Late-onset tumors in rhabdoid tumor predisposition syndrome type-1 (RTPS1) and implications for surveillance.

Rhabdoid tumor predisposition syndrome type-1 (RTPS1) is characterized by germline pathogenic variants in SMARCB1 and development of INI1-deficient rhabdoid tumors in early childhood. Due to its poor prognosis, the risk of subsequent tumor development and the impact of surveillance at later ages are poorly understood. We retrospectively reviewed individuals referred to the Cancer Genetics Program at The Hospital for Sick Children for SMARCB1 genetic testing and/or surveillance for RTPS1. In addition, to explore characteristics of late-onset tumors in RTPS1, a literature review was conducted. Of eighty-three individuals (55 probands and 28 family members), 12 probands and 4 family members were genetically confirmed with RTPS1. Four pediatric probands with RTPS1 underwent surveillance. An additional three individuals, including one patient with 22q11.2 distal deletion without history of tumor, one patient with negative genetic testing results but clinically diagnosed with RTPS1, and one sibling identified through cascade testing, underwent surveillance. Three patients with RTPS1 developed tumors between the ages of 9 and 17, including malignant rhabdoid tumors (N = 3), schwannomas (N = 4), and epithelioid malignant peripheral nerve sheath tumor (N = 1). Three of these lesions were asymptomatically detected by surveillance. A literature review revealed 17 individuals with RTPS1 who developed INI1-deficient tumors after age five. Individuals with RTPS1 remain at elevated risk for developing INI1-deficient tumors after the peak age of rhabdoid tumor in early childhood. Extension of surveillance beyond 5 years of age could lead to improved survival and reduced morbidity for these patients, and prospective evaluation of revised approaches will be important.

Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop.

Genetic predisposition to neuroblastoma (NB) is relatively rare. Only 1% to 2% of patients have a family history of NB, 3% to 4% of cases present with bilateral or multifocal primary tumors, and occasional patients have syndromes that are associated with increased NB risk. Previously, a germline pathogenic variant (GPV) in PHOX2B was associated with Hirschsprung disease and congenital central hypoventilation syndrome. Recently, certain GPVs were shown to be responsible for congenital central hypoventilation syndrome and NB predisposition. Also, several groups determined that activating GPVs in ALK accounted for a substantial number of familial NB. Finally, there are additional genes and cancer predisposition syndromes in which NB occurs with greater frequency or that have been associated with NB based on genome-wide association studies. We review the evidence for all these genes and whether there is sufficient evidence to warrant surveillance. We review recommended surveillance for hereditary patients with NB, including minor updates to surveillance recommendations that were published previously in 2017.

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Metastatic pancreatic cancer with multiple metastases confined to the large intestine: a case report and literature review.

The incidence and mortality rate of pancreatic cancer are increasing worldwide. Regional lymph nodes, liver, lung, and peritoneum are common sites of metastasis from pancreatic cancer, but the gastrointestinal tract is rare as a metastatic organ from pancreatic cancer. An 80-year-old man was referred to our department for a hypovascular pancreatic mass on contrast-enhanced computed tomography (CECT). Endoscopic ultrasound-guided fine needle aspiration revealed adenocarcinoma, and he was diagnosed with pancreatic cancer. No lymph nodes or distant metastases were detected by either CECT or gadolinium-enhanced magnetic resonance imaging, and we evaluated this case as borderline resectable. However, total colonoscopy for positive fecal occult blood tests revealed a reddish and hemorrhagic mucosal thickening in the ascending and sigmoid colon and rectum, which was inconsistent with primary colorectal cancer. Biopsy specimens from these sites revealed cytokeratin (CK)7-positive and CK20- and CDX2-negative adenocarcinoma, consistent with cancer of pancreatic origin. The patient underwent palliative chemotherapy with gemcitabine but died from COVID-19 infection eight months after diagnosis. Performing total colonoscopy as a preoperative screening is important for accurate cancer staging of patients with possible resectable pancreatic cancer.

Consensus framework for conducting phase I/II clinical trials for children, adolescents, and young adults with pediatric low-grade glioma: Guidelines established by the International Pediatric Low-Grade Glioma Coalition Clinical Trial Working Group.

Within the last few decades, we have witnessed tremendous advancements in the study of pediatric low-grade gliomas (pLGG), leading to a much-improved understanding of their molecular underpinnings. Consequently, we have achieved successful milestones in developing and implementing targeted therapeutic agents for treating these tumors. However, the community continues to face many unknowns when it comes to the most effective clinical implementation of these novel targeted inhibitors or combinations thereof. Questions encompassing optimal dosing strategies, treatment duration, methods for assessing clinical efficacy, and the identification of predictive biomarkers remain unresolved. Here, we offer the consensus of the international pLGG coalition (iPLGGc) clinical trial working group on these important topics and comment on clinical trial design and endpoint rationale. Throughout, we seek to standardize the global approach to early clinical trials (phase I and II) for pLGG, leading to more consistently interpretable results as well as enhancing the pace of novel therapy development and encouraging an increased focus on functional endpoints as well and quality of life for children faced with this disease.

Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project.

PURPOSE: This single-center, prospective molecular profiling study characterizes genomic alterations and identifies therapeutic targets in advanced pediatric solid tumors. METHODS: As part of the TOP-GEAR (Trial of Onco-Panel for Gene profiling to Estimate both Adverse events and Response by cancer treatment) project at the National Cancer Center (NCC), Japan, we enrolled pediatric patients with a refractory or recurrent disease during August 2016-December 2021 and performed genomic analysis of matched tumors and blood using originally developed cancer gene panels, NCC Oncopanel (ver. 4.0) and NCC Oncopanel Ped (ver. 1.0). RESULTS: Of 142 patients (age, 1-28 years) enrolled, 128 (90%) were evaluable for genomic analysis; 76 (59%) patients harbored at least one reportable somatic or germline alteration. The tumor samples were collected during the initial diagnosis in 65 (51%) patients, after treatment initiation in 11 (9%) patients, and upon either disease progression or relapse in 52 (41%) patients. The leading altered gene was TP53, followed by MYCN, MYC, CDKN2A, and CDK4. The commonly affected molecular processes were transcription, cell-cycle regulation, epigenetic modifiers, and RAS/mitogen-activated protein kinase signaling. Twelve (9%) patients carried pathogenic germline variants in cancer-predisposing genes. Potentially actionable findings were identified in 40 (31%) patients; to date, 13 (10%) patients have received the recommended therapy on the basis of their genomic profiles. Although four patients had access to targeted therapy through clinical trials, the agents were used in nine patients in an off-label setting. CONCLUSION: The implementation of genomic medicine has furthered our understanding of tumor biology and provided new therapeutic strategies. However, the paucity of proposed agents limits the full potential of actionability, emphasizing the significance of facilitating access to targeted cancer therapies.

Analysis of prognostic factors in patients with self-expandable metallic stents for treatment of malignant gastric outlet obstruction.

BACKGROUND AND AIM: Self-expandable metallic stents (SEMSs) are widely accepted as a less-invasive treatment for malignant gastric outlet obstruction (GOO). However, the factors related to prognosis and stent dysfunction after SEMS placement are not well known, and we aimed to investigate them. METHODS: This was a single-center retrospective cohort study of 212 malignant strictures in 207 patients. Factors related to prolonged overall survival (OS) and time to recurrent GOO (TRGOO) after SEMS placement were evaluated. RESULTS: Improvement of oral intake was confirmed in 179 patients (86%). The median OS was 65 days. A Cox proportional hazards model revealed that lower cancer stage, lower performance status score at the time of SEMS placement, and administration of chemotherapy after SEMS placement were significant predictive factors for prolonged OS. The median OS was 182 days in the group of SEMS followed by chemotherapy (group A) and 43 days in the group of SEMS alone (group B) (p< .0001). Chemotherapy after SEMS implantation contributed to the prolongation of survival in gastric cancer (hazard ratio (HR), 0.12) and pancreatic cancer (HR, 0.41). Furthermore, the cumulative incidence rates of stent dysfunction on day 120 after SEMS placement were 30% in group A and 61% in group B (p=.03). Notably, the preventive effect of chemotherapy on stent dysfunction was significant in pancreatic cancer. CONCLUSIONS: SEMS is a treatment with high technical and clinical success rate for malignant GOO. Furthermore, subsequent chemotherapy prolongs OS especially in gastric cancer, and TRGOO in pancreatic cancer.

Genetic predisposition to cancers in children and adolescents.

PURPOSE OF REVIEW: Childhood cancer is rare, but it remains the leading cause of disease-related mortality among children 1-14 years of age. As exposure to environmental factors is lower in children, inherited genetic factors become an important player in the cause of childhood cancer. This review highlights the current knowledge and approach for cancer predisposition syndromes in children. RECENT FINDINGS: Current literature suggests that 10-18% of paediatric cancer patients have an underlying genetic susceptibility to their disease. With better knowledge and technology, more genes and syndromes are being discovered, allowing tailored treatment and surveillance for the probands and their families.Studies have demonstrated that focused surveillance can detect early malignancies and increase overall survival in several cancer predisposition syndromes. Various approaches have been proposed to refine early tumour detection strategies while minimizing the burden on patients and families. Newer therapeutic strategies are being investigated to treat, or even prevent, tumours in children with cancer predisposition. SUMMARY: This review summarizes the current knowledge about different cancer predisposition syndromes, focusing on the diagnosis, genetic counselling, surveillance and future directions.

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

DNA methylation array analysis for diffuse leptomeningeal glioneuronal tumor with conspicuous hypothalamic mass. A case report.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioneuronal neoplasm newly included in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Owing to the wide spectrum of its histopathological and radiological features, accurate diagnosis can be challenging. Recently, molecular testing including DNA methylation array has been introduced with the possibility of improving diagnostic accuracy and contributing to the subtyping especially for brain tumors with ambiguous histology. Two molecularly distinct subtypes of DLGNT have been reported: methylation class-1 (MC-1) with an indolent clinical course and MC-2, the latter aggressive. Herein, we report a case of a 14-year-old girl with a conspicuous hypothalamic mass lesion and diffuse leptomeningeal enhancement on magnetic resonance imaging. Biopsy specimens obtained from the hypothalamic lesion endoscopically were mainly composed of oligodendrocyte-like cells. However, it was difficult to make a definite diagnosis from these non-specific histological findings. Thus, DNA methylation array analysis was performed additionally by using formalin-fixed, paraffin-embedded tissue, resulting in a diagnosis of "MC-1 subtype of DLGNT" with a high calibrated score (0.99). Consequently, she was treated conservatively, with neither progression of the tumor nor aggravation of symptoms for the next 12 months. It was concluded that DNA methylation array analysis for DLGNT, a rare glioneuronal tumor, could be a powerful tool not only for accurate diagnosis but also decision-making in selecting the best treatment.

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors.

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Molecular analyses of rosette-forming glioneuronal tumor of the midbrain tegmentum: A report of two cases and a review of the FGFR1 status in unusual tumor locations.

Background: Rosette-forming glioneuronal tumor (RGNT) is a rare tumor that arises primarily in the posterior fossa, with molecular features of FGFR1 mutation. A previous study reported that brainstem RGNT accounts for only 2.7% cases; therefore, midbrain RGNT is infrequent. Case Description: The authors encountered two cases of RGNT located in the midbrain tegmentum (Case 1: 23-year-old woman and Case 2: 18-year-old boy), both exhibiting similar cystic components with gadolinium-enhanced cyst walls on preoperative magnetic resonance imaging, surgically resected through the occipital transtentorial approach. Histological findings in both cases comprised two characteristic architectures of neurocytic and glial components, typical of RGNT. Molecular assessment revealed no FGFR1 mutation in the initial specimen, but revealed FGFR1 K656E mutation in the recurrent specimen in Case 1 and showed no FGFR1 mutation but showed TERT C228T mutation in Case 2. Neither case revealed IDH1/2, BRAF, H3F3A K27, H3F3A G34, or HIST1H3B K27 mutations. DNA methylation-based classification (molecularneuropathology.org) categorized both cases as RGNT, whose calibrated scores were 0.99 and 0.47 in Cases 1 and 2, respectively. Conclusion: Midbrain tegmentum RGNTs exhibited typical histological features but varied FGFR1 statuses with TERT mutation. RGNT in rare locations may carry different molecular alterations than those in other common locations, such as the posterior fossa.

Diffusely infiltrating glioma with CREBBP-BCORL1 fusion showing overexpression of not only BCORL1 but BCOR: A case report.

BCORL1 encodes a transcriptional corepressor homolog to BCOR. BCORL1 rearrangements have been previously described as rare events, and among them, CREBBP-BCORL1 has been reported only in 2 cases of ossifying fibromyxoid tumors. Herein, we present the first case of diffusely infiltrating glioma with CREBBP-BCORL1 involving a 17-year-old female patient. Histologically, the tumor was composed of a diffusely infiltrative proliferation of small tumor cells with moderate cellularity showing prominent microcystic formation. DNA methylation analysis revealed that the current case and a previously reported anaplastic ependymoma with EP300-BCORL1 were clustered together in close proximity to but distinct from methylation class high-grade neuroepithelial tumor with BCOR alteration. RNA sequencing demonstrated high mRNA expression of not only BCORL1 but BCOR, and the latter was compatible with diffuse nuclear expression of BCOR detected by immunohistochemistry. Our findings suggest that central nervous system tumors with CREBBP/EP300-BCORL1 may exhibit diverse morphologies but form a distinct DNA methylation group and that BCORL1 fusion genes may lead to upregulation of both BCOR and BCORL1.