The microtubule targeting agent ST-401 triggers cell death in interphase and prevents the formation of polyploid giant cancer cells.

Microtubule targeting agents (MTAs) are commonly prescribed to treat cancers and predominantly kill cancer cells in mitosis. Significantly, some MTA-treated cancer cells escape death in mitosis, exit mitosis and become malignant polyploid giant cancer cells (PGCC). Considering the low number of cancer cells undergoing mitosis in tumor tissues, killing them in interphase may represent a favored antitumor approach. We discovered that ST-401, a mild inhibitor of microtubule (MT) assembly, preferentially kills cancer cells in interphase as opposed to mitosis, a cell death mechanism that avoids the development of PGCC. Single cell RNA sequencing identified mRNA transcripts regulated by ST-401, including mRNAs involved in ribosome and mitochondrial functions. Accordingly, ST-401 induces a transient integrated stress response, reduces energy metabolism, and promotes mitochondria fission. This cell response may underly death in interphase and avoid the development of PGCC. Considering that ST-401 is a brain-penetrant MTA, we validated these results in glioblastoma cell lines and found that ST-401 also reduces energy metabolism and promotes mitochondria fission in GBM sensitive lines. Thus, brain-penetrant mild inhibitors of MT assembly, such as ST-401, that induce death in interphase through a previously unanticipated antitumor mechanism represent a potentially transformative new class of therapeutics for the treatment of GBM.

Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas: Molecular Genetic Analysis of 13 Cases.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare malignancy regarded as a subvariant of pancreatic ductal carcinoma (PDAC) characterized by variable prognosis. UCOGC shows a strikingly similar spectrum of oncogenic DNA mutations to PDAC. In the current work, we analyzed the landscape of somatic mutations in a set of 13 UCOGC cases via next-generation sequencing (NGS). We detected a spectrum of pathogenic or likely pathogenic mutations similar to those observed in PDAC following previously published results (10 KRAS, 9 TP53, 4 CDKN2A, and 1 SMAD4, CIC, GNAS, APC, ATM, NF1, FBXW7, ATR, and FGFR3). Our results support the theory that UCOGC is a variant of PDAC, despite its unique morphology; however, a UCOGC-specific genomic signature as well as predictive markers remain mainly unknown. Programmed death ligand 1 (PD-L1) status remains an important predictive marker based on previous studies.

Evaluation of the relationship between the expression of AgNOR and Ki67 with the recurrence rate in central granulomatous giant cell lesions: A case-control.

OBJECTIVES: Giant cell granuloma is a local nonneoplastic lesion that is divided into two categories, based on its site of occurrence: Central and peripheral giant cell granuloma. Central giant cell granuloma is an intraosseous lesion that has a tendency to recure even in surgically treated cases. Several studies have proven that there is an association between different lesions clinical behavior and their histological features. The aim of this study was to evaluate the expression of AgNOR and Ki67 in lesions with and without recurrency. MATERIAL AND METHODS: Files and records of 35 patients who had been histologically diagnosed with central giant cell granuloma were investigated. Histological features were studied after performing AgNOR staining and Ki67 marker. The data were analyzed by chi-square, Fisher, and T-test. RESULTS: Acquired data indicated that the count of AgNOR staining and Ki67 marker was significantly higher in lesions with recurrency than the lesions with no recurrency. The same results were attained from Ki67 intensity. CONCLUSION: The current study indicated that AgNOR staining and Ki67 marker have prognostic value in predicting recurrency of central giant cell granuloma lesions.

Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization.

Polyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that the sphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role in depolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking the expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization.

Unraveling the Uncommon: A Case Report of Giant Cell Myocarditis and Examination of Existing Literature.

BACKGROUND Idiopathic giant cell myocarditis (IGCM) is an uncommon and frequently fatal type of myocarditis. It primarily affects young individuals and has the potential to result in heart failure and life-threatening arrhythmias. IGCM seems to be dependent on activation of CD4-positive T lymphocytes and can show improvement with treatment aimed at reducing T-cell function. We present a case of a 65-year-old patient who presented with features of acute heart failure refractory to guideline-directed medical therapy (GDMT), due to IGCM. A review of the natural history and treatment of IGCM is also presented. CASE REPORT A 65-year-old woman with multiple comorbidities was admitted to our hospital for ventricular tachycardia in the setting of progressive non-ischemic heart failure, unresponsive to GDMT. This led to further investigation, including an endomyocardial biopsy, which revealed inflammatory infiltration, with multinucleated giant cells and lymphocytes in the absence of granuloma formation, prompting a diagnosis of IGCM. An implantable cardioverter-defibrillator (ICD) was placed for secondary prevention of sudden cardiac death and the patient was initiated on combined immunosuppressive therapy. Owing to numerous comorbidities, she was determined to be unsuitable for a heart transplant. Unfortunately, she eventually died from complications secondary to the disease. CONCLUSIONS IGCM remains a challenging clinical diagnosis with a poor long-term outcome without heart transplantation. This case highlights the importance of considering atypical causes of heart failure in patients who do not respond to conventional therapies. Early recognition and appropriate management, involving medical and interventional approaches, are crucial in improving outcomes for patients with IGCM.

Giant cell angiofibroma of gingiva in tuberous sclerosis complex: a case report and literature review.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare, complex genetic disorder characterized by hamartomas and neoplastic lesions in various organ systems. With the development of radiology and gene testing, the diagnostic criteria for TSC were updated in 2012 at the International Consensus Conference. Intraoral fibromas have long been associated with TSC. However, the incidence of giant cell angiofibroma (GCA) in TSC patients is extremely rare. Here, we report the first case of GCA in the gingival tissue of a patient with TSC. CASE PRESENTATION: A 41-year-old woman first visited the Department of Oral and Maxillofacial Surgery, Chonnam National University Dental Hospital, complaining of gingival enlargement. Clinical examination revealed several manifestations associated with TSC, including intraoral fibromas, facial angiofibromas, dental enamel pits, ungual fibromas, "confetti" skin lesions, hypomelanotic macules, and a shagreen patch. Intraoral examination revealed a 6.0 × 5.0 cm gingival overgrowth on the left mandible. Surgical excision was performed, and subsequent histopathological examination confirmed the diagnosis of GCA. There was no evidence of recurrence within the 24- months of surgery. CONCLUSIONS: We report the first case of GCA in the gingival tissue of a patient with TSC. This report would contribute to an improved understanding of this rare disease. However, further case reports are necessary to clarify the relationship between GCA and TSC.

Giant cell collagenomas associated with Cowden syndrome: A case report.

Storiform collagenoma, also known as sclerotic fibroma, is a relatively rare benign cutaneous tumor consisting of a proliferation of fibroblasts that shows increased production of type I collagen. It may appear as a solitary, sporadic lesion, or, especially when multiple, associated with Cowden syndrome. Giant cell collagenoma has a histopathologic appearance similar to that of storiform collagenoma with the addition of floret-type giant cells. Herein, we report the finding of multiple giant cell collagenomas arising in an individual with Cowden syndrome. In a review of the published literature, this histopathologic variant appears to be rarely observed in association with Cowden syndrome.

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis.

Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.

Elastofibromatous changes in giant cell fibroma and amalgam tattoo: Unusual findings in common oral lesions.

Several cases of elastofibromatous lesion affecting the oral mucosa have been reported. Clinically, these lesions may appear as small exophytic lesions or less often as white lesions. Therefore, fibrous hyperplasia and leukoplakia are not uncommonly considered in clinical differential diagnosis. Microscopically, elastic and fibrous connective tissue deposition is seen. Rarely, elastofibromatous changes can be detected when assessing intraoral lesions, including cysts, salivary gland neoplasms, and epithelial dysplasia. Here we report two oral lesions showing elastofibromatous changes, expanding their clinicopathological spectrum. The first case was a 46-year-old man with a history of asymptomatic nodular lesion on the palate 1 year ago, diagnosed as giant cell fibroma with elastofibromatous changes. The second case was a 79-year-old woman who presented a pigmented and mildly symptomatic lesion on the mandibular alveolar mucosa several months ago, diagnosed as amalgam tattoo associated with elastofibromatous changes.

A case of spindle and giant cell-type undifferentiated carcinoma of the extrahepatic bile duct.

Spindle and giant cell type undifferentiated carcinoma of the extrahepatic bile duct is an uncommon malignancy. We report a case involving the common bile duct in a 72-year-old male with jaundice who was admitted to our hospital. Diagnostic imaging, including abdominal computed tomography and magnetic resonance imaging, revealed a mass in the distal common bile duct, accompanied by dilatation of both intra- and extrahepatic bile ducts and regional lymph node enlargement. Endoscopic retrograde cholangiography demonstrated stenosis in the distal common bile duct, with a biopsy confirming adenocarcinoma. The patient underwent endoscopic retrograde biliary drainage followed by a subtotal stomach-preserving pancreaticoduodenectomy with regional lymphadenectomy. Microscopic examination revealed that the tumor predominantly comprised spindle and giant atypical cells within the stroma. Immunohistochemical analysis showed the tumor cells expressing cytokeratins and mesenchymal markers, confirming the diagnosis of spindle and giant cell type undifferentiated carcinoma of the common bile duct. Ki-67 labeling index was observed to be above 80%. Postoperatively, intra-abdominal lymph node recurrence was noted at two months, and multiple liver metastases were identified at three months. The patient died seven months post-surgery. The literature pertaining to this rare disease is reviewed and discussed.

