Ectopic cervical thymoma in myasthenia gravis: a case report.

BACKGROUND: Ectopic cervical thymoma (ECT) is an extremely rare tumor, especially in association with myasthenia gravis (MG). CASE PRESENTATION: We report a case of myasthenia gravis with an ectopic thymoma in the neck, whose myasthenic symptoms significantly improved after complete removal of the mass. A 55-year-old woman with generalized myasthenia gravis (MG) experienced worsening neuromuscular weakness after abruptly discontinuing pyridostigmine. Testing revealed acetylcholine receptor-antibody (AChR-Ab) positivity and a cervical mass initially thought to be thyroid or parathyroid was identified as a thymoma, type A. Post-surgery and radiation therapy, her myasthenic symptoms improved significantly with less prednisone and pyridostigmine requirements over time and no need for additional immunotherapies. CONCLUSIONS: Diagnosing ECTs is challenging due to rarity, atypical locations, and inconclusive fine needle aspiration cytology (FNAC) results, often misinterpreted as thyroid or parathyroid lesions. As proper management of patients with MG, including thymectomy, offers favorable clinical outcomes such as significant improvement in myasthenic complaints and reduced immunosuppressive medication requirements, clinicians should be vigilant of the ectopic locations of thymomas to ensure timely diagnosis and intervention.

Erdheim-Chester Disease: Investigating the Correlation between Targeted Treatment Therapy and Disease Outcomes.

A retrospective analysis of 20 adult patients with histopathological and clinical diagnoses of ECD was conducted at a single institution over a twenty-year period (2002-2022). Clinical responses were compared on the basis of treatments rendered, which included chemotherapy, immunotherapy, systemic corticosteroids, surgery and radiation, or targeted agents, referring to any small molecular inhibitors. Treatment response evaluation varied by the anatomic site(s) of disease, the extent of disease at diagnosis, and the imaging modality employed. In this analysis, patients were treated with a combination of targeted agents, myelosuppressive therapies, and radiation at various points in their disease courses. Of these, the most common treatment modality rendered was targeted therapy, employed in 11 of 20 patients. Partial responses or better were observed in 15 of 20 patients. Rates of stable disease trended towards being more frequent with targeted therapy versus conventional therapy but did not reach significance (p = 0.2967). Complete response rates trended towards being more common with conventional therapy than molecular (p = 0.5) but were equivocal overall. Trends of peripheral blood absolute monocytes with relation to disease activity were reviewed as recent literature implied that monocyte levels surrounding disease progression were of potential prognostic significance in histiocytic diseases. Amongst the patients who progressed at any point during their treatment course, absolute monocyte count (in K/µL) was identified at the closest available timepoint prior to or following disease progression and at the lowest value (nadir) following re-institution of therapy prior to any additional agent(s) being employed. There was no statistically significant difference in either of these monocyte values nor in disease outcomes with respect to treatments rendered within our cohort. However, our cohort consists of a heterogenous population of patients with ECD with data that highlights several trends over a longitudinal period, spanning the advent of targeted therapy. Significant differences are anticipated in ongoing analyses.

Tumor microenvironment deconvolution identifies cell-type-independent aberrant DNA methylation and gene expression in prostate cancer.

BACKGROUND: Among men, prostate cancer (PCa) is the second most common cancer and the second leading cause of cancer death. Etiologic factors associated with both prostate carcinogenesis and somatic alterations in tumors are incompletely understood. While genetic variants associated with PCa have been identified, epigenetic alterations in PCa are relatively understudied. To date, DNA methylation (DNAm) and gene expression (GE) in PCa have been investigated; however, these studies did not correct for cell-type proportions of the tumor microenvironment (TME), which could confound results. METHODS: The data (GSE183040) consisted of DNAm and GE data from both tumor and adjacent non-tumor prostate tissue of 56 patients who underwent radical prostatectomies prior to any treatment. This study builds upon previous studies that examined methylation patterns and GE in PCa patients by using a novel tumor deconvolution approach to identify and correct for cell-type proportions of the TME in its epigenome-wide association study (EWAS) and differential expression analysis (DEA). RESULTS: The inclusion of cell-type proportions in EWASs and DEAs reduced the scope of significant alterations associated with PCa. We identified 2,093 significantly differentially methylated CpGs (DMC), and 51 genes associated with PCa, including PCA3, SPINK1, and AMACR. CONCLUSIONS: This work illustrates the importance of correcting for cell types of the TME when performing EWASs and DEAs on PCa samples, and establishes a more confounding-adverse methodology. We identified a more tumor-cell-specific set of altered genes and epigenetic marks that can be further investigated as potential biomarkers of disease or potential therapeutic targets.

