Citations

AbstractBackgroundScleroderma, also referred to as systemic sclerosis, is a multifaceted autoimmune condition characterized by abnormal fibrosis and impaired vascular function. Pathologically, it encompasses the persistent presence of inflammation, abnormal collagen buildup, and restructuring of blood vessels in various organs, resulting in a wide range of clinical symptoms. This review incorporates the most recent scientific literature on scleroderma, with a particular emphasis on its pathophysiology, clinical manifestations, diagnostic approaches, and treatment options.MethodologyA comprehensive investigation was carried out on numerous databases, such as PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar, to collect pertinent studies covering diverse facets of scleroderma research.ResultsScleroderma presents with a range of systemic manifestations, such as interstitial lung disease, gastrointestinal dysmotility, Raynaud's phenomenon, pulmonary arterial hypertension, renal complications, neurological symptoms, and cardiac abnormalities. Serological markers, such as antinuclear antibodies, anti‐centromere antibodies, and anti‐topoisomerase antibodies, are important for classifying diseases and predicting their outcomes.DiscussionThe precise identification of scleroderma is crucial for promptly and correctly implementing effective treatment plans. Treatment approaches aim to improve symptoms, reduce complications, and slow down the progression of the disease. An integrated approach that combines pharmacological agents, including immunosuppressants, endothelin receptor antagonists, and prostanoids, with nonpharmacological interventions such as physical and occupational therapy is essential for maximizing patient care.ConclusionThrough the clarification of existing gaps in knowledge and identification of emerging trends, our goal is to improve the accuracy of diagnosis, enhance the effectiveness of therapeutic interventions, and ultimately enhance the overall quality of life for individuals suffering from scleroderma. Ongoing cooperation and creative research are necessary to advance the field and achieve improved patient outcomes and new therapeutic discoveries.

Abstract Objectives Lumbar spine surgery is a common procedure for treating disabling spine‐related pain. In recent decades, both the number and cost of spine surgeries have increased despite technological advances and modification in surgical technique. For those patients that have continued uncontrolled back and/or lower extremity pain following lumbar spine surgery, spinal cord stimulation (SCS) has emerged as a viable treatment option. However, the impact of lumbar spine surgical history remains largely unstudied. Specifically, the current study considers the impact of number of prior lumbar spine surgeries on pain relief outcomes following SCS implantation. Materials and Methods We queried the electronic medical record of five separate pain practices for all patients who have undergone a SCS implant between January 1, 2017, and March 1, 2020. Inclusion criteria consisted of any patients with an SCS implant who underwent a prior lumbar spine surgery. The primary outcome was the mean calculated percentage pain relief in patients based on number of prior lumbar spine surgeries. Results There was a total of 1974 total SCS implant cases identified across five separate pain clinics. There was no difference in mean calculated pain relief in patients with one prior spine surgery versus those with two or more prior spine surgeries (28.2% vs. 25.8%, adjusted β‐coefficient –3.1, 95% CI –8.9 to 2.7, p = 0.290). Similarly, when analyzing number of spine surgeries as a continuous variable, there was no association between number of spine surgeries and calculated pain relief (adjusted β‐coefficient –1.5, 95% CI –4.0 to 1.1, p = 0.257). Additionally, after patients were stratified based on waveform, there was no association between number of prior lumbar spine surgeries (analyzed both as a categorical and continuous variable) and calculated percentage pain relief. Conclusions This multicentered retrospective study found that there was no significant difference in pain scores in individuals who received SCS following one or more lumbar spine surgeries. Additionally, the waveform of the SCS device had no statistically significant impact on post‐operative pain scores following one or more lumbar spine surgeries.

PURPOSE Accurate understanding of the genomic and transcriptomic data provided by next-generation sequencing (NGS) is essential for the effective utilization of precision oncology. Molecular tumor boards (MTBs) aim to translate the complex data in NGS reports into effective clinical interventions. Often, MTB treatment recommendations differ from those in the NGS reports. In this study, we analyze the discordance between these recommendations and the rationales behind the discordances, in a non–high-income setting, with international input to evaluate the necessity of MTB in clinical practice. METHODS We collated data from MTB that were virtually hosted in Chennai, India. We included patients with malignancies who had NGS reports on solid tissue or liquid biopsies, and excluded those with incomplete data. MTB forms and NGS reports of each clinical case were analyzed and evaluated for recommendation concordance. Concordance was defined as an agreement between the first recommendation in the MTB forms and the therapeutic recommendations suggested in the NGS report. Discordance was the absence of the said agreement. The rationales for discordance were identified and documented. RESULTS Seventy MTB reports were analyzed with 49 cases meeting the inclusion criteria. The recommendation discordance was 49% (24 of 49). Discordant recommendations were mainly due to low level of evidence for the drug (75% of cases). CONCLUSION The discordance between MTB and NGS vendor recommendations highlights the clinical utility of MTB. The educational experiences provided by this initiative are an example of how virtual academic collaborations can enhance patient care and provider education across geographic borders.

The 2023 Precision Oncology Summit was held in San Francisco on October 7 th and 8 th , focusing on actionable strategies addressing personalized treatment to improve patient outcomes. This manuscript summarizes the discussion and key learning points from “The Revolution in Germline DNA Testing” session.

