Similar Histology Research Articles

Exploring the molecular landscape of cutaneous mixed tumors characterized by TRPS1::PLAG1 gene fusion.

The histological similarities between pleomorphic adenomas (PAs) and cutaneous mixed tumors (CMTs) found in certain facial regions can create a diagnostic challenge. Molecular findings reveal common genetic profiles, particularly PLAG1 rearrangements in both PA and CMT. Although molecular distinctions have received limited attention, our observations indicate multiple cases of CMTs carrying the TRPS1::PLAG1 fusion. This clinical experience has driven our investigation into the potential diagnostic utility of TRPS1::PLAG1 fusions for determining tumor origin. Two cohorts consisting of 46 cases of CMT and 45 cases of PA of the salivary glands were obtained from French institutions and reviewed by specialists in each subspecialty. RNA sequencing analysis was conducted to identify the molecular features of cases harboring PLAG1. Clinical, pathological, and molecular data were collected. In this study, cases of CMT exhibited recurrent gene fusions, primarily TRPS1::PLAG1 (74%). These tumors shared characteristic histological features, including tubuloductal differentiation in 55% of cases and squamous metaplasia in varying proportions. In contrast, cases of PA had gene fusions involving PLAG1 with various gene partners, with only one case in which TRPS1::PLAG1 was identified. This disparity was also observed at the transcriptomic level between TRPS1::PLAG1 CMTs and other tumors. However, TRPS1 immunostaining did not correlate with TRPS1::PLAG1 fusion. In conclusion, we report that recurrent TRPS1::PLAG1 fusion CMTs exhibit similar characteristic histological features, including tubuloductal differentiation that is associated with squamous metaplasia in around half of cases. Detection of this fusion could be valuable in correctly identifying the origin of these tumors. © 2024 The Pathological Society of Great Britain and Ireland.

LONG-TERM SURVIVAL OF TANYCYTIC EPENDYMOMA OF LATERAL VENTRICLE WITH ADJACENT FRONTAL LOBE INVASION: CASE REPORT AND LITERATURE REVIEW

Abstract AIMS Tanycytic ependymoma (TE) of lateral ventricle is a rare variant of ependymoma often challenging to diagnose due to its distinctive histological features and similarity to other central nervous system neoplasms. This report presents a case of TE in a 48 years-old lady with 20 years of long-term survival and provides a comprehensive review of the literature to elucidate the clinical, radiological, and pathological characteristics of this entity. METHOD A 48-year-old woman presented with a left lateral ventricular tumor invading the left frontal lobe and pericallosal region, subsequently diagnosed as TE after stereotactic biopsy followed by radical radiotherapy. Epidemiological features, preoperative and postoperative radiological surveillance, and functional performance after adjuvant radiotherapy were reviewed. Additionally, we review the current literature to explore current perspective of TE. Three major medical database engines, PubMed (Medline), Scopus (ELSEVIER), and Cochrane were used to conduct a thorough literature search. RESULTS The patient exhibited notable neurological improvement following stereotactic biopsy and radical radiotherapy, with long-term surveillance demonstrating stability and reduction in tumor size over a 20-year period. Our literature review underscores the rarity of TE and its diagnostic challenges, emphasizing the importance of histopathological examination and immunohistochemical analysis for accurate diagnosis. TE exhibit unique ultrastructural features, requiring meticulous examination for proper classification. Additionally, we discuss the implications of TE’s histological resemblance to other intramedullary tumors and its potential impact on therapeutic decisions. CONCLUSION Tanycytic ependymomas pose diagnostic dilemmas due to their morphological overlap with other CNS tumors. However, heightened awareness among clinicians and pathologists is crucial for accurate identification and appropriate management. Further research into the molecular mechanisms underlying TE is warranted to enhance diagnostic precision and refine treatment strategies, ultimately improving patient outcomes.

Characterization of Endothelial Cell Subclusters in Localized Scleroderma Skin with Single-Cell RNA Sequencing Identifies NOTCH Signaling Pathway

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression.