Investigating the correlation between small molecular inhibitor utilization, peripheral blood monocytes, and treatment outcomes in Rosai Dorfman disease.

Rosai Dorfman disease (RDD) is a non-Langerhans cell histiocytic neoplasm characterized by sinus histiocytosis with variable emperipolesis. There is a limited understanding of the factors that contribute to disease progression. Traditional management of RDD consists of local therapies (resection, radiation) for localized disease and myelosuppression for systemic disease; targeted medications have also recently been introduced into clinical practice as an additional therapeutic modality. The goals of this study are to compare the impact of targeted therapies to conventional management of RDD and identify trends in laboratory data that may provide insight into disease progression. A retrospective analysis was conducted at a single institution over a 20-year period in 35 adult patients with histopathologic evidence of RDD without confounding secondary malignancies. Clinical data points included laboratory evaluation, molecular diagnostics, imaging, and therapies rendered. Binary data was utilized for statistical analysis and comparison of outcomes by treatment type and utilization of targeted agents. Evaluation of treatment response varied based on anatomic disease sites and baseline imaging modality. To standardize the radiographic analysis, we included PERCIST (if PET was utilized) or RECIST assessments (in the cases of CT or MR imaging). Conventional therapies rendered included local treatment (surgery, radiation, intralesional injections), systemic corticosteroids, immunotherapy, and chemotherapy while targeted agents included only small molecule inhibitors. In this analysis, primary disease was identified in cutaneous, osseous, and CNS structures (17, 11, and 6/35 patients respectively). Management consisted of surgery (12/35 patients), steroid and myelosuppressive therapies (9/35 each), immunotherapy (5/35), and targeted molecular agents (5/35). In evaluating outcomes, the proportion of partial responses was substantially higher in recipients of molecular as compared to conventional therapy (4/5 patients compared to 6/29) while complete responses were more common in the conventional therapy cohort (12/29 compared to 1/5). Lastly, an evaluation of peripheral blood absolute monocytes in all patients who had progressed on therapy identified a significant decrease in pre-progression values as compared to values following therapy re-institution (averages of 0.70 and 0.27 K/µL, respectively; p = 0.0002, 95% CI 0.652-0.2360). Larger-scale studies are needed to further evaluate the relevance of the monocyte trends that were identified in terms of their relationship to disease status. This study is the largest analysis of Rosai Dorfman disease, that we are aware of, from a single institution. In this cohort, the utilization of small molecule inhibitors corresponded to a greater increase in partial responses than conventional therapies, although the opposite effect has been observed in complete responses. This finding can be attributed to the recent introduction of targeted agents and shorter follow-up. We anticipate higher complete response rates with the use of small molecule in ongoing analyses over a longer follow-up period. The recognition of relative monocyte elevation prior to disease progression is an intriguing and to our knowledge, novel finding in the field of Rosai Dorfman disease. Future studies aimed at elucidating the implications of this trend are in progress.

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell-type deconvolution applied to human blood epigenetic clocks.

