Medullary Carcinoma Research Articles

Abstract 2702: Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab

Abstract Renal medullary carcinoma (RMC) is a rare but highly aggressive SMARCB1-deficient kidney cancer that mainly afflicts young individuals of African descent and has few treatment options. Despite the advancements in immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. The majority of RMC patients treated with ICT have experienced aggressively progressive disease as the best response. This hyperprogression was confirmed in our prospective clinical trial of nivolumab plus ipilimumab specifically designed for RMC patients (ClinicalTrials.gov identifier: NCT03274258). To elucidate the mechanisms of resistance to ICT in RMC, we generated high-quality single-cell RNA sequencing data on 23,880 cells from 7 patients at baseline and 2 patients exhibiting hyperprogression after ICT intervention. Our analysis revealed that RMC tumor cells undergo a distinct transcriptional reconfiguration following ICT therapy. This reconfiguration is manifested by upregulation of S100A9 and activation of the MEK/ERK pathway, indicating that RMC tumor cells adopt myeloid-affiliated transcriptional circuits, potentially promoting cell proliferation and leading to hyperprogression. Using a mouse model of RMC, we further demonstrated in a controlled setting that ICT causes hyperprogressive disease via activation of MEK/ERK pathway and an increase of S100A9 positive tumor cells. This process can be reversed by inhibiting master regulators of this “myeloid mimicry” mechanism, such as the CEBPB/p300 complex in our mouse model of RMC, thus restoring sensitivity to ICT. These findings provide novel insights into RMC resistance to ICT and suggest valuable directions for the development of therapeutic strategies. Citation Format: Melinda Soeung, Xinmiao Yan, Li Zhang, Luigi Perelli, Jianfeng Chen, Becky Slack Tidwell, Hania Khan, Courtney N. Le, Truong N. Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Ziheng Chen, Sebastian R. Lundgren, Ningping Feng, Ciro Zanca, Menuka Karki, Niki Marie Zacharias Millward, Rong He, Rahul A. Sheth, Bathala K. Tharakeswara, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Edwin R. Parra-Cuentas, Hsinyi Lu, Cara Haymaker, Ignacio I. Wistuba, Andrew Futreal, Timothy Heffernan, Andrea Viale, Giulio F. Draetta, Nizar M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2702.

Abstract 4627: Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment

Abstract Background: Cancers of unknown primary (CUP) is a heterogenous group of malignancies characterized by distant metastases in the absence of detectable primary. Specifics subgroups of CUP that share similarities with cancers of known primary beneficiate from tissue-tailored therapeutic strategies. The objective of this study was to characterize the clinical and biological presentation of a cohort of patients with suspected CUP of renal origin (rCUP) and to evaluate their optimal therapeutic management. Methods: All Patients with rCUP identified prospectively between 2020 and 2023 within the French National Multidisciplinary Tumor Board for CUP were included. Centralized pathological review and immunohistochemical stainings were performed. Whole Exome Sequencing (WES), whole transcriptomic sequencing (RNAseq) and application of the deep-learning based algorithm TransCUPtomics for prediction of tissue of origin, and DNA methylation analysis were performed and compared to public renal cell carcinomas (RCC). Progression Free Survival (PFS) and Overall Survival (OS) were calculated using Kaplan-Meier estimates. Results: 23 patients were included. The median age at diagnosis was 57 yo and 17/23 were male. The most common metastatic sites were the bones (N=17) and the lymph nodes (N=14). 19/23 patients presented with at least two distinct distant metastatic sites. Genomic analyses performed in 10 patients led to the identification of recurrent inactivating mutations in genes commonly altered in RCC, including NF2 (N=7), SETD2 (N=3), or VHL (N=1). 10/11 samples analyzed by RNAseq were predicted as RCC by the TransCUPtomics classifier based on their gene expression profiles. DNA methylation profiling performed in 7 samples showed major similarity with known RCC subtypes.Centralized pathological review and integration of molecular characteristics led to the final diagnoses of papillary RCC (N=2), clear cell RCC (N=7), renal medullary carcinoma (N=1), TFEB-amplified RCC (N=1) and unclassified RCC (N=12). 20/23 patients received at least one line of systemic treatment based on the renal origin, including anti-angiogenic TKI, anti-PD1/PDL1 antibody, anti-CTLA4 antibody or mTOR inhibitor. The median PFS under the first renal-oriented systemic treatment was 5 months and 10 patients remained progression-free for more than 6 months under tailored-treatment. The median OS was 31 months, and 11 patients are still alive in October 2023. Conclusions: This study shows that rCUP represent a new entity within CUPs that shares major similarities with classical RCC despite the more frequent presentation of unfavorable prognostic factors. Prolonged survival can be observed with renal-tailored systemic treatment, supporting the individualization of these patients within CUP. Citation Format: Nicolas Jacquin, Julien Masliah-Planchon, Guillaume Grisay, Ronan Flippot, Riwan Brillet, Célia Dupain, Maud Kamal, Isabelle Guillou, Nadège Gruel, Nicolas Servant, Pierre Gestraud, Jennifer Wong, Vincent Cockenpot, Andreia Goncalves, Janick Selves, Hélène Blons, Etienne Rouleau, Oliver Delattre, Christophe Le Tourneau, Ivan Bièche, Yves Allory, Laurence Albigès, Sarah Watson. Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4627.

