Management of Pediatric Tumors With Vascular Extension

Background: Pediatric tumors can present with vascular extension to the inferior vena cava and right atrium, which impacts the surgical strategy and can be challenging during surgical treatment. Wilms tumor (WT) is the most common retroperitoneal tumor that can present with vascular extension, but also adrenal tumors, clear cell tumors from the kidney, and hepatoblastomas can present with this situation. Surgical aims include obtaining complete tumor resection without risk for patients, to avoid severe bleeding, cardiac arrest, and embolization, and to avoid cardiac bypass if possible.Objective: To describe and discuss the surgical strategies to deal with pediatric tumors with vascular extension and propose a protocol.Method: Retrospectivly review the experience of treating patients with vascular extension in a single institution, describing different scenarios and a decision making fluxogram based on the preoperative evaluation regarding the surgical techniques and the need for cardiac bypass that are adequate for each situation. Image studies are important to guide the surgical strategy. Depending on the quality of image available, computerized tomography (CT) or magnetic resonance imaging (MRI) can be enough to give the information needed for surgical decisions. Ultrasonography (US) with Doppler is helpful to confirm diagnosis and describes factors to guide the adequate surgical strategy, like the upper level extension and presence or absence of blood flow around the thrombus. Neoadjuvant chemotherapy is indicated in most cases, in order to reduce the upper level of extension (and avoid the need for cardiac bypass) and to lower the risk of embolization. The approach is based on the upper level of the thrombus and can include cavotomy or cavectomy, sometimes with cardiac bypass and cardiac arrest with hypothermia, when the thrombus reaches the diaphragmatic level or above. Pathology analysis of the thrombus can guide staging and the need for radiotherapy postoperatively.Results: A decision making fluxogram protocol is presented focusing on the surgical treatment of such condition.Conclusion: Surgery strategy is highly impacted by the presence of vascular extension in pediatric tumors. Surgeons should be aware of potential complications and how to prevent them. Such cases should be treated in reference centers.

Tracing and Targeting the Origins of Childhood Cancer

Despite the success of treating childhood cancers with cytotoxic agents, novel therapeutic strategies are required to achieve the next leap in cure rates. A promising avenue may be to target the origin of childhood cancers. Here, we review recent advances in tracing the origins of pediatric tumors. Cancer-to-normal cell comparisons by single-cell mRNA sequencing reveal the fetal state of cancer cells, as well as their cell of origin. Recent phylogenetic analyses have uncovered large tissue-resident precursor clones to childhood cancers, which already possess key genomic alterations leading to tumor formation. Both the transcriptional fetalness and genomic status of the premalignant tissue bed provide further avenues for targeted therapy. Overall, these advances begin to describe the precise origins of pediatric tumors and pave the way for novel methods in detecting, treating, and perhaps even preventing childhood cancers. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Presentation of Acute Lymphoblastic Lymphoma and Colorectal Carcinoma in the Context of Constitutional Mismatch Repair Deficiency Syndrome (CMMRD): a Case Report with Literature Review

Introduction: Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive disease-carrying an increased risk of cancers (pediatric tumors of central nervous system, haemato-lymphoid malignancies along with gastrointestinal (GI) cancer(s), which are usually seen in the second and third decade) leading to syndromic presentation. Causal mutations are detected in DNA mismatch repair (MMR) genes, including MLH1, PMS2, MSH2, and MSH6 that are also known for their established role in Lynch syndrome. We describe a case of CMMRD with an earlier (first decade of life) presentation of mediastinal acute lymphoblastic lymphoma and colorectal malignancy. Case Presentation: A five-year-old boy presented with respiratory complaints, bilateral cervical lymphadenopathy, multiple café au lait macules (CALMs) on the lower back, history of parental consanguinity with the death of three sisters due to brain tumor within 6 months of diagnosis. Computerized tomographic (CT) scan chest revealed a huge mediastinal mass. The patient underwent a trucut-biopsy of the mass. The results were significant for a pre T-cell acute lymphoblastic lymphoma. Suspicion of CMMRD was raised based on a combination of factors described above. A panel of mismatch repair (MMR) proteins was applied on the biopsy tissue that revealed loss of nuclear expression of MLH1 and PMS2 immunostaining in tumor cells with positive external controls. While on maintenance therapy for lymphoma, about a year later, the patient developed sub-acute intestinal obstruction due to a stenosing polypoidal circumferential tumor in the mid-sigmoid colon found on flexible sigmoidoscopy that was followed by endoscopic biopsies and insertion of a fully-covered self-expanding metallic adult biliary stent with a diameter of 10 mm and length of 6 cm leading to immediate relief of obstruction. Biopsies revealed adenocarcinoma with neuroendocrine differentiation. Metastatic tumor deposits were seen in the omentum, anterior abdominal wall, and the left peritoneal wall. Practical Implications: Earlier (first decade) presentation of gastrointestinal malignancy warrants that an earlier screening through radiological scans for any possible tumors and MMR protein expression analysis (loss in tumor plus normal non-tumor cells) are essential in patients having CALMs and family history of pediatric tumors.

