Disseminated Disease Research Articles

P11.46.A ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. MATERIAL AND METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.

P-097 Single-cell RNA sequencing of circulating tumor cells in precursor myeloma patients reveals early mechanisms of disease dissemination

P-097 Single-cell RNA sequencing of circulating tumor cells in precursor myeloma patients reveals early mechanisms of disease dissemination

Application of an Optimal Control Therapeutic Approach for the Memory-Regulated Infection Mechanism of Leprosy through Caputo–Fabrizio Fractional Derivative

Leprosy (Hansen’s disease) is an infectious, neglected tropical skin disease caused by the bacterium Mycobacterium leprae (M. leprae). It is crucial to note that the dynamic behavior of any living microorganism such as M. leprae not only depends on the conditions of its current state (e.g., substrate concentration, medium condition, etc.) but also on those of its previous states. In this article, we have developed a three-dimensional mathematical model involving concentrations of healthy Schwann cells, infected Schwann cells, and M. leprae bacteria in order to predict the dynamic changes in the cells during the disease dissemination process; additionally, we investigated the effect of memory on system cell populations, especially on the M. leprae bacterial population, by analyzing the Caputo–Fabrizio fractionalized version of the model. Most importantly, we developed and investigated a fractionalized optimal-control-induced system comprising the combined drug dose therapy of Ofloxacin and Dapsone intended to achieve a more realistic treatment regime for leprosy. The main goal of our research article is to compare this fractional-order system with the corresponding integer-order model and also to distinguish the rich dynamics exhibited by the optimal-control-induced system based on different values of the fractional order ζ∈(0,1). All of the analytical results are validated through proper numerical simulations and are compared with some real clinical data.

Pore-forming activity of S. pneumoniae pneumolysin disrupts the paracellular localization of the epithelial adherens junction protein E-cadherin.

Streptococcus pneumoniae, a common cause of community-acquired bacterial pneumonia, can cross the respiratory epithelial barrier to cause lethal septicemia and meningitis. S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers robust neutrophil (PMN) infiltration that promotes bacterial transepithelial migration in vitro and disseminated disease in mice. Apical infection of polarized respiratory epithelial monolayers by S. pneumoniae at a multiplicity of infection (MOI) of 20 resulted in recruitment of PMNs, loss of 50% of the monolayer, and PMN-dependent bacterial translocation. Reducing the MOI to 2 decreased PMN recruitment two-fold and preserved the monolayer, but apical-to-basolateral translocation of S. pneumoniae remained relatively efficient. At both MOI of 2 and 20, PLY was required for maximal PMN recruitment and bacterial translocation. Co-infection by wild-type S. pneumoniae restored translocation by a PLY-deficient mutant, indicating that PLY can act in trans. Investigating the contribution of S. pneumoniae infection on apical junction complexes in the absence of PMN transmigration, we found that S. pneumoniae infection triggered the cleavage and mislocalization of the adherens junction (AJ) protein E-cadherin. This disruption was PLY-dependent at MOI of 2 and was recapitulated by purified PLY, requiring its pore-forming activity. In contrast, at MOI of 20, E-cadherin disruption was independent of PLY, indicating that S. pneumoniae encodes multiple means to disrupt epithelial integrity. This disruption was insufficient to promote bacterial translocation in the absence of PMNs. Thus, S. pneumoniae triggers cleavage and mislocalization of E-cadherin through PLY-dependent and -independent mechanisms, but maximal bacterial translocation across epithelial monolayers requires PLY-dependent neutrophil transmigration.

NTRK expression is common in xanthogranuloma and is associated with the solitary variant.

Previously identified mutually-exclusive driver genes in juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) include mutations in MAP kinase pathway genes such as MAP2K1, BRAF, ARAF, KRAS, NRAS, PIK3CD as well as fusions in BRAF and ALK, with a subset of cases with no identified driver yet. NTRK fusion has been identified in rare cases. We identified two consecutive index cases of localized JXG or AXG with NTRK1 fusion by next-generation sequencing (NGS) and confirmed by pan-NTRK immunostain. We expanded the study to a total of 50 cases of JXG and AXG using screening by pan-NTRK immunostain. We confirmed the specificity of our approach with negative results in 5 cases of histiocytic neoplasia lacking an NTRK fusion by NGS and 14 cases of non-neoplastic histiocytic disease. We found 23 cases of JXG or AXG with overexpression of NTRK by immunostain, and these cases were restricted to localized disease (23 of 43 cases, 53.5%) rather than disseminated disease (zero of seven cases). NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.

