Challenges and Opportunities in Developing an Oncology Clinical Trial Network in the United States Veterans Affairs Health Care System: The VA STARPORT Experience.

The United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)-the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation.

Optogenetic Regulation of EphA1 RTK Activation and Signaling.

Eph receptors are ubiquitous class of transmembrane receptors that mediate cell-cell communication, proliferation, differentiation, and migration. EphA1 receptors specifically play an important role in angiogenesis, fetal development, and cancer progression; however, studies of this receptor can be challenging as its ligand, ephrinA1, binds and activates several EphA receptors simultaneously. Optogenetic strategies could be applied to circumvent this requirement for ligand activation and enable selective activation of the EphA1 subtype. In this work, we designed and tested several iterations of an optogenetic EphA1 - Cryptochrome 2 (Cry2) fusion, investigating their capacity to mimic EphA1-dependent signaling in response to light activation. We then characterized the key cell signaling target of MAPK phosphorylation activated in response to light stimulation. The optogenetic regulation of Eph receptor RTK signaling without the need for external stimulus promises to be an effective means of controlling individual Eph receptor-mediated activities and creates a path forward for the identification of new Eph-dependent functions.

Literature-Based Discovery to Elucidate the Biological Links between Resistant Hypertension and COVID-19.

Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin-angiotensin-aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%.

Patient Outcomes After Unsuccessful Endoscopic Sialolith Extraction.

OBJECTIVE/HYPOTHESIS: To evaluate clinical outcomes following failed endoscopic extraction of salivary calculi and to assess any relation between clinical outcome and calculi location, number, size, and mobility. If sialendoscopy fails to extract the calculus, subsequent spontaneous passage of the calculus out of the ductoglandular system or secondary effects of sialendoscopy could mitigate the clinical impact of a residual sialolithiasis. STUDY DESIGN: Prospective observational study. METHODS: Prospective comparative study of endoscopic procedures for sialolithiasis performed in the Manukau Surgery Center, in Auckland, New Zealand, from 2010 to 2020. The recurrent symptoms and the variables related to the need for additional surgical intervention for salivary calculi were analyzed. RESULTS: Among the 465 sialendoscopy procedures, 154 (33.1%) were for obstructive sialolithiasis. Among these, there were 30 (19.4%) with unsuccessful stone extraction with re-operation for these failures performed in 14 of the 27 failed submandibular cases (52%) and 2 of the 3 parotids (66.7%). Location of calculi was a significant factor in predicting the need of further surgery. Patients with perihilar stones were 5 times more likely to have a failed procedure (P = .001). If the stone was intraglandular, the likelihood increased to 8.5 times (P = .005). The likelihood for a revision procedure increased almost 11 times if the stone was intraglandular (P = .004). Calculi size, mobility, multiple calculi, and presence of concurrent stenosis did not correlate with need for further surgery. CONCLUSIONS: A significant proportion of "failed" sialendoscopy did not require further intervention. Stone location was a significant factor in predicting a failed procedure and the need for re-intervention. Laryngoscope, 132:1029-1033, 2022.

The Manukau Salivary Symptoms Score for Assessing the Impact of Sialendoscopy in Recurrent Obstructive Sialadenitis.

OBJECTIVE: To examine the Manukau Salivary Symptom Score (MSSS) questionnaire as a validated tool to assess obstructive sialadenitis-specific symptoms to both indicate disease severity and assess the outcome after sialendoscopic procedures. STUDY DESIGN: A prospective observational study was performed from 2010 to 2019 comprising 164 patients undergoing sialendoscopy for nonneoplastic chronic obstructive salivary gland disease (COSGD). SETTING: Department of Otolaryngology-Head and Neck Surgery at the Manukau Surgical Centre, Auckland, New Zealand, between June 2010 and September 2019. METHODS: A prospective observational study was performed from 2010 to 2019 comprising 164 patients undergoing sialendoscopy for nonneoplastic COSGD. Patients completed the MSSS preoperatively and at postoperative follow-up. Statistical tests were used to compare pre- and postoperative answers. Cronbach's α was used to measure internal consistency. Finally, construct validity was determined by comparing the 5-question MSSS questionnaire to the preexisting 20-question Chronic Obstructive Sialadenitis Symptoms (COSS) questionnaire. RESULTS: Postoperatively, patients had significant improvements in pain, eating, talking, swelling, and quality of life (P < .001). The MSSS questionnaire was found to have high internal consistency (α = 0.938). Questions in the MSSS had a very strong positive correlation with 3 COSS questions, a strong positive correlation with 8, a moderate positive correlation with 4, and a weak positive correlation with 1. Four COSS questions were not considered relevant and were not included in the MSSS questionnaire. CONCLUSION: The MSSS questionnaire is a simple, validated questionnaire that is useful for assessing the impact of sialendoscopy in patients with COSGD.

Homozygous Factor V Leiden presenting as irreversible chronic colon ischemia resulting from inferior mesenteric vein thrombosis.

A 42-year-old man presented with 6 months of unexplained left lower quadrant abdominal pain and hematochezia accompanied by weight loss despite extensive evaluations. Stool studies for pathogens were unrevealing, but an abdominal contrast-enhanced computed tomography revealed findings of chronic inferior mesenteric vein thrombosis. Colonoscopy demonstrated ulcerated strictures and gangrene confined to the sigmoid and descending colons, and biopsies confirmed changes of chronic irreversible colon ischemia. A homozygous Factor V Leiden mutation was diagnosed. The patient underwent colectomy and was treated with lifelong anticoagulation. While mesenteric venous thrombosis is a well-recognized cause of colon ischemia in hypercoagulable states, thrombosis of the inferior mesenteric vein is uncommon; when chronic it is rarely clinically apparent. Similarly, while Factor V Leiden mutation is a common hereditary thrombophilia, it uncommonly causes mesenteric venous thrombosis, and homozygotes of the mutation typically present earlier in the fourth decade and with non-mesenteric venous thromboembolism. This case is valuable and adds to the existing literature in describing a rare, clinically atypical, and late index presentation of homozygous Factor V Leiden mutation as chronic inferior mesenteric vein thrombosis yielding irreversible colon ischemia.

FANCA Promotes DNA Double-Strand Break Repair by Catalyzing Single-Strand Annealing and Strand Exchange.

FANCA is a component of the Fanconi anemia (FA) core complex that activates DNA interstrand crosslink repair by monoubiquitination of FANCD2. Here, we report that purified FANCA protein catalyzes bidirectional single-strand annealing (SA) and strand exchange (SE) at a level comparable to RAD52, while a disease-causing FANCA mutant, F1263Δ, is defective in both activities. FANCG, which directly interacts with FANCA, dramatically stimulates its SA and SE activities. Alternatively, FANCB, which does not directly interact with FANCA, does not stimulate this activity. Importantly, five other patient-derived FANCA mutants also exhibit deficient SA and SE, suggesting that the biochemical activities of FANCA are relevant to the etiology of FA. A cell-based DNA double-strand break (DSB) repair assay demonstrates that FANCA plays a direct role in the single-strand annealing sub-pathway (SSA) of DSB repair by catalyzing SA, and this role is independent of the canonical FA pathway and RAD52.