Giant cell myocarditis with prolonged cardiac standstill after drug-induced hypersensitivity syndrome: a case report.

Giant cell myocarditis (GCM) is a rare but fatal disease that can lead to cardiac failure. Survival with a cardiac standstill requires mechanical circulatory support or a biventricular assist device (BiVAD) and prolonged survival is extremely rare. Drug-induced hypersensitivity syndrome (DIHS) is a severe cutaneous adverse reaction. Some cases of DIHS are reportedly associated with the onset of GCM. We present a case of a 28-year-old woman who developed GCM during steroid tapering after DIHS. She went into continuous cardiac standstill but survived for 74 days under BiVAD support. Our case is noteworthy because the histopathologic specimens obtained on three occasions contributed to the diagnosis of this particular condition over time. We also reviewed previous literature on concomitant cases of GCM and DIHS. We found that two are potentially associated and most cases of GCM occur within 3 months of DIHS during steroid tapering.

Quercetin inhibits SARS-CoV-2 infection and prevents syncytium formation by cells co-expressing the viral spike protein and human ACE2.

BACKGROUND: Several in silico studies have determined that quercetin, a plant flavonol, could bind with strong affinity and low free energy to SARS-CoV-2 proteins involved in viral entry and replication, suggesting it could block infection of human cells by the virus. In the present study, we examined the ex vivo ability of quercetin to inhibit of SARS-CoV-2 replication and explored the mechanisms of this inhibition. METHODS: Green monkey kidney Vero E6 cells and in human colon carcinoma Caco-2 cells were infected with SARS-CoV-2 and incubated in presence of quercetin; the amount of replicated viral RNA was measured in spent media by RT-qPCR. Since the formation of syncytia is a mechanism of SARS-CoV-2 propagation, a syncytialization model was set up using human embryonic kidney HEK293 co-expressing SARS-CoV-2 Spike (S) protein and human angiotensin converting enzyme 2 (ACE2), [HEK293(S + ACE2) cells], to assess the effect of quercetin on this cytopathic event by microscopic imaging and protein immunoblotting. RESULTS: Quercetin inhibited SARS-CoV-2 replication in Vero E6 cells and Caco-2 cells in a concentration-dependent manner with a half inhibitory concentration (IC50) of 166.6 and 145.2 µM, respectively. It also inhibited syncytialization of HEK293(S + ACE2) cells with an IC50 of 156.7 µM. Spike and ACE2 co-expression was associated with decreased expression, increased proteolytic processing of the S protein, and diminished production of the fusogenic S2' fragment of S. Furin, a proposed protease for this processing, was inhibited by quercetin in vitro with an IC50 of 116 µM. CONCLUSION: These findings suggest that at low 3-digit micromolar concentrations of quercetin could impair SARS-CoV-2 infection of human cells partly by blocking the fusion process that promotes its propagation.

Clear cell renal cell carcinoma with syncytial giant cells: Not that rare.

Syncytial giant cells (SGCs) are neoplastic giant cells of epithelial origin. The nuclear morphology of SGCs is uniform and similar to those of adjacent mononuclear tumor cells. Clear cell renal cell carcinoma (ccRCC) with SGCs is a rare microscopic morphology. In this study, the clinical and pathological data of 16 ccRCC cases with SGCs were retrospectively reviewed. The incidence of SGCs in pathological stages pT3 and above (12.1%, 8/66) was significantly higher than that in pT1 and pT2 (2.6%, 8/306) (P = 0.002). The incidence of SGCs in the WHO/ISUP nuclear grade 3 or 4 ccRCC (12.4%, 14/113) was significantly higher than that in grade 1 or 2 (0.8%, 2/259) (P < 0.001). Two forms of SGCs were observed, some exhibited nuclear pyknosis and degeneration. Of the 16 cases, eight cases were accompanied by necrosis and seven cases had lymphovascular invasion. Both SGCs and mononuclear tumor cells were positive for ccRCC markers (PAX8, CAIX, CD10 and Vimentin). None of the SGC nuclei were positive for Ki-67. Follow-up information was available on 14 patients, with a median follow-up time of 27.5 months. Ten patients were alive without disease, three were alive with metastatic disease, and one patient died 10 months after surgery. These findings indicated that SGCs are not rare, especially in ccRCC with high nuclear grade and pathological stage, and often co-exist with other adverse prognostic features. SGCs may be senescent tumor cells, the presence of SGCs should not be considered as Fuhrman and WHO/ISUP nuclear grading 4.

