Systemic Disease Progression Research Articles

Association of cell-free DNA, micro-RNA 21, and micro-RNA 146a levels with rheumatoid arthritis activity.

Rheumatoid arthritis (RA) is a progressive systemic autoimmune disease characterized by chronic inflammation of synovial joints and impaired immunological tolerance. It ultimately results in irreversible joint degeneration. This study aimed to measure Cell-Free DNA (cf-DNA), miR-21, and miR-146a and assess their disease activity levels in RA. This case-control trial was conducted on 80 subjects (patients and control groups). Cases were categorised into two groups: Group I: 20 cases with active disease and Group II: 20 cases with inactive disease. Group III (control): 40 healthy subjects with matched age and sex. The DAS-28 score was used to assess the RA disease activity. This study demonstrated that miRNA21, miRNA 146a, and cf-DNA significantly increased in both active and inactive groups compared to controls (P-value < 0.001). In addition, there was a significant increase in the active group compared to the inactive group (P-value < 0.001). In the active group, miRNA 146a and cf-DNA exhibited a significant positive correlation with the DAS-28 score and clinical manifestations, including morning stiffness, joint tenderness, and swelling. The linear regression analysis revealed that the primary predictors of miRNA21, miRNA 146a, and cf-DNA levels are the DAS-28 score, ESR, and disease duration. miRNA 146a can be considered a valuable marker for disease activity in RA patients. Furthermore, cf-DNA is suggested to indicate inflammatory conditions; however, MiR21 did not show a significant association with disease activity.

Inflammatory disease progression shapes nanoparticle biomolecular corona-mediated immune activation profiles

Polymeric nanoparticles (NPs) are promising tools used for immunomodulation and drug delivery in various disease contexts. The interaction between NP surfaces and plasma-resident biomolecules results in the formation of a biomolecular corona, which varies patient-to-patient and as a function of disease state. This study investigates how the progression of acute systemic inflammatory disease influences NP corona compositions and the corresponding effects on innate immune cell interactions, phenotypes, and cytokine responses. NP coronas alter cell associations in a disease-dependent manner, induce differential co-stimulatory and co-inhibitory molecule expression, and influence cytokine release. Integrated multi-omics analysis of proteomics, lipidomics, metabolomics, and cytokine datasets highlight a set of differentially enriched TLR4 ligands that correlate with dynamic NP corona-mediated immune activation. Pharmacological inhibition and genetic knockout studies validate that NP coronas mediate this response through TLR4/MyD88/NF-κB signaling. Our findings illuminate the personalized nature of corona formation under a dynamic inflammatory condition and its impact on NP-mediated immune activation profiles and inflammation, suggesting that disease progression-related alterations in plasma composition can manifest in the corona to cause unintended toxicity and altered therapeutic efficacy.

P0481 Real-World Analysis of Disease Progression in Ulcerative Colitis: A Comparative Study Across Diagnostic Eras at a Tertiary IBD Center

