bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anaplastic thyroid carcinoma: a genome-based search for new targeted therapy options
Authors: Zhang X , Jansen S , Chen N , Dooley L M , Hammer R , Pavlick D C , Hiemenz M , Dougherty K C 
Published: October 2024

Abstract

Introduction/Objective
Anaplastic thyroid carcinoma (ATC) is a rare, aggressive thyroid cancer. Precision medicine, particularly gene-targeted therapy has emerged as a promising avenue in cancer treatment. However, few targeted therapies have been approved for ATC. Here, we present a genome-based search for new targeted therapy options using next-generation sequencing (NGS) data of 727 ATC cases.

Methods/Case Report
Deidentified NGS results in 727 ATC cases were obtained from Foundation Medicine. A search of the literature and genomic databases (TCGA, My Cancer Genome, and DGIdb) was performed to analyzed frequency of gene mutations and corresponding gene targeted drugs.

Results (if a Case Study enter NA)
Remarkably, 99.17% of the 727 ATC cases had at least one targeted drug option available. Among the 254 unique genes identified with pathogenic mutations, 150 (59.06%) were found to have at least 1 corresponding targeted drug. Among the top 35 most frequently mutated genes (frequency &gt; 2.0%), 27 (80.00%) had available targeted therapies. Notably, most drug categories (70.83%) exhibited multi-gene targeting capabilities. The drug categories based on the percentage of genes targeted from highest to lowest are Serine/Threonine and Tryosine kinase inhibitors, therapeutic antibodies, MEK inhibitors, CDK inhibitors, AKT inhibitors, PI3K inhibitors and immunotherapies. There are an additional 16 drug categories that target 1 to 5 of the 35 frequently mutated genes identified.
Of particular interest is MTAP, a previously unreported frequently mutated gene which is most often deleted (14.77%). Several drugs are undergoing phase 1 and/or phase 2 clinical trials for MTAP-deleted solid tumors. MTAP loss holds promise for identifying expanding therapeutic options in ATC.

Conclusion
Our genome-based analysis indicates that 99.17% of the 727 ATC cases have targeted drug options, targeting 59.06% of identified gene mutations. Among the 24 categories of targeted drugs 17 (70.83%) target more than one gene. The 2018 FDA approval of combination BRAF/MEK inhibitor therapy for management of BRAF V600E-positive ATC was a major first step in gene targeted therapies. Besides that, Tyrosine kinase inhibitors, mTOR inhibitor, PPAR-γ agonist, ALK inhibitor, VEGF inhibitor and several combined treatment and immunotherapeutic agents are currently being tested in ATC clinical trials. These promising findings highlight the expanding repertoire of gene-targeted therapy options in ATC and emphasizes the importance of combined strategies and identifying driver mutations.
Regional distribution of anaplastic thyroid cancer in the United States
Authors: Kovalenko M , Hammer R , Chen N , Haithcoat T , Dooley L M 
Published: October 2024

Abstract

Introduction/Objective
Anaplastic thyroid cancer (ATC) is an aggressive rare malignancy found in less than 2% of thyroid cancer patients. Its low occurrence rate presents challenges for collecting sufficiently large cohorts at a single institution, making statistical analysis about the disease’s spread, geographical distribution, and prevalence difficult. Nationwide data lakes such as Oracle EHR Real-World Data (ORWD, formerly Cerner Real World Data) offer a boost in cohort sizes and an opportunity to study ATC’s geographical distribution and assess regional differences.

Methods/Case Report
We searched ATC distribution across US regions defined by ZIP codes recorded in ORWD using multiple coding parameters, including ICD9, ICD10, and SNOMED as well as direct text searches for “anaplastic thyroid carcinoma”. We analyzed the geographical associations defined by ORWD (region) with sex, race, and age of ATC onset using the Fisher’s exact test. We combined 10 regions into 4 representative groups because of the small sample size. The groups are West Coast including the Rockies, Midwest from North Dakota to Texas, East Coast, and New England.

Results (if a Case Study enter NA)
Search for ATC condition codes in ORWD produced only 200 region-coded patient records across the US using multiple methods to try and identify cases. The mid-section of the US and coastal regions shows the highest numbers of ATC patients while New England and South regions show the lowest. While more women have ATC overall, the East Coast group has significantly more males (p value = 0.04). ATC is a predominantly white disease (79.8% overall) with black population increasing in East Coast group and other races (Asian/Undeclared) in West Coast (p-value &lt; 0.001). There appears to be no significant association between age of ATC onset and the geographical groups.