Inter and Intraserotype Variations of Streptococcus Pneumoniae Pathogenicity in Mice and Rabbits

The small mammalian labratory animals, the mice and the rabbits were tempted to be pathogenicity models for S. pneumoniae serotypes 1 and 6, the infecting doses were 0.3ml for mice and 0.5 ml for rabbits. These infectious doses were rated to a count of 1X 10 to 7 CFU/ml. The infection routes were intrapreritoneal for mice and intranasal for rabbits. The gold standard criteria for pathogenicity were the death end point DEP.DEP was up to 24hr for mice and ranged from four to 14 days in rabbits. Mice was more susciptable than rabbits for S. pneumoniae serotypes infections. Autopsy cultures of blood, lungs, liver and kideys were producing same infecting serotype both from mice and rabbits. This isolation profile was indicating bacterimic state induced by infection. Different serotypes have shown different death end points duration time. There were inter and intraserotype variations in DEP. Moderate to severe respiratory disease conditions RDC was noted in mice while mild RDC in rabbits. Both of the tested models were similar lung histology to man. The histological features of this experimental infections have shown that the infected mice and rabbits were of bronchopneumonia type. It appears that both mice and rabbits were standing as valid laboratory animal models for these local clinical isolates of S. pneumoniae serotypes.

Differential diagnosis between rheumatoid nodules and fibrocaseous tubercles in the lung: A case series

The histological similarities between rheumatoid nodules and post-primary fibrocaseous tubercles in the lung may present a significant challenge in differential diagnosis. Differential diagnosis of fibrocaseous tubercles and rheumatoid nodules is crucial in clinical practice, particularly due to the high risk of co-existing fibrocaseous tuberculosis in rheumatoid arthritis. This condition increases the likelihood of military dissemination and mortality, especially in elderly patients, with elderly women being at the greatest risk. This case series aims to differentiate these two pathological entities based on the clinical histories and histological analyses of surgical specimens from two patients. The main histological marker for RhNod is the presence of vascular remnants within the fibrinoid necrotic area, reflecting the vascular origin of RhNods. Additional supporting evidence for the rheumatoid nature of the process includes the presence of inflamed blood vessels elsewhere in the lung (such as non-specific, fibrinoid necrotic, and/or granulomatous autoimmune vasculitis), as well as the potential presence of co-existent interstitial pneumonitis, with or without pleuritis. In contrast, the necrotic tuberculous process is characterized by coalescent necrosis that does not respect anatomical borders and lacks structural remnants of lung tissue, which is a hallmark of tuberculosis pathology.

Latent stem cell-stimulating radially aligned electrospun nanofibrous patches for chronic tympanic membrane perforation therapy

