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BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy. However, in developing countries the incidence rate is higher. The understanding of molecular alterations is essential for evaluating possible targets for more effective systemic therapies. METHODS: We retrospectively collected clinical data of metastatic PSCC (mPSCC) patients who had received at least one prior systemic treatment from 3 Brazilian hospitals. Tumor samples were evaluated using the next-generation sequencing (NGS) Foundation One DX and immunohistochemistry (IHC). The objective was to identify and describe somatic genomic alterations known to be functional or pathogenic and their association with survival outcomes. RESULTS: Twenty-three patients were identified, 22 and 18 patients had tumor samples analyzed by IHC and NGS, respectively. PD-L1 expression (CPS ≥ 1%) was positive in 14 patients (63.6%). Regarding the genomic alterations, 16 patients (88.9%) had some clinically relevant genomic alterations. TP53, TERT, CDKN2A, PIK3CA, NOTCH1, and CDKN2B loss were identified in 66.7%, 50%, 50%, 33.3%, 27.8%, and 22.2% of the patients, respectively. No MSI or TMB high (≥10 mutations/MB) cases were identified. NOTCH1 mutation was identified only in HPV-negative patients and it was associated with worse OS (yes: 5.5 vs no: 12.8 months, P = .049) and progression-free survival (yes: 5.5 vs no: 11.7 months, P = .032). CONCLUSION: This study demonstrated that molecular alterations in mPSCC from developing countries are similar to those from developed countries. Predictive biomarkers for immunotherapy response such as TMB high or MSI were not identified. Specific gene mutations may identify patients with worse prognoses and open new avenues for therapeutic development.

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Worldwide, breast cancer (BC) is one of the most common cancers in women and is responsible for the highest number of cancer-related deaths among women, with a special clinical behavior and therapy response. Triple-negative breast cancer (TNBC) is seen as a highly invasive BC, characterized by a short survival, higher mortality, recurrence, and metastasis when it is compared to the other BC subtypes. The molecular subtyping of TNBC based on mRNA expression levels does not accurately reflect protein expression levels, which impacts targeted therapy effectiveness and prognostic predictions. Most TNBC cases exhibit a high frequency of homologous recombination (HR) DNA repair deficiency (HRD) signatures and are associated with a complex genomic profile. Biomarker research in TNBC includes investigating genetic mutations, gene expression patterns, immune system-related markers, and other factors that can provide valuable information for diagnosis, treatment selection, and patient outcomes. Additionally, these biomarkers are often crucial in the development of personalized and precision medicine approaches, where treatments are customized to each patient's unique characteristics. This ongoing research is essential for improving the management and outcomes of TNBC, which is a challenging and heterogeneous form of breast cancer. The findings of this research have practical implications for refining treatment strategies, particularly in selecting appropriate systemic therapies and integrating traditional treatment modalities like surgery and radiotherapy into comprehensive care plans for TNBC patients.

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Melanoma pathogenesis, conventionally perceived as a linear accumulation of molecular changes, discloses substantial heterogeneity driven by non-linear biological processes, including the direct transformation of melanocyte stem cells. This heterogeneity manifests in diverse biological phenotypes and developmental states, influencing variable responses to treatments. Unveiling the aberrant mechanisms steering melanoma initiation, progression, and metastasis is imperative. Beyond mutations in oncogenic and tumor suppressor genes, the involvement of distinct molecular pathways assumes a pivotal role in melanoma pathogenesis. Ultraviolet (UV) radiations, a principal factor in melanoma etiology, categorizes melanomas based on cumulative sun damage (CSD). The genomic landscape of lesions correlates with UV exposure, impacting mutational load and spectrum of mutations. The World Health Organization's 2018 classification underscores the interplay between sun exposure and genomic characteristics, distinguishing melanomas associated with CSD from those unrelated to CSD. The classification elucidates molecular features such as tumor mutational burden and copy number alterations associated with different melanoma subtypes. The significance of the mutated BRAF gene and its pathway, notably BRAFV600 variants, in melanoma is paramount. BRAF mutations, prevalent across diverse cancer types, present therapeutic avenues, with clinical trials validating the efficacy of targeted therapies and immunotherapy. Additional driver mutations in oncogenes further characterize specific melanoma pathways, impacting tumor behavior. While histopathological examination remains pivotal, challenges persist in molecularly classifying melanocytic tumors. In this review, we went through all molecular characterization that aid in discriminating common and ambiguous lesions. Integration of highly sensitive molecular diagnostic tests into the diagnostic workflow becomes indispensable, particularly in instances where histology alone fails to achieve a conclusive diagnosis. A diagnostic algorithm based on different molecular features inferred by the various studies is here proposed.