Xanthogranulomatous Epithelial Tumors and Keratin-Positive Giant Cell Rich Tumors of Soft Tissue and Bone: Two Sides of the Same Coin.

Xanthogranulomatous epithelial tumor is a recently described soft tissue tumor characterized by subcutaneous location, partial encapsulation, a xanthogranulomatous inflammatory cell infiltrate, and keratin-positive mononuclear cells. It shares some morphologic features with keratin-positive, giant cell-rich soft tissue tumors. Both have recently been shown to harbor HMGA2::NCOR2 fusions. The relationship between these tumors and their differential diagnosis with other osteoclast-containing soft tissue tumors is discussed.

Keratin-Positive Giant Cell-Rich Tumor of Bone Harboring an HMGA2::NCOR2 Fusion: Two Cases, Including a Patient With Metastatic Disease, and Review of the Literature.

Giant cell-rich lesions of bone represent a heterogeneous group of entities which classically include giant cell tumor of bone, aneurysmal bone cyst, nonossifying fibroma, and Brown tumor of hyperparathyroidism. A recently described subset of giant cell-rich tumors involving bone and soft tissue has been characterized by recurrent HMGA2::NCOR2 fusions and keratin expression. The overlapping clinical, radiographic, and morphological features of these giant cell-rich lesions provide a unique diagnostic challenge, particularly on biopsy. We present 2 additional cases of keratin-positive giant cell-rich tumor of bone with HMGA2::NCOR2 fusions, including 1 patient who developed metastatic disease.

A unique case of lymphoepithelioma-like HCC with osteoclast-like giant cells: CT imaging features with pathologic correlations.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, with several histological variants being reported in literature. Hereby, we describe a case of a 77-year-old man with chronic liver disease referred to our department for performing a computed tomography (CT) due to a liver mass discovered at an abdominal ultrasound follow-up. At CT, a large, ill-defined lesion in the third hepatic segment was detected, characterized by progressive and delayed enhancement with minimal retraction of the hepatic capsule, associated with perihepatic adipose tissue inhomogeneity, mimicking a cholangiocarcinoma. At histopathological evaluation, the lesion turned out to be an HCC with lymphoepithelioma-like component and osteoclastic-like giant cells. This report focuses on the clinicopathological and radiological features of this unique case.

CSF1 expression in xanthogranulomatous epithelial tumor/keratin-positive giant cell-rich tumor.

"Xanthogranulomatous epithelial tumor" (XGET) and "keratin-positive giant cell-rich soft tissue tumor" (KPGCT), two recently described mesenchymal neoplasms, likely represent different aspects of a single entity. Both tumors are composed of only a small minority of tumor cells surrounded by large numbers of non-neoplastic inflammatory cells and histiocytes, suggesting production of a paracrine factor with resulting "landscape effect," as seen in tenosynovial giant cell tumor. Recent evidence suggests that the paracrine factor in XGET/KPGCT may be CSF1, as in tenosynovial giant cell tumor. We hypothesized that CSF1 is overexpressed in XGET/KPGCT. To test our hypothesis, we performed quantitative real time PCR (qPCR) for CSF1 expression and CSF1 RNAscope chromogenic in situ hybridization (CISH) on 6 cases of XGET/KPGCT. All cases were positive with CSF1 CISH and showed increased expression of CSF1 by qPCR. Our findings provide additional evidence that the CSF1/CSF1R pathway is involved in the pathogenesis of XGET/KPGCT. These findings suggest a possible role for CSF1R inhibition in the treatment of unresectable or metastatic XGET/KPGCT.

High-throughput screening of genetic and cellular drivers of syncytium formation induced by the spike protein of SARS-CoV-2.

Mapping mutations and discovering cellular determinants that cause the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to induce infected cells to form syncytia would facilitate the development of strategies for blocking the formation of such cell-cell fusion. Here we describe high-throughput screening methods based on droplet microfluidics and the size-exclusion selection of syncytia, coupled with large-scale mutagenesis and genome-wide knockout screening via clustered regularly interspaced short palindromic repeats (CRISPR), for the large-scale identification of determinants of cell-cell fusion. We used the methods to perform deep mutational scans in spike-presenting cells to pinpoint mutable syncytium-enhancing substitutions in two regions of the spike protein (the fusion peptide proximal region and the furin-cleavage site). We also used a genome-wide CRISPR screen in cells expressing the receptor angiotensin-converting enzyme 2 to identify inhibitors of clathrin-mediated endocytosis that impede syncytium formation, which we validated in hamsters infected with SARS-CoV-2. Finding genetic and cellular determinants of the formation of syncytia may reveal insights into the physiological and pathological consequences of cell-cell fusion.