Abstract Background Ulcerative colitis (UC) is a chronic condition characterized by a relapsing-remitting course, leading to cumulative systemic damage and disease progression. This progression may include extension of colitis, new extraintestinal manifestations (EIMs), dysplasia/colorectal cancer (CRC), and the need for colectomy. This study aimed to compare disease progression based on the time of diagnosis, to assess the impact of new therapeutic options. Methods Retrospective study at Reina Sofía University Hospital, analyzing all UC patients diagnosed within the past 10 years (2014-2023, cohort B) and a matched cohort diagnosed prior to 2014 (cohort A). Disease progression was defined as the first occurrence of new EIMs, new dysplasia/CRC, need for colectomy, or progression of UC extension. Kaplan-Meier analysis was used to calculate time to progression events. Results Of 643 patients identified, 72 were excluded, leaving 571 for analysis. Among them, 194 (34%) were diagnosed before 2014 and 377(66%) within the last decade (2014-2023). Median age at diagnosis was 39.5 years (IQR 27.3–54.2), and 304 (53.2%) were male. Initial disease extent was: proctitis 147(25.7%), left-sided colitis 203 (35.6%) and pancolitis 191 (33.5%). At diagnosis, 40 (7%) had EIMs. During a median follow-up of 7.1 years (3.7–13.3), 223(39.1%) patients experienced disease progression, including extension of colitis in 57(10%) cases, new EIMs in 114 (20%), colectomy in 46 (8.1%), and dysplasia/CRC in 56(9.8%). Patients diagnosed within the last decade showed a shorter time to progression compared to those diagnosed prior to 2014 (log-rank test, p&amp;lt;0.0001). This trend was also observed for new EIMs (p=0.01), dysplasia/CRC (p&amp;lt;0.0001), and disease extension (p=0.014) (Figure 1B-E). However, no significant difference was found in time to colectomy between groups (p=0.31) (Figure 1F). First maintenance therapy was mesalazine in 366(97.9%) of patients diagnosed within the last decade compared to those diagnosed previously 178(96.7%). Corticosteroids were used at some point in 379(69.4%), median number of corticosteroid courses of 2(1-4). Advanced therapy during follow-up was prescribed in 94(24.9%) of patients diagnosed in the last decade compared to 66(34%) of those diagnosed previously, p=0.022. However, time to advanced therapy prescription was significantly shorter in patients with recent diagnosis (log-rank test p=0.014) (Figure 1A) Conclusion A substantial proportion of patients with UC experienced disease progression within a follow-up period of less than 10 years. Despite the availability and earlier use of advanced therapeutic options, disease progression was observed to occur sooner in patients diagnosed within the last decade, compared to those diagnosed before 2014.

Promoting Prevention and Targeting Remission of Asthma: A European Forum for Research and Education in Allergy and Airway Diseases Consensus Statement on Raising the Bar in Asthma Care.

Asthma is a common multifaceted respiratory disease with a major impact on quality of life. Despite increased insights into mechanisms underlying various asthma phenotypes and endotypes and the availability of targeted biologic treatment options, the disease remains uncontrolled in a substantial proportion of patients with risk of exacerbations, requiring systemic corticosteroids, and with progressive disease. Current international guidelines advocate a personalized management approach to patients with uncontrolled severe asthma. The European Forum for Research and Education in Allergy and Airway Diseases asthma expert panel was convened to discuss strategies to optimize asthma care and to prevent systemic corticosteroid overuse and disease progression. In this meeting report, we summarize current concepts and recommendations and provide a rationale to implement personalized asthma management at earlier stages of the disease. The ultimate goal is to move away from the current one-size-fits-most concept, which focuses on a symptom-driven treatment strategy, and shift toward a phenotype- and endotype-targeted approach aimed at curbing the disease course by improving clinical outcomes and preserving health-related quality of life. Herein, we provide a consensus view on asthma care that advocates a holistic approach and highlight some unmet needs to be addressed in future clinical trials and population studies.

Anti-inflammatory potential of Curcuma heyneana: An in vitro and in silico investigation

Rheumatoid arthritis (RA) is a progressive and chronic systemic autoimmune disease. However, currently treatment is often carried out using NSAIDs and corticosteroids. Although it reduces symptoms, this treatment has a high rate of side effects. This study aims to determine the anti-inflammatory property of Curcuma heyneana so that it can be used as an alternative treatment for RA. Based on author knowledge, this study on C. heyneana from the Indonesian region for the treatment of RA is still limited. C. heyneana’s rhizome was extracted by maceration with ethanol followed by fractionation process using n-hexane, ethyl acetate, and n-butanol. The anti-inflammatory invitro activities were determined by heat-induced hemolysis, effect on protein denaturation, and cyclooxygenases (COX) inhibition assay. Molecular docking of major predictive compounds was performed by AutoDock Vina. The results showed that some fractions of C. heyneana contained terpenoids, flavonoids, and alkaloids. The ethyl acetate fraction exhibited the highest anti-inflammatory activity, which was attributed to the presence of curcuminoids. Molecular docking studies further confirmed the potential of demethoxycurcumin, a curcuminoid identified in the ethyl acetate fraction, to inhibit COX-2. These findings suggest that C. heyneana, particularly its previously unreported curcuminoid-rich fractions, holds promise as a natural anti-inflammatory agent. Further research is warranted to explore the therapeutic potential of this plant in the management of RA and other inflammatory disorders.

