BACKGROUND: Crizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS).
METHODS: We searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib.
RESULTS: Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate).
CONCLUSIONS: The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

BACKGROUND: Methylation analysis has become a powerful diagnostic tool in modern neurooncology. This technique is valuable to diagnose new brain tumor types.
OBJECTIVE: To describe the MRI and histological pattern of neuroepithelial tumor with PLAGL1 gene fusion.
METHODS: We present a 6-year-old patient with small right frontal intraaxial tumor causing drug resistant epilepsy. Despite indolent preoperative clinical course and MRI features suggesting glioneuronal tumor, histological evaluation revealed characteristics of high-grade glioma, ependymoma and neuroblastoma.
RESULTS: Methylation analysis of tumor DNA confirmed a new type of a recently discovered neoplasm - neuroepithelial tumor with PLAGL1 fusion (NET PLAGL1). PCR confirmed fusion of PLAGL1 and EWSR1 genes. No seizures were observed throughout the follow-up period. There was no tumor relapse a year after surgery.
CONCLUSIONS: Methylation analysis in neurooncology is essential for unclear tumor morphology or divergence between histological and clinical data. In our case, this technique confirmed benign nature of tumor, and we preferred follow-up without unnecessary adjuvant treatment.
Определение метиляционного профиля генома опухоли становится значимым способом диагностики новообразований центральной нервной системы. На основании этой методики также возможно выявлять новые классы опухолей головного мозга.
UNASSIGNED: Описать результаты магнитно-резонансной томографии (МРТ) и гистологическую картину нейроэпителиальной опухоли со слиянием гена PLAGL1.
UNASSIGNED: Представлено клиническое наблюдение ребенка 6 лет с внутримозговой опухолью лобной доли и фармакорезистентной эпилепсией. По рентгенологическим характеристикам, до операции предполагалась доброкачественная глионейрональная опухоль, однако гистология соответствовала новообразованию, имевшему черты злокачественной глиомы, эпендимомы и нейробластомы.
UNASSIGNED: Проведен метиляционный анализ ткани опухоли, показавший, что она относится к недавно описанному новому классу — «нейроэпителиальная опухоль со слиянием гена PLAGL1». Тест полимеразной цепной реакции подтвердил слияние генов PLAGL1 и EWSR1. После операции отмечено прекращение приступов, спустя 1 год на МРТ рецидива опухоли не определялось.
UNASSIGNED: Метиляционный анализ в нейроонкологии играет решающую роль в случаях неоднозначной морфологии опухоли, расхождения ее гистологической и клинико-рентгенологической картины. В приведенном клиническом примере стало возможным доказать доброкачественный характер опухоли и выбрать выжидательную тактику, избежав адъювантного лечения у ребенка.

ALK-fused Spitz melanocytic neoplasms are a distinct subgroup of melanocytic lesions exhibiting unique histopathologic characteristics. These lesions often manifest as exophytic or polypoid tumors, characterized by fusiform-to-epithelioid melanocytes arranged in a nested, fascicular, or plexiform growth pattern. Several fusion partners of the ALK gene have been identified in spitzoid melanocytic neoplasms, with TPM3 and DCTN1 being the most prevalent. Less common fusion partners include NPM1, TPR, CLIP1, GTF3C2, EEF2, MYO5A, KANK1, and EHBP1. The MLPH gene, which encodes melanophilin (MLPH), playing a crucial role in regulating skin pigmentation by acting as a linker between RAB27A and myosin Va during melanosome transport, has also recently been recognized as a rare fusion partner of ALK in Spitz melanocytic neoplasms. Currently, there exists a sparse documentation within English literature, illustrating a limited number of cases featuring MLPH::ALK fusion in Spitz melanocytic neoplasms. In this report, we present two additional cases, including a previously unreported instance of Spitz melanoma, contributing to the expanding knowledge on ALK-fused Spitz melanocytic neoplasms. In addition, we provide a comprehensive review of the clinical, histopathologic, and molecular features observed in documented cases with this novel fusion.

Calcified chondroid mesenchymal neoplasm is a recently recognized bone and soft tissue entity primarily found in the extremities and the temporomandibular joint. This neoplasm is typically driven by the fusion of the FN1 gene with a kinase. In this case report, we provide a detailed account of a rare superficial calcified chondroid mesenchymal neoplasm located on the left big toe, characterized by an FN1::FGFR2 fusion. The tumor exhibited a peripheral collarette and consisted of large intradermal histiocytoid to epithelioid cells with no mitotic activity. These cells displayed fine chromatin and abundant pale eosinophilic cytoplasm, forming a swirling syncytium. They were interspersed with localized areas of glassy chondromyxoid matrix containing randomly mineralized calcific material and isolated osteoclast-like giant cells. RNA sequencing confirmed the presence of an FN1 (exon 29)::FGFR2 (exon 7) gene fusion. Our report emphasizes the importance for dermatopathologists to consider this entity when evaluating superficial lesions displaying mesenchymal, chondroid, and calcified attributes.

The lysine(K)-specific methyltransferase 2A gene (KMT2A), previously known as mixed lineage leukemia (MLL), frequently rearranged in acute leukemia, belongs to one of the most promiscuous genes and has been found fused to more than 80 different partners. KMT2A::SEPTIN6 fusion is a relatively uncommon rearrangement observed in pediatric acute myeloid leukemia (AML) patients, some of which may harbor other mutations. We herein report a case of AML-M4-infant with KMT2A::SEPTIN6 fusion and DIS3 variant. The 8-month-old girl presented with leukocytosis, anemia and thrombocytopenia. A bone marrow smear disclosed that 64% of the total nucleated cells were blasts. Karyotype analysis showed 46,X,t(X;11)(q24;q23)[10]/46,XX[10]. Fluorescence in situ hybridization analysis suggested a possible break in the KMT2A gene. After whole transcriptome sequencing, Exon 9 of KMT2A was fused in-frame with Exon 2 of SEPTIN6. This is a typical type of chromosomal rearrangement leading to the KMT2A::SEPTIN6 fusion. Meanwhile, DIS3 variant [c.2065C>T, p.R689X, variant allele frequency (VAF): 39.8%] was identified. KMT2A::SEPTIN6 fusion has been associated with the pathogenesis of AML, whereas DIS3 variants are relatively rare genetic events in pediatric AML. Regrettably, the relatives disagreed with the combination chemotherapy, and the patient eventually died of progressive disease. In conclusion, our findings provide a foundation for a better understanding of the genotypic profile of KMT2A::SEPTIN6 associated AML, and the co-existence of KMT2A::SEPTIN6 and DIS3 variant might contribute to the disease progression and transformation of AML.

OBJECTIVE: Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type.
RESULTS: Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival.
CONCLUSIONS: EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a distinctive tumor composed of spindle cells accompanied by mixed inflammatory cells, and immunohistochemical positivity for ALK (anaplastic lymphoma kinase protein) can be detected in half of IMTs. The diagnosis of ALK-negative IMT could be a challenge. Recently, the fusions of some kinase genes, such as RET, NTRK1, ROS1, etc., are revealed in ALK-negative IMT.
METHODS: A 19-year-old woman presented with swelling of the left upper arm. Magnetic resonance imaging (MRI) scan revealed a tumor in the left postbrachium extended to the left axillary, serratus anterior muscle, and latissimus dorsi muscle. Histopathologically, the irregular-circumscribed tumor was composed of dense spindle-shaped cells with eosinophilic abundant cytoplasm and hyalinized mesenchyme in an inflammatory background. Immunohistochemically (IHC), tumor cells were positive for SMA, MDM2, and p16; the cells were negative for desmin, MyoD1, Myogenin, pan-cytokeratin, S100, SOX10, HMB45, Malen-A, CD34, CD31, CD99, and ALK. By RNA-based NGS, a novel fusion between TPD52L2 3\' end of exon 1-4 and ROS1 5\' end of exon 36-43 was revealed. ROS1 IHC staining was negative. The final diagnosis of IMT with TPD52L2-ROS1 fusion was made. Subsequently, the patient experienced a good clinical response to Crizotinib, and clinical follow-up showed stable disease after 9 months.
CONCLUSIONS: This report expands the spectrum of ROS1 gene rearrangements in the IMT and highlights the importance of molecular analysis of IMT for getting a diagnostic clue and determining potential therapeutic strategies.

Spindle cell/sclerosing rhabdomyosarcoma (SSRMS) is a clinicopathologically and molecularly heterogeneous disease. Gene fusions have been identified in intraosseous SSRMS, consisting predominantly of EWSR1/FUS::TFCP2 and MEIS1::NCOA2. The former often follow an aggressive clinical course; there is limited clinical follow-up available for the latter. We report here a new case of the very rare intraosseous SSRMS with MEIS1::NCOA2 gene fusion and include the detailed treatment course and 52 months of clinical follow-up. SSRMS with MEIS1::NCOA2 gene fusion appears biologically distinct from other intraosseous SSRMS, following a course characterized by local recurrence with rare reports of metastasis to date.

Eccrine poroma (EP) is a relatively rare benign adnexal neoplasm that usually affects elderly patients. Its pathogenesis is still under investigation, but recent gene studies have revealed gene fusions as key incidences resulting in oncogenetic pathways. It often presents as a solitary, firm papule, mostly asymptomatic, located on the soles or palms. Due to its clinical and dermoscopic variability, it is characterized as the great imitator. We performed a literature review, aiming to summarize current data on the pathogenetic mechanisms, new dermoscopic features, and novel diagnostic tools that may aid in early diagnosis and proper management of this rare adnexal tumor. Furthermore, we reviewed the possible pathogenetic associations between EP and its malignant counterpart, namely eccrine porocarcinoma. This systematic approach may aid in understanding the pathogenetic mechanisms and how to use novel histopathologic markers and imaging methods to overcome the diagnostic dilemma of this rare tumor.

OBJECTIVE: NUTM1-rearranged sarcoma is an emerging entity that differs from NUT carcinoma at the molecular level, with most of the former tumours harbouring fusions involving genes in the MYC-associated factor X dimerization (MAD) transcription family (MXD1, MXD4, MXI1 [or MXD2], and MGA). MGA::NUTM1 is one of the most recently described novel gene fusions associated with NUTM1-rearranged sarcoma. Herein we describe the clinicopathologic features of three sarcomas with an MGA::NUTM1 fusion.
RESULTS: The three study patients were male, with an age range of 10-28 years. The tumour sites were deep soft tissue of the thigh, the chest wall, and the pelvis. All three tumours were aggressive, with multiple recurrences and metastases. Histologically, the tumours were composed of monotonous spindle, round, or epithelioid cells in variably hyalinized stroma and prominent aggregates of amianthoid fibre-like collagen or collagen rosettes. Mitotic activity was relatively low (5-12 mitotic figures per 10 hhpf). All tumours tested expressed NUT, with one tumour having S100 protein expression and two tumours having CD99 and CD56 expression. The genetic breakpoints were MGA exon 21, MGA exon 22, and NUTM1 exon 3.
CONCLUSIONS: MGA::NUTM1 sarcoma often exhibits hyalinized stroma with amianthoid fibre-like collagen or collagen rosettes in the presence of monotonous round, epithelioid, or spindle cell morphology. NUT immunohistochemistry and molecular testing can help confirm the diagnosis.