Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

Sporadic neurofibroma of facial nerve presenting as parotid gland tumor: a rare case report.

Intraparotid gland neurofibroma is a rare benign tumor that arises from Schwann cells of the facial nerve within the parotid gland. This case report discusses a 41-year-old woman who experienced a painless preauricular swelling on her right side for over 5 years. Clinical examination and ultrasound revealed a well-defined mass in the parotid gland. The patient underwent total mass excision, resulting in transient facial nerve dysfunction but complete recovery. These tumors often manifest as solitary masses in the parotid region and may compress nearby structures, causing facial paralysis or numbness. Their diagnosis can be challenging due to similarities with other parotid gland tumors and possible associations with neurofibromatosis. Managing intraparotid tumors, including neurofibromas, involves a multidisciplinary approach with input from cytopathologists, radiologists, and surgeons.

A Second Space Age Spanning Omics, Platforms, and Medicine Across Orbits.

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, countries, and space-related entities has enabled a"Second Space Age." This new era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, encompassing multi-omic, single-cell, and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring, and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics (PGx), as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this review, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration (NASA), Japan Aerospace Exploration Agency (JAXA), European Space Agency (ESA), and other space agencies, and also detail the commercial spaceflight sector's (e.g. SpaceX, Blue Origin, Axiom, Sierra Space) entrance into aerospace medicine and space biology, the first aerospace medicine biobank, and the myriad upcoming missions that will utilize these tools to ensure a permanent human presence beyond LEO, venturing out to other planets and moons.

Direct RNA sequencing of astronaut blood reveals spaceflight-associated m6A increases and hematopoietic transcriptional responses.

The advent of civilian spaceflight challenges scientists to precisely describe the effects of spaceflight on human physiology, particularly at the molecular and cellular level. Newer, nanopore-based sequencing technologies can quantitatively map changes in chemical structure and expression at single molecule resolution across entire isoforms. We perform long-read, direct RNA nanopore sequencing, as well as Ultima high-coverage RNA-sequencing, of whole blood sampled longitudinally from four SpaceX Inspiration4 astronauts at seven timepoints, spanning pre-flight, day of return, and post-flight recovery. We report key genetic pathways, including changes in erythrocyte regulation, stress induction, and immune changes affected by spaceflight. We also present the first m6A methylation profiles for a human space mission, suggesting a significant spike in m6A levels immediately post-flight. These data and results represent the first longitudinal long-read RNA profiles and RNA modification maps for each gene for astronauts, improving our understanding of the human transcriptome's dynamic response to spaceflight.

Lingual osteoma presenting as a solitary painless lesion: Report of a rare case with review of the literature.

Lingual osteoma, a rare, benign bone tumor that primarily affects the posterior tongue, can be difficult to diagnose. This study aims to report a case of osteoma affecting the tongue in a 17-year-old female. The patient had a foreign body sensation and a progressively growing lesion for 3 years and underwent clinical examination and diagnostic procedures. A well-defined, smooth-surfaced, white mass was discovered in the posterior third of the tongue. The 1.5 × 1 × 0.4 cm mass was completely excised under local anesthesia and histopathologically confirmed as a benign lingual osteoma. The 2-month post-operative outcome was uneventful. The rarity of lingual osteoma, as well as the fact that it is often asymptomatic, makes diagnosis difficult. The diagnosis entails a proper clinical examination, imaging studies, and histopathological analysis. Surgical intervention, primarily aimed at complete excision while preserving tongue function, remains the primary treatment option. Successful excision entails educating healthcare professionals about this rare benign bony tumor to ensure the best possible patient outcomes.

Identification of severely injured children at very low risk of emergent surgery: A national trauma registry study.