Abstract 3853: T cell ferroptosis attenuates antitumor immune responses in sickle cell disease

Abstract Background: Sickle cell disease (SCD) is the most common inherited blood disorder and arises from homozygosity for the HbS mutation (GAG>GTG: βGlu6Val) leading to the production of abnormal hemoglobin that cause sickle shaped red blood cells (RBCs). Individuals with SCD are at higher risk than the general population for developing hematologic malignancies or solid tumors such as renal medullary carcinoma (RMC). Although relatively rare, RMC is one of the most aggressive kidney cancers and is the third most common kidney cancer among children and young adults who harbor sickle hemoglobinopathies such as SCD or sickle cell trait (SCT) which occurs due to heterozygosity for the HbS mutation. Molecular profiling studies have shown that most cases involve biallelic inactivation of the SMARCB1 gene, either through simultaneous hemizygous loss and translocation or by homozygous loss. The loss of SMARCB1 and subsequent dysregulation of chromatin remodeling are key factors contributing to the development and progression of renal medullary carcinoma. Despite manifesting an inflamed tumor immune microenvironment, RMC consistently demonstrates resistance to conventional immune checkpoint inhibitors (ICI). Ameliorating the efficacy of immunotherapy of RMC is vital for research and potential therapeutic interventions by targeting CD8+ T cells. Methods: CyTOF was performed by using the spleen of WT mice and SCD mouse model. mRNA was isolated from CD8+ T cells of Peripheral Blood Mononuclear Cell (PBMC) collected from healthy donors and SCD patients followed by bulk RNA sequencing. Hi-C was conducted using CD8+ T cells isolated from PBMC of healthy donors and SCD patients. We employed DNA FISH (Fluorescence in Situ Hybridization) to examine alterations in gene architecture within CD8+ T cells under varying conditions. Results: RMC tumors exhibit accelerated tumor growth and reduced numbers of tumor resident CD8+ T cells in SCD mice model compared with WT control. CD8+ T cells in the SCD associated tumor microenvironment (TME) are subjected to ferroptosis by downregulation of SLC7A11; however, SMARCB1 loss promotes the resistance of RMC tumor cells to ferroptosis. Genomic architecture of CD8+ T cells is altered under SCD conditions, potentially contributing to immune dysfunction. Conclusions: Our research has identified significant alterations in the 3D genome architecture of CD8+ T cells in individuals with SCD. These alterations lead to transcriptional inhibition of SLC7A11, resulting in CD8+ T cell ferroptosis and a hindered anti-tumor immune response in RMC. These findings elucidate the mechanistic relationship of SCD with ICI resistance in cancers such as RMC and provide novel avenues for therapeutically sensitizing tumors to immunotherapies in individuals with SCD. Keywords: Sickle Cell Disease, Renal Medullary Carcinoma, SMARCB1, Ferroptosis, Genomic Architecture Alteration, Hi-C, SLC7A11 Citation Format: Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Giannicola Genovese, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin. T cell ferroptosis attenuates antitumor immune responses in sickle cell disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3853.

Uveal metastasis arising from thyroid neoplasms: A case study synthesis.

We systematically reviewed the case report literature to identify cases of uveal metastases originating from thyroid cancer (TC), evaluate factors and indications in uveal metastases from TC, and provide clinical insights through recent case studies. Web of Science, Medline, and Scopus databases were searched for case reports or series reporting uveal metastasis from a thyroid neoplasm. Articles published in any language from inception through November 2022 were searched and screened independently by two reviewers. The quality of the included studies was assessed using the JBI Critical Appraisal Checklist for Case Reports. A total of 1049 records were screened, resulting in the identification of 46 cases from 43 studies. The mean (SD) age at uveal metastases diagnosis was 58.44 (±17.99) years with the median (interquartile range) of 56.5 (29.75) (range, 20-83 years), with 34.8% of cases (16/46) cases reported in elderly patients (>64 years). The sample consisted of 56.5% (26/46) male patients. Uveal metastases were observed in the right eye in 16 cases, the left eye in 19 cases, and both eyes in 11 cases. Choroidal involvement was present in 84.8% of cases (39/46) cases. Papillary carcinoma was the most common thyroid cancer type (34.8%, 16/46), followed by follicular carcinoma (32.6%, 15/46), and medullary carcinoma (21.7%, 10/46). Uveal metastases have been observed to appear in metastatic TC, and physicians should approach ocular symptoms cautiously in cases that accompany a neck mass or a history of previous TC.