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INTRODUCTION: The financial impact of breast cancer has been discussed due to its high incidence and the increased costs of systemic therapy and is even more relevant in countries with low and medium socioeconomic development. OBJECTIVE: To evaluate the financial viability of using the MammaPrint™ (MP) genetic signature in a public and private system in a country with a medium socioeconomic development index. MATERIAL AND METHOD: A pharmacoeconomic trial with a cost-benefit analysis evaluating the reduction in costs of chemotherapy, support drugs, and materials used during chemotherapy infusion in high-risk hormone receptor-positive (HR+) breast cancer patients submitted to analysis using the MammaPrint™ genetic signature. RESULTS: The value of using MammaPrint™ in the Unified Health System (SUS) would bring an additional cost of US$ 1,334.56 per patient in the over-50 age group. In private medicine, the use of MammaPrint™ in the same population would result in cost savings ranging from US$ 2,422.53 to US$ 9,989.95 per patient. CONCLUSION: The use of MP in RH + breast cancer patients with high clinical risk and low genomic risk in Brazil leads to significant savings in resources when applied to supplementary healthcare. In the SUS, reducing the costs of MP for large-scale use could make its application viable. These values need to be re-evaluated in each institution, using the methodology applied in the trial, adjusting according to costs, to obtain a result that reflects its reality.

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Cancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well-characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune-related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor-infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor.

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Background: Aplastic anemia (AA), characterized by hematopoietic stem cell deficiency, can evolve into different hematologic malignancies. Our understanding of the genetic basis and mechanisms of this progression remains limited. Methods: We retrospectively studied 9 acquired AA patients who later developed hematologic malignancies. Data encompassed clinical, laboratory, karyotype, and next-generation sequencing (NGS) information. We explored chromosomal alterations and mutation profiles to uncover genetic changes underlying the transition. Results: Nine AA patients developed myelodysplastic syndrome (seven patients), acute myeloid leukemia (one patient), or chronic myelomonocytic leukemia (one patient). Among eight patients with karyotype results at secondary malignancy diagnosis, monosomy 7 was detected in three. Trisomy 1, der(1;7), del(6q), trisomy 8, and del(12p) were detected in one patient each. Among three patients with NGS results at secondary malignancy diagnosis, KMT2C mutation was detected in two patients. Acquisition of a PTPN11 mutation was observed in one patient who underwent follow-up NGS testing during progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Conclusion: This study highlights the genetic dynamics in the progression from AA to hematologic malignancy. Monosomy 7's prevalence and the occurrence of PTPN11 mutations suggest predictive and prognostic significance. Clonal evolution underscores the complexity of disease progression.

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A 50-year-old man with a history of total gastrectomy, distal pancreatectomy, splenectomy, and Roux-en-Y reconstruction was admitted to our hospital with a gallbladder tumor that had infiltrated the liver and abdominal wall. Because malignant cells were not collected during the percutaneous biopsy, we planned to perform an endoscopic ultrasound-guided fine-needle biopsy with a 22-G Franseen needle using a forward-viewing echoendoscope. Using intermittent manual compression, the forward-viewing echoendoscope reached the duodenum under fluoroscopic guidance. Endoscopic ultrasound-guided fine-needle biopsy was performed using a 22-G needle and 20-mL syringe and yielded a sufficient specimen with a single puncture. Malignant cells were promptly identified during on-site evaluation. The composition of the specimen (> 20% cancer cells and tissue area exceeding 25 mm2) enabled comprehensive genomic profiling. Subsequently, high-tumor mutational burden was diagnosed based on comprehensive genomic profiling, and pembrolizumab was initiated as a second-line therapy. Even in cases involving Roux-en-Y reconstruction, endoscopic ultrasound-guided fine-needle biopsy using a forward-viewing echoendoscope can result in collection of a high-quality specimen.