OBJECTIVE: The number of pediatric trauma patients requiring surgical interventions has been steadily decreasing allowing for a judicious approach to immediately available resources. This study aimed to derive and validate a prediction rule that reliably identifies injured children who are at very low risk for requiring emergency surgery upon emergency department (ED) arrival. METHODS: A retrospective cohort study of data included in the Israeli National Trauma Registry from January 1, 2011, through December 31, 2020, was conducted. We included children aged 0-14 years who presented to EDs from the scene of injury and were hospitalized. We excluded patients transferred between facilities or with isolated burns. The primary outcome was emergency operative intervention (EOI) performed within one hour of ED arrival. We tested mechanism, GCS, heart rate, and blood pressure as candidate predictors. We then randomized patients to two cohorts, derived and internally validated a prediction rule. RESULTS: During the study period, 83,859 children met enrollment criteria. The median age was 6 years (IQR 2-10) and 56,867 (67.8 %) were male; 75,450 (90.0 %) sustained blunt trauma. One hundred sixty-nine (0.20 %) children underwent EOI. In the derivation and validation cohorts, 34,138 (81.4 %) and 34,271 (81.7 %) patients, were classified as low risk based on blunt trauma mechanism, normal GCS (15), and low-risk heart rate (according to age). Of those, 8 (0.02 %) and 13 (0.04 %) required an EOI, respectively. In the validation cohort, the prediction rule for EOI had a sensitivity of 84 % (95 % CI 75-91), a specificity of 82 % (95 % CI 81-82), and a negative predictive value of 99.96 % (95 % CI 99.94-99.98). Among children with an Injury Severity Score>15, the sensitivity was 87 % (95 % CI 77-94), the specificity of 57 % (95 % CI 54-59), and the negative predictive value was 98.97 % (95 % CI 98.13-99.44). CONCLUSIONS: A limited set of physiologic parameters, readily available at hospital admission can effectively identify injured children at very low risk for emergent surgery. For these children, immediate deployment of surgical resources may not be necessary.

Utilization and outcomes of expanded criteria donors in adults with congenital heart disease.

BACKGROUND: Use of donation after circulatory death (DCD) and hepatitis C virus (HCV) positive donors in heart transplantation have increased the donor pool. Given poor waitlist outcomes in the adult congenital heart disease (ACHD) population, we investigated waitlist outcomes associated with willingness to consider DCD and HCV+ offers and post-transplant outcomes following HCV+ and DCD transplantation for these candidates. METHODS: Using the United Network for Organ Sharing database, we identified adult ACHD candidates and recipients listed or transplanted, respectively, between 01/01/2016 and 09/30/2023 for the HCV analysis and between 12/01/2019 and 09/30/2023 for the DCD analysis. Among candidates, we compared the cumulative incidence of transplant, with waitlist death/deterioration as a competing risk, by willingness to consider HCV+ and DCD offers. Among recipients of HCV+ (vs HCV-) and DCD (vs brain death [DBD]) transplants, we compared perioperative outcomes and post-transplant survival. RESULTS: Of 1,436 ACHD candidates from 01/01/2016 to 09/30/2023, 37.0% were willing to consider HCV+ heart offers. Of 886 ACHD candidates from 12/01/2019 to 09/30/2023, 15.5% were willing to consider DCD offers. On adjusted analysis, willingness to consider HCV+ offers was associated with 84% increased likelihood of transplant, and willingness to consider DCD offers was associated with 56% increased likelihood of transplant. Of 904 transplants between 01/01/2016 and 09/30/2023, 6.4% utilized HCV+ donors, and of 540 transplants between 12/01/2019 and 09/30/2023, 6.9% utilized DCD donors. Recipients of HCV+ (vs HCV-) and DCD (vs DBD) heart transplants had similar likelihood of perioperative outcomes and 1-year survival. CONCLUSIONS: ACHD candidates who were willing to consider HCV+ and DCD offers were more likely to be transplanted and had similar post-transplant outcomes compared to recipients of HCV- and DBD organs.

Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight.

Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a "spaceflight signature" of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Outcomes of Bladder Washout for the Treatment of Recurrent Urinary Tract Infections After Renal Transplantation.