EPID-13. PREDICTORS OF HISTOPATHOLOGIC RESULTS OF BRAIN BIOPSY IN PATIENTS SUSPECTED OF SECONDARY CNS LYMPHOMA

Abstract Patients suspected of secondary CNS lymphoma (SCNSL) often undergo brain biopsies. Recent studies doubt biopsy utility due to high SCNSL diagnosis rates. We sought to enumerate histopathologic biopsy results in suspected SCNSL patients to evaluate utility of biopsy. We furthermore assess clinical and radiographic factors based on ability to distinguishing SCNSL from non-SCNSL. 109 patients with non-CNS lymphoma who subsequently presented with brain lesions that underwent biopsy at MD Anderson Cancer Center were included. Histopathologic diagnoses were obtained. Pre-operative imaging was assessed for contemporary radiologic diagnoses by obtaining the leading differential reported at the time of the study. Subsequently, a staff neuroradiologist, blinded to biopsy outcomes and clinical considerations, provided a retrospective diagnosis. 61 patients had SCNSL whereas 48 did not. Non-SCNSL biopsy results included infection (n=16, 33%), glioma (n=12, 25%), nonspecific (n=12, 25%), and other metastases (n=3, 6%). Patients with non-indolent lymphoma (DLBCL, mantle cell, Burkitt’s, and lymphoblastic lymphoma) were more likely to have SCNSL on biopsy (p&amp;lt;0.001, OR 12.55). Patients with SCNSL had shorter time interval since initial diagnosis (median 18.1mo vs. 63.2mo, p=0.008). Systemic progression of disease at biopsy was not associated with SCNSL (p=0.35). There was no difference in age, stage, LDH, Albumin, ECOG, IPI, anatomic location, or B-symptoms at times of diagnosis or neurosurgery. No patient had positive CSF cytology prior to biopsy. Neither retrospective nor contemporary radiographic diagnoses had sufficient accuracy to replace biopsy. A positive retrospective diagnosis trended towards association with SCNSL pathology (sensitivity=0.94, specificity=0.23, PPV=0.65, NPV=0.70, p=0.08). A positive contemporary diagnosis was associated with SCNSL pathology (sensitivity=0.67, specificity=0.73, PPV=0.76, NPV=0.64, p&amp;lt;0.001). Similar biopsy proportions yielded SCNSL and non-SCNSL. Although some factors are associated with SCNSL, none can reliably distinguish patients. Given the divergent treatments for the reported pathologies, our study reiterates the necessity of biopsy in suspected SCNSL.

Is pancreatic adenosquamous carcinoma (PASC) a surgical disease? A large healthcare system review

IntroductionPancreatic cancer represents an increasing cause of cancer-related deaths. Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreas cancer. Optimal treatment is not well-defined. This review aims to provide a detailed analysis of the natural history, management, and outcomes of the patients with PASC within a single large healthcare system. Materials and methodsA large healthcare database was used to retrospectively identify all patients with histological diagnosis of PASC from 2010 to 2020. The cohort was evaluated as a whole and according to the following management modalities: operative, non-metastatic non-operative, and patients with metastatic disease. Abstracted data included patient characteristics, oncologic characteristics at presentation, and details of surgical and non-surgical treatment. ResultsIn total, 60 patients with PASC were identified. All patients had confirmed histopathological diagnosis of PASC. Mean age at the time of diagnosis was 70.9 years, and 28 patients were male (46.7 %). Most patients presented with pancreas head tumors (60 %). Thirty-four patients presented with non-metastatic disease (56.6 %). The operative group consisted of 17 patients (28.3 %). Most patients received adjuvant systemic therapy (70.6 %). Majority of patients experienced recurrence (76.5 %), with median time to recurrence at 6.5 months. Median overall survival in the operative group was 19.1 months. Seventeen patients with non-metastatic disease (28.3 %) did not undergo resection. Median overall survival of this cohort was 3.3 months. Systemic chemotherapy was used in 8 patients. Approximately half of patients with non-metastatic disease (9/17) did not receive any treatment due to rapid physical deterioration or poor functional status at baseline. Median survival for the non-treatment group was 1.7 months. At presentation, 26 patients (43.3 %) had metastatic disease. Most common site of metastasis was the liver. Median survival for patients with metastatic disease was 3.1 months. DiscussionPASC is a distinct entity from glandular PDAC, and it appears to be a more aggressive disease process. Complete resection confers survival benefit but is not curative. Furthermore, few patients undergo surgery, even with seemingly resectable disease. Systemic therapy administration is limited in many patients due to physiologic decline. Dismal clinical course and poor survival is universal among all patients who do not undergo any treatment modality, regardless of metastatic status. Globally grim prognosis appears to be due early systemic effects, disease progression and lack of effective systemic therapy. ConclusionsPASC remains a poorly understood cancer and portends particularly poor prognosis. It is associated with a rapid clinical decline, poor response to systemic therapy, early recurrence, and poor overall survival. However, ability to treat with surgery and chemotherapy may best prolong survival. SynopsisPancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer. In this study, we evaluated 60 patients with PASC. PASC is a systemic disease characterized by rapid clinical decline, poor response to systemic therapy, early recurrence, and poor survival. Despite resection or systemic therapy, patients succumb rapidly.

Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma.

We explored the utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) sequencing as a noninvasive diagnostic tool for detecting central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma (DLBCL). Secondary CNS involvement in DLBCL, although rare (~5% of cases), presents diagnostic and prognostic challenges during systemic disease progression or relapse. Effective treatment is impeded by the blood-brain barrier. This was a prospective cohort study (Samsung Lymphoma Cohort Study III) involving 17 patients with confirmed CNS involvement. High-throughput sequencing was conducted using targeted gene panels designed to detect low-frequency variants and copy number alterations pertinent to lymphomas in ctDNA extracted from archived CSF samples. Despite challenges such as low DNA concentrations affecting library construction, the overall variant detection rate was 76%. Detected variants included those in genes commonly implicated in CNS lymphoma, such as MYD88. The study highlights the potential of CSF ctDNA sequencing to identify CNS involvement in DLBCL, providing a promising alternative to more invasive diagnostic methods such as brain biopsy, which are not always feasible. Further validation is necessary to establish the clinical utility of this method, which could significantly enhance the management and outcomes of DLBCL patients with suspected CNS involvement.

Morphological Characteristics of the Ulna Fracture Zone in Rats Undergoing Therapy With Modified Mesenchymal Stem Cells in Experimental Osteoporosis

Osteoporosis is a progressive systemic disease characterized by a decrease in bone density. This leads to increased bone fragility and a higher likelihood of fractures. New approaches to cellular therapy have been developed for the effective treatment of this pathology, based on the use of modified osteophilic polymers with mesenchymal stem cells (MSCs) for local action on damaged bone areas. The aim of the study was to morphologically assess the effectiveness of modified osteophilic polymer MSCs on reparative osteogenesis processes during the post-traumatic period in animals with a fracture of the ulna and underlying osteoporosis. Material and methods. The experiment involved Wistar rats (females, n=40; 200–300 g, 3 months old). Osteoporosis was simulated by bilateral ovariectomy, and the fracture was simulated through diaphysis osteotomy of the ulna. All rats were randomly distributed into four groups: Group I (control, n=10; buffered solution); Group II (n=10; osteophilic polymer, 1 mg/ml); Group III (n=10; MSC suspension, 1×106); Group IV (n=10; modified osteophilic polymer MSCs, 1×106). The experiment results were evaluated in 1 and 6 months after the fracture. Results. MSCs were applied after exposure to the osteophilic polymer to restore the pool of osteoblast precursors in the fracture area of the ulna in experimental osteoporosis. In all animals, regeneration foci with varying degrees of structural and functional maturation of cellular and intercellular substrates were formed in the fracture area. The most pronounced processes of bone tissue restoration were observed with the use of modified osteophilic polymer MSCs. This is likely associated with the high concentration of modified osteophilic polymer MSCs and their retention in zones of damaged bone regeneration, subsequently stimulating osteogenesis. The paradigm of provisionality, as a universal model manifestating histogenesis and organogenesis, was utilized to gain a more comprehensive biological understanding and interpretation of the observed changes. Conclusion. MSCs applied after exposure to an osteophilic polymer significantly enhance the process of reparative osteogenesis in fractures of long bones in patients with estrogen-induced osteoporosis, thus making this technology promising for combined therapy.

