The novel SARS-CoV-2 Omicron variant may increase the risk of re-infection and vaccine breakthrough infections as it possesses key mutations in the spike protein that affect neutralizing antibody ...response. Most studies on neutralization susceptibility were conducted using specimens from adult COVID-19 patients or vaccine recipients. However, since the paediatric population has an antibody response to SARS-CoV-2 infection that is distinct from the adult population, it is critical to assess the neutralization susceptibility of pediatric serum specimens. This study compared the neutralization susceptibility of serum specimens collected from 49 individuals of <18 years old, including 34 adolescent BNT162b2 (Pfizer-BioNTech) vaccine recipients, and 15 recovered COVID-19 patients aged between 2 and 17. We demonstrated that only 38.2% of BNT162b2 vaccine recipients and 26.7% of recovered COVID-19 patients had their serum neutralization titre at or above the detection threshold in our live virus microneutralization assay. Furthermore, the neutralizing antibody titer against the Omicron variant was substantially lower than those against the ancestral virus or the Beta variant. Our results suggest that vaccine recipients and COVID-19 patients in the pediatric age group will likely be more susceptible to vaccine breakthrough infections or reinfections due to the Omicron variant than previous variants.
Neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm is a recently described soft tissue tumor entity that occurs predominantly in children and young adults. The diagnosis of ...this tumor is difficult due to the nonspecific and highly variable morphology, yet it is of clinical relevance because of the availability of highly effective TRK inhibitors. In this article, we report the case of a 40-year-old female who presented with a mass in the left calf. Histologic examination revealed a low-grade sarcoma consisting of monomorphic spindle cells accompanied by abundant myxoid stroma, a feature that had not been emphasized in the reported cases of NTRK-rearranged tumors. The tumor cells expressed CD34 and S100 but not SOX10, and they showed positive staining for pan-TRK. Next-generation sequencing showed the presence of LMNA-NTRK1 fusion. The patient developed several episodes of lung metastases that eventually became unresectable. TRK inhibitor was given that led to near-complete resolution of the tumors.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Purpose
SETD2
is one of the key epigenetic regulatory genes involved in histone modifications. Its alterations were potentially oncogenic and commonly found in cancers. Interestingly, SETD2 is one of ...the most frequent mutated genes found exclusively in phyllodes tumor of the breast (PT). However, little has been done to further characterize
SETD2
alterations in PT.
Methods
In this study, we examined the alterations of
SETD2
gene and protein expression in a large cohort of PTs. Their correlations with SETD2 downstream target, H3K36me3 expression, and clinicopathologic features in PT were also assessed.
Results
SETD2
mutation was found in 15.9% of our cases and was mostly predicted to be damaging mutations. Interestingly,
SETD2
mutations were associated with lower H3K36me3 expression, particularly those with damaging mutations (
p
= .041). Neither SETD2 mutations nor H3K36me3 expression was associated with PT grading and other clinicopathological features. By contrast, the SETD2 protein expression cannot reflect its mutation status and showed a different trend of clinicopathological correlations from H3K36me3.
Conclusions
Our findings may suggest a potential involvement of epigenetic regulation via
SETD2
alterations and downstream H3K36me3 on PT development.