Conclusion
The data shows geographic differences in distribution of ATC although this preliminary analysis neither explains the nature of these differences nor allows for a clearer view. The rarity of the disease complicates data analysis. This study was also limited by number of cases retrievable from the database itself and lack of granularity in coding available for ATC to find cases of interest, highlighting the difficulty of accurate tumor classifications in large data lakes. Further research into geographical distribution and environmental factors (radioactivity, pollution) of thyroid cancer using more advanced tools, such as GeoSpark, are planned.
Rare Encounter: A Study of Oral Cavity Kaposi Sarcoma in Two Cases
Authors: Jabbar M , Yin J , Zenezan D , Proca D , Kuklani R 
Published: October 2024

Abstract

Introduction/Objective
Kaposi Sarcoma (KS) of the oral cavity, is an unusual vascular endothelial neoplasm and is the most common malignancy affecting the skin and internal organs in patients with AIDS. The tumor is caused by Human herpesvirus 8 (HHV-8). It rarely metastasizes and can be treated and totally cured by treating the AIDS disease.
The oral cavity may be the only/ first site of KS, and therefore, is important in the diagnosis. The lesions present as multiple red-purple macules that develop into plaques or nodules. The hallmark microscopic features are spindle cell proliferation and irregular small, vascular slits, which often run parallel to the epithelium, as well as extravasated RBCs, with hemosiderin deposition and hyaline globules in 50% of lesions. HHV-8 nuclear staining is positive in all cases, which is crucial to differentiate it from other conditions with positivity for spindled cell markers: CD34, CD31, ERG, and FVIII R. The tumor can also be positive for lymphatic-specific markers (D2-40, LYVE-1, VEGFR3, and PROX1)

Methods/Case Report
We reviewed retrospectively archived cases from our TUH oral pathology database with available H&E slides diagnosed for Kaposi sarcoma between 2013 – 2023. We retrieved two confirmed cases, and we reviewed the slides and clinical information.

Results (if a Case Study enter NA)
Data were colleceted and analysed.

Conclusion
Incorporating Kaposi sarcoma into the differential diagnosis of pigmented red-purple vascular lesions in the oral cavity is of paramount importance. Detection of Kaposi sarcoma in this region bears significant prognostic implications, often serving as an initial sign of Kaposi sarcoma and indicating HIV infection. Lesions typically localize on the palate and gingiva.
Heightened awareness of this clinical entity is crucial for facilitating early detection and treatment with antiretroviral drugs. Furthermore, the differential diagnosis for lesions with similar clinical presentations encompasses a broad spectrum, including benign conditions such as pyogenic granuloma, hemangioma, bacillary angiomatosis, and even granulation issue, as well as malignant tumors like angiosarcoma. It is noteworthy that considering Kaposi sarcoma in this context prompts pathologists to prioritize ordering stains for HHV-8. This diagnostic approach is supported by the exceptional sensitivity and specificity of HHV-8 stains, which exhibit 99% sensitivity and 100% specificity for diagnosing Kaposi sarcoma, while consistently yielding negative results in all other entities within the differential diagnosis.
Co-existence of Myelodysplastic Disorders and Plasma Cell Neoplasms: Case Series
Authors: Baban Y , jum’ah H , Ayub S 
Published: October 2024

Abstract

Introduction/Objective
The development of myelodysplastic syndrome (MDS) in patients with plasma cell neoplasm (PCN) receiving treatment is well reported. However, co-occurrence of both, without any chemotherapy history, is sparsely documented in the literature. We aim to highlight the possible association between both.

Methods/Case Report
Database search was done using Epic Slicer-Dicer for cases with biopsy proven co-existing MDS and PCN (from 2010-2022). The patients’ charts were reviewed to collect and analyze the clinical features.

Results (if a Case Study enter NA)
We identified 3 patients, all in their seventies on presentation:
First patient: man, presented with unexplained chronic anemia. Serum protein electrophoresis (SPEP) showed elevated levels of monoclonal IgG kappa (4.2 g/dl). Evaluation of the BM biopsy revealed MDS with low blasts (WHO-5) with IgG plasma cell myeloma (56% Kappa-restricted plasma cells). Chromosome analysis revealed normal karyotype. Molecular studies were not done.
Second patient: man, with Rheumatoid Arthritis and anemia. SPEP revealed biclonal IgG lambda (2.0 g/dl). BM biopsy indicated 5-8% lambda-restricted plasma cell proliferation. Anemia was managed with darbopoetin, but without improvement. The patient did not get chemotherapy. Follow-up BM biopsy was done, showing MDS with low blasts and ringed sideroblasts (WHO-5) alongside the PCN. FISH showed two abnormal IGH rearrangement populations.
Chromosome analysis revealed normal karyotype. Molecular studies were not done.
Third patient: woman, with pancytopenia. SPEP indicated monoclonal protein IgG lambda (1.8 g/dl). BM biopsy revealed 10% lambda-restricted plasma cell proliferation, coexisting with MDS with increased blasts grade 2 (WHO-5). Molecular studies showed: 2-FLT3 L601_K602insNFREYEYDL and ASXL1 E635fs*15. Chromosome analysis revealed normal karyotype.
No in common clinical findings found during chart reviewing the cases.

Conclusion
Further investigating the underlying pathology, bone marrow microenvironment, and molecular and cytogenetics abnormalities in a larger number of patients with co-existing MDS and PCN is important. Also, if there was an association, it is important to study the sequence of occurrence between them.
DEVELOPMENT OF SYSTEMIC MASTOCYTOSIS AFTER BONE MARROW TRANSPLANTATION FOR AN ACUTE MYELOID LEUKEMIA: DONOR DERIVEN DISEASE OR SYSTEMIC MASTOCYTOSIS WITH AN ASSOCIATED MYELOID NEOPLASM
Authors: Rusnak K R , Nozad S 
Published: October 2024

Abstract

Introduction/Objective
Systemic mastocytosis may have variable presentation ranging from an indolent disease to an aggressive form. Systemic mastocytosis with an associated myeloid neoplasm can occur simultaneously, or within an interval of a myeloid neoplasm and should meet the diagnostic criteria of both entities.

Methods/Case Report
Herein, we present a patient with history of acute myeloid leukemia with KMT2A(11q23) amplification who initially underwent an allogeneic hematopoietic stem cell transplantation from a matched sibling donor. One year later, the patient developed isolated central nervous system relapse, as well as evidence of molecular relapse in the bone marrow and underwent a second allogeneic transplantation, but this time, from a matched unrelated donor.
The 100 days post second transplant bone marrow biopsy was negative for involvement by acute myeloid leukemia and the chimerism study revealed evidence of total engraftment with 100% donor cells. Additionally, Fluorescence in situ hybridization analysis detected no evidence of KMT2A amplification. However, morphologic examination of the bone marrow biopsy demonstrated involvement by systemic mastocytosis with multiple dense aggregates of CD117 and tryptase positive mast cells showing spindled cell morphology. Mast cells were positive for CD25 and demonstrated negative expression of CD2 and CD30. PCR analysis of the peripheral blood did not detect evidence of KIT mutation, but serum tryptase was elevated.

Results (if a Case Study enter NA)
NA

Conclusion
This case highlights a rare instance of systemic mastocytosis in the setting of remission from an acute myeloid leukemia in a post transplantation bone marrow and represents a diagnostic challenge. While development of systemic mastocytosis in a patient with prior history of an acute myeloid leukemia suggests the possibility of systemic mastocytosis with an associated myeloid neoplasm, some other features including the complete remission and total engraftment of the post transplantation bone marrow with 100% donor cells, raise the possibility of a donor driven disease.
Myeloid Sarcoma of Conjunctiva in a patient with JAK2-positive myeloid neoplasm: two distinct myeloid neoplasms sequentially arising from a common precursor
Authors: Hanan A , Altaf S , Khan A , Zhang X , Cocker R 
Published: October 2024

Abstract

Introduction/Objective
Myeloid sarcoma (aka granulocytic sarcoma or chloroma), a rare type of myeloid neoplasm is characterized by the presence of myelogenous blastic cells outside of the bone marrow either before, during or after the development of leukemia. Presentation in the orbit is extremely rare, unlike other body parts. We report a case of myeloid sarcoma of conjunctiva in a patient with JAK2-positive myeloid neoplasm.