Pathological complete response of locally advanced triple-negative breast cancer: case report

Background. Triple-negative breast cancer is the most aggressive molecular subtype among breast malignancies. Due to the high proliferative activity of tumor cells and the lack of targets for targeted therapy, neoadjuvant chemotherapy plays the main role in complex treatment of this subtype. The optimal time to start neoadjuvant chemotherapy is defined as less than 8 weeks. Delays in time to treatment initiation may adversely affect treatment outcomes, as well as cause local or systemic disease progression. Achieving complete pathological response after neoadjuvant chemotherapy reduces the relative risk of relapse by more than 70 %, which, in turn, leads to a significant improvement in long-term survival of these patients. Description of the clinical case. A 32-year-old woman came to the clinic 15 months after being diagnosed with triple-negative breast cancer. The patient was treated with alternative medicine methods for 15 months, and upon admission to the hospital, the patient had pronounced local tumor growth with massive decay, tumor lysis syndrome and nutritional disorders. We decided to perform neoadjuvant chemotherapy: 12 cycles of weekly paclitaxel + carboplatin, followed by 4 cycles of dose-dense doxorubicin + cyclophosphamide. Chemotherapy resulted in a significant reduction in tumor size and improvement of health status of the patient. There were no clinically significant side effects requiring hospitalization or dose reduction. Upon completion of neoadjuvant treatment, the patient underwent mastectomy. The histological examination revealed a complete pathological response of the primary tumor and regional lymph nodes. The patient underwent adjuvant external beam radiation therapy. The patient is alive 3 years after diagnosis and 1.5 years after treatment completion. She plans delayed breast reconstruction with contralateral breast augmentation. Conclusion. This is a rare case of locally advanced triple-negative breast cancer with pathological complete response to neoadjuvant chemotherapy 15 months after diagnosis.

Vascular network-mediated systemic spread of Pseudomonas syringae pv. actinidiae causes the bacterial canker of kiwifruit

Pseudomonas syringae pv. actinidiae (Psa) causes destructive kiwifruit bacterial canker by invading vascular tissues across multiple plant organs. However, the cellular mechanism underlying its systemic transmission and cell-to-cell movement within these specialized vascular conduits remains unclear. In this study, a Psa-GFP strain and various microscopic techniques were used to investigate the interaction between kiwifruit and Psa. Our results reveal that Psa strategically exploits host vascular conduits for systemic movement, with the xylem vessel being the predominant avenue. In the phloem, Psa exhibits adaptive alteration in bacterial shape to traverse sieve pores, facilitating its systemic spread along sieve tubes and inducing phloem necrosis. Within the xylem, Psa breaches pit membranes to migrate between adjacent vessels. Furthermore, phloem fibers act as an initial barrier at the early stages of infection, delaying Psa's entry into vascular tissues during its journey to the xylem. Additionally, at the junctions of stem–stem or stem-leaf, branch trace or leaf trace mediates the bacterial organ-to-organ translocation, thus facilitating the systemic progression of disease. In conclusion, our findings shed light on the cellular mechanism employed by Psa to exploit the woody plant's vascular network for infection, thereby enhancing a better understanding of the biology of this poorly defined bacterium. These insights carry implications for the pathogenesis of Psa and other vascular pathogens, offering theoretical guidance for effective control strategies.

THE CHOICE OF ANESTHESIA METHOD FOR HYBRID ANGIOPLASTY. CLINICAL OBSERVATION

Many patients presenting for surgical revascularization of the lower extremities have progressive systemic atherosclerotic disease affecting not only the peripheral extremities, but also the coronary, cerebral, and renal vessels. Vascular patients are therefore considered high perioperative risk patients, making them a real challenge even for experienced anesthesiologists. This article analyzes a clinical case of hybrid angioplasty of lower extremity vessels in a patient with generalized atherosclerotic lesions under regional anesthesia with ultrasound navigation. Analysis of the clinical case and its analysis shows that regional anesthesia provides reliable protection against surgical stress with minimal impact on the body and should be used in patients with concomitant cardiac and pulmonary pathologies.

Transcriptomic analyses of lung tissues reveal key genes associated with progression of systemic sclerosis-interstitial lung disease (SSc-ILD)

Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50% of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD. Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n=18) and control lung tissue (n=6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis. To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (cdkn2c) was overexpressed (P=0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (peli1) showed lower expression (P=0.0012). Additionally, in all four groups, cdkn2c and peli1 gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of cdkn2c showed consistent results with the nS analysis. More cdkn2c and less peli1 expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, cdkn2c (p18) to be associated with fibrosis progression.