Chronic tympanic membrane (TM) perforation is a tubotympanic disease caused by either traumatic injury or inflammation. A recent study demonstrated significant progress in promoting the regeneration of chronic TM perforations through the application of nanofibers with radially aligned nanostructures and controlled release of growth factors. However, radially aligned nanostructures with stem cell-stimulating factors have never been used. In this study, insulin-like growth factor binding factor 2 (IGFBP2)-incorporated radially aligned nanofibrous patches (IRA-NFPs) were developed and applied to regenerate chronic TM perforations. The IRA-NFPs were prepared by electrospinning 8 wt% polycaprolactone in trifluoroethanol and acetic acid (9:1). Random nanofibers (RFs) and aligned nanofibers (AFs) were successfully fabricated using a flat plate and a custom-designed circular collector, respectively. The presence of IGFBP2 was confirmed via Fourier transform infrared spectroscopy and the release of IGFBP2 was sustained for up to 20 days. In vitro studies revealed enhanced cellular proliferation and migration on AFs compared to RFs, and the incorporation of IGFBP2 further promoted these effects. Quantitative real-time PCR revealed mRNA downregulation, correlating with accelerated migration and increased cell confluency. In vivo studies showed IGFBP2-loaded RF and AF patches increased regeneration success rates by 1.59-fold and 2.23-fold, respectively, while also reducing healing time by 2.5-fold compared to the control. Furthermore, IGFBP2-incorporated AFs demonstrated superior efficacy in healing larger perforations with enhanced histological similarity to native TMs. This study, combining stem cell stimulating factors and aligned nanostructures, proposes a novel approach potentially replacing conventional surgical methods for chronic TM perforation regeneration. Statement of significanceChronic otitis media (COM) affects approximately 200 million people worldwide due to inflammation, inadequate blood supply, and lack of growth factors. Current surgical treatments have limitations like high costs and anesthetic risks. Recent research explored the use of nanofibers with radially aligned nanostructures and controlled release of growth factors to treat chronic tympanic membrane (TM) perforations. In this study, insulin-like growth factor binding protein 2 (IGFBP2)-incorporated radially aligned nanofibrous patches (IRA-NFPs) were developed and applied to regenerate chronic TM perforations. We assessed their properties and efficacy through in vitro and in vivo studies. IRA-NFPs showed promising healing capabilities with chronic TM perforation models. This innovative approach has the potential to improve COM management, reduce surgery costs, and enhance patient safety.

Synchronous multiple primary malignancies or transdifferentiation?-A diagnostic challenge in a case of Xeroderma pigmentosum.

A diagnosis of synchronous tumors is always questionable when they show similar histology. We present a case of synchronous tumors, i.e. melanoma (MM) arising from the scalp and angiosarcoma (AS) from the cheek in a patient of Xeroderma pigmentosum (XP). The presence of melanin in AS of the cheek led to a differential diagnosis and a possibility of transdifferentiation of malignant melanoma in the first instance. Immunohistochemistry (IHC) was negative for melanoma markers (Melan A, SOX-10 & S 100) and positive for vascular markers (ERG, CD31 & CD34) ruling out transdifferentiation and concluding the cheek swelling as angiosarcoma. The presence of non-cutaneous malignancies is rare in XP and the presence of MM in a nearby site and the melanin pigment in the cutaneous malignancy mislead the diagnosis. The morphology of the tumor was the key which led to the further workup of the case.

Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

A clinical, cyto-histopathological and immunohistochemical study of spindle cell lesions of breast in a tertiary care hospital

Spindle cell lesions in the breast are a diverse group of entities that can be either benign or malignant. Spindle cell lesions often pose a challenge to the diagnosing clinician because of the vast differential diagnoses, the rarity of these lesions and the histological similarities. We aim to conduct this study to profile these rare lesions of the breast and correlate the cyto-histopathological features on FNAC with immunohistochemical characteristics to determine its efficacy.A total 260 patients, suffering from spindle cell lesions of the breast, attending the outpatient and in-patient services were included in this 5 year study (3 years of retrospective cases and 2 years of prospective cases) conducted at Department of Pathology, JNMCH, AMU, Aligarh.: Only Diagnosed cases of Spindle cell lesions of breast were included in the study. The study sample comprised of 260 cases (105 cytological cases and 220 histopathological cases with 65 cases that are common to both) Apart from diagnosed cases of Spindle cell lesions of breast all other breast lesions either reactive benign or malignant were excluded.Total number cases of breast lesions received in the Department of Pathology during 5 year study period were 15,270 out of which 9700 cases were of Histopathology and 5570 were of Cytopathology. Among 15,270 cases, a total number of 15,010 (98.29%) cases belonged to non-spindle cell lesions which were excluded from the study and the remaining cases i.e., 260 (1.7%) cases diagnosed as spindle cell lesions of breast constituted the study group. Of the total260 cases, 105 cases were of cytopathology and 220 cases were of histopathology and cases common to both i.e., those cases which had cyto-histopathological correlation were 65 cases (20%). The highest incidence of spindle cell lesions occurred in 4 decade of life comprising of 126/260 cases (48.46%).Spindle cell lesions are not so common in breast, accounts for 1.7% of cases only. The workup involves thorough histopathological examination due to considerable morphological overlap and an elaborate IHC studies since no single Immunohistochemical marker is sufficient/specific to clinch the final diagnosis. Hence, it is difficult to make the final diagnosis of spindle cell lesions of breast on histopathology alone in majority.