TIPS-08 ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with international sites opening imminently.

Neonatal herpes simplex virus infection: From the maternal infection to the child outcome.

This review examines the recent literature on the management of herpes simplex virus (HSV) infections in neonates. We summarized the three clinical categories of maternal HSV infection during pregnancy (primary first episode, nonprimary first episode, or recurrent episode) and the mechanisms of fetal damage. Considering when the transmission of the infection from the mother to the fetus/newborn occurs, three types of neonatal infection can be distinguished: intrauterine infection (5% of cases), postnatal infection (10% of cases), and perinatal infections (85% of cases). Neonatal presentation could range from a limited disease with skin, eye, and mouth disease to central nervous system disease or disseminated disease: the treatment with acyclovir should be tailored according to symptoms and signs of infection, and virological tests. These children need a multidisciplinary follow-up, to timely intercept any deviation from normal neurodevelopmental milestones. Prevention strategies remain a challenge, in the absence of an available vaccine against HSV.

Identification of risk factors associated with leptomeningeal disease after resection of brain metastases.

Resection of brain metastases (BMs) may be associated with increased risk of leptomeningeal disease (LMD). This study examined rates and predictors of LMD, including imaging subtypes, in patients who underwent resection of a BM followed by postoperative radiation. A retrospective, single-center study was conducted examining overall LMD, classic LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression, Cox proportional hazards, and random forest analyses were performed to identify risk factors associated with LMD. Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD, with 19 cases (8.8%) of cLMD and 28 cases (12.9%) of nLMD. Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from the date of LMD diagnosis compared with nLMD (median 2.4 vs 6.9 months, p = 0.02, log-rank test). Cox proportional hazards analysis identified cerebellar/insular/occipital location (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.73-6.11, p = 0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p = 0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p = 0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an area under the receiver operating characteristic curve of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Tumor location, absence of extracranial disease at the time of surgery, ventricle contact, and increased tumor volume were associated with LMD. Further work is needed to determine whether escalating therapies in patients at risk of LMD prevents disease dissemination.

Fusion transcriptome profiling defines the monoclonal origin of multifocal epithelioid haemangioma of bone.

Epithelioid haemangioma (EH) of bone remains a highly controversial entity. Indeed, the WHO classifies EHs of soft tissues as benign tumours, whereas bone EHs are considered intermediate-locally aggressive tumours due to common multifocal presentation and local destructive growth. To gain insights into theclinical behaviour and biology of EH of bone we retrospectively analysed 42 patients treated in a single institution from 1978 to 2021. Multifocal presentation was detected in 17 of 42 patients (40%) primarily as synchronous lesions. Patients were treated with curettage (57%), resection (29%) or biopsy, followed by radiotherapy or embolisation (14%). Follow-up (minimum 24 months) was available for 38 patients, with only five local recurrences (13%) and no death of disease. To clarify whether the synchronous bone lesions in multifocal EH represent multicentric disease or clonal dissemination, four cases were profiled by RNA-sequencing. Separate lesions from the same patient, which showed a similar transcriptional profile, expressed the same fusion transcript (involving FOS or FOSB) with identical gene breakpoints. These results indicate that, in EH of bone, multifocal lesions are clonally related and therefore represent the spread of a same neoplastic clone rather than simultaneous independent tumours. This finding is in apparent contradiction with the benign clinical course of the disease, and suggests that tumour dissemination in bone EH probably reflects a phenomenon of passive spreading, with tumour cells colonising distal sites while maintaining their benign biological nature.

The Current and Future States of Diagnostic Tests for Histoplasmosis with a Focus on People with HIV and Disseminated Histoplasmosis.

Histoplasmosis is caused by Histoplasma capsulatum and, although endemic in large parts of the world, is often underrecognized in many locations. In addition to underrecognition, inadequate availability of diagnostic tests is a major contributor to poor outcomes in disseminated disease in people with HIV. For those with advanced HIV and disseminated disease, antibody testing is less useful. Culture and histopathology can be useful in this situation, but each has limitations, including variable sensitivity by site and, in the case of culture, the need for a biosafety level three laboratory and a long period of growth. Antigen testing has proven useful for disseminated histoplasmosis due to the excellent sensitivity of urine. Yet, turnaround is slower than ideal due to use in a limited number of centers. The development of lateral flow assays has the potential to make for true rapid point-of-care assays for histoplasmosis, but in order to meet that promise, the tests must be widely available and affordable.