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Cancer genomic profile (CGP) testing, which is covered by the national health insurance system in Japan, has been introduced as a routine clinical practice. However, the effects of CGP testing on prognoses remain unclear. Drug accessibility rates and prognoses after CGP testing were retrospectively investigated in 713 patients who underwent CGP testing examined by our molecular tumor board between November 2019 and October 2022,. Overall survival (OS) was examined using the log-rank test and the Kaplan-Meier method. The median age of patients (326 males and 387 females) was 58 years (12-85 years). CGP testing revealed one or more gene mutations in 681 cases (95.5%), among which actionable gene mutations were detected in 439 (61.6%). Although treatment options were recommended for 285 cases (40.0%) by the molecular tumor board, only 45 received treatment based on their gene mutations. During the median observation period of 8.6 months, 351 (49.2%) patients died of the exacerbation of existing diseases. No significant differences were observed in OS between patients treated with and without genomically matched therapy (p = 0.285). According to clinical responses to treatment based on gene mutations, median OS was significantly longer in patients who achieved partial response and stable disease (26.5 months; 95% CI 14.4-38.6) than in those with progressive disease and not evaluated (9.8 months; 95% CI 5.8-13.8, p = 0.013). Responses to treatment based on gene mutations may improve prognoses, and it is important to increase the drug accessibility rate after CGP testing.

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BACKGROUNDS: Endometrial carcinoma (EC) is one of the most commonly diagnosed gynecologic malignancy in China. However, the genetic profile of Chinese EC patients has not been well established yet. METHODS: In current study, 158 Chinese EC patients were subjected to next-generation sequencing assay (74 took testing of EC-related 20-genes panel, and 84 took the expanded panel). Of the 158 patients, 91 patients were performed germline mutation testing using the expanded panel. Moreover, the public datasets from TCGA and MSKCC were utilized to compare the genomic differences between Chinese and Western EC patients. The proteomic and transcriptomic from CPTAC and TCGA were derived and performed unsupervised clustering to identify molecular subtypes. RESULTS: Among the 158 patients analyzed, a significant majority (85.4%) exihibited at least one somatic alteration, with the most prevalent alterations occurring in PTEN, PIK3CA, TP53, and ARID1A. These genomic alterations were mainly enriched in the PI3K, cell cycle, RAS/RAF/MAPK, Epigenetic modifiers/Chromatin remodelers, and DNA damage repair (DDR) signaling pathways. Additionally, we identified ten individuals (11.0%) with pathogenic or likely pathogenic germline alterations in seven genes, with the DDR pathway being predominantly involved. Compared to Western EC patients, Chinese EC patients displayed different prevalence in AKT1, MET, PMS2, PIK3R1, and CTCF. Notably, 69.6% of Chinese EC patients were identified with actionable alterations. In addition, we discovered novel molecular subtypes in ARID1A wild-type patients, characterized by an inferior prognosis, higher TP53 but fewer PTEN and PIK3CA alterations. Additionally, this subtype exhibited a significantly higher abundance of macrophages and activated dendritic cells. CONCLUSION: Our study has contributed valuable insights into the unique germline and somatic genomic profiles of Chinese EC patients, enhancing our understanding of their biological characteristics and potential therapeutic avenues. Furthermore, we have highlighted the presence of molecular heterogeneity in ARID1A-wild type EC patients, shedding light on the complexity of this subgroup.

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PURPOSE: To map current literature and provide an overview of upcoming future diagnostic and prognostic methods for upper tract urothelial carcinoma (UTUC), including translational medical science. METHODS: A scoping review approach was applied to search the literature. Based on the published literature, and the experts own experience and opinions consensus was reached through discussions at the meeting Consultation on UTUC II in Stockholm, September 2022. RESULTS: The gene mutational profile of UTUC correlates with stage, grade, prognosis, and response to different therapeutic strategies. Analysis of pathway proteins downstream of known pathogenic mutations might be an alternative approach. Liquid biopsies of cell-free DNA may detect UTUC with a higher sensitivity and specificity than urinary cytology. Extracellular vesicles from tumour cells can be detected in urine and may be used to identify the location of the urothelial carcinoma in the urinary tract. 3D microscopy of UTUC samples may add information in the analysis of tumour stage. Chemokines and chemokine receptors were linked to overall survival and responsiveness to neoadjuvant chemotherapy in muscle-invasive bladder cancer, which is potentially also of interest in UTUC. CONCLUSION: Current diagnostic methods for UTUC have shortcomings, especially concerning prognostication, which is important for personalized treatment decisions. There are several upcoming methods that may be of interest for UTUC. Most have been studied for urothelial carcinoma of the bladder, and it is important to keep in mind that UTUC is a different entity and not all methods are adaptable or applicable to UTUC.

