetal cardiovascular MRI in the prenatal diagnosis and follow‐up of fetuses with congenital heart disease.Level of Evidence3Technical EfficacyStage 3

Abstract Context Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia. Objectives The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT’s role for dystonia. Methods A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review. Results Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson’s disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia. Conclusions Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.