Methods/Case Report
An 84-year-old man presented with bilateral conjunctival masses which on biopsy showed diffuse involvement by blasts, immunohistochemically expressing positivity for myeloperoxidase, CD33, CD68, CD34 (partial), CD117 (partial) but were non-reactive to CD15, CD3 and PAX5. Next generation sequencing (NGS) revealed mutations in NRAS, ASXl1 and TET2 genes, consistent with the diagnosis of myeloid sarcoma (MS) of the conjunctiva. While patient’s past medical history included status post radiation and chemotherapy for prostate cancer and colonic adenocarcinoma respectively. it was also significant for a JAK 2 positive myeloproliferative neoplasm (MPN), six-years prior to current presentation. At the time he was treated with hydroxyurea for 5 years but developed neutrophilic leukocytosis and transfusion-dependent anemia. Subsequently a treatment regimen including ruxolitinib and pacritinib was initiated but without clinical and hematological improvements. NGS of the initial JAK2-positive MPN revealed ASXL1, JAK2 and TET2 mutations. Of note are the similarities and variations in the molecular signatures of patient’s initial MPN and current conjunctival MS. While the two neoplasms carried an identical TET2 mutation with highest variant allelic frequency, they are different in other mutations.

Results (if a Case Study enter NA)
NA

Conclusion
Our case illustrates an unusual manifestation of myeloid sarcoma localized to the conjunctiva. The identification of clonal relatedness on NGS with distinct mutations, adds complexity to our understanding of tumor origin. It highlights a series of events which may have contributed to this phenomenon, including consequence of therapy, clonal evolution with molecular discordance or origin as a totally independent entity. This report underscores the importance of genetic profiling in guiding prognosis and treatment strategies in such settings.
Hemophagocytic Lymphohistiocytosis (HLH): A Clinical and Pathological Grading System Based on the Presence of Hemophagocytosis
Authors: Reid J , Demianets R , Rezk S 
Published: October 2024

Abstract

Introduction/Objective
Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of disorders resulting from uncontrolled immune activation leading to severe hyperinflammation. The syndrome can be primary (genetic) or secondary to infections, malignancies, or autoimmune diseases. The diagnosis of HLH is challenging due to its nonspecific clinical presentation and the overlap with other conditions. This study aims to establish a reliable diagnostic approach for HLH by evaluating the accuracy of bone marrow histomorphological criteria in diagnosing the disease.

Methods/Case Report
We conducted a retrospective analysis of clinical and pathological data from patients diagnosed with HLH over a 12year period and included 38 patients with suspected HLH. A grading system for hemophagocytosis was developed based on the extent and frequency of hemophagocytic activity observed in bone marrow biopsies. Hemophagocytosis is categorized into four grades: Grade 0 indicates its absence, Grade 1 describes mild hemophagocytosis with less than 2 histiocytes containing hemophagocytosis per slide, Grade 2 denotes moderate hemophagocytosis with 3 to 5 histiocytes per slide, and Grade 3 signifies severe hemophagocytosis with more than 5 histiocytes per slide. Clinical data, comprising laboratory parameters and treatment outcomes, were analyzed in relation to the histologic grading of hemophagocytosis.

Results (if a Case Study enter NA)
Among the cases, grade 1 had 1 resolved case, 4 cases meeting 2 criteria all resolved, and 13 cases meeting 4 or more criteria resulted in 5 deaths and 8 resolutions. Grade 2 included 10 cases, with 2 meeting 2 criteria and resolving, and 8 meeting 4 or more criteria resulting in 5 deaths and 3 resolutions. Grade 3 comprised 10 cases, with 3 meeting 3 criteria and resolving, 3 meeting 5 or 7 criteria resulting in 1 death and 2 resolutions each, and 4 meeting 6 or 8 criteria resulting in 2 deaths and 2 resolutions each.

Conclusion
In our retrospective analysis of bone marrow biopsies from 38 patients with suspected HLH, our results indicate that the presence and extent of hemophagocytosis strongly suggest HLH. Implementing these criteria significantly improved diagnostic accuracy, reducing misdiagnosis rates and enabling timely therapy initiation. This study underscores the value of bone marrow histomorphological criteria in diagnosing HLH and stresses their importance in the standard diagnostic process for suspected HLH cases.
NPM1 Minimal Residual Disease Detection at Any Time by Clinical Next Generation Sequencing Predicts Poor Survival in Acute Myeloid Leukemia
Authors: Sallman D , Xie Z , Chan O , Shao R , Song J , HUSSAINI M O 
Published: October 2024