Combination of Muller matrix imaging polarimetry and artificial intelligence for classification of mice skin cancer tissue in-vitro and in-vivo

Mueller matrix imaging polarimetry is a fast and non-invasive technique for discriminating between different types of biological samples based on the characteristics of polarized light interacting with them. Combining Mueller matrix imaging polarimetry with artificial intelligence provides further advantages in detecting different kinds of medical conditions in an automated manner. Accordingly, the present study proposes a method based on Mueller matrix polarimetry and machine learning algorithms for discriminating between (1) four different types of mice skin tissues (normal, acanthosis, papilloma, and squamous cell carcinoma); (2) two types of mice skin tissues which show histological similarities to human equivalents (normal and squamous cell carcinoma); and (3) 7,12-dimethylbenz[a]anthracene/estrogen-induced mice skin tissues. Five machine learning classifiers, namely Random Forest, Support Vector Machine, K-Nearest Neighbor, Gradient Boosting, and Gaussian Naïve Bayes, are considered in the first and second applications, while three models (Support Vector Machine, K-Nearest Neighbor, Gradient Boosting) are considered in the third application. For each application, the features which dominate the machine learning prediction performance are determined through multivariate correlation matrix analysis, kernel density estimation, and Analysis of Variance tests. The experimental results show that the Random Forest model achieves the highest classification accuracy (93.55 %) for the first application, while the Support Vector Machine model yields the highest accuracy for both the second and third applications (97.66 % and 100 %, respectively). Overall, the proposed framework consisting of Mueller matrix imaging polarimetry and machine learning provides a strong foundation for the on-going development of screening and diagnosis methods for human skin cancer.

HGG-46. PEDIATRIC RADIATION-INDUCED GLIOMA PATIENT SAMPLES AND NOVEL PATIENT-DERIVED MODELS REVEAL TRANSLATIONALLY RELEVANT TREATMENT SUSCEPTIBILITIES AND POTENTIAL GERMLINE RISK FACTORS

Abstract BACKGROUND Pediatric radiation-induced glioma (RIG) is an incurable secondary high-grade glioma (HGG) afflicting up to 4% of children who previously received cranial radiotherapy (RT) for other malignancies. RIG accounts for up to 10% of pediatric brain tumor deaths. It has no known genetic risk factors nor effective treatment and is uniformly fatal, partly due to extremely limited available models. Our recent molecular characterization of patient samples showed that while RIG and primary pediatric HGG share histological similarities, their genetic alterations and gene expression profiles differ. METHODS We obtained germline DNA sequencing from 28 RIG patients and 112 matched controls who received RT but did not develop RIG. In addition, we developed cell culture and murine orthotopic patient-derived xenograft (PDX) models from four RIGs. We conducted single-cell RNA-seq (scRNA-seq), drug screening/validation, and CRISPR functional screening on our novel models. RESULTS Germline mutations in TP53, PARP10, POLI, DCLRE1A, and MLH3 were more common in RIG patients than controls (p&amp;lt;0.002). Our matched cell culture and PDX models of RIG represent the genetic diversity of the disease. The PDX models form tumors in 30-120 days and closely recapitulate human RIG by histology and scRNA-seq. They show susceptibility across models to DNA-damaging treatments (etoposide, irinotecan, radiation), as well as MEK, PARP, and proteasome inhibition, with orthogonal supporting findings via CRISPR screening. Several two-treatment combinations also show efficacy and synergy across models, including radiation and trametinib in vivo (logrank p=0.029). Discussion: RIG is an understudied but major cause of pediatric CNS tumor mortality that differs genetically from primary pediatric HGG. Our findings suggest specific germline alterations in DNA repair pathways may put some patients at higher risk of developing RIG after cranial RT. We also introduce the first set of patient-derived RIG models in order to advance translational RIG research, with characterization of translationally relevant treatment susceptibilities.

Comparative Proteomics Analysis Reveals Distinct Molecular Phenotype and Biomarkers in Patients with Erythrodermic Atopic Dermatitis and Erythrodermic Psoriasis.

Erythrodermic atopic dermatitis (EAD) and erythrodermic psoriasis (EP) are rare yet debilitating inflammatory skin disorders that propose challenges in diagnosis and discovering effective therapeutic targets. Despite their clinical and histological similarities, the underlying molecular mechanisms and systemic biomarkers of these diseases are substantially unclear. In this study, we sought to investigate the differential serum proteome of EP and EAD patients and identify biomarkers for these two subtypes of erythroderma. We recruited 14 EAD patients, 14 EP patients and 14 healthy controls. Serum samples were collected and analyzed using the Olink high-throughput platform to assess the levels of 269 inflammation-/immune response-/cardiovascular-related biomarkers. Both EAD and EP patients exhibited enhanced immune activation and dysregulated cardiovascular profiles compared to healthy controls. EAD demonstrated a more pronounced inflammation tone, characterized by Th1/Th2/Th22/IL-1-dominant patterns, as well as increased TNF superfamily, Th17, and apoptosis markers. Conversely, EP displayed inflammation with Th1/Th17/TNF-skewing and mild Th2 upregulation, along with notable increases in epidermal-development markers. Disease severity in EAD was strongly correlated with apoptosis/Th2 markers, while correlated with Th17 markers in EP. Furthermore, a panel of eight markers (IL-17A/IL-17C/PI3/CCL20/SH2D1A/SIRT2/DFFA/IL-13) was identified that effectively discriminated between EP and EAD, with an Area Under the Curve greater than 0.8. Our study comprehensively characterizes the circulating molecular profiles in EAD and EP patients, providing insights into the similarities and complexities of their inflammation phenotypes. The identified serum biomarkers have the potential to differentiate between EP and EAD, which could aid in the diagnosis and guiding tailored therapeutics.

Histologic Assessment of Lumbosacral Transitional Vertebrae Pseudoarticulation as a Source of Pain in Bertolotti Syndrome

BackgroundBertolotti's Syndrome (BS) is characterized by chronic pain and functional impairment associated with lumbosacral transitional vertebrae (LSTVs). The study aimed to investigate the histological characteristics of the pseudoarticulation between the enlarged transverse process and sacrum seen in Castellvi 2a LSTV and explore the involvement of nervous tissue in pain generation. MethodsImmunohistochemical analysis using S100 protein staining was performed to assess the presence of nerve tissue. ResultsThese changes included fibrillation, chondrocyte cloning, alterations in the proteoglycan matrix, and focal chondrocyte necrosis. Notably, no nerve tissue was observed in any of the specimens, as confirmed by negative S100 protein staining. ConclusionThe study findings suggest that nerve tissue is not involved in the nociceptive mechanisms underlying pain in BS. The histological similarities between the pseudoarticulation and osteoarthritic joints indicate that the pseudoarticulation itself may be a significant source of pain in BS. These insights contribute to our understanding of the pathophysiology of BS and support treatment paradigms prioritizing pain control with medications such as NSAIDs before considering surgical intervention. Future studies with larger sample sizes and in vivo models are needed to further validate these findings and explore the changes in joint histology under biomechanical forces in LSTVs.

Zebrafish as a Human Muscle Model for Studying Age-Dependent Sarcopenia and Frailty.

