Citations

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 > 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.

Background: This study aimed to evaluate and compare the outcomes of proximal row carpectomy (PRC) with interposition arthroplasty using dorsal wrist capsule interposition, lateral meniscus allograft, or dermal allograft in patients with lunate facet/capitate degeneration. Methods: Patients who underwent PRC with interposition arthroplasty between 2010 and 2022 at a single institution were identified. Preoperative and postoperative visual analog scale (VAS) pain, functional outcomes, and complications were recorded. Results: Twenty-one patients (11 dorsal capsule, 6 meniscus, 4 dermal matrix) were identified with a mean follow-up of 65.8 months. Postoperative pain and functional outcome scores significantly improved. The mean postoperative Quick Disabilities of the Arm, Shoulder, and Hand score was 20.3. In total, 89.5% of patients returned to work, including 75% of manual laborers. Conclusions: No significant differences were found between dorsal capsular flap versus allograft groups. Proximal row carpectomy with interposition arthroplasty is an effective motion-sparing procedure for patients with proximal capitate and/or lunate fossa arthritis, improving pain and function.

ObjectiveNot much is known regarding musculoskeletal ultrasound (MSUS) practices of rheumatologists in the United States. We sought to determine the current use of MSUS among past participants of the Ultrasound School of North American Rheumatologists (USSONAR) training program and, by extension, MSUS‐practicing rheumatologists and to understand barriers to its MSUS use.MethodsAn online survey was sent to 374 participants in the eight‐month USSONAR blended course (Fundamentals in Musculoskeletal Ultrasound and Train the Trainer) between 2009 and 2020. Each respondent had a unique identifier linked to their total number of submitted practice scans and examination scores during training.ResultsThe survey response rate was 28.1% (105 of 374), comprising 82% adult and 18% pediatric rheumatologists. Of the respondents, 71% were MSUS certified: 86.7% performed and/or interpreted diagnostic MSUS, 81.0% performed/interpreted procedural MSUS, 59.8% billed for at least 50% of diagnostic studies, and 78.8% billed for at least 50% of procedural studies. The top reasons for not doing diagnostic and procedural ultrasonography were lack of administrative support and limited time, respectively. For 25% of diagnostic ultrasonography and 12.9% of procedural ultrasonography, billing was done <50% of the time. Of the respondents, 78.0% reported that USSONAR training made them better rheumatologists.ConclusionMost USSONAR‐trained rheumatologists are certified, practicing both diagnostic and procedural MSUS and billing for most of their work. However, a substantial number of studies are not being billed due to time constraints, limited administrative support, and legal liability. Participants agreed that USSONAR training made them better rheumatologists.

Abstract Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide–treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

Purpose of review Persistent air leaks, defined as an air leak extending beyond 5 days, pose a significant challenge for cardiothoracic surgeons and pulmonologists. Although current guidelines advocate for surgical intervention as the primary treatment, many patients may not suitable candidates for immediate return to the operating room. Alternatively, conservative management, which involves watchful waiting for pleural healing, often results in prolonged hospital stays and increased morbidity. Recent findings Although current guidelines advocate for surgical intervention as the primary treatment, many patients may not suitable candidates for immediate return to the operating room. Alternatively, conservative management, which involves watchful waiting for pleural healing, often results in prolonged hospital stays and increased morbidity. For patients who are not surgical candidates, use of autologous blood patch, pleurodesis or endobronchial valves may offer a viable alternative to conservatively manage air leak. Summary This review evaluates the various noninvasive therapies that have been explored, including sealants, Heimlich valves, chemical and autologous blood patch pleurodesis, and endo and intrabronchial valves. Although these alternatives show promise, further research is needed to compare these treatments before they can be recommended in new guidelines.