Abstract

Introduction/Objective
Acute Myeloid Leukemia (AML) is a deadly disease that accounts for 80% of adult leukemia cases and carries a 5-year survival rate of only 31.7%. Historically, prognosis hinged heavily on cytogenetic stratification, but more recently minimal residual disease (MRD) has emerged as a crucial prognostic marker. Flow cytometry, PCR, and NGS can all be employed for MRD detection, but each carries its own limitations. Though technically challenging, NGS has the advantage being able to simultaneously assay multiple mutations, thus providing for broader applicability. NPM1 is the most prevalently mutated gene in AML (25-35%). In this study, one of the largest of its kind, we investigate the feasibility and impact of NPM1 MRD detection by clinical NGS.

Methods/Case Report
IRB approval was obtained. We reviewed the medical record and clinical laboratory data sets from AML patients treated at Moffitt Cancer Center who had NPM1 status assessed by clinical NGS, Testing was performed at LabPMM (San Diego, CA). DNA was extracted, and NPM1 exon 12 was amplified. PCR products were sequenced on an Illumina MiSeq. The clinically reportable assay sensitivity was 5 x 10-5 though lower levels were detected on review of raw data. Kaplan-Meier analysis was conducted for overall survival assessment. Since patients often had multiple tests, we divide patients into those with NPM1+ at any time and NPM1 always negative.

Results (if a Case Study enter NA)
There was a total of 140 patients. Overall, 346 tests were conducted, with an average of 2.5 tests/patient. There were 85 patients (60%) who underwent serial testing. MRD+ patients (n=80) had a mean age of 66 years, while MRD- patients (n=60) had a mean age of 58 years. MRD+ patients exhibited a mean overall survival of 29.3 months versus 43.6 months for MRD- patients (p=0.005.)

Conclusion
Through our study encompassing a large patient cohort of 140 patients and nearly 350 testing data points, we confirm the feasibility and clinical utility of NPM1 MRD evaluation by NGS. The significantly poorer survival in patients who were MRD+ at any time during their disease provides a scientific rationale for serial NGS testing to enable risk stratification of NPM1+ AML patients.
Unexpected Presentations of Histiocytic Disorders as Mass Lesions in the Central Nervous System and Spine
Authors: Cutshall H , Post G , Gokden M 
Published: October 2024

Abstract

Introduction/Objective
A number of neoplastic and non-neoplastic hematolymphoid lesions can involve the CNS and spine. The majority are lymphomas, but some are rare lesions that mimic primary neoplasms clinically, radiologically, and even pathologically. Here, we present our experience of such cases.

Methods/Case Report
Pathology archives were searched, and five cases representing different challenges were identified to review clinical, radiological, and pathologic features. Case 1. 31-year-old female presented with vision changes and hearing loss and numerous supratentorial extra-axial masses, suspicious for meningiomatosis.
Extensive lymphoplasmacytic infiltrate was seen at Intraoperative consult (IOC). Final diagnosis was Rosai-Dorfman disease with features of IgG4 related disease. Case 2. 31-year-old female with Chronic myeloid leukemia (CML), which progressed to AML presented with a right frontal brain mass. IOC displayed atypical hematolymphoid infiltrate. Final diagnosis was myeloid sarcoma. Case 3. 29-year-old male presented with a T10 vertebral lesion. IOC showed hypercellular tissue with atypia and was deferred. Subsequently, histiocytic sarcoma was diagnosed. Case 4. 22-year- old male presented with a T3-T4 intradural, extramedullary mass radiologically thought to be a meningioma. No IOC was requested. Final diagnosis was juvenile xanthogranuloma. Case 5. 36-year-old male presented with a C7-T1 dura-based mass. IOC revealed granulomatous inflammation, eventually resulting in a diagnosis of non-necrotizing granulomatous inflammation, suggesting sarcoidosis.

Results (if a Case Study enter NA)
NA

Conclusion
These cases highlight the importance of incorporating all clinical and radiological findings into pathologic evaluation, while being alert for mimickers and pitfalls. Both practicing general surgical pathologists and neuropathologists should remain alert to such unexpected and unusual cases especially at the time of IOC and initiate appropriate work-up with expedited diagnostic protocols such as intraoperative cultures, flow cytometry, and cytogenetics, as the differential diagnosis is broad with inflammatory, infectious, and neoplastic possibilities, presenting a variety of challenges.