Concordance and Prognostic Relevance of Different Definitions of Systemic Sclerosis Interstitial Lung Disease Progression.

Rationale: Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a common complication that has a varied progression rate and prognosis. Different progression definitions are available, including minimal clinically important worsening of FVC, EUSTAR (European Scleroderma Trials and Research Group) progression, OMERACT (Outcome Measures in Rheumatology Clinical Trials) progression, and Erice ILD working group progression. Pulmonary function and symptom changes may act as specific confounding factors when applying these definitions in SSc. Objectives: To assess the concordance and prognostic value of four different definitions in patients with SSc-ILD overall and in specific clinical groups. Methods: Progression status in consecutive patients with SSc-ILD was assessed over 24 months, and 60-month disease-related mortality risk was compared between progressors and nonprogressors using four definitions. Measurements and Main Results: Among 245 patients, 26 SSc-related deaths were reported. Mortality was linked to progression for minimal clinically important worsening of FVC (hazard ratio [HR], 2.27; 95% confidence interval [CI], 1.03-4.97), OMERACT (HR, 2.90; 95% CI, 1.28-6.57), and Erice definitions (HR, 2.69; 95% CI, 1.23-5.89). The association between progression and mortality was poor in patients with disease duration ≥3 years, mild functional impairment, and pulmonary artery systolic pressure ≥40 mm Hg. Erice criteria appeared superior in patients with duration ≥3 years, limited cutaneous variant, and pulmonary artery systolic pressure <40 mm Hg. OMERACT criteria performed better in diffuse cutaneous variant patients with severe functional impairment. Conclusions: The four evaluated definitions of progression in SSc-ILD are not interchangeable, resulting in up to one-third of cases being classified differently on the basis of adopted criteria and presenting different prognostic values, particularly within specific clinical groups.

Stereotactic radiosurgery in patients with small cell lung cancer and 1-10 brain metastases: A multi-institutional, phase II, prospective clinical trial.

2020 Background: Stereotactic radiosurgery (SRS) as opposed to whole brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases. Brain metastases from small cell lung cancer (SCLC), however, represent an exception to this dogma, given that prior trials evaluating SRS in lieu of WBRT excluded patients with SCLC due to the historical role of prophylactic cranial irradiation (PCI) and concerns relating to neurologic decline and death when WBRT is omitted from upfront management. We conducted a prospective, multi-center, phase II trial of SRS in patients with SCLC and 1-10 brain metastases to determine how rates of neurologic death compared to historical controls managed with WBRT. Methods: Following approval from the Dana-Farber/Harvard Cancer Center IRB, we opened a single-arm, multi-center, phase II trial to investigate SRS in patients with SCLC and 1-10 brain metastases naïve to prior brain-directed radiation including PCI (NCT03391362). Prior resection of a brain metastasis was permitted. Patients with leptomeningeal disease were excluded. Metastases &lt;2cm in maximal size were generally managed with SRS to 20 Gy; larger tumors, or those near sensitive structures, were dose reduced to 16-19 Gy or managed with fractioned SRS (SRT) to 30 Gy in 5 fractions. Gross totally resected brain metastases received SRT to 25 Gy in 5 fractions. We sought to determine, as the primary endpoint, whether or not use of SRS in lieu of WBRT would lead to meaningfully higher rates of neurologic death (HR 1.61, corresponding to a 1-year event rate of 26.7% relative to a historical 1-year rate of 17.5% in patients previously managed with WBRT at our center), with 90% power and a one-sided alpha error of 5%. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression / systemic symptoms of a life-threatening nature and was assessed by a panel of 2-3 neuro-radiation oncologists. Results: Between 3/2018 – 4/2023, 100 patients were enrolled across 4 centers. The median age was 68 years (IQR 63 – 74 years). The median number of brain metastases was 2 (IQR 1 – 3); 16 (16%) of patients underwent prior neurosurgical resection. On study, 66 (66%) patients were treated with SRS alone while 32 (32%) were treated with SRT to at least 1 site; 2 patients died of systemic disease progression before study treatment. The median overall survival was 10.3 months. In total, 19 neurologic deaths were observed, relative to 62 systemic deaths. The neurologic death rate at 1 year was 11.0% (95% CI 4.8% – 17.2%). Conclusions: Our prospective, multi-institutional study demonstrated modest rates of neurologic death when SRS as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases and represents the largest prospective experience to date. Clinical trial information: NCT03391362 .