Molecularly Defined Renal Carcinomas

RCC has witnessed a significant increase in its incidence over the last five decades, ranking as the ninth most common cancer globally. Although survival rates have improved substantially, RCC remains one of the deadliest urological cancers. Traditionally, RCC subtypes were classified based on histopathological features. However, in recent years, there has been a paradigm shift towards molecular and genomic characterization of RCC, leading to the recognition of distinct molecular subtypes. The 2022 World Health Organization (WHO) classification introduced a new category called “molecularly defined renal carcinomas,” encompassing various subtypes, including SMARCB1-deficient medullary carcinoma, ALK-rearranged RCC, FH-deficient RCC, SDH-deficient RCC, ELOC-mutated RCC, TFEB-altered RCC, and TFE3-rearranged RCC. These molecular subgroups have significant consequences for diagnosis, prognosis, and treatment. Molecularly defined RCCs are frequently underrepresented in clinical trials, encouraging additional research to identify beneficial therapeutics. Immune checkpoint inhibitors and tyrosine- kinase inhibitors have shown promising results in some subtypes, while others may benefit from specific inhibitors targeting their molecular drivers. Additionally, these classifications have important prognostic implications, guiding treatment decisions and genetic counseling.

Primary Papillary Colonic Adenocarcinoma With PDGFRA Mutation. A New Morphological Subtype? A Case Report and Review of Literature.

Classic colon carcinomas are defined as adenocarcinomas, characterized by groups of medium/large cells with basophilic and polymorphous nuclei and an eosinophilic elongated cytoplasm, that rearrange on glandular structures. Signs of poor prognosis include high tumor budding, lymphovascular and perineural invasion, poor differentiation, positive margins, and CDX2 loss. Less frequent colon carcinoma subtypes are: mucinous, medullary, signet-ring cell, squamous cell, small cell and undifferentiated carcinoma, among others. In the following case report, we present a 65-year-old woman with a T2N0Mx colon carcinoma with a remarkable papillary and follicular histological appearance. The immunohistochemical stains confirmed an intestinal origin (CDX2+) and excluded a thyroid, gynecological, and urological metastasis, with tumor cells negative for GATA3, PAX8, TTF-1, and thyroglobulin. There was no loss of mismatch repair proteins and p53 showed a wild-type staining. next generation sequencing showed a platelet-derivated growth factor receptor alpha (PDGFRA) mutation. To the best of our knowledge, there have been only two examples of primary papillary colon carcinoma reported in the literature, and neither of them with a PDGFRA mutation. We describe one tumor and discuss its pathological features.

CT features based preoperative predictors of aggressive pathology for clinical T1 solid renal cell carcinoma and the development of nomogram model

BackgroundWe aimed to identify preoperative predictors of aggressive pathology for cT1 solid renal cell carcinoma (RCC) by combining clinical features with qualitative and quantitative CT parameters, and developed a nomogram model.MethodsWe conducted a retrospective study of 776 cT1 solid RCC patients treated with partial nephrectomy (PN) or radical nephrectomy (RN) between 2018 and 2022. All patients underwent four-phase contrast-enhanced CT scans and the CT parameters were obtained by two experienced radiologists using region of interest (ROI). Aggressive pathology was defined as patients with nuclear grade III-IV; upstage to pT3a; type II papillary renal cell carcinoma (pRCC), collecting duct or renal medullary carcinoma, unclassified RCC or sarcomatoid/rhabdoid features. Univariate and multivariate logistic analyses were used to determine significant predictors and develop the nomogram model. To evaluate the accuracy and clinical utility of the nomogram model, we used the receiver operating characteristic (ROC) curve, calibration plot, decision curve analysis (DCA), risk stratification, and subgroup analysis.ResultsOf the 776 cT1 solid RCC patients, 250 (32.2%) had aggressive pathological features. The interclass correlation coefficient (ICC) of CT parameters accessed by two reviewers ranged from 0.758 to 0.982. Logistic regression analyses showed that neutrophil-to-lymphocyte ratio (NLR), distance to the collecting system, CT necrosis, tumor margin irregularity, peritumoral neovascularity, and RER-NP were independent predictive factors associated with aggressive pathology. We built the nomogram model using these significant variables, which had an area under the curve (AUC) of 0.854 in the ROC curve.ConclusionsOur research demonstrated that preoperative four-phase contrast-enhanced CT was critical for predicting aggressive pathology in cT1 solid RCC, and the constructed nomogram was useful in guiding patient treatment and postoperative follow-up.