Aging is a significant risk factor for various human disorders, and DNA methylation clocks have emerged as powerful tools for estimating biological age and predicting health-related outcomes. Methylation data from blood DNA has been a focus of more recently developed DNA methylation clocks. However, the impact of immune cell composition on epigenetic age acceleration (EAA) remains unclear as only some clocks incorporate partial cell type composition information when analyzing EAA. We investigated associations of 12 immune cell types measured by cell-type deconvolution with EAA predicted by six widely-used DNA methylation clocks in data from >10,000 blood samples. We observed significant associations of immune cell composition with EAA for all six clocks tested. Across the clocks, nine or more of the 12 cell types tested exhibited significant associations with EAA. Higher memory lymphocyte subtype proportions were associated with increased EAA, and naïve lymphocyte subtypes were associated with decreased EAA. To demonstrate the potential confounding of EAA by immune cell composition, we applied EAA in rheumatoid arthritis. Our research maps immune cell type contributions to EAA in human blood and offers opportunities to adjust for immune cell composition in EAA studies to a significantly more granular level. Understanding associations of EAA with immune profiles has implications for the interpretation of epigenetic age and its relevance in aging and disease research. Our detailed map of immune cell type contributions serves as a resource for studies utilizing epigenetic clocks across diverse research fields, including aging-related diseases, precision medicine, and therapeutic interventions.

Detailed immune profiling in pediatric Crohn's disease using methylation cytometry.

DNA methylation has been extensively utilized to study epigenetic patterns across many diseases as well as to deconvolve blood cell type proportions. This study builds upon previous studies examining methylation patterns in paediatric patients with varying stages of Crohn's disease to extend the immune profiling of these patients using a novel deconvolution approach. Compared with control subjects, we observed significantly decreased levels of CD4 memory and naive, CD8 naive, and natural killer cells and elevated neutrophil levels in Crohn's disease. In addition, Crohn's patients had a significantly elevated neutrophil-to-lymphocyte ratio. Using an epigenome-wide association approach and adjusting for potential confounders, including cell type, we observed 397 differentially methylated CpG (DMC) sites associated with Crohn's disease. The top genetic pathway associated with the DMCs was the regulation of arginine metabolic processes which are involved in the regulation of T cells.

Exploring the Molecular Landscape of Myelofibrosis, with a Focus on Ras and Mitogen-Activated Protein (MAP) Kinase Signaling.

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized clinically by cytopenias, fatigue, and splenomegaly stemming from extramedullary hematopoiesis. MF commonly arises from mutations in JAK2, MPL, and CALR, which manifests as hyperactive Jak/Stat signaling. Triple-negative MF is diagnosed in the absence of JAK2, MPL, and CALR but when clinical, morphologic criteria are met and other mutation(s) is/are present, including ASXL1, EZH2, and SRSF2. While the clinical and classic molecular features of MF are well-established, emerging evidence indicates that additional mutations, specifically within the Ras/MAP Kinase signaling pathway, are present and may play important role in disease pathogenesis and treatment response. KRAS and NRAS mutations alone are reportedly present in up to 15 and 14% of patients with MF (respectively), and other mutations predicted to activate Ras signaling, such as CBL, NF1, BRAF, and PTPN11, collectively exist in as much as 21% of patients. Investigations into the prevalence of RAS and related pathway mutations in MF and the mechanisms by which they contribute to its pathogenesis are critical in better understanding this condition and ultimately in the identification of novel therapeutic targets.

New approaches to tackle cytopenic myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation. Despite sharing this pathogenic feature, MF disease behavior can vary widely. MF can generally be categorized into 2 distinct subgroups based on clinical phenotype: proliferative MF and cytopenic (myelodepletive) MF. Compared to proliferative phenotypes, cytopenic MF is characterized by lower blood counts (specifically anemia and thrombocytopenia), more frequent additional somatic mutations outside the Jak/STAT pathway, and a worse prognosis. Cytopenic MF presents unique therapeutic challenges. The first approved Jak inhibitors, ruxolitinib and fedratinib, can both improve constitutional symptoms and splenomegaly but carry on-target risks of worsening anemia and thrombocytopenia, limiting their use in patients with cytopenic MF. Supportive care measures that aim to improve anemia or thrombocytopenia are often ineffective. Fortunately, new treatment strategies for cytopenic MF are on the horizon. Pacritinib, selective Jak2 inhibitor, was approved in 2022 to treat patients with symptomatic MF and a platelet count lower than 50 × 109/L. Several other Jak inhibitors are in development to extend therapeutic benefits to those with either anemia or thrombocytopenia. While many other novel non-Jak inhibitor therapies are in development for MF, most carry a risk of hematologic toxicities and often exclude patients with baseline thrombocytopenia. As a result, significant unmet needs remain for cytopenic MF. Here, we discuss clinical implications of the cytopenic MF phenotype and present existing and future strategies to tackle this challenging disease.