Currently, there is an increase in the aging of the population, which represents a risk factor for many diseases, including sarcopenia. Sarcopenia involves progressive loss of mass, strength, and function of the skeletal muscle. Some mechanisms include alterations in muscle structure, reduced regenerative capacity, oxidative stress, mitochondrial dysfunction, and inflammation. The zebrafish has emerged as a new model for studying skeletal muscle aging because of its numerous advantages, including histological and molecular similarity to human skeletal muscle. In this study, we used fish of 2, 10, 30, and 60 months of age. The older fish showed a higher frailty index with a value of 0.250 ± 0.000 because of reduced locomotor activity and alterations in biometric measurements. We observed changes in muscle structure with a decreased number of myocytes (0.031 myocytes/μm2 ± 0.004 at 60 months) and an increase in collagen with aging up to 15% ± 1.639 in the 60-month group, corresponding to alterations in the synthesis, degradation, and differentiation pathways. These changes were accompanied by mitochondrial alterations, such as a nearly 50% reduction in the number of intermyofibrillar mitochondria, 100% mitochondrial damage, and reduced mitochondrial dynamics. Overall, we demonstrated a similarity in the aging processes of muscle aging between zebrafish and mammals.

A phase II study of lurbinectedin with or without avelumab in small cell carcinoma of the bladder (LASER).

TPS4629 Background: Small cell carcinoma of the bladder (SCCB) is a rare, aggressive malignancy accounting for &lt;1% of all bladder malignancies. Given its rarity, few prospective randomized trials have been completed in SCCB. Most therapeutic evidence comes from retrospective case series and due to its histologic similarity to small cell lung cancer (SCLC), current guidelines recommend bladder cancers with any component of small cell histology be treated similarly to SCLC. Lurbinectedin is a novel alkylating agent which recently received accelerated approval from the FDA as a second line treatment for SCLC after demonstrating an overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months (Trigo et al., Lancet Oncol, 2020). Avelumab is an anti-PD-L1 antibody FDA approved as maintenance treatment for patients with locally advanced or metastatic urothelial cancer (UC) without progression on frontline chemotherapy. Case reports have demonstrated that second line options in SCLC, including immunotherapy, appear to have some efficacy in SCCB. The purpose of this study is to assess the efficacy of lurbinectedin, either alone or in combination with avelumab, in participants with SCCB or other high grade neuroendocrine tumors (HGNETs) of the urinary tract. Methods: LASER (NCT06228066) is a phase II, multisite, open label, nonrandomized study with two cohorts. Eligible patients must have pathologically confirmed SCCB or other HGNETs of the urinary tract. Patients with mixed histologies, with any component of neuroendocrine tumor, are eligible. Patients must have received or be ineligible/refused frontline platinum/etoposide therapy. Participants in Cohort 1 must have received prior immune checkpoint inhibitors (ICIs) or be ineligible for treatment with ICI. These patients will receive lurbinectedin 3.2mg/m2 IV every 21 days. Participants in Cohort 2 must be ICI naïve but eligible to receive them. These patients will receive lurbinectedin 3.2mg/m2 IV and avelumab 800mg IV every 21 days. The primary endpoint for both cohorts is ORR, with key secondary endpoints including clinical benefit rate, PFS, OS, and DoR. The study will be conducted using a Simon minimax two stage design to rule out an ORR of 5% in favor of an ORR of 25% or greater in each cohort. If 1 of the first 12 patients has a response accrual will continue up to 16 evaluable patients per cohort. Accrual ceiling will be set at 35 patients. Exploratory objectives include analyzing peripheral immune subsets, DNA and RNA sequencing of tumors, and measurement of ctDNA and CTCs. Clinical trial information: NCT06228066 .

Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients

PurposeA large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease.MethodsDNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3).ResultsThe DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls.ConclusionThis is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.