Breast Cancer Metastasis: Markers and MCDM Models

Breast Cancer, The most common type of disease and related to cancer in women the main cause of death is a major concern. Breast cancer metastasis, rather than the primary tumour, is what kills most people with breast cancer. In 2017, there were over 250,000 new cases of breast cancer found in the country, and roughly 12% of American women will be diagnosed with the disease at some point in their lifetime. Breast cancer may spread to neighbouring lymph nodes and distant organs after developing locally at first. Prognostic indicators are especially utilised to analyse community breast cancer screening and to evaluate systemic disease progression at primary diagnosis. The topic of organ involvement in metastasis and current and new approaches for identifying it are reviewed.The goal of this thesis is to address Scale weights relate to GRA numerals with interval values. The Gray Relational Analysis (GRA) method is an extension of MCDM problems using unknowable information. It simply establishes several optimization models based on the fundamental principle of the conventional GRA approach, the determination of scale weights. Non-specific invasive ductal carcinoma, aggressive lobular cancer, lobular and ductal characteristics, mixed type, Mucinous carcinoma, and Medullary carcinoma taken this alternative in this method and evaluation parameters is lung, pleura, liver, bone, adrenal glands, gastrointestinal tract, skin, brain, pancreas and kidney. Traditional from this analysis Basic idea of GRA method Determines the long-range solution from the short-range and negative-best solution, but the comparison of these distances is not considered significant. As a result, Medullary carcinoma has been ranked first; Similarly, Ladakh is ranked low. This paper showing, Mucinous carcinoma is low affect diseases and Invasive ductal carcinoma, not otherwise specified is most affect in breast cancer.The hypothesis that breast cancers may naturally possess the ability to metastasize is supported by new molecular tools like DNA microarrays. These findings have significant ramifications for metastatic research and prognosis prediction.

P-68 Misdiagnosed calcitonin negative Medullary thyroid carcinoma as Hurthle cell thyroid adenoma with fine needle aspiration biopsy

Abstract Introduction Medullary carcinoma is a rare thyroid carcinoma, that originates from the malignant proliferation of parafollicular C cells. Medullary thyroid cancer produces calcitonin, and elevated calcitonin level is an essential feature of this tumor, so, most of them are associated with high levels of calcitonin. Calcitonin-negative medullary carcinoma of the thyroid gland is an extremely rare entity and poorly understood primary neuroendocrine carcinoma that is characterized by classic medullary carcinoma of the thyroid morphology without raised serum calcitonin levels. Fine needle biopsy (FNAB) is a diagnostic test done in people with suspected thyroid cancer and it is very important for timely diagnosis and treatment of medullar thyroid cancer, especially when calcitonin levels are in normal range. Clinical Case A 35-year-old woman visited an endocrinologist due to swelling on the left side of the neck. Thyroid ultrasound showed hypoechogenic, heterogenous nodule in the left lobe with dimensions 29×28×35 mm and calcifications. Laboratory tests were normal: thyroid stimulating hormone (TSH) 3,0 mlU/ml; free T4 14,3 pmol/l; anti –thyroid peroxidase antibody (ATPO) 20IU/ml; human thyroglobulin 35IU/ml; calcitonin <2 pg/ml; carcinoembryonic acid (CEA) 0.742ng/ml. The FNAB were performed, with cytological finding for classification group I. Four months after the first biopsy, the FNAB was repeated and Hürthle cells were found, with pronounced degenerative changes as well as pronounced cytological atypia, cytological findings correspond to classification group III. Computed tomography of the neck was performed preoperatively and it showed hypodense nodule (slightly smaller than 4 cm) with numerous calcifications, and no significantly enlarged lymph nodes. Left lobectomy was performed with histopathological findings for Medullary thyroid carcinoma. Immunohistochemical tumor cells were positive for chromogranin A, CD56, focally for thyroglobulin and CK 19, and negative for S-100 and NSE. RET gene mutation analysis was performed and it was negative. Additional diagnostic tests were performed for MEN2A and MEN 2B and they were excluded. Postoperative levels of calcitonin and CEA were in normal range. Conclusion Normal calcitonin levels do not exclude medullar carcinoma. Follow-up and monitoring of the patients with thyroid nodules is very important for timely diagnososis and treatment of medullar carcinoma.