Fat Embolism Syndrome With Cerebral Involvement: An Underrecognized Complication of Long Bone Fractures.

Fat embolism syndrome (FES) occurs when fat particles are aberrantly distributed into the microcirculation, and it often manifests as either hypoxemia, neurological deficit, or petechial rash. Although cases have been reported in the literature since the twentieth century, no formal diagnostic criteria have been universally adopted, and FES remains a diagnostic challenge. We present a unique case of FES from a long bone fracture, leading to pulmonary embolism with paradoxical arterial embolization and cerebral infarction, and provide a review of the related literature.

Primary lung sarcoma with gastric metastasis and morphological divergence presenting as melena.

A 61-year-old man was admitted to the medical intensive care unit following a 2-week history of weakness, lightheadedness and melena resulting in an acute anaemia. Upper endoscopy revealed multiple large gastric masses without evidence of active bleeding. CT of the chest revealed a large right upper lobe mass with bony destruction of the third rib and invasion into the anterior chest wall and mediastinum, as well as a soft-tissue density in the left kidney. Biopsy and histopathological review of both pulmonary and gastric masses revealed two distinct sarcomatous malignancies that, while both from a primary lung source, differed in their morphology. Natural history and behaviour are not well understood in sarcomas due to their rarity, but abdominal metastasis is considered an uncommon event in the progression of the disease. Gastrointestinal bleeding as the presenting symptom of a primary lung sarcoma is an atypical finding with no previously reported cases.

The First Case of Ignatzschineria ureiclastica/larvae in the United States Presenting as a Myiatic Wound Infection.

Ignatzschineria is a recently identified genus of bacteria that has been isolated from the digestive tract of multiple flies associated with decomposing tissue. Species within this genus are rarely implicated in human disease, and less than 10 cases worldwide have been documented in the literature. Although there have been several documented cases of Ignatzschineria indica bacteremia in the United States (with one previous case in Louisville, KY), this case represents the first documented case of Ignatzschineria ureiclastica/larvae bacteremia in the United States. The natural insect host of this bacteria, parasitic flies that are commonly found among sheep and other livestock, may pose a public health hazard in the city and implicate geographic spread of this bacteria species and its host.

Ophthalmic anterior segment metastasis masquerading as uveitis.

Ocular malignancies are rare, with many cancers of the eye being the result of metastases, the most common of which result from primary tumours of breast, lung and gastrointestinal tract. Diagnosis is often made at a late stage in the disease course, leading to poorer outcomes. Disease-directed therapy in the presence of ocular metastases varies based on the primary tumour and patient performance status but generally involves systemic treatment, either with chemotherapy or involved-field radiation. We herein present an interesting case of ocular malignancy with neuroendocrine small cell features of pulmonary origin in a patient with no prior oncological history. Meticulous ophthalmic examination led to the diagnosis of small cell lung carcinoma with anterior segment metastasis. The patient underwent six cycles of systemic chemotherapy with a favourable response, resulting in improvement in vision and regression of the ocular lesion.

The Clinical Characteristics of Multiple Myeloma in the Acute Care Setting: Case Presentation and Clinical Recommendations.