P16 Expression in Multinucleated Stromal Cells of Fibroepithelial Polyps of the Anus (FEPA): A Comprehensive Review and Our Experience

Fibroepithelial polyps of the anus (FEPA) are a common benign polypoid proliferation of the stroma covered by squamous epithelium. They are also an often-overlooked part of pathological practice. Currently, immunohistochemistry (IHC) for p16 is the only recommended test for anal intraepithelial neoplasia, but the expression of p16 in stromal multinucleated atypical cells in FEPA has not been described. We aimed to evaluate the expression of p16 in stromal multinucleated atypical cells in FEPA and its role as a diagnostic biomarker to determine the origin of the atypical multinucleated cells in the stroma of FEPA and to rule out the possibility of a neoplastic process. Therefore, we researched a series of 15 FEPA in middle-aged patients histologically and by IHC. Examination of the subepithelial connective tissue from the FEPA showed bizarre, multinucleated cells, while their causal relationship with human papillomavirus (HPV) infection was rejected. In all cases, these cells showed mild to moderate atypical nuclear features and positive expression for p16, while the overlying squamous epithelium was negative. We concluded that FEPA are benign lesions in the stroma where mononuclear and multinucleated (sometimes atypical) cells showing fibroblastic and myofibroblastic differentiation can be found. Nevertheless, we believe that these cells have a practical diagnostic significance, although sometimes the presence of giant cells is difficult to establish, especially in the inflammatory context. The histological similarity between FEPA and normal anal mucosa supports the hypothesis that FEPA may represent the reactive hyperplasia of subepithelial fibrous connective tissue of the anal mucosa.

Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding.

Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In the latter, tumor budding (TB) is widely recognized as a negative prognostic parameter. The aim of this study was to evaluate the prognostic role of TB in ITAC and to correlate it with other established or emerging biomarkers of the disease, such as p53 and deficient DNA mismatch repair (MMR) system status/microsatellite instability (MSI). We retrospectively analyzed 32 consecutive specimens of patients with ITAC diagnosis treated in two institutions in Northern Italy. We reviewed surgical specimens for TB evaluation (low-intermediate/high); p53 expression and MMR proteins were evaluated via immunohistochemistry. Results were retrospectively stratified using clinical data and patients' outcomes. According to bud counts, patients were stratified into two groups: intermediate/high budding (>4 TB) and low budding (≤4 TB). Patients with high TB (>4) have an increased risk of recurrence and death compared to those with low TB, with a median survival of 13 and 54 months, respectively. On multivariate analysis, considering TB, therapy, and stage as covariates, TB emerged as an independent prognostic factor net of the stage of disease or type of therapy received. No impact of p53 status as a biomarker of prognosis was observed and no alterations regarding MMR proteins were identified. The results of the present work provide further significant evidence on the prognostic role of TB in ITAC and underline the need for larger multicenter studies to implement the use of TB in clinical practice.

Tissue Options for Construction of the Neovaginal Canal in Gender-Affirming Vaginoplasty.

Gender-affirming vaginoplasty (GAV) comprises the construction of a vulva and a neovaginal canal. Although technical nuances of vulvar construction vary between surgeons, vulvar construction is always performed using the homologous penile and scrotal tissues to construct the corresponding vulvar structures. Therefore, the main differentiating factor across gender-affirming vaginoplasty techniques is the tissue that is utilized to construct the neovaginal canal. These tissue types vary markedly in their availability, histology, and ease of harvest and have different advantages and disadvantages to their use as neovaginal lining. In this narrative review, the authors provide a comprehensive overview of the tissue types and associated operative approaches used for construction of the neovagina in GAV. Tissue choice is guided by several factors, such as histological similarity to natal vaginal mucosa, tissue availability, lubrication potential, additional donor site morbidity, and the specific goals of each patient. Skin is used to construct the neovagina in most cases with a combination of pedicled penile skin flaps and scrotal and extra-genital skin grafts. However, skin alternatives such as peritoneum and intestine are increasing in use. Peritoneum and intestine are emerging as options for primary vaginoplasty in cases of limited genital skin or revision vaginoplasty procedures. The increasing number of gender-affirming vaginoplasty procedures performed and the changing patient demographics from factors such as pubertal suppression have resulted in rapidly evolving indications for the use of these differing vaginoplasty techniques. This review sheds light on the use of less frequently utilized tissue types described for construction of the neovaginal canal, including mucosal tissues such as urethral and buccal mucosa, the tunica vaginalis, and dermal matrix allografts and xenografts. Although the body of evidence for each vaginoplasty technique is growing, there is a need for large prospective comparison studies of outcomes between these techniques and the tissue types used to line the neovaginal canal to better define indications and limitations.