Baicalin Promotes Apoptosis of Human Medullary Breast Cancer via the ERK/p38 MAPK Pathway

Objectives The present study aims to examine the effects of baicalin on the human medullary breast carcinoma (MBC) cell line Bcap-37 and to determine whether baicalin regulates Bcap-37 cell apoptosis through the ERK/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Materials and Methods 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Transwell assay were utilized to measure the effects of baicalin on the proliferation and migration ability of Bcap-37 cells, respectively. Flow cytometer analysis was implied to detect the effects of baicalin on Bcap-37 cell apoptosis. Real-time quantitative polymerase chain reaction (RT-PCR) was conducted to observe the influence of baicalin on mRNA expressions of apoptosis-related genes. Western blot was executed to further explore the action of baicalin on apoptosis-related proteins. PD98059 (a specific inhibitor of ERK) and SB203580 (a specific inhibitor of p38 MAPK) were used to further clarify the intrinsic mechanism of baicalin regulating apoptosis in Bcap-37 cells. Results Compared with the control group, baicalin significantly inhibits the proliferation activity of Bcap-37 cells in a concentration- and time-dependent manner, with a p-value < 0.05. The transwell assay indicated that the migration viability of cells decreased further, followed by the increased concentration of baicalin, and the p-value had a statistical difference. Besides, flow cytometry was conducted to assess the effects of baicalin on the early and late apoptosis rates of Bcap-37 cells, and results showed that baicalin highly promoted the apoptosis level both at the early and late stages with a statistical difference in a concentration-dependent manner ( p < 0.05). Results of RT-PCR presented that, compared with the control group, baicalin significantly activated the mRNA expression of Bax, p38, and p-ERK1 and abolished the mRNA expression of Bcl-2 in every dosing group in a concentration-dependent way ( p < 0.05). Western blot exhibited that, compared with the control group, baicalin promoted the protein expression of caspase-3, caspase-9, Bax, p38, P-ERK, and p53 while playing an opposite function to Bcl-2 in each dosing group ( p values have statistical differences). At last, PD98059 and SB203580 were applied to explore the potential mechanism of baicalin in apoptosis promotion. And results revealed that, compared with the group treated with baicalin alone, protein expression of Bax, p38, p-ERK, caspase-3, and caspase-9 was downregulated obviously in the group treated with both baicalin and PD98059 or SB203580 ( p < 0.05). The p53 expression inhibition showed a difference only when compared to the group adding PD98059. Compared with the blank group, a statistical difference was only observed in Bcl-2 expression in the group treated with baicalin in combination with PD98059 or SB203580 ( p < 0.05). Interestingly, a p53 expression difference was only displayed between the blank group and the group treated with baicalin and SB203580 ( p < 0.05). Conclusion Our study observed that baicalin inhibits the proliferation and migration ability of Bcap-37 cells. In addition, baicalin induces cell apoptosis via the ERK/p38 MAPK signal pathway.

Comparative analysis of mammary lump histology and elasto-graphy results at a tertiary hospital

In the majority of India's metropolitan populations, mammary carcinoma has become the commonest type of carcinoma. A non-invasive imaging method called mammary sono-elasto-graphy can reveal information about mammary lesions. Aims & objectives: In the current research, we examined the diagnostic efficacy of elasto-graphy and histopathological findings of mammary lumps. Material and Methods: The current investigation involved Female patients had solid mammary lesions less than 3 cm in size that were visible on sonography. Classified as BI RADS 3 and 4 lesions, these lesions. Results: 252 female patients had U.S.G. elastography, followed by biopsy or surgery, and histopathology reports were available during the research period. Histopathologically, 104 (41.72%) samples were benign, and the remaining 148 (58.73%) were malignant. Age, B.I.R.A.D.S., Elastography Score, and Strain Ratio were all statistically higher in malignant cases than in benign patients (p 0.001). According to Histo-pathological analysis, fibroadenoma (77.03%) accounted for the majority of benign lesions, followed by Abscess (5.41%), sclerosing adenosis (1.35%), benign fibroepithelial lesion (6.76%), and fibrocystic disease (9.46%). Conversely, poorly differentiated invasive carcinoma (5.77%), invasive ductal carcinoma (67.31%), and invasive mucinous carcinoma (13.46%), IL.C. (5.77%), medullary carcinoma (1.92%), papillary carcinoma (1.92%), and phylloid (1.92%) made up the bulk of malignant cases, Excellent results were noticed with the combination of Ultrasound Score + Elastography Score + Strain Ratio, with scores of 96.00%, 96.05%, 96.03%, 94.12%, and 97.33%, respectively, for susceptibility, accuracy, diagnostic accuracy, and N.P.V. and PPV. Conclusion: The ability to distinguish between benign and malignant mammary masses using ultra-sound elasto-graphy, strain elasto-graphy, and ultra-sound score has good susceptibility, accuracy, and diagnostic accuracy.

Comparison of the prognosis of medullary breast carcinoma and invasive ductal carcinoma: a SEER-based study.

Medullary breast carcinoma (MBC) is a rare type of breast cancer. Our study aimed to compare the differences in clinical characteristics and prognosis between MBC and invasive ductal carcinoma (IDC), and to further develop and validate nomograms to predict overall survival (OS) and cancer-specific survival (CSS) in MBC patients. A total of 179,613 patients from the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2015, including 596 MBC patients, were analyzed using the Kaplan-Meier method and propensity score matching (PSM) to compare patients' OS and CSS. Cox proportional hazard regression model was used to determine independent prognostic factors for OS and CSS in MBC patients. Nomograms were constructed based on Cox regression analysis whereas receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the predictive accuracy. There were significant differences in the clinical characteristics between MBC and IDC. According to the logrank test, MBC had better OS and CSS than IDC before and after PSM. Cox multivariate analysis showed that age, race, tumor size, lymph node (LN), and radiation therapy were independent prognostic factors for OS, whereas age, tumor size, American Joint Committee on Cancer (AJCC) stage, laterality, type of surgery, and chemotherapy were independent prognostic factors for CSS. Nomograms of OS and CSS were constructed based on independent prognostic factors. MBC had better OS and CSS than IDC. Nomograms based on clinicopathological features were sufficiently accurate in predicting the OS and CSS for MBC patients, which can effectively predict the survival risk of MBC patients and guide clinicians to provide more effective treatment measures.

Screening for medullary carcinoma in people with thyroid nodules

Screening for medullary carcinoma in people with thyroid nodules

TLR3 agonism augments CD47 inhibition in acute myeloid leukemia.

CD47-SIRPa is a myeloid check point pathway that promotes phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in acute myeloid leukemia (AML), with its blockade leading to cell clearance. ALX90 is an engineered fusion protein with high affinity for CD47. Composed of the N-terminal D1 domain of SIRPα genetically linked to an inactive Fc domain from human immunoglobulin (Ig) G, ALX90 is designed to avoid potential toxicity of CD47-expressing red blood cells. Venetoclax (VEN) is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore apoptosis in malignant cells. In AML, VEN is combined with azanucleosides to induce superior remission rates, however treatment for refractory/relapse is an unmet need. We questioned whether the anti-tumor activity of a VENbased regimen can be augmented through CD47 inhibition (CD47i) in AML and how this triplet may be enhanced. Human AML cell lines were sensitive to ALX90 and its addition increased efficacy of a VEN plus azacitidin (VEN+AZA) regimen in vivo. However, CD47i failed to clear bone marrow tumor burden in PDX models. We hypothesized that the loss of resident macrophages in the bone marrow in AML reduced efficiency of CD47i. Therefore, we attempted to enhance this medullary macrophage population with agonism of TLR3 via polyinosinic:polycytidylic acid (poly(I:C)), which led to expansion and activation of medullary macrophages in in vivo AML PDX models and potentiated CD47i. In summary, the addition of poly(I:C) can enhance medullary macrophage populations to potentiate the phagocytosis merited by therapeutic inhibition of CD47.

The diagnostic performance of microRNAs expression levels in cellular aspirate of solitary thyroid nodule overrides that of cytology

Background: Evaluation of the diagnostic performance of estimated expression levels of microRNAs 203a, 206 and 576 in the cellular aspirate of solitary thyroid nodule (STN) in comparison to cytological examination for identification of malignant TN. Methods: The 74 patients with STN underwent clinical and US evaluation and gave blood samples for estimation of serum levels of thyroglobulin (TG) and anti-thyroglobulin antibodies (ATG). Then, fine-needle aspiration was performed to obtain cellular aspirate for cytological examination and estimation of levels of microRNAs. The appropriate surgical procedure was undertaken and the excised specimens were sent for pathological diagnosis. Results: Pathologically, 19 nodules had papillary thyroid carcinoma (PTC), 6 nodules had follicular carcinoma and one medullary carcinoma, while 48 nodules were benign nodules. Cytological examination diagnosed malignancy in 5 specimens, while specimens were suspicious of malignancy, 25 specimens were diagnosed as benign and 14 specimens as non-diagnostic. Serum levels of TG and ATG were significantly higher with malignancy. Expression levels of miR-203a and 206 were significantly lower, while miR-576 were significantly higher in malignant than benign aspirates. Multivariate regression analysis showed more significant ability for miR-576 level than cytological examination as screening and for miR-203a than miR-206 as diagnostic for malignant aspirate and for PTC Conclusions: Estimation of expression levels of microRNAs in cellular aspirate of STN is feasible and accurate for detection of the malignancy. Down-expression of miR-203a and over-expression of miR-576 in tissue aspirate are more diagnostic for TC and can specify PTC cases out of other TC cases.