Abstract Many germline BRCA2 missense variants of uncertain significance (VUS) remain to be clinically classified as pathogenic or benign. Here we identify 70 missense VUS in the DNA binding domain (DBD) of BRCA2 that partially reduced homologous recombination DNA repair activity of the protein in a homology directed DNA repair cell-based assay. CRISPR/cas9-based knockin of these variants reduced cell survival of haploid cells and conferred increased sensitivity to the PARP inhibitor Olaparib. Sequence alignment analysis found that the variants were highly conserved across species from pufferfish to human. Structural analysis showed that these variants are located predominantly in unstructured regions of the DBD. Case-control association studies showed that the hypomorphic variants conferred moderate risks of breast (OR:2.85; 95%CI:1.43-5.88) and ovarian cancer (OR:3.37; 95%CI:1.30-8.54) that were significantly different from risks associated with known pathogenic and benign variants. Cumulative lifetime risks of breast and ovarian cancer among carriers were estimated at 25% and 4.7%, respectively. Age at diagnosis of breast cancer among hypomorphs carriers was 55 years of age as opposed to 48 years of age for carriers of pathogenic variants. In addition, the combination of functional and other genetic data in an ACMG/AMP-like variant classification model reclassified 39 variants as likely pathogenic. This novel group of low penetrance missense variants further calibrate BRCA2 variant classification methods and have significant implications for the management of variant carriers. Citation Format: Huaizhi (Gilbert) Huang, Chunling Hu, Jie Na, Mohamed Abozaid, Amik Munankarmy, Tara Rao, Carolyn A. Dunn Lumby, Paulo Cilas Morais Lyra, Ronan E. Couch, Benjamin R. Persons, Eric C. Polley, Rachid Karam, Tina Pesaran, Siddhartha Yadav, Alvaro N.A. Monteiro, Nicholas J. Boddicker, Susan M. Domchek, Marcy E. Richardson, Fergus J. Couch. Functional and clinical characterization of hypomorphic missense variants in the BRCA2 cancer predisposition gene [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR09.

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

PURPOSE To develop recommendations for germline mutation testing for patients with breast cancer. METHODS An ASCO–Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS BRCA1/ 2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/ 2 testing, regardless of family history. BRCA1/ 2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/ 2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history. Additional information is available at www.asco.org/breast-cancer-guidelines .

Abstract Context Circulating lactate concentration is an important determinant of exercise tolerance. Objective This work aimed to determine the role of hyperglycemia on lactate metabolism during exercise in individuals with type 1 diabetes (T1D). Methods The protocol at the University of Virginia compared 7 T1D participants and 7 participants without diabetes (ND) at euglycemia (5.5 mM) or hyperglycemia (9.2 mM) in random order in T1D and at euglycemia in ND. Intervention included [1-13C] lactate infusion, exercise at 65% maximal oxygen uptake (VO2max), euglycemia, and hyperglycemia visits. The main outcome measure was lactate turnover before, during, and after 60 minutes of exercise at 65% VO2max. Results A 2-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND individuals (P = .76) and concordant with plasma volume (∼40 mL/kg). Circulating lactate concentrations were higher (P &lt; .001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise-induced lactate appearance did not differ (P = .13) between hyperglycemia and euglycemia. However, lactate clearance (CL) was lower (P = .03) during hyperglycemia than euglycemia in T1D participants. There were no differences in any of the aforementioned parameters between T1D and ND participants during euglycemia. Conclusion Hyperglycemia modulates lactate metabolism during exercise by lowering CL, leading to higher circulating lactate concentrations in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance both for providers and recreationally active people with T1D.

Abstract Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing-based functional characterization of 97% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants that is encoded by exons 15 to 26. The assay was based on deep sequence analysis of surviving endogenously targeted haploid cells. A total of 7013 SNVs were characterized as functionally abnormal (n=955), intermediate/uncertain, or functionally normal (n=5224) based on 95% agreement with ClinVar known pathogenic and benign standards. Results were validated relative to batches of nonsense and synonymous variants and variants evaluated using a homology directed repair (HDR) functional assay. Breast cancer case-control association studies showed that pooled SNVs encoding functionally abnormal missense variants were associated with increased risks of breast and ovarian cancer (odds ratio (OR) 3.89, 95%CI: 2.77-5.51). In addition, 86% of tumors associated with abnormal missense SNVs displayed loss of heterozygosity (LOH), whereas 26% of tumors with normal variants had LOH. The functional data were added to other sources of information in a ClinGen/ACMG/AMP-like model and 700 functionally abnormal SNVs, including 220 missense SNVs, were classified as pathogenic or likely pathogenic, while 4862 functionally normal SNVs, including 3084 missense SNVs, were classified as benign or likely benign. These classified variants can now be used for risk assessment and clinical care of variant carriers and the remaining functional scores can be used directly for clinical classification and interpretation of many additional variants.

Therapeutic plasma exchange (TPE) is a treatment paradigm used to remove harmful molecules from the body. In short, it is a technique that employs a process that functions partially outside the body and involves the replacement of the patient’s plasma. It has been used in the ICU for a number of different disease states, for some as a first-line treatment modality and for others as a type of salvage therapy. This paper provides a brief review of the principles, current applications, and potential future directions of TPE in critical care settings.