Background Current literature suggests that anywhere from 2.9-27% of renal transplant recipients (RTR) will develop recurrent urinary tract infections (UTIs) (≥2 UTIs over six months or ≥3 UTIs over 12 months). Recurrent UTIs are of particular importance to RTR given its increased risk for allograft fibrosis and overall patient survival. Alternative solutions are needed for the management of recurrent UTIs, especially given the vulnerability of RTR to UTIs. We hypothesize that bladder washout (BW) reduces the incidence and recurrence of UTIs in RTR. Methods This is a retrospective study evaluating the utility of BW procedures on RTR diagnosed with recurrent UTIs between December 2013 and July 2021 at a single center. Results A total of 106 patients were included in the study with a total of 118 BW performed. 69% of patients were successfully treated with BW, meaning they no longer met the criteria for recurrent UTIs (<1 UTI) in the six-month post-BW period. The mean number of UTIs was 2.76 (range 2-7) before the BW and 1.16 (range 0-5) after the BW. On average, there were 1.60 fewer UTIs in the post-BW period compared to the pre-BW period (p<0.0001). There is no statistically significant difference in success rates stratified by bacterial class (p=1) or antimicrobial resistance class (p=0.6937). Conclusion BW decreased the incidence of UTIs in the six-month post-operative period as nearly 70% of patients did not have UTI recurrence. This data provides evidence that BW may have utility in transplant recipients with recurrent UTIs. We hope this will stimulate further prospective randomized studies in this area.

Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential, and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

The Impact of Local Programmatic Decisions on Outcomes in Transplant-Listed Adults With Congenital Heart Disease.

BACKGROUND: We investigated variables impacting waitlist times and negative waitlist outcomes in adults with congenital heart disease (ACHD) who were waiting for orthotopic heart transplant (OHT) after the 2018 allocation change. METHODS: Adult candidates for OHT who were listed between 10/18/2018 and 12/31/2022 in the United Network for Organ Sharing database were categorized as ACHD vs non-ACHD. Waitlist time and time to upgrade for those upgraded into status 1-3 were compared by using rank-sum tests. Death/delisting for deterioration was assessed by using Fine-Gray subdistribution hazard ratios (SHRs). RESULTS: Of 15,424 OHT candidates, 589 (3.8%) were ACHD. ACHD vs non-ACHD candidates had less urgent status at initial listing (4.2% vs 4.7% listed at status 1; 17.2% vs 23.7% listed at status 2; P < 0.001), but not final listing (5.9% vs 7.6% final status 1; 35.6% vs 36.8% final status 2; P < 0.001). ACHD vs non-ACHD candidates upgraded into status 1 (65.0 vs 30.0 days; P = 0.09) and status 2 (113.0 vs 64.0 days; P = 0.003) spent longer times on the waitlist. ACHD vs non-ACHD candidates spent longer times waiting for an upgrade into status 1 (51.4 vs 17.6 days; P = 0.027) and status 2 (76.7 vs 34.7 days; P = 0.003). Once upgraded, there was no difference between groups in waitlist time to status 1 (9.7 vs 5.5 days = 0.66). ACHD vs non-ACHD candidates with a final status of 1 (20.0% vs 8.6%; SHR 2.47 [95%CI = 1.19-5.16]; P = 0.02) and 2 (8.9% vs 2.3%; SHR 3.59 [95%CI = 2.18-5.91]; P < 0.001) experienced higher rates of death and deterioration. CONCLUSIONS: ACHD candidates have longer waitlist times, have lower priority status at initial listing, wait longer for upgrades, and have higher mortality rates at the same final status as non-ACHD candidates, suggesting that they are being upgraded too late.

Meta-analysis: Incidence of cirrhosis and hepatocellular carcinoma in patients with Fontan palliation.

BACKGROUND AND AIMS: The Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta-analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery. METHODS: A literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy. RESULTS: A total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient-years (95% CI 0.57-1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient-years (95% CI 1.24-2.08) and 32.2% (95% CI 25.8%-39.4%), respectively. The incidence of HCC was 0.12 per 100 patient-years (95% CI 0.07-0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient-years (95% CI 0.12-0.35) and 3.9% (95% CI 2.2%-6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis. CONCLUSION: The incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at-risk patients in order to streamline surveillance for these highly morbid conditions.