Clinical applications of artificial intelligence and radiomics in neuro-oncology imaging

This article is a comprehensive review of the basic background, technique, and clinical applications of artificial intelligence (AI) and radiomics in the field of neuro-oncology. A variety of AI and radiomics utilized conventional and advanced techniques to differentiate brain tumors from non-neoplastic lesions such as inflammatory and demyelinating brain lesions. It is used in the diagnosis of gliomas and discrimination of gliomas from lymphomas and metastasis. Also, semiautomated and automated tumor segmentation has been developed for radiotherapy planning and follow-up. It has a role in the grading, prediction of treatment response, and prognosis of gliomas. Radiogenomics allowed the connection of the imaging phenotype of the tumor to its molecular environment. In addition, AI is applied for the assessment of extra-axial brain tumors and pediatric tumors with high performance in tumor detection, classification, and stratification of patient’s prognoses.

A case of NTRK-rearranged Spindle cell tumor in a Pediatric patient

Introduction/Objective Recent studies continue to demonstrate that NTRK fusions occur more frequently in pediatric than in adult patients involving a broader panel of fusion partners as well as a wider range of pediatric tumors than previously recognized. The identification of these NTRK fusions has facilitated precision cancer diagnosis and TRK inhibitor targeted therapy. With the recent FDA approval of larotrectinib and entrectinib for the treatment of adult and pediatric NTRK-positive, unresectable solid tumors, identification of these fusions directly impacts patient care. Methods/Case Report Our patient, a 10 year old female presented with a large right sided buttock mass and pressure effects from the tumor. An incisional biopsy showed a moderately moderately cellular tumor with a collagenous and partially myxoid stroma. The atypical cells had ovoid nuclei with vesicular chromatin, minimal to no atypia, and rare mitotic activity (<2/30 high-power fields), as well as fibrous tissue that appeared as ropy collagen. Some of the blood vessels were rimmed by a hyalinized cuff. A mild inflammatory component, namely scattered lymphocytes and fewer plasma cells were noted. Immunohistochemistry showed: SMA(faint+), S100(+), CD34(+), CD31(+), FLI1(+), NTRK(+). Negative for ALK1, desmin, SOX10, EMA, keratin AE1/3, CAM5.2, D2-40, myogenin, MUC4, TLE1, STAT6, BCOR, ERG. Both INI1 and H3K27me3 were retained. Proliferative rate by Ki-67 was low, showing <2% positivity. Next generation sequencing revealed the following: LMNA-NTRK1 fusion; CD36 N53fs*24 and CDKN2A/B CDKN2A loss exon 1. Thus, the histologic, immunophenotypic, and molecular findings together supported a diagnosis of NTRK-rearranged spindle cell tumor. This entity has alternately been termed lipofibromatosis-like tumor. Following confirmation of NTRK fusion, she was treated with oral TRK inhibitor with near total response. With this NTRK-rearranged spindle cell tumor’s minimal mitotic activity, absence of necrosis, and low cellularity, the behavior of this tumor was expected to be indolent rather than aggressive. However, the patient was presented for assessment and management at a recent tumor board about 8 months after her initial diagnosis as she had residual/recurrent tumor. Results (if a Case Study enter NA) NA Conclusion Our case highlights the clinical utility of screening for NTRK fusions in all pediatric tumors.

Neuroblastoma Cells Depend on CSB for Faithful Execution of Cytokinesis and Survival

Neuroblastoma, the most common extra-cranial solid tumor of early childhood, is one of the major therapeutic challenges in child oncology: it is highly heterogenic at a genetic, biological, and clinical level. The high-risk cases have one of the least favorable outcomes amongst pediatric tumors, and the mortality rate is still high, regardless of the use of intensive multimodality therapies. Here, we observed that neuroblastoma cells display an increased expression of Cockayne Syndrome group B (CSB), a pleiotropic protein involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division, and were recently found to confer cell robustness when they are up-regulated. In this study, we demonstrated that RNAi-mediated suppression of CSB drastically impairs tumorigenicity of neuroblastoma cells by hampering their proliferative, clonogenic, and invasive capabilities. In particular, we observed that CSB ablation induces cytokinesis failure, leading to caspases 9 and 3 activation and, subsequently, to massive apoptotic cell death. Worthy of note, a new frontier in cancer treatment, already proved to be successful, is cytokinesis-failure-induced cell death. In this context, CSB ablation seems to be a new and promising anticancer strategy for neuroblastoma therapy.