Rapid Course Research Articles

DECREASED HEALTHCARE UTILIZATION IN UNINSURED PATIENTS WITH PERIANAL CROHN’S DISEASE UNDERGOING PROCTECTOMY

Abstract INTRODUCTION Perianal Crohn's disease (CD) is a debilitating subtype affecting nearly 20% of CD patients, primarily characterized by the presence of perianal fistulas. It is associated with poor health outcomes, significantly decreased quality of life, and is an independent predictor of work disability. Proctectomy is generally reserved for patients with severe, refractory disease. Social determinants of health, including health insurance status, can impact the progression and outcomes of chronic diseases. Here we examine healthcare utilization and clinical characteristics of patients with perianal CD who undergo proctectomy for those with and without health insurance. METHODS This retrospective study follows perianal CD patients who underwent a proctectomy from 2008 to 2021 at Mount Sinai Hospital. We collected demographic, insurance status, and clinical data, such as diagnosis-to-surgery time, hospitalization rates, number of MRIs utilized, and number of medications utilized (Tables 1 and 2). Univariate analysis comparing patients with and without insurance was performed using Chi-Square or Fisher's Exact Tests. RESULTS Our study included 130 patients (50.8% female) with a mean age of 52.0 ± 14.9 years. The majority were insured (n = 106, 81.5%). Results were significant for a shorter diagnosis-to-surgery time in the uninsured group (6.9 vs. 11.1 years, p = 0.050), fewer hospitalizations (p = 0.002), MRIs (p = 0.008), clinic visits (p = 0.007), as well as reduced use of antibiotics (p = 0.016), and biologics (p =0.001) in the uninsured group (Tables 1 and 2). Data trended towards a later mean age at the time of diagnosis in the uninsured group (37.8 vs. 33.1 years, p=0.241). There was no statistical difference between the groups regarding race, comorbidities, extraintestinal manifestations, presence of skin tags, strictures, and fissures, presence of proctitis or abscess at proctectomy, age at proctectomy, surgical approach, number of lifetime GI surgeries, endoscopies, or corticosteroid treatments. DISCUSSION Our findings suggest that the uninsured patients with perianal CD have decreased utilization of healthcare resources compared to the insured group. This disparity, combined with the observed trend of older age at, and therefore likely delay of, CD diagnosis and treatment may contribute to a more rapid and severe CD course, ultimately leading to a shorter diagnosis-to-surgery interval. This study was limited by a small, single-center population sample, as well as other confounding factors associated with lack of insurance. Future research will include multivariate analysis to identify specific discrepancies in annual healthcare utilization between these populations, evaluate the contribution of race and language to this issue, and investigate the role that a decreased delay in diagnosis could play in preventing last resort proctectomy. Table 1 Patient Characteristics Table 2 Comparison of Healthcare Utilization by Insurance Status