Neuro-oncologic Emergencies.

Neuro-oncologic emergencies have become more frequent as cancer remains one of the leading causes of death in the United States, second only to heart disease. This article highlights key aspects of epidemiology, diagnosis, and management of acute neurologic complications in primary central nervous system malignancies and systemic cancer, following three thematic classifications: (1) complications that are anatomically or intrinsically tumor-related, (2) complications that are tumor-mediated, and (3) complications that are treatment-related. The main driver of mortality in patients with brain metastasis is systemic disease progression; however, intracranial hypertension, treatment-resistant seizures, and overall decline due to increased intracranial burden of disease are the main factors underlying neurologic-related deaths. Advances in the understanding of tumor-specific characteristics can better inform risk stratification of neurologic complications. Following standardized grading and management algorithms for neurotoxic syndromes related to newer immunologic therapies is paramount to achieving favorable outcomes. Neuro-oncologic emergencies span the boundaries of subspecialties in neurology and require a broad understanding of neuroimmunology, neuronal hyperexcitability, CSF flow dynamics, intracranial compliance, and neuroanatomy.

Rapid non-invasive tracking of splenomegaly with hands-free 3D ultrasound for on-demand assessment of immune disorders and cancer

Abstract Splenomegaly is an important measure of cancer progression and immune disorders. Magnetic resonance imaging (MRI) and computed tomography (CT) are the standard in the field but are not optimal for preclinical studies due to their high cost, low throughput and reliance on contrast agents for soft tissue. Here, we report the use of a novel 3D automated ultrasound scanner (Vega, Revvity Inc.) for the rapid assessment of spleen volume in two murine models (cancer and lupus). Cancer cohort: Tumor-bearing (4T1 breast cancer, right flank) mice were imaged alongside control mice at five timepoints over 25 days. Spleen volume was found to increase 18-fold (30±3 mm3 to 545±105 mm3) after 25 days of tumor growth (938±77 mm3). Lupus cohort: MRL/lpr mice were allowed to age until they developed lymphoproliferation (12-14 weeks) and then imaged biweekly until 20 weeks of age. A 300-fold increase in calculated spleen volume by 18 weeks of age in MRL/ lpr mice was observed. Kidney volume doubled and a statistical increase (p&amp;lt;0.05) in vascular density was observed (using acoustic angiography), indicating systemic disease progression. Average acquisition times for both cohorts were 30 seconds per mouse, showing excellent applicability of spleen volume as a measurement of disease progression compared to more laborious techniques (e.g. MRI). Future work in this area will explore the application of machine learning and AI-assisted auto segmentation tools for higher throughput data analysis.

Proteomic and Transcriptomic Analysis of Human Colonoids Exposed to Bacterial Serine Protease, EspP

Gut regeneration mechanisms remain an important, yet elusive, facet of intestinal injury research. The intestinal epithelium must be intact for critical gut functions to remain in place, yet injury via microbe interactions or environmental toxicants is common. EspP is a potent serine protease that functions as a cytotoxin and is secreted by enterohemorrhagic Escherichia coli. This bacterial toxin has been recently shown to cause significant colonic epithelial damage in human colonoids. Previous proteomics and single cell RNA-seq analysis of human colonoids exposed to EspP found that there is a marked expansion of enteroendocrine cells (EECs) at acute exposures. There is also an increase in vascular endothelial growth factor (VEGF)A and B, but the reasons for this remains unknown. Therefore, our goals are to understand the effects of altered secretory lineage differentiation upon EspP exposure during EHEC infection and characterize angiogenesis as a key factor in disease progression. We hypothesize that EspP induced EEC differentiation leads to increased enterohormone section, such as 5-HT, which ultimately influences the mucosal immune response and indirectly leads to increased VEGFA and VEGFB expression. Together, these factors promote systemic disease progression through epithelial-endothelial interactions. Human colonoids derived from healthy adult colonic biopsies (UNM IRB approved study 18-626 and 18-171) were established and shown to physiologically model the colonic epithelia. Colonoids were acutely exposed to EspP. Control and EspP-exposed colonoids (n=3 unique donors) were dissociated into single cells and processed for droplet-based single cell sequencing (scRNA-seq) or tandem mass spectrometry. The scRNA-seq data was analyzed using the Seurat pipeline and integrated with the proteomics dataset. scRNA-seq results identified a 4-fold expansion of EECs, with increases in EEC hormones 5-HT and PYY as well as a 2-fold expansion of VEGF expression. These transcriptomic changes seen were validated in colonoids (&gt;5 biologically unique human donors) via RNA FISH and immunofluorescence. Our results demonstrate that acute EspP exposure directly induces transcriptomic and cellular changes in intestinal epithelia independent of microbiota, stroma, and immune cells. As EEC expansion is seen broadly in disease states from colorectal cancer to celiac disease, determining the role of enterohormones upon these changes, as well as the function of EECs during acute injury, will fill a gap in knowledge relevant to a wider problem of intestinal dysfunction. This work was supported by grants from the National Institutes of Health: K01DK106323, R56ES034400, P42ES025589; and AGA SURF. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Stereotactic Radiosurgery for Patients with Brain Metastases from Hepatopancreaticobiliary Cancers.