Redefining Renal Cell Carcinoma: A Molecular Perspective on Classification and Clinical Implications

Renal cell carcinoma (RCC) is the most common primary tumour of the kidney. RCC is a clinically and pathologically heterogenous entity, which has traditionally been classified under two broad categories: clear-cell and non-clear cell. With improved molecular diagnostic methodologies and genetic testing, the classification of RCC has shifted from a morphological basis to a molecular/genetic focus, and has been systematically updated to reflect these advancements. The new 2022 World Health Organization (WHO) classification of RCC is the most recent of these updates, and contains significant changes, as compared to the previous 2016 classification. The most substantial of these changes is the establishment of a new category of molecularly-defined RCC, including TFE3-rearranged RCC, TFEB-altered RCC, ELOC-mutated RCC, fumarate hydratase-deficient RCC, succinate dehydrogenase-deficient RCC, ALK-rearranged RCC, and SMARCB1-deficient renal medullary carcinoma. In this narrative review, the authors briefly summarise the histopathological characteristics, clinical course, current treatment standards, and future treatment directions of each of these molecularly-defined RCC subtypes.

Carcinoembryonic antigen (CEA) expression in human tumors: A tissue microarray study on 15,413 tumors

Abstract Introduction/Objective Carcinoembryonic antigen (CEA; CEACAM5) is a cell surface glycoprotein which constitutes an attractive therapeutic target and serum CEA is used for cancer monitoring. CEA is overexpressed in various cancers, but the reported prevalence data vary considerably for many tumor types. Methods/Case Report To comprehensively determine CEA expression in normal and neoplastic tissues, a tissue microarray containing 15,413 samples from 120 different tumor types and subtypes as well as 76 different normal tissue types were analyzed by immunohistochemistry. Results (if a Case Study enter NA) CEA positivity occurred in 65 of 120 tumor categories including 49 entities with at least one strongly positive case. CEA positivity was most common in colorectal carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1%-80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), squamous cell carcinomas of various sites (30.2%-69.1%), and small cell carcinomas of the lung (64.3%), the urinary bladder (38.9%), and the prostate (50.0%). High CEA expression was linked to high grade (p<0.0001) and invasive growth (p<0.0001) in urothelial carcinoma. Reduced CEA expression was associated with mismatch repair deficiency (p<0.0001) but not with pT and pN stage in colorectal cancer. Conclusion In summary, CEA is abundantly expressed in a broad range of epithelial neoplasms. Our data thus identify various tumor entities where CEA positive cancers might best benefit from CEA serum monitoring and anti- CEA therapies.

Cystic pheochromocytoma: a rare variant of adrenal gland tumor case report

Abstract Introduction/Objective Pheochromocytoma is the primary adrenal medullary tumor in adults. Patients usually present with sustained or sporadic hypertension. The tumors are almost always solid. Cystic pheochromocytoma (CP) is extremely rare with only a few cases reported in the literature. Patients with CP may be asymptomatic and normotensive and be diagnosed incidentally on imaging or intraoperatively. Methods/Case Report We report a case of an 82-year-old male with a large CP who presented with back pain. The patient was hypertensive preoperatively (140/85 mmHg). Imaging showed a 5.4 cm complex right adrenal mass that could not be further classified. Labs showed markedly increased 24hr urine normetanephrine (1342 ug/24hr). The patient was presumed to have a pheochromocytoma and was preoperatively treated with an alpha-blocker. At surgery an 8.0 cm multiloculated cystic adrenal mass was removed, and grossly the specimen consisted of a brown, multicystic mass filled with brown liquid. Histology revealed the septa to contain nests of polygonal cells with vacuolated to basophilic granular cytoplasm with moderate nuclear pleomorphism . Immunohistochemical staining was positive for synaptophysin, chromogranin and S-100, which confirmed the diagnosis of CP. Patient’s postoperative blood pressure was 130/60 mmHg. Results (if a Case Study enter NA) NA Conclusion Cystic pheochromocytoma has to be in the differential for a retroperitoneal cystic mass in order that clinicians, radiologists as well as pathologists undertake proper patient management and diagnosis.