BIOCHEMICAL MARKERS OF BLOOD SERUM AND ARTICULAR CARTILAGE IN DIFFERENT FORMS OF IDIOPATHIC COXARTHROSIS PROGRESSION

Deformation due to arthrosis of the hip joint affects 40 % of the total number of patients with osteoarthritis, which is from 7 to 25 % of the adult population. For the activity of the pathological process evaluation we studied biochemical changes in the metabolism of collagen, namely: glycosaminoglycans (GAG), hydroxyproline (HP) fractions, collagenase, hyaluronidase activity, etc. Objective. To determine the biochemical changes in blood serum and articular cartilage depending on the form of progression of idiopathic coxarthrosis. Methods. 23 patients were examined (8 (34.8 %) men, 15 (65.2 %) women, age 45‒75 years and more) with idiopathic arthrosis of the hip joint IV stage (Kellgren–Lawrence). Progression forms of idiopathic coxarthrosis were distinguished: group I — rapid (the period from the initial to the final stage of the disease was 5 years and less), II — moderate (5‒10 years), III — slow (over 10 years). Collagenase activity, HP fractions, total GAG content were determined in patients’ blood serum, and collagen content was determined in the cartilage tissue of the femoral head. Results. Compared with the age reference norm in the blood serum of patients of group I activity collagenase increased to 114 %, in II and III — 122 and 135 %, respectively; the content of the free fraction of GP — up to 111, 169, 128 %, respectively; GAG concentrations — up to 110, 122, and 135 %, respectively; protein-bound HP was reduced to 60% in group II, up to 84 % — in group III. In cartilage tissue, the GAG content decreased in group III to 63 %, II — 55 %, I — 47 %; collagen — 32, 25, 24 % in accordance. Conclusions. The course of idiopathic coxarthrosis is determined by metabolic changes in the components of the organic basis of connective and cartilaginous tissues in blood serum. The most profound changes were found in the synthetic phase of HP metabolism, especially in the group with a rapid course disease. A decrease in the content of organic components of connective tissue (GAG and collagen) was determined

Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.

Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS). Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States. Neurologists (n = 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline inHRQoL and increased burden. Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.

Chapter 23 - Infectious leukoencephalopathies

Leukoencephalopathy from infectious agents may have a rapid course, such as human simplex virus encephalitis; however, in many diseases, it may take months or years before diagnosis, such as in subacute sclerosing panencephalitis or Whipple disease. There are wide geographic distributions and susceptible populations, including both immunocompetent and immunodeficient patients. Many infections have high mortality rates, such as John Cunningham virus and subacute sclerosing panencephalitis, although others have effective treatments if suspected and treated early, such as herpes simplex encephalitis. This chapter will describe viral, bacterial, and protozoal infections, which predominantly cause leukoencephalopathy. We focus on the clinical presentation of these infectious agents briefly covering epidemiology and subtypes of infections. Next, we detail current pathophysiologic mechanisms causing white matter injury. Diagnostic and confirmatory tests are discussed. We cover predominantly MRI imaging features of leukoencephalopathies, and in addition, summarize the common imaging features. Additionally, we detail how imaging features may be used to narrow the differential of a leukoencephalopathy clinical presentation. Lastly, we present an outline of common treatment approaches where available.

Two Cases of Gastric Adenocarcinoma with Enteroblastic Differentiation which Demonstrated Rapid Progressive Courses.

We herein report two extremely rare cases of gastric adenocarcinoma with enteroblastic differentiation (GAED) that underscore the aggressive nature of GAED. Case 1: ESD was scheduled for early-stage gastric cancer, however, the tumor increased in size drastically and the morphology changed to type "0-I + IIc" in one month. Surgery was performed and the patient was diagnosed with GAED. Case 2: ESD was performed for early-stage gastric cancer, and the pathological findings revealed GAED. The horizontal margin was positive for clear cells in the muscularis mucosa. Additional surgery was performed; however, recurrence occurred one year later. Therefore, the treatment strategies should be carefully considered for GAED.

Symmetrical Peripheral Gangrene resulting from application of henna: a rare clinical occurrence

Symmetrical Peripheral Gangrene (SPG) is a rare clinical syndrome characterized by bilateral symmetric distal limb ischemia leading to gangrene with no evidence of major vascular occlusive disease. The peripheral pulses are usually palpable as a result of the sparing of larger vessels. The mechanism of vascular occlusion is poorly understood. Disseminated intravascular coagulation has been implicated as the final common pathway in its pathogenesis. Initial management is resuscitation followed by amputation when the gangrene becomes demarcated. We report a rare case of symmetrical peripheral gangrene of both hands and feet in a 28-year-old female who presented with pain and darkening of all her fingers and toes for 2 days following the application of henna, with no medical history of the known predisposing conditions. She had amputation of the digits of her hands and tarsometatarsal amputation of her feet bilaterally. She had an uneventful postoperative period and was discharged to see the outpatient department. While reported cases of SPG due to numerous etiologies can be found in the literature, this is to our findings the first time we are seeing it resulting from the cosmetic use of henna. The intriguing case presented here was brought about by the application of henna used as a cosmetic agent and was characterized by a very rapid clinical course with no other apparent predisposing etiology.