Abstract PO2-16-11: Real-World Data of Neuroendocrine Neoplasms of Breast

Abstract Background: Primary neuroendocrine neoplasms (NEN) of breast are rare and heterogeneous. WHO has classified NENs of non-endocrine organs into three distinct categories in 2022, however real-world data on outcomes of patients with NENs of non-endocrine organs under this new classification system are still sparse. Real world experience regarding demography, clinical presentation, treatment response, and prognosis can help identify potential areas of improvement in the management of breast NEN. Methods: Here, we present our findings from patients with NEN of breast in the Cleveland Clinic Foundation between 2000 and 2023. Pathology reports were reviewed to confirm NEN of breast origin. Neuroendocrine differentiation was determined by tumor histology and immunohistochemistry (IHC). For metastatic tumors at presentation, primary organ was determined by IHC and clinical presentation. Overall survival (OS) was from date of diagnosis of NEN. Recurrence is redemonstration of tumor following curative intent therapy, and progression is increase in tumor burden. T-test and log-rank test were used in statistical analyses. Results: Total of 97 patients were identified. Of these, 79 presented with localized disease, 18 were metastatic at presentation. 88 (91%) were invasive ductal carcinoma (IDC), and 64 (81%) were local disease at presentation and rest were metastatic. Gender spread was 92:5 (F:M). Patients with ER + disease was 84/96, PR + disease was 71, and 4/93 patients had overexpression of HER2. Median age was 70 at diagnosis. 11 patients underwent neoadjuvant chemotherapy, 15 patients underwent adjuvant chemotherapy (AC), and 58/84 patients underwent hormonal adjuvant therapy. For localized disease, median recurrence free survival (RFS) was 165 months (144-NA), and recurrence rate was 8/79 (10%). Recurrence rate for local IDC was 10% (6/64). Patients with metastatic disease at presentation had a median progression free survival (PFS) of 30 months, and progression rate was 7/18 (39%). For patients with metastatic disease, median lines of palliative therapy used was 2, with median duration of first line treatment being 3.5 months, and 10 months for second line. Most common surgical procedure was mastectomy, with 37% of patients undergoing management. Median duration from diagnostic biopsy to definitive surgery was 1 month. Median follow up was 28 months. Most common hormonal adjuvant option was anastrozole (58%), most common AC regimen was docetaxel and cyclophosphamide (39%), and most common first line palliative agent was letrozole (42%). Patients who underwent AC did not reach median OS, and patients who did not receive AC had a median OS of 148 months (p=0.8). Patients with grade 3 tumors had a median OS of 58.6 months, and grade 1 and 2 had a median OS of 148.1 months (p=0.5). Discussion: Current treatment strategies for NEN of breast mirror those of non-NEN of breast with similar histology and stage based on extrapolation of data. Recurrence rate was similar between IDC and SPC. In our cohort, survival was not significantly dependent on grade and use of AC. This might be due to the number of patients included in our study, as there was a non-significant trend towards lower OS in patients with high-grade neoplasms, and further limitations from retrospective design of study. Further research towards benefit of AC in NEN of breast and prognostic value of grading is necessary to explore management options in comparison to non-NEN of the breast. Citation Format: Serhan Unlu, Olisaemeka Ogbue, Gloria Lewis, Abdo Haddad, Hamed Daw, Baidehi Maiti. Real-World Data of Neuroendocrine Neoplasms of Breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-11.