The role of circulating tumor DNA in diagnosis and optimization of treatment of localized and local pancreatic cancer

Pancreatic cancer (PC) is a malignant highly aggressive tumor that arises and grows under conditions of inflammation and tissue hypoxia. In PC, one of the key processes in progression is epithelial-mesenchymal transition, which leads to early dissemination and rapid realization of metastatic disease, which accounts for low overall survival rates. The tumor, by releasing a wide range of different molecules (circulating DNA, exosomes, proteins and lipids), allows to identify and use them as potential, diagnostic and prognostic biomarkers.This review introduces readers to the liquid biopsy technique. The main applications of the technique in patients with ductal adenocarcinoma of the pancreas are shown. Liquid biopsy is a modern diagnostic method of molecular oncology, the principle of which is to detect circulating tumor cells, DNA, exosomes in biological fluids. Publications evaluating the potential of the method to assess minimal residual disease, evaluate tumor response to systemic therapy, and determine prognosis are discussed. Liquid biopsy is particularly relevant in cases of malignant tumors of difficult localization, in particular, PC. Modern methods of morphological verification of pancreatic tumors (fine needle biopsy under endosonographic control and percutaneous biopsy) have essential disadvantages: low information value, multiple repeated interventions, postmanipulative complications (pancreatitis, bleeding, etc.). Taking into consideration obvious advantages and perspectives of this method over traditional methods of morphological verification, liquid biopsy seems to be a promising diagnostic tool in personalized oncology for pancreatic cancer.

Glucose metabolism and its role in the maturation and migration of human CD1c+ dendritic cells following exposure to BCG.

Tuberculosis (TB) still kills over 1 million people annually. The only approved vaccine, BCG, prevents disseminated disease in children but shows low efficacy at preventing pulmonary TB. Myeloid dendritic cells (mDCs) are promising targets for vaccines and immunotherapies to combat infectious diseases due to their essential role in linking innate and adaptive immune responses. DCs undergo metabolic reprogramming following exposure to TLR agonists, which is thought to be a prerequisite for a successful host response to infection. We hypothesized that metabolic rewiring also plays a vital role in the maturation and migration of DCs stimulated with BCG. Consequently, we investigated the role of glycolysis in the activation of primary human myeloid CD1c+ DCs in response to BCG. We show that CD1c+ mDC mature and acquire a more energetic phenotype upon challenge with BCG. Pharmacological inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) decreased cytokine secretion and altered cell surface expression of both CD40 and CCR7 on BCG-challenged, compared to untreated, mDCs. Furthermore, inhibition of glycolysis had differential effects on infected and uninfected bystander mDCs in BCG-challenged cultures. For example, CCR7 expression was increased by 2-DG treatment following challenge with BCG and this increase in expression was seen only in BCG-infected mDCs. Moreover, although 2-DG treatment inhibited CCR7-mediated migration of bystander CD1C+ DCs in a transwell assay, migration of BCG-infected cells proceeded independently of glycolysis. Our results provide the first evidence that glycolysis plays divergent roles in the maturation and migration of human CD1c+ mDC exposed to BCG, segregating with infection status. Further investigation of cellular metabolism in DC subsets will be required to determine whether glycolysis can be targeted to elicit better protective immunity against Mtb.

Global reach of over 20years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community.

Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements.

A Case of Mycobacterium avium Complex Vertebral Osteomyelitis in a Patient With Human Immunodeficiency Virus

Abstract Mycobacterium avium complex (MAC) infection is one of the most common bacterial opportunistic infections in persons living with human immunodeficiency virus (PLWH). Mycobacterium avium complex infections are caused by either M. avium or Mycobacterium intracellulare, which are nontuberculous mycobacterial species. Mycobacterium avium complex is prevalent in soil, water, and animals in the environment. Mycobacterium avium complex infections are commonly seen in persons with CD4 counts less than 50 cells/μL and are the most common cause of disseminated disease in immunocompromised patients. Vertebral osteomyelitis caused by MAC, however, remains uncommon in PLWH, with few cases reported in the literature (Lancet Infect Dis. 2004;4:557–565; Infect Dis Clin Pract. 2001;10:17–20). We present a case of vertebral osteomyelitis secondary to MAC in a person with human immunodeficiency virus and compare 10 other cases reported in the literature. Our case also highlights the importance of resuming secondary MAC prophylaxis when CD4 counts decline below 100 cells/μL in PLWH.