Spindle cell rhabdomyosarcomas: With TFCP2 rearrangements, and novel EWSR1::ZBTB41 and PLOD2::RBM6 gene fusions. A study of five cases and review of theliterature.

Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

Improved mortality prediction for pediatric acute liver failure using dynamic prediction strategy.

To develop and validate a prediction tool for pediatric acute liver failure (PALF) mortality risks that captures the rapid and heterogeneous clinical course for accurate and updated prediction. Data included 1144 participants with PALF enrolled during three phases of the PALF registry study over 15 years. Using joint modeling, we built a dynamic prediction tool for mortality by combining longitudinal trajectories of multiple laboratory and clinical variables. The predictive performance for 7-day and 21-day mortality was assessed using the area under curve (AUC) through cross-validation and split-by-time validation. We constructed a prognostic joint model that combines the temporal trajectories of international normalized ratio, total bilirubin, hepatic encephalopathy, platelet count, and serum creatinine. Dynamic prediction using updated information improved predictive performance over static prediction using the information at enrollment (Day 0) only. In cross-validation, AUC increased from 0.784 to 0.887 when measurements obtained between Days 1 and 2 were incorporated. AUC remained similar when we used the earlier subset of the sample for training and the later subset for testing. Serial measurements of five variables in the first few days of PALF capture the dynamic clinical course of the disease and improve risk prediction for mortality. Continuous disease monitoring and updating risk prognosis are beneficial for timely and judicious medical decisions.

Clinical characteristics and progression of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET rearrangements: a retrospective cohort study.

Patients harboring anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangements are usually diagnosed at a relatively late stage with nodal and distant metastasis, and rapid progression course of ALK/RET fusion-positive lung cancer were well-known. However, clinical characteristics and course of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET fusions are poorly described. Identifying patients with gene fusions at early stage may offer surgical options that could cure those patients. We retrospectively included patients with surgically resected pre-/minimally invasive lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations or ALK/RET rearrangements, and further compared the patient clinical characteristics, nodule natural course, and survival outcomes. Radiological characteristics including ground-glass component, cystic airspace, pleural attachment, etc. were specially assessed for this study. EGFR (exons 18-22) was detected by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the ALK/RET rearrangements. Lung cancer-specific survival (LCSS), relapse-free survival (RFS), and overall survival (OS) were all evaluated. Of 238 patients with pre-/minimally invasive lung adenocarcinomas, 226 patients had EGFR mutations, 7 patients had ALK fusions, and 5 patients had RET fusions. Average age at surgery was 45.3 years for ALK/RET-positive group and 52.6 years for EGFR-positive group (P=0.049). Radiologically, among the 12 patients with ALK/RET fusions, the majority of lesions (10/12) manifested as mixed ground-glass opacities (mGGOs), which was significantly more prevalent when compared with patients with EGFR mutations (83.4% vs. 24.3%, P<0.001). Moreover, a substantial proportion of cystic airspace was found in ALK/RET-positive group but not in EGFR-positive group (66.7% vs. 14.2%, P<0.001). Among four patients with ALK/RET fusions undergoing surveillance over 1 year before surgery, two of them developed rapid radiologic progression. The 5-year LCSS and RFS were 100%, 100% for ALK/RET-positive group, and 100%, 100% for EGFR-positive group, respectively. ALK/RET-positive pre-/minimally invasive lung adenocarcinomas were mostly characterized as mGGOs with cystic airspace developing rapid nodule progression, and no recurrence occurred during long-term follow-up after resection. This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.

Does subtyping of high-grade pulmonary neuroendocrine carcinomas have an impact on therapy selection?