The role of stereotactic radiosurgery (SRS) for patients with brain metastases from hepatopancreaticobiliary (HPB) cancers has yet to be established. The authors present a single-institution experience of patients with HPB cancers who underwent SRS when their cancer spread to the brain. We surveyed our Gamma Knife SRS data base of 18,000 patients for the years 1987-2022. In total, 19 metastatic HPB cancer patients (13 male) with 76 brain metastases were identified. The median age at SRS was 61 years (range: 48-83). The primary cancer sites were hepatocellular carcinoma (HCC, 11 patients), cholangiocarcinoma (CCC, 2 patients), and pancreatic carcinoma (PCC, 6 patients). The median Karnofsky Performance Score (KPS) was 80 (range: 50-90). Two patients underwent pre-SRS whole-brain fractionated radiation therapy (WBRT) and eight patients underwent pre-SRS surgical resection. All SRS was delivered in single session. The median margin dose was 18 Gy (range: 15-20). The median cumulative tumor volume was 8.1 cc (range: 1.0-44.2). The median patient overall survival (OS) after SRS was 7 months (range 1-79 months). Four patients had documented local tumor progression after SRS at a median time of 8.5 months (range: 2-15) between SRS and progression. Out of 76 treated tumors, 72 tumors exhibited local control. The local tumor control rate per patient was 78.9%. The local tumor control per tumor was 94.7%. Four patients developed new brain metastases at a median of 6.5 months (range: 2-17) after SRS. No patient experienced adverse radiation effects (AREs). At the last follow-up, 18 patients had died, all from systemic disease progression. Metastatic spread to the brain from HPB cancers occurs late in the course of the primary disease. In this study, all deceased patients ultimately died from primary disease progression. SRS is a non-invasive strategy that maximally preserves quality of life, and our results reported favorable outcomes compared to the existing literature. SRS should be considered as one of the primary management strategies for patients with brain metastatic spread from HPB cancer.

Systematical mutational analysis of teriparatide on anti-osteoporosis activity by alanine scanning

Osteoporosis is a progressive systemic skeletal disease that decreases bone density and bone quality, making them fragile and easy to break. In spite of effective anti-osteoporosis potency, teriparatide, the first anabolic medications approved for the treatment of osteoporosis, was proven to exhibit various side effects. And the relevant structure–activity relationship (SAR) of teriparatide was in need. In this work, we performed a systematical alanine scanning against teriparatide and synthesized 34 teriparatide derivatives. Their biological activities were evaluated and the importance of each residue for anti-osteoporosis activity was also revealed. A remarkable decrease in activity was observed for alanine replacement of the residue Gly12, His14, Ser17, Arg20 and Leu24, showcasing the important role of these residues in teriparatide on anti-osteoporosis activity. On contrary, when Gly13 and Gln30 were mutated to Ala, the peptide derivatives exhibited the significantly increased activities, demonstrating that these two residues could be readily replaced. Our research expanded the peptide library of teriparatide analogues and presented a potential opportunity for designing the more powerful anti-osteoporosis peptide agents.