Gene Transcriptional Profiles of Individuals with HbS Trait Are Different from Individuals without HbS Trait

Background: Although hemoglobin S (HbS) trait has historically been considered a relatively benign condition, emerging data support it is a risk factor for several clinical manifestations such as thrombosis, exertional-related complications, renal medullary cell carcinoma, chronic kidney disease, and osteonecrosis. Data also support HbS trait mice have an intermediary behavioral pain phenotype between control and sickle cell disease (SCD) mice. Despite these emerging data regarding the clinical phenotype associated with HbS trait, little is known about the biology of this condition. To investigate the biology of HbS trait, we analyzed gene expression profiles in healthy individuals with HbS trait and compared these to individuals without HbS trait and individuals with SCD. We hypothesized that those with HbS trait will have gene expression patterns that are different than individuals without HbS trait and those with SCD. Methods: Plasma samples were obtained from individuals with SCD and healthy Black individuals during baseline health. Systematic HbS trait testing was completed for all healthy controls. Plasma-based transcription analyses were conducted. Briefly, gene transcription was assessed in healthy blood donor peripheral blood mononuclear cells (PMBCs) after being co-cultured with participant plasma. PMBCs served as sensors to plasma born factors that induced gene transcription which was then measured with an Affymetrix array. Gene transcription profiles were analyzed to identify differentially expressed transcripts between individuals with SCD at baseline health and healthy controls with and without HbS trait that exhibited a fold change of |Log2R|>0.263, ANOVA p<0.05. Further, differentially expressed transcripts were also assessed between those with and without HbS trait using the same fold change cutoff. Mean gene expression heat maps of these differentially expressed transcripts were created using Genesis for three groups: individuals with SCD, individuals with HbS trait, and individuals without HbS trait. An annotated heat map of differentially expressed genes between those with and without HbS trait was also created. Results: Plasma-induced mean gene expression signatures were obtained from 87 individuals with SCD at baseline health and 52 healthy Black controls; 30 (58%) had documented HbS trait and 22 (42%) did not. Mean age of SCD patients during baseline health was 14.5 (SD 14.2) years, 51.7% were female, and 70.1% had HbSS/HbSβ 0thal. Mean age of Black controls with HbS trait was 28.4 (SD 12.8) years, and 80.6% were female and mean age of those without HbS trait was 20.5 (SD 18.2) years and 70.8% were female. Figure 1 shows the mean plasma-induced gene expression profiles for individuals with SCD at baseline health and healthy Black controls with and without HbS trait. Data show controls with HbS trait have intermediary gene expression patterns between those without HbS trait and those with SCD. We found 43 transcripts were significantly differentially expressed between those with and without HbS trait. Figure 2 displays the annotated heat map of these 43 differentially expressed transcripts. Conclusions: Healthy individuals with HbS trait have transcriptional signatures that are intermediary between those without HbS trait and those with SCD. Further, individuals with and without HbS trait have differentially expressed transcripts suggesting different biological processes in HbS trait may play a role in the pathophysiology of clinical complications in individuals with HbS trait. These findings also underscore the need to account for HbS trait status of healthy controls when including them as a comparison group for individuals with SCD in biological investigations. Further work is needed to understand the biological meaning behind these findings.

International medullary thyroid carcinoma grading system: an Indian tertiary care centre experience.

Medullary carcinoma (MTC) is a rare neuroendocrine thyroid neoplasm. The international medullary thyroid carcinoma grading scheme (IMTCGS), which has prognostic significance, has been introduced recently. The present study graded MTC cases using the IMTCGS and evaluated it in our study cohort. All MTC thyroidectomy cases over 6years were evaluated. Low-grade (LG) and high-grade (HG) were compared. Survival analysis included overall survival (OS), loco-regional free survival and distant metastasis free survival (DMFS). Of 32 cases, 31.25% were HG and 68.75% LG. The mean age was 44.0years and M:F ratio 1:1.146. HG patients were older and had tumour cells with high-grade nuclear features and prominent nucleoli and showed distant metastasis. Necrosis was found more in patients with high grade nuclear features. There was discordance between the high Ki67 (60%) and increased mitotic activity (20%). Univariate survival analysis revealed poor DMFRS and OS in the cohorts with high grade, Ki67 > 5% and coagulative necrosis. The multivariate cox regression analysis showed IMTCGS significantly associated with overall survival (HR 28.30, p = 0.009) and DMFS (HR 15.70, p = 0.02). This is the first Indian study evaluating IMTCGS, a very simple and convenient grading system that can be readily used in any tertiary health care centre. IHC for Ki 67 should mandatorily be done irrespective of the low mitotic activity on the HPE and necrosis should be diligently searched in cases with high-grade nuclear morphology. HG MTC cohorts were associated with poor OS as well as DMFRS.