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinomas (LCNEC) are characterized by a rapid progressive course. Therapy for SCLC has not much changed for decades, and in LCNEC controversies exist, favoring either SCLC-like or non-small cell lung cancer (NSCLC)-like therapy. Three subtypes of SCLC identified in cell cultures, namely ASCL1, NeuroD1, and POU2F3 have been confirmed by immunohistochemistry. The fourth type based on the expression of YAP1 was questioned, and another type, inflamed SCLC, was proposed. SCLC and LCNEC samples were investigated by immunohistochemistry for different subtypes. Additionally, immunohistochemical markers as potential tools to identify patients who might respond to targeted treatment were investigated. For validation a biopsy set was added. ASCL1, NeuroD1, and POU2F3 were expressed in different percentages in SCLC and LCNEC. Similar percentages of expression were found in biopsies. ATOH was expressed in combination with one of the subtypes. YAP1 and TAZ were expressed in some SCLC and LCNEC cases. HES1 expression was seen in few cases. Predominantly stroma cells expressed programmed cell death ligand 1 (PD-L1). The dominant MYC protein was N-MYC. Aurora kinase A (AURKA) was expressed in the majority of both carcinomas, whereas fibroblast growth factor receptor 2 (FGFR2) in few. SCLC and LCNEC can be subtyped into ASCL1-, NeuroD1-, and POU2F3-positive types. AURKA expression and positivity for N-MYC protein was not associated with subtypes. AURKA and FGFR2 are both possible targets for inhibition in SCLC and LCNEC, but patients' selection should be based on expression of the enzyme. Combined chemo- and immunotherapy might be decided by PD-L1 staining of stroma cells.

Management of intrasellar arachnoidocele

Arachnoidocele in its sellar location is not common. The variability of its clinical signs and the lack of standard treatment make the management complex. The authors report a clinical case through which therapeutic modalities will be discussed. We report a case of a 42-year-old patient who complained of intermittent headaches of progressively increasing intensity over the past 2 years. The persistence of the headaches despite analgesic treatment had motivated the performance of a brain CT scan and then an MRI which had objectified the presence of an intrastellararachnoidocele. The endocrine laboratory function was normal. Short-term treatment with morphine and corticosteroids had achieved a rapid and long-lasting course after a 2-year follow-up. Endoscopic surgery is a treatment option for sellar arachnoidocele. The indication must take into account the clinical and radiological elements because some sellar arachnoidocele evolve favorably under drug treatment.

A Prospective, Phase-II Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax (GIVeRS) in Patients with Richter's Syndrome