Pneumothorax occuring during the final stage of treatment in miliary tuberculosis patients

Air in the pleural space can cause lung collapse and respiratory discomfort, which can be life-threatening in very ill patients, making pneumothorax a medical emergency. Since tubercle bacilli can travel through the blood to the lungs and other organs, Miliary Tuberculosis (TB) is a disseminated disease that can be lethal. We present a case of a 36-year-old male with Pneumothorax Occuring during the Final Stage of Treatment in Million Tuberculosis Patients. The patient is currently undergoing outpatient treatment of miliary TB for the 11th month and so far his condition is getting better, however was admitted to the emergency unit of the hospital, diagnosed with left pneumothorax based on clinical, laboratory, and radiology showing. In meanwhile, 88% of the room air was saturated with oxygen, necessitating Intensive Care Unit treatment with HFNC FiO2 100 Flow 60, followed by high consentration oxygen therapy with a non-rebreathing mask (NRM) of 15 litres/minute. Combivent inhalation and pulmicort inhalation were given every 15 minutes. The family refused to install a water sealed drainage or chest tube in the patient. The patient was also given treatments with ceftriaxone, citicolin, methylprednisolone, omeprazole and the advanced phase of tuberculosis drugs namely Rifampicin 450 mg and Isoniazid 300 mg. On the 6th day of treatment in the ICU, the patient's condition improved and the pneumothorax decreased. In this case, the likelihood of Pneumothorax in patients with miliary tuberculosis needs to be emphasized, as well as the importance of evaluation and strict follow-up to prevent the occurrence of pneumothorax.

Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients.

Human adenoviruses (HAdVs) of the F species are commonly responsible for acute gastroenteritis. A few cases of systemic infections have been described in adults or children who have received a hematopoietic stem cell transplant (HSCT), but with no report of liver cytolysis. Since January 2022, several countries have reported an increase in cases of acute hepatitis of unknown cause in children. Adenovirus species F type 41 (HAdV-F41)infection was predominantly identified. The objective of this study is to describe HAdV-F41 infections diagnosed since January 2022 in adult HSCT recipients in two French hospitals. All four patients had diarrhea and liver cytolysis at the time of diagnosis of infection. HAdV viremia was observed in three patients (#1, #3, and #4), but no disseminated disease was reported. HAdV whole genome sequencing and metagenomics characterization were performed on stool and blood samples. The complete HAdV-F41 genome sequence was obtained for three patients and phylogenetic analysis showed that the strains consisted of similar lineage (2b). We did not identify any new HAdV-F41 strains. Metagenomics analysis found adeno-associated virus 2 and torque-teno virus infection in patient #1 and Epstein-Barr virus in patient #4. This is the first case series reporting liver cytolysis during HAdV-F41 infection in adult HSCT patients.

Imaging Findings in Aspergillosis: From Head to Toe.

Aspergillosis is a mycotic infection induced by airborne fungi that are ubiquitous. Inhalation of Aspergillus conidia results in transmission through the respiratory tract. The clinical presentation is dependent on organism and host specifics, with immunodeficiency, allergies, and preexisting pulmonary disease constituting the most important risk factors. In recent decades, the incidence of fungal infections has increased dramatically, due in part to the increased number of transplants and the pervasive use of chemotherapy and immunosuppressive drugs. The spectrum of clinical manifestations can range from an asymptomatic or mild infection to a swiftly progressive, life-threatening illness. Additionally, invasive infections can migrate to extrapulmonary sites, causing infections in distant organs. Recognition and familiarity with the various radiological findings in the appropriate clinical context are essential for patient management and the prompt initiation of life-saving treatment. We discuss the radiological characteristics of chronic and invasive pulmonary aspergillosis, as well as some of the typically unexpected extrapulmonary manifestations of disseminated disease.

Paecilins Q and R: Antifungal Chromanones Produced by the Endophytic Fungus Pseudofusicoccum stromaticum CMRP4328.

Chemical investigation of the endophyte Pseudofusicoccum stromaticum CMRP4328 isolated from the medicinal plant Stryphnodendron adstringens yielded ten compounds, including two new dihydrochromones, paecilins Q (1: ) and R (2: ). The antifungal activity of the isolated metabolites was assessed against an important citrus pathogen, Phyllosticta citricarpa. Cytochalasin H (6: ) (78.3%), phomoxanthone A (3: ) (70.2%), phomoxanthone B (4: ) (63.1%), and paecilin Q (1: ) (50.5%) decreased in vitro the number of pycnidia produced by P. citricarpa, which are responsible for the disease dissemination in orchards. In addition, compounds 3: and 6: inhibited the development of citrus black spot symptoms in citrus fruits. Cytochalasin H (6: ) and one of the new compounds, paecilin Q (1: ), appear particularly promising, as they showed strong activity against this citrus pathogen, and low or no cytotoxic activity. The strain CMRP4328 of P. stromaticum and its metabolites deserve further investigation for the control of citrus black spot disease.