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BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

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Introduction: Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined. Methods and materials: Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM. Results: The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038). Conclusions: Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM.

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The value of endometrial scratch in women with recurrent embryo transfer has been controversial. Endometrial scratch is often performed in the mid-luteal phase of the cycle preceding embryo transfer but there is little scientific evidence if it affects the whole genome transcriptomic profile of peri-implantation endometrium in the following cycle. A prospective longitudinal cohort study was conducted in a university assisted reproductive unit. A total of eight women with recurrent implantation failure (RIF) were included. Each participant had endometrial biopsy twice, first biopsy on day LH + 7 in natural cycle and second on day LH + 7 of the following cycle. R package was used to identify differentially expressed genes between the sample and enriched gene ontology. However, the paired sample showed no significant difference, neither known endometrial receptive gene set nor other genes, before and after the endometrial scratch. It suggests that endometrial scratch performed during previous mid-luteal phase did not affect the transcriptomic profiles of endometrium on day LH + 7 in women with RIF.

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BACKGROUND: Neuroendocrine neoplasms (NENs) represent clinically and genetically heterogeneous malignancies, thus a comprehensive understanding of underlying molecular characteristics, prognostic signatures, and potential therapeutic targets is urgently needed. METHODS: Next-generation sequencing (NGS) and immunohistochemistry were applied to acquire genomic and immune profiles of NENs from 47 patients. RESULTS: Difference was distinguished based on differentiation grade and primary localization. Poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumors (NETs) harbored distinct molecular features; we observed that tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in NECs versus NETs. Notably, we identified a 7-gene panel (MLH3, NACA, NOTCH1, NPAP1, RANBP17, TSC2, and ZFHX4) as a novel prognostic signature in NENs; patients who carried mutations in any of the 7 genes exhibited significantly poorer survival. Furthermore, loss of heterozygosity (LOH) and germline homogeneity in human leukocyte antigen (HLA) are common in NENs, accounting for 39% and 36%, respectively. Notably, HLA LOH was an important prognostic biomarker for a subgroup of NEN patients. Finally, we analyzed clinically actionable targets in NENs, revealing that TMB high (TMB-H) or gene mutations in TP53, KRAS, and HRAS were the most frequently observed therapeutic indicators, which granted eligibility to immune checkpoint blockade (ICB) and targeted therapy. CONCLUSION: Our study revealed heterogeneity of NENs, and identified novel prognostic signatures and potential therapeutic targets, which directing improvements of clinical management for NEN patients in the foreseeable future.

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Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract, which consists of bladder cancer (BC) for 90%, while 5% to 10%, of urinary tract UC (UTUC). BC and UTUC are characterized by distinct phenotypical and genotypical features as well as specific gene- and protein- expression profiles, which result in a diverse natural history of the tumor. With respect to BC, UTUC tends to be diagnosed in a later stage and displays poorer clinical outcome. In the present review, we seek to highlight the individuality of UTUC from a biological, immunological, genetic-molecular, and clinical standpoint, also reporting the most recent evidence on UTUC treatment. In this regard, while the role of surgery in nonmetastatic UTUC is undebated, solid data on adjuvant or neoadjuvant chemotherapy are still an unmet need, not permitting a definite paradigm shift in the standard treatment. In advanced setting, evidence is mainly based on BC literature and retrospective studies and confirms platinum-based combination regimens as bedrock of first-line treatment. Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Moreover, atezolizumab performed well as a maintenance treatment, while pembrolizumab as a single agent achieved promising outcomes in second-line setting. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment.

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Adenoid cystic carcinoma of the Bartholin's gland (ACCBG) is a rