Citations

Abstract This publication represents the first part of an update to the clinical practice guideline on the diagnosis and management of group A streptococcal (Streptococcus pyogenes or GAS) pharyngitis, developed by the Infectious Diseases Society of America (IDSA). Diagnosis of GAS pharyngitis by clinician judgment alone is unreliable, and unselective testing incurs cost and inconvenience for individuals at low risk of having GAS infection. Clinical scoring systems have been used to quantify the probability of a positive GAS throat culture based on standardized criteria such as the presence of fever; tonsillar enlargement or exudate; tender and enlarged anterior cervical lymph nodes; and the absence of cough. The goal of this article is to determine whether a scoring system should be used to decide which patients should have a diagnostic test performed by rapid antigen detection test, molecular methods, and/or throat culture. We performed a systematic review of randomized and nonrandomized studies that compared the use of a clinical scoring system to clinician judgment alone in predicting the outcome of a throat culture. Evidence from studies in children and adults suggests the diagnostic accuracy of a clinical scoring system is comparable to or slightly higher than clinician judgment alone. However, the studies are limited due to small size, lack of uniformity in outcome measures, and incomplete data. The consensus of the panel is that the balance of benefits and harms favors use of a clinical scoring system as part of the evaluation of patients with sore throat. The principal utility of using a scoring system is to identify patients with low probability of GAS pharyngitis and to reduce unnecessary testing.

Abstract While the clinical focus on the sentinel lymph node biopsy (SLNB) is the presence of intra- or extra-nodal metastases, preclinical studies suggest that tumor-draining SLNB-associated vascular architecture and adhesion properties are altered regardless of SLNB positivity. Human intravital microscopy (HIVM) has defined blood vessel abnormalities that may impact lymphocyte adhesion and systemic drug delivery at primary melanoma sites. In this pilot study of HIVM during melanoma SLNB, we sought to determine the feasibility of obtaining HIVM observations of SLNB-associated vessels. We successfully performed HIVM in all 20 SLNB patients, and 7 were found to have nodal micrometastases by standard pathology. HIVM was capable of identifying both functional and non-functional SLNB-associated vessels based on the presence or absence of fluorescent dye uptake, respectively. Comparing vessel characteristics as a secondary objective, no statistically significant differences were noted in the diameter, flow rate, functionality, or shear stress of SLNB-associated blood vessels between positive and negative SLNBs, which may likely have been a reflection of the minimal disease burden. Nonetheless, these initial observations provide the framework to optimize future trials of HIVM in cancer patients.

ABSTRACT The Mayo Foundation Special Purpose Processor Development Group has been supporting a serial link development effort. In order to characterize serial link performance, two versions of a multi-chip module (MCM) test vehicle were assembled to study the effects of the substrate and the integrated circuit input/output buffer technologies on basic signal integrity performance parameters at data rates of 2.5 GHz. The difference between the test vehicles was the substrate technology used: ceramic and laminate. This paper describes the steps taken to develop an assembly process for the ceramic version of the test vehicle. The ceramic test vehicle consisted of a high thermal coefficient of expansion ceramic substrate, 2 CMOS chips with IBM high lead content (hereafter: “high lead”) bumps, 16 surface mount (SMT) capacitors, and an interposer. Assembly processes needed to be developed for SMT attach of the capacitors, flip-chip attach of the chips, and ball grid array (BGA) attach of the interposer. Based on Mayo's suite of assembly equipment, three process flows could have been used to attach the capacitors and the chips to the substrate: High lead attach of the capacitors and chips; Eutectic attach of capacitors, high lead attach of chips; Eutectic attach of the capacitors and chips. Assembly process flow 1 required the least number of steps. Therefore, it was initially selected as the process flow. However, this process flow was found to be unsatisfactory due to problems with flux charring around the capacitors and a high incidence of chip to substrate opens. Assembly process flow 2 was then evaluated. Assembly process flow 3 was considered the least desirable because eutectic solder paste had to be coated on the substrate die pads and Mayo did not have capability to do this. In order to develop the capacitor and die attach processes and to set up the interposer attach process, two assembly test vehicles were built on glass substrates. A capacitor attach process was devised that involved stenciling the eutectic solder paste, placing the capacitors, and then reflowing the assembly. The flip-chip attach process development required greater effort. Experimental matrices were run that allowed an assessment of bond strength as a function of flux quantity, bond force, and reflow temperature and time. Water-soluble flux was used for the chip attach process, so a de-fluxing process had to be developed. The chips then needed to be underfilled. The underfill dispense pattern and substrate heating were evaluated. The interposer was attached using eutectic solder paste stenciled on the back of the substrate. A BGA style attach process was set up to do this. The result of this process development activity was the successful assembly of 21 modules with no defects. Lessons were learned during the assembly process development regarding the difficulties associated with attaching components with high lead solder.

Abstract Purpose: Colorectal Cancer (CRC) is a leading cause of death from cancer globally. Surgery is the mainstay of treatment for localized CRC; however, little is known about survival outcomes following CRC surgery in low- and middle-income countries (LMICs). In this study, we examine the published literature for data on long-term outcomes following CRC resections in LMICs. Methods: We systematically reviewed PubMed, Web of Science, Embase, and Global Index Medicus for original research articles reporting survival data after CRC resection with curative intent in LMICs, published between January 2005 and May 2022. LMICs were defined according to the 2020 World Bank categories. We excluded studies without English full text or involving pediatric populations (<18 years), non-primary colorectal, benign disease, and endoscopic/transanal resection only. Studies from China dominated the published literature and were excluded. Abstracts and full texts were reviewed by two independent reviewers, and a third reviewer resolved conflicts. Disease-free survival (DFS) and overall survival (OS) data were extracted, and random effects modelling was used to estimate the pooled survival rates. Results: Our search returned 32,261 articles. After deduplication, 20,729 abstracts were assessed for eligibility, with 154 articles meeting inclusion criteria, representing a total of 20,589 CRC patients. 98 (63.6%) studies were from upper-middle-income (UM) countries, 55 (35.7%) from lower-middle-income (LM) countries and only one was from a low-income (L) country. Notably, only 27 (20%) of the 137 LMICs were represented in the literature. Turkey accounted for the highest frequency (29%) of included articles. Most (60%) of the studies were retrospective cohort design, and only three (3) were randomized controlled trials. The pooled 5-year OS estimate was 88% (95% CI: 77–95) for Stage I disease, 76% (69–81) for Stage II, and 57% (49–64) for Stage III. 5-year DFS estimates were 82% (71–90), 76% (67–84), and 59% (51–65) for stages I, II and III respectively. Survival rates varied considerably between income groups, with the strongest disparity seen with Stage III OS data at 18 months: 89% in UM, 86% in LM, and 50% in L (p=0.0005). Conclusion: With the rising incidence of CRC in LMICs, our work highlights the dearth of data on long-term outcomes following CRC operations in LMICs and emphasizes the urgent need for research capacity building, especially in low-income countries. Citation Format: Oluwasegun Afolaranmi, Thomas M. Diehl, Sehar Salim Virani, Qiuyu Yang, Kenechukwu Okwunze, Adel H. Khan, Nabiha Akhlaq Mughal, Daniel Schroeder, Sheida Pourdashti, Leslie Christensen, Sadaf Khan, Syed Nabeel Zafar. Survival Following Colorectal Cancer Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 13th Annual Symposium on Global Cancer Research; 2025 Sep 16. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(12_Suppl):Abstract nr 84.

Abstract Background This phase 1 study aimed to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary efficacy of rucaparib (RUB), a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, combined with liposomal irinotecan (nal‐IRI) and 5‐fluorouracil (5‐FU) in metastatic gastrointestinal (GI) cancers. RUB targets DNA repair pathways, showing efficacy in tumors with homologous recombination deficiency, such as BRCA mutations. Preclinical data suggest synergy with irinotecan, but overlapping toxicities pose challenges. Methods Eighteen patients with metastatic GI cancers, who previously progressed on at least one systemic therapy, were enrolled. A novel sequential dosing regimen, informed by nal‐IRI pharmacokinetic analysis, was used. Twelve patients were evaluable for dose‐limiting toxicity (DLT) and 12 for response per Response Evaluation Criteria in Solid Tumors v1.1 criteria. Results The MTD was established as RUB 600 mg twice daily, nal‐IRI 50 mg/m 2 , and 5‐FU 2400 mg/m 2 over 46 hours. The objective response rate (ORR) was 33% (4 of 12), and the disease control rate (DCR) was 75% (9 of 12). Common grade 3 adverse events included diarrhea (33%) and neutropenia (25%), with no grade 4/5 events. Responses were notable in patients with somatic ATM and BRCA mutations, especially those with prior platinum exposure. No DLTs occurred at the recommended phase 2 dose. Conclusions This optimized dosing schedule successfully established the MTD for RUB with nal‐IRI and 5‐FU, overcoming prior challenges with PARP inhibitor and irinotecan combinations. The promising ORR and DCR support further evaluation of this regimen in advanced GI malignancies.

Background: Sleep is vital for an athlete’s recovery, physical and mental health, and athletic performance. The impact on circadian rhythm from long-distance travel across multiple time zones has not been studied using wearable technology in female professional tennis players. Hypothesis: Travel between time zones in female professional tennis players leads to circadian desynchronization, causing disruption in sleep patterns, changes in physiologic parameters, and decreased athletic performance. Study Design: Retrospective cohort study. Level of Evidence: Level 3. Methods: A total of 52 female professional tennis players consented to wear, and share the data of, WHOOP 3.0 while traveling and competing on the Women’s Tennis Association (WTA) Tour. Linear mixed models examined the relationship between (1) travel and sleep/recovery and (2) sleep/recovery and match performance. Results: Sleep duration without travel averaged 437 minutes (436.8 ± 2.8). On the first night after travel, for every hour time zone difference (TZD) traveled regardless of direction, players slept 11 minutes less (−11.3 ± 0.96; P < 0.05). Eastward travel further reduced sleep (−24.5 ± 4.2; P < 0.05), while westward travel increased sleep duration (+30.0 ± 4.2; P < 0.05). These effects were reduced on the subsequent 2 nights. Conclusion: Sleep duration reduction was most prominent on the first night after travel, particularly with eastward travel, but improved on subsequent nights. The number of time zones crossed predictably increases the vulnerability for insufficient sleep duration, whereby a 2-hour TZD easterly, and 4-hour TZD westerly, reduces sleep duration <7 hours on the first night. No significant correlation was found between sleep disruption and competition performance in our female professional tennis population. Clinical Relevance: The findings suggest that professional tennis players should, and generally do, arrive at competition locations with enough time to resynchronize their circadian rhythm to the destination time zone; particularly if traveling eastward.

Abstract Description Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity, partially driven by sex hormones. While androgens are known to suppress anti-tumor T cell immunity in certain solid tumors, we found that androgens instead enhance anti-tumor immunity in brain tumors. Upon castration, tumor growth was accelerated in brain tumor models, while the opposite effect was observed for tumors located outside the brain. Decreased T cell function was observed in both tumors and peripheral lymphoid organs in castrated mice, indicated by reduced anti-tumor cytokines and increased T cell exhaustion. Mechanistically, this systemic immunosuppression was driven by hyperactivation of the hypothalamus-pituitary-adrenal (HPA) axis in castrated mice with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in these mice, confirming the role of HPA axis dysregulation. This mechanism was brain-specific rather than GBM-specific, as hyperactivation of the HPA axis was also observed with intracranial implantation of non-GBM tumors. Furthermore, elevated production of proinflammatory cytokines (IL-1β, TNF) in the brain of castrated mice was identified as a driver of HPA axis activation. Taken together, these findings reveal unique endocrine-mediated mechanisms by which brain tumor modulate systemic immunity in the androgen-deprived setting and highlight the importance of organ-specific effects of anti-tumor immunity. Funding Sources NIH P01CA245705; NIH R35NS127083; American Brain Tumor Association; Cleveland Clinic; Case comprehensive cancer center Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description Developing a universal influenza vaccine requires understanding how lung-resident memory CD4+ T cells are formed. These cells remain in the lung for a long time and strengthen the immune response to secondary infections. Tissue-resident helper cells (TRH), a subset of memory T cells, share characteristics with follicular helper cells (TFH) and boost the IgA and IgG production by lung-resident B cells. TRH cells express elevated levels of the extracellular ATP (eATP) sensor P2RX7. Here we demonstrate that P2RX7 ablation on T cells impairs the establishment of flu-specific TRH cells. P2RX7-induced decrease of TRH cells negatively impacted the protection against homologous challenge, since T cell-specific P2RX7-KO mice exhibit worse control of viral load than WT mice. P2RX7-KO mice also showed a reduction in flu-specific lung-resident germinal center-like B cells and lower levels of IgA and IgG in the lungs. P2RX7-KO did not induce major changes in the numbers of TFH-induced responses in the draining lymph nodes. Our single-cell RNAseq showed reduced expression of mitochondrial genes in P2RX7-KO TRH cells, which reflects decreased mitochondrial content presence in these cells. We observed an aberrant metabolic pathway usage by P2RX7-KO TRH cells, which beyond having less mitochondria also cease to utilize glycolytic metabolism to support protein synthesis. Our findings suggest the eATP-P2RX7 axis is required to establish TRH cells that protect against influenza. Funding Sources Mayo Clinic and National Institutes of Health (NIH - H.B.d.S.: R01 AI170649) Topic Categories Mucosal and Regional Immunology (MUC)

Abstract Description Hematopoiesis declines with age due to intrinsic and extrinsic dysregulation resulting in diminished lymphopoiesis. Hoxa9 is a pleiotropic hematopoietic regulator necessary for stem/progenitor cell (HSPC) maintenance and lymphoid differentiation. Interestingly, bone marrow (BM) HSPC and B lineage compartments of young hoxa9-/- mice mimic that which accompanies aging. Hoxa9 is a negative regulator of p16ink4a, a cyclin-dependent kinase inhibitor upregulated in hoxa9-/- HSPCs and a gatekeeper of the G1 to S cell cycle checkpoint. We hypothesized that increased expression of p16ink4a contributes to the HSPC and/or B progenitor alterations due to hoxa9-deficiency. Interestingly, BM B lymphopoiesis was normalized in hoxa9-/-p16ink4a-/- (DKO) mice, but alterations were less obvious in HSPCs. Flow analysis of the HSPC compartment proliferation showed contraction of unbiased but not myeloid-biased progenitors prior to lineage fate commitment. hoxa9-/- CFU-PreB were blunted then rescued by p16ink4a co-ablation. Primary BM transplant demonstrates DKO like hoxa9-/- has reduced reconstitution efficiency but differs with superior B lineage reconstitution similar to controls. Bioinformatic analysis of recent open access CUT&RUN data in HSPCs confirms Hoxa9 binds promoters in genes relevant to G1 to S cell cycle checkpoint, these findings currently being validated. Our work emphasizes HSPC regulatory factors as crucial targets in combating age-associated maladies of the immune system. Funding Sources Supported by NIH R01AG076163 Topic Categories Hematopoiesis and Immune System Development (HEM)