BI04 Cutaneous cryptococcosis: a post-transplant cat among the pigeons

Abstract Cryptococcosis is an infection caused by the encapsulated yeasts Cryptococcus neoformans and Cryptococcus gattii, which are opportunistic pathogens that mainly affect immunocompromised individuals. Infection is primarily by inhalation and causes pulmonary disease; haematogenous dissemination may affect other organs, particularly the central nervous system, with 10% of disseminated cryptococcosis affecting the skin. Primary cutaneous cryptococcosis due to direct skin inoculation is less common and rarely disseminates. We describe a kidney transplant recipient with disseminated cryptococcosis who presented with skin lesions in the early post-transplant period. As previously observed in a transplant patient with primary cutaneous cryptococcosis under our care, we propose that a history of close contact with urban pigeons was the source of infection. A 48-year-old man who had been transplanted in 2014 presented in May 2022 with a 3-cm-diameter, well-demarcated ulcer on his right shoulder which had been slowly enlarging over 6 weeks in close proximity to his recent COVID-19 vaccination site. Swab was positive for C. neoformans, serology was positive for cryptococcal antigen, chest X-ray showed a 14-mm nodule in the right lung and magnetic resonance imaging of the brain was normal. He was admitted by the transplant team and treated for presumed disseminated cryptococcal infection with intravenous AmBisome® and flucytosine for 2 weeks, and subsequently oral fluconazole. In view of his atypical presentation, we directly questioned him about previous skin disorders and possible sources of infection. It emerged that 6 months earlier, he had noticed multiple lesions on his legs but did not report this as they spontaneously resolved. Mobile phone images showed 0.5–1-cm umbilicated, red–purple nodules consistent with possible primary cutaneous cryptococcosis. We discovered that his balcony was covered in pigeons and their droppings, and he had unsuccessfully asked his local council to provide bird netting. This was the most likely source of his infection, although it is uncertain whether his skin involvement was primary, secondary or both, due to ongoing pigeon exposure. A 54-year-old female patient under our care who had previously presented 3 months post-transplant with extensive noduloulcerative umbilicated lesions confirmed on biopsy to be primary cutaneous cryptococcosis also had close contact with pigeons and their droppings in the immediate post-transplant period. The incidence of cryptococcosis in immunocompromised patients is increasing and cutaneous involvement may be the first manifestation of disseminated disease. The clinical spectrum of skin lesions is highly polymorphic, making diagnosis challenging. However, it should be considered in immunocompromised patients presenting with atypical skin lesions, particularly in the early post-transplant period.

The Impacts of Angiotensin Receptor Blockers (ARBs) or Angiotensin-Converting Enzyme Inhibitors (ACEIs) on Patients with Stereotactic Body Radiation Therapy (SBRT) for Early-Stage NSCLC

Purpose: Stereotactic body radiation therapy (SBRT) has emerged as an alternative to surgery for patients with inoperable early-stage non-small cell lung cancer (NSCLC). The majority of inoperable NSCLC patients are elderly and frequently have comorbidities including cardiovascular diseases for which they frequently receive angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs). The interactions of these medications with SBRT are not clear. The objective of the current study is to investigate the interaction of ARBs and ACEIs with SBRT for the outcomes of early-stage NSCLC. Methods and Materials: A retrospective chart review of patients treated with SBRT for Stage I and II NSCLC (AJCC 7th edition) at a single institution between 2006 and 2017 was conducted. Information on the use of ARBs, ACEIs, demographics, and tumor-related factors was collected. Kaplan-Meier and Cox proportional hazard analyses were performed to assess the impact of ARBs and ACEIs combined with SBRT respectively on the treatment outcomes of these patients. Results: In total, 116 patients were included in the study, among whom 38/116 (32.76%) received ACEIs, and 20/116 (17.24%) received ARBs. In the multivariable analysis, the use of ARBs, but not ACEIs, with SBRT, was significantly associated with the increased risk of dissemination (Hazard Ratio (HR): 2.97; CI: 1.40-6.27; p < 0.004) compared to SBRT without ARBs. The tumor size of > = 3 cm was associated with significantly decreased time to local failure and OS compared to tumor size <3cm. Conclusion: In the current retrospective study, the use of ARBs, in combination with SBRT, was associated with a significantly increased risk of disease dissemination in early-stage NSCLC compared to SBRT alone. The findings warrant further investigations on the concurrent use of ARBs, ACEIs, and other medicines used for chronic diseases with SBRT for early-stage NSCLC.