Background: Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). RS is characterized by a rapid clinical course, low responses to therapy, and poor long-term survival. Chemoimmunothreapy for RS achieves overall response rates of 40% to 60%, and median progression-free survival (PFS) and overall survival (OS) of 3 to 10 months and 6 to 21 months, respectively. More recently, single targeted agents of either ibrutinib or venetocolax have been shown some clinical activity in RS. Furthermore, ibrutinib combined with venetoclax with or without anti-CD20 antibodies has a synergistic activity in CLL, resulting in deep and prolong responses along with a good safety profile. Methods: This is a prospective phase 2, open-label, non-randomized, single-arm, multi-center study aimed to assess the efficacy and safety of ibrutinib, venetoclax, and obinutuzumab in treatment-naïve or relapsed/refractory patients with biopsy-confirmed RS to DLBCL (NCT04939363). The experimental regimen consisted of 12 months of fixed-duration treatment with obinutuzumab, ibrutinib, and venetoclax. Obinutuzumab was administered at a dose of 100 mg intravenously on day 1, 900 mg on day 2, and then 1000 mg on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, obinutuzumab at a dose of 1000 mg was administered. Ibrutinib was administered at a dose of 560mg orally daily initiated together with the first obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment 28-day cycles. Venetoclax was given at a dose of 400 mg orally daily for 12 treatment cycles after an accelerated ramp-up phase from day 15 in cycle 1. The primary endpoint was investigator-assessed overall response rate (ORR) defined as the proportion of patients who achieve complete metabolic response (CR) and partial metabolic response (PR) determined by PET-CT imaging at 6 months per Lugano 2014 criteria. Other key endpoints included; investigator-assessed ORR at 3 and 12 months, PFS, Duration of response (DOR), OS, and safety. Results: From August 2021 until the data cut-off on July 20, 2023, a total of 10 patients with RS were enrolled. Median age was 76.0 (range, 62‒88) years and 70% were male. Six patients were treatment-naïve, 4 had relapsed/refractory RS, 50% had extra-nodal disease, 70% had elevated LDH, 70% were double or triple expressors, and the median number of prior therapies among the R/R patients was 1 (Table 1). Median follow-up was 255 days (95% CI, 158.7-351.3), median treatment duration was 160 days (range: 29-362) and treatment is still ongoing in 3 patients. At 3 and 6 months, the ORRs were 70.0% (7/10) and 22.2% (2/9), respectively, and CR rates (CRRs) were 40.0% (4/10) and 11.1% (1/9), respectively. At the data cutoff, 6/10 (60.0%) patients progressed and 5/10 (50.0%) died. The median PFS was 162 days (95% CI, 66.9-257.1), median DOR 272 days, and median OS was 228 days (95% CI: 184.2-271.8). The causes of death included RS in 2 patients and one case each of Covid-19, secondary malignancy, and general deterioration. Most common related treatment-emergent AEs (TEAEs) of all grades were neutropenia 40%, thrombocytopenia 50%, diarrhea 40%, and skin rash 50%, 2 patients developed Covid-19 who recovered during the protocol. None of the patients developed tumor lysis syndromes. Conclusions: In patients with RS triplet treatment with ibrutinib, venetoclax, and obinutuzmab was well tolerated, achieved high rates of early metabolic response (ORR-70% and CRR-40%) at 3 months. Given the high early response rate but subsequent progression, this triplet therapy may serve as a bridge to consolidation with cellular therapy.

BIRTH INJURY, DUCHENNE-ERBʼS OBSTETRIC PALSY. DIAGNOSIS AND TREATMENT (LITERATURE REVIEW)

Obstetric practice dates back thousands of years, providing assistance to women in labor is often complicated by the rapid course of labor, pelvic presentation of the fetus, shoulder dystocia with a possible clavicle fracture. Damage to CV–CVI roots, classic Duchenne–Erb palsy, accounts for 46 % of the total number of obstetric palsies. Objective. To analyze the scientific and medical literature in order to identify historical scientific and practical information about the study of childbirth injuries, and, in particular, Duchenne–Erb's obstetric palsy. Methods. To study and analyze sources of scientific and medical information, publications from Google search engines, electronic databases PubMed, Google Scholar, archival medical journals. Results. The first data on obstetric paralysis were provided by Duchesne in 1872, highlighting thorough reports on upper extremity muscle damage. Subsequently, in 1874, Erb performed electrical stimulation of the affected muscles, finding out the zone of neurological damage. The history of the development and formation of this scientific issue is quite ambiguous, because it borders on two medical fields: neurosurgery and orthopedics. According to literary sources, it is obvious that the pathohistology and pathophysiology of the direct injury zone (roots CV–CVI), delayed changes in the function of the upper limb, and the latest diagnostic technologies simplify the understanding of the presentation. The existing methods of operative interventions allow physicians to improve the child's life. However, the question remains open regarding the use of certain operative interventions in relation to the child's age and further rehabilitation. Conclusions. Despite a significant stratum of scientific and practical research on Duchenne–Erb's obstetric palsy, there are still a number of questions regarding the diagnosis and treatment of children with this abnormality. The search for improving the functional state of the upper limb in children should continue.

Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS-FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS-FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes.

THU013 A Rare Case of Ectopic Cushing’s Syndrome Caused By Metastatic Parotid Gland Carcinoma

Abstract Disclosure: E. Punni: None. I. Goyal: None. Introduction: Ectopic Cushing’s Syndrome (ECS) is a rare condition that accounts for only a small percentage of all Cushing’s syndrome cases. Although rare, the typical tumors associated with ECS are small cell lung carcinomas, bronchial carcinoids, pancreatic neuroendocrine tumors, medullary thyroid carcinomas, thymic carcinoids and pheochromocytomas. Metastatic acinic cell carcinoma (ACC) of the parotid gland has very rarely been associated with ectopic Cushing’s syndrome. Case Presentation: A 67-year-old Caucasian male with a known diagnosis of high grade metastatic ACC of the parotid gland presented to the hospital with progressively worsening proximal muscle weakness and bilateral lower extremity edema of 6 weeks duration. A month prior to presentation, he developed persistent hypokalemia requiring potassium supplementation and was diagnosed with new onset type 2 diabetes mellitus. Laboratory results on admission were remarkable for low potassium at 2.5 mEq/L (N: 3.5-5.3 meq/L), a random cortisol level of 107 mcg/dL (N: 6 - 30 mcg/dL), and an ACTH level of 485 pg/mL (N: 7.2 - 63.3 pg/mL). Subsequently, a 24-hour urine cortisol was &amp;gt; 1600 ug/24 hours (N 5-64 ug/24 hours). A 1 mg dexamethasone suppression test failed to suppress an 8 a.m. cortisol with level of 110.8 mcg/dl (N &amp;lt; 1.8 mcg/dl). Following, an 8 mg dexamethasone suppression test also failed to suppress 8 a.m. cortisol with a value of 100.8 mcg/dl. A MRI of the pituitary with and without contrast showed mild diffuse enlargement of the pituitary gland concerning for pituitary hyperplasia. At the time, ECS was highly suspected given the rapid course of patient’s presentation, known metastatic malignancy, and failed 8 mg dexamethasone suppression test. An inferior petrosal sinus sampling (IPSS) could not be performed given the patient’s guarded condition. Instead, a PET/CT Ga-68 DOTA-TATE scan obtained showed widespread DOTA-TATE avid malignancy concerning for neuroendocrine type tumor. Patient was a poor surgical candidate, therefore bilateral adrenalectomy could not be performed for the rapid treatment of ECS. Patient was started on a steroidogenesis inhibitor ketoconazole. However, he elected to undergo hospice care and passed away shortly after. Conclusion: This case is particularly interesting given that metastatic ACC of the parotid gland causing ECS is rare with only a few cases reported in the literature. This case highlights the importance of maintaining a high degree of suspicion for diagnosing ECS especially when patients present with rapid onset of signs and symptoms of Cushing’s syndrome and a known underlying malignancy. Recognizing less common causes of ECS may prompt early diagnosis and intervention. Presentation: Thursday, June 15, 2023

Rapidly progressive multiple system atrophy in a patient carrying LRRK2 G2019S mutation.

Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.

Live attenuated vaccines and layered defense strategies to combat infections caused by nonencapsulated Yersinia pestis

IntroductionPlague is an ancient disease caused by Yersinia pestis, a widely disseminated Tier 1 pathogen that poses significant public health and biothreat risks. The rapid course and high mortality of pneumonic plague limit the efficacy of antibiotic treatment and mandate the need for an effective, licensed, and readily available vaccine. New candidate vaccines are being developed; however, their efficacy in nonhuman primates, optimal vaccination schedule and immune response, duration of protection, and breadth of coverage against various virulent strains are inadequately understood. In the current work, we explored homologous and heterologous vaccination schemes using the sensitive BALB/c mouse models of bubonic and pneumonic plague challenged with Y. pestis strain C12. This strain, a derivative of the wild-type strain CO92, lacks the anti-phagocytic F1 capsule yet remains highly virulent. Protection against such nonencapsulated strains has been particularly elusive.MethodsWe tested the efficacy of live attenuated vaccine (LAV) derivatives of Y. pestis CO92 or C12 with a deletion of a type 3 secretion-associated gene (ΔyscN) or the pgm pigmentation locus, and they were cured of the pPst (PCP1) plasmid (CO92 pgm− pPst−). The LAVs were evaluated alone or accompanied by a dose of a protein subunit vaccine (rF1V or rV).ResultsThe most protective and immunogenic vaccination scheme, as tested under a variety of conditions in bubonic and pneumonic plague models, was heterologous vaccination with a LAV and the recombinant rF1V or rV protein subunit vaccine. Furthermore, in the heterologous scheme, different LAVs and subunit vaccines could be substituted, affording flexibility in vaccine component selection. We also evaluated a novel intervention strategy consisting of vaccination and post-exposure antibiotic treatment. The layering of vaccination with the LAVs and post-exposure treatment with streptomycin was synergistic, extending the time after the Y. pestis C12 challenge when treatment remained effective and affording a sparing of antibiotics.ConclusionThe current work defined effective and flexible vaccination and treatment interventions that successfully prevented lethal infection with virulent, nonencapsulated Y. pestis.

Pathological role of methionine in the initiation and progression of biliary atresia.

Methionine (Met) is an essential amino acid, and its excessive dietary intake and/or its metabolism disturbance could lead to accumulation/depletion of hepatic Met and some of the key intermediates of these pathways, which would interfere normal liver function and would be associated with liver diseases. Biliary atresia (BA) is a life-threatening disease characterized by inflammatory fibrosclerosing changes of the intrahepatic and extrahepatic biliary systems and is the primary cause of obstructive neonatal cholestasis with a rapid course of liver failure. However, its pathogenesis remains unknown. Previous studies reported elevated Met level in patients with obstructive cholestasis, suggesting a potential link between Met and BA. This paper reviews the Met metabolism in normal conditions and its dysregulation under abnormal conditions, the possible causes of hypermethioninemia, and its connection to BA pathogenesis: Abnormal hepatic level of Met could lead to a perturbation of redox homeostasis and mitochondrial functions of hepatocytes, enhancement of viral infectivity, and dysregulation of innate and adaptative immune cells in response to infection/damage of the liver contributing to the initiation/progression of BA.

Novel histotypes of sporadic Creutzfeldt–Jakob disease linked to 129MV genotype

The MV1 and MV2 subtypes of sporadic Creutzfeldt–Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type (“MV2-1”). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 (“MV1-2”), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel “C-PL” histotypes are distinct entities rather than intermediate forms between “C” and “C-K” groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.

A rare case of acute basophilic leukemia

Acute basophilic leukemia is an extremely rare form of acute myeloid leukemia and diagnosis is based on morphological, cytochemical and ultrastructural analyses of basophils and blastic cells. It is usually characterized by a very rapid clinical course, symptoms of hyperhistaminemia and resistance to therapy. A 73 year-old male presented with itching, thrombocytopenia and leukocytosis. There was no hepatosplenomegaly. In the flow cytometry evaluation of peripheral blood, CD123 positive myeloid blasts were detected at the rate of 60%. Also, CD13 and CD33 were positive, while CD34, CD117, HLA DR and myeloperoxidase (MPO) were negative. These findings were considered as consistent with ABL. Following, the diagnosis of ABL was confirmed by bone marrow evaluation including cytomorphological and immunohistochemical studies. On the other hand, cytogenetical analyses of bone marrow showed the presence of the Philadelphia chromosome.The patient received one cycle of a chemotherapy regimen including cytarabine and idarubicin with imatinib support, but he died on the 10th hospital day. Considering that ABL behaves in a very malignant fashion, and a more aggressive treatment approach is necessary for patients with this specific subtype of AML.