SETD2
mutations may occur early in the pathogenic process of PTs and its loss per se may not be sufficient for progression to malignancy. Exclusive alterations of
SETD2
in PT can be used as markers for the diagnosis of fibroepithelial lesions. The association of H3K36me3 with SETD2 mutations may also indicate the value of evaluation of H3K36me3 expression in the diagnosis of fibroepithelial lesions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Undifferentiated mesenchymal neoplasms can be morphologically subclassified based on cell shape; epithelioid tumors may be diagnostically challenging, particularly since they can show morphologic and ...immunohistochemical overlap with epithelial neoplasms. Following the recent report of an NR1D1::MAML1 gene fusion in an undifferentiated pediatric neoplasm, we performed a retrospective archival review and identified four additional cases of undifferentiated mesenchymal neoplasms with NR1D1‐rearrangement. All four tumors occurred in adult women. The tumors involved superficial and/or deep soft tissues of the extremities or abdomen. Morphologically, they showed a spectrum of overlapping features. In addition to epithelioid cells, two cases also had a prominent spindle cell component. Two cases also had admixed polygonal cells containing prominent cytoplasmic vacuoles with amorphous debris. The immunophenotype was nonspecific but all cases had at least focal keratin expression; this was extensive in two tumors. Targeted RNA‐sequencing revealed two cases each with NR1D1::MAML1 and NR1D1::MAML2 gene fusions. One patient developed lung and liver metastases, and one patient required amputation due to multifocal disease and underlying bone involvement. This study confirms undifferentiated NR1D1‐rearranged sarcoma represents a distinct mesenchymal neoplasm with an epithelioid morphology and potential for aggressive behavior. Further, we offer new insight into the spectrum of clinical, morphologic, immunohistochemical, and molecular findings possible in these rare neoplasms. An awareness of this entity is especially important given the potential for misclassification as a carcinoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Spindle cell/sclerosing rbabdomyosarcoma (RMS) is a recently characterized variant of RMS with several distinct molecular subtypes. We describe an example occurring in the tongue of a 10-year-old boy ...with a novel
DCTN1::ALK
fusion. The tumor exhibited infiltrative growth and was comprised of fascicles and focally whorls of spindle cells with eosinophilic cytoplasm, in a collagenous or myxoid stroma. Moderate cytologic atypia, mitotic activity (2/10 HPFs), and perineural invasion were identified. The tumor cells expressed actin, desmin, MyoD1, myogenin, and ALK. An in-frame fusion between
DCTN1
exon 26 and
ALK
exon 20 was detected by RNA sequencing, which was confirmed by split reads and supported by FISH studies. The tumor showed an indolent behavior with local recurrence 3 years after excision. This study broadens the molecular spectrum of spindle cell/sclerosing RMS and this molecular aberration may represent a potential therapeutic target for unresectable or disseminated disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Nasopharyngeal carcinoma (NPC) is a peculiar Epstein Barr virus (EBV)-associated malignancy that is prevalent in South-East Asia. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) ...isomerizes specific phosphorylated amino acid residues, which makes it an important regulator in cell survival and apoptosis. In this study, we investigated the contribution made by PIN1 in NPC tumorigenesis and PIN1's potential role as a therapeutic target.
The expression of PIN1 was examined in a panel of NPC cell lines, xenografts and primary tumors. The functional roles of PIN1 in NPC cells were elucidated by the knockdown and overexpression of PIN1 in in vitro and in vivo nude mice models by siRNA and lenti-viral transfection, respectively. The antitumor effects of the PIN1 inhibitor Juglone in NPC cells were also evaluated.
We revealed the consistent overexpression of PIN1 in almost all EBV-associated NPC cell lines, xenografts and primary tumors. PIN1 suppression was capable of inhibiting cyclin D1 expression and activating caspase-3 in NPC cells. It positively regulated NPC cell proliferation, colony formation and anchorage-independent growth. The inhibition of PIN1 suppressed tumor growth in vitro and in vivo.
This study demonstrates the oncogenic role of PIN1 in NPC tumorigenesis, and shows that its overexpression can enhance tumor cell growth via the upregulation of cyclinD1. Our findings inform the development of novel treatments targeting PIN1 for NPC patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Fibroblastic/myofibroblastic neoplasms represent a broad, and occasionally diagnostically challenging, category of soft tissue neoplasms. A subset of these tumors defy conventional ...classification. However, with the advent of next‐generation sequencing, the identification of disease‐defining molecular alterations is gradually improving their subclassification. Following identification of two index cases of a distinctive fibroblastic neoplasm with a fusion gene involving PRRX1 and NCOA1, we performed a retrospective review to further characterize this entity. We identified two additional cases, including one with a fusion between PRRX1 and NCOA2. The average patient age was 38 years, and three patients were female. Two tumors occurred on the neck, and the others involved the groin and thigh. Tumors were centered in the subcutis and ranged from 2.3 to 14.0 cm (average 5.8 cm). Morphologically, they were predominantly hypocellular, with focal hypercellularity. They were composed of monomorphic spindle‐stellate cells with a vague fascicular pattern. The nuclei were bland with only rare mitotic activity, and occasional multinucleation. The intervening stroma was typically abundant and ranged from myxoid to collagenous, with frequent rope‐like collagen bundles. Three of the cases had a prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn‐like vessels. Immunohistochemistry was negative for desmin, smooth muscle actin, S100, CD34, keratin, and epithelial membrane antigen. Each of the patients was treated by simple excision and none of the tumors were associated with local recurrence or metastasis. Based on their unique morphological and molecular attributes, we believe this represents a novel fibroblastic tumor for which we have tentatively proposed the name “PRRX‐NCOAx‐rearranged fibroblastic tumor.”
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Patients with pulmonary large-cell carcinoma (LCC) have poor prognosis and limited treatment options. The identification of clinically actionable molecular alterations helps to guide personalized ...cancer treatment decisions.
A consecutive cohort of 789 resected NSCLC cases were reviewed. Fifty-nine NSCLC cases lacking morphologic differentiation, accounting for 7.5% of all resected NSCLCs, were identified and further characterized by immunohistochemistry according to the 2015 WHO lung tumor classification. Molecular alterations were investigated by multiple technologies including target capture sequencing, immunohistochemistry, and fluorescence in situ hybridizations.
Of 59 NSCLC cases lacking morphologic differentiation, 20 (33.9%) were reclassified as adenocarcinoma (LCC-AD), 14 (23.7%) as squamous cell carcinoma (LCC-SqCC), and 25 (42.4%) as LCC-Null. Approximately 92% of LCC-Null, 95% of LCC-AD, and 86% of LCC-SqCC harbored clinically relevant alterations. Alterations characteristic of adenocarcinoma (EGFR, KRAS, ALK receptor tyrosine kinase ALK, ROS1, and serine/threonine kinase 11 STK11) were detected in the LCC-AD subgroup but not in LCC-SqCC, whereas squamous-lineage alterations (phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha PIK3CA, SRY-box 2 SOX2, fibroblast growth factor receptor 1 FGFR1, and AKT1) were detected in the LCC-SqCC subgroup but not in the LCC-AD group. Although some LCC-Null tumors displayed a genetic profile similar to either adenocarcinoma or squamous-cell carcinoma, more than half of the LCC-Null group were completely devoid of recognizable lineage-specific genetic profiles. High programmed death ligand 1 expression and high frequency of cell cycle regulatory gene alterations were found in the LCC-Null group offering alternative options of targeted therapy.
This comprehensive molecular study provided further insight into the genetic architecture of LCC. The presence of clinically actionable alterations in a majority of the tumors allowed personalized treatment to emerge.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Key Clinical Message
When faced with a slowly enlarging firm mass in the parotid gland accompanied by a histological picture of unusual sclerosis with abundant Langerhans cells and eosinophilic ...infiltrates, sclerosing mucoepidermoid carcinoma with eosinophilia should be considered as one of the differential diagnoses. Further studies are warranted for accurate diagnosis and appropriate treatment.
Sclerosing mucoepidermoid carcinoma of the salivary gland with eosinophilia is a rare tumor mostly negative for the MAML2 rearrangement commonly seen in salivary mucoepidermoid carcinoma. It was not listed as an entity in the 2022 WHO Classification of Head and Neck Tumors. We presented one case initially diagnosed as Langerhans cell histiocytosis and recurred as a frankly invasive carcinoma. Molecular studies showed CSF1 gene derangement and provided new understanding concerning the Langerhans cell and eosinophilic reaction. Further molecular studies on this entity would throw light on its oncogenesis and refine its nomenclature.
Sclerosing mucoepidermoid carcinoma with eosinophilia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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