Granulomatous mastitis in accessory breast tissue: A rare presentation and surgical management.

Granulomatous mastitis (GM) in accessory breast tissue is rare. The present study aimed to report a rare case of GM in accessory breast tissue. A 39-year-old female patient presented with right axillary discomfort and swelling for ~5 days. On clinical examination, a tender, firm lump was detected in the right axillary region. The ultrasound showed diffuse parenchymal heterogeneity and surrounding edema in the right accessory breast associated with reactive axillary lymph nodes. Following unresponsiveness to conservative treatment, a surgical procedure was performed in the form of an excisional biopsy and the lesion was diagnosed as GM. During the six-month follow-up, there were no recurrences. The exact cause of GM remains uncertain and the etiology within accessory breast tissue is even less understood. Proposed mechanisms suggest that it may result from an exaggerated immune response triggered by various factors, such as infection, autoimmunity or hormonal fluctuations. GM in accessory breast tissue is a rare and challenging clinical condition to be diagnosed. Due to the rarity of this condition, it highlights the importance of including GM in the differential diagnosis of axillary masses.

Carcinoma arising from thyroglossal duct remnants.

Thyroglossal duct cysts (TGDCs) are unusual remnants of the thyroid gland that are rarely observed in association with carcinoma. The present study aimed to showcase the clinical characteristics, diagnosis and management of patients with TGDC carcinoma. It was a single-center study conducted from February 2016 to February 2020. The study involved the retrospective analysis of a series of cases with TGDC carcinoma. A total of 10 patients were included in the study, of whom eight (80%) were females. Their age ranged from 25 to 48 years with a mean age of 39.1 years. A total of five cases (50%) underwent only Sistrunk's procedure, four patients (40%) underwent total thyroidectomy along with Sistrunk's procedure and one patient (10%) was treated by Sistrunk operation and lobectomy. In all of the cases (100%), histopathological examination confirmed papillary thyroid carcinoma in TGDCs. In addition, in the thyroid tissue, 2 cases (20%) also had papillary thyroid carcinoma and 3 cases (30%) had papillary thyroid microcarcinoma. Radioiodine was administered in one patient (10%) with suppressive thyroxine. A three-year follow-up with ultrasound revealed no suspicious lesions in any of the cases. Although rare, carcinoma may develop in the thyroglossal cysts. In this situation, both the thyroid gland and different lymph node compartments should be evaluated for malignancy. Surgical intervention is the cornerstone of management.

Titanium Allergy: A Retrospective Review of 166 Patch Tested Patients.

Background: Although most patients do not develop hypersensitivity reactions to metals in implanted devices, when they do occur, significant morbidity can result. Titanium-based systems are often considered as an alternative option in metal-allergic patients; however, there are few studies published on titanium allergy and allergic reactions to titanium in implants may be overlooked in clinical practice. Methods: Our aim was to further characterize a single institution's experience with titanium patch testing and evaluation of titanium allergy. We performed a retrospective medical record review of 166 patients evaluated for titanium contact allergy between January 2018-August 2023. Of the 166 patients in our cohort, 67 were referred for pre-implant patch testing and 64 for post-implant patch testing; 35 were tested for reasons unrelated to an implant. Results: Twenty-six of the 166 patients were PTP to titanium (15.7% positive rate). Titanium PTP rates were higher for post-implant cases (28.1%, 18/64) compared to pre-implant cases (6.0%, 4/67) (χ2 9.97, p = 0.002). Among 18 titanium PTPs identified for the 64 post-implant cases, 8 were likely relevant, 8 possibly relevant, and 2 not likely relevant. Conclusions: Further studies should be performed to evaluate the incidence of allergy to titanium implants and to continue surveillance of changes in sensitization rates.