The acute complications of multiple myeloma can be varied and devastating, including electrolyte derangements, renal failure, and infections amongst others. The varying pathological mechanisms behind these complications make the management of patients presenting with multiple myeloma a complicated and sometimes tenuous process. The patient compliance can further exacerbate these difficulties. The patient discussed in this case initially presented with newly developed altered mental status, fatigue, epistaxis, and an ecchymotic rash. Laboratory testing and imaging would conclude a diagnosis of multiple myeloma, but unfortunately treatment was cut short. Admission at a later date would show rapidly deteriorating condition with new lung consolidations and worsening laboratory findings. Herein the authors discuss the clinical findings of patients with acute manifestations of multiple myeloma, their prognostic value, and the implications of patient compliance and early intervention in the setting of multiple myeloma.

Management of thrombocytopenia in a patient with a mechanical mitral valve undergoing autologous hematopoietic stem cell transplantation: case report and review of literature.

Mechanical mitral valves require life-long anticoagulation with Vitamin K Antagonists (VKA), targeted to an international normalized ratio (INR) of 2.5-3.5. While complications, including valve thrombosis and bleeding, are well known, there is a paucity of data on the management of mechanical mitral valves in patients with thrombocytopenia. Due to an increased bleeding risk, the presence of a mechanical mitral valve is considered by some providers as an exclusion criterion for autologous hematopoietic stem-cell transplantation (HSCT). Presented here is a case of a patient with multiple myeloma who successfully underwent autologous HSCT with simultaneous alterations in VKA therapy for continued anticoagulation in the setting of an underlying mechanical mitral valve.

Digital Whole Slide Imaging Compared With Light Microscopy for Primary Diagnosis in Surgical Pathology.

CONTEXT.­: The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility. OBJECTIVE.­: To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology. DESIGN.­: The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review. RESULTS.­: The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, -0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities. CONCLUSIONS.­: WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity.

We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of "sclerosing epithelioid mesenchymal neoplasm" of the pancreas.

Acquired factor X deficiency in a patient with multiple myeloma: a rare case highlighting the significance of comprehensive evaluation and the need for antimyeloma therapy for bleeding diathesis.

Factor X deficiency is a rare bleeding disorder that can be associated with life-threatening bleeding events. Factor X deficiency can either be inherited or acquired. Acquired cases of factor X deficiency can be seen in patients with plasma cell dyscrasias as well as amyloidosis. Coagulopathy, with clinically relevant bleeding events, although rare, is not an unusual phenomenon for patients with systemic amyloidosis. However, clinically relevant bleeding in patients with symptomatic multiple myeloma, without associated amyloidosis, has not been reported in literature before. We present a rare case of multiple myeloma without concomitant amyloidosis that presented with life-threatening bleeding from acquired deficiency of factor X and responded remarkably to treatment for underlying multiple myeloma. This case not only highlights the diagnostic workup required in patients with factor X deficiency but also provides the principles of management of acquired coagulopathy in plasma cell dyscrasias.

Bilateral Vocal Fold Paralysis After Epidural Anesthesia.

Cranial neuropathies are known potential complications of spinal anesthesia, with most reports describing upper cranial nerve involvement. Intrathecal hypotension resulting in traction injury of the cranial nerves is the likely mechanism of injury. Unilateral vagal neuropathy was first described recently. The patient discussed in this case presented with hoarseness and dysphagia after receiving epidural anesthesia for childbirth. Following videostroboscopy and laryngeal electromyogram, she was diagnosed with bilateral vocal fold paralysis. The patient was managed conservatively with expectant management. She exhibited complete spontaneous recovery, as has been the natural history previously described for similar injuries. The proposed mechanism for this patient, and in others described in the literature, is puncture of the dura with subsequent egress of cerebrospinal fluid, leading to intracranial hypotension and traction on cranial nerves. Unilateral vocal fold paralysis following spinal anesthesia has been reported in one case series consisting of three patients, but this represents the first case of bilateral paralysis. Spontaneous resolution has been observed in all patients. Patients presenting with idiopathic vocal fold paralysis, in summary, should be questioned about recent history of epidural or spinal anesthesia, as a positive history may point to transient intrathecal hypotension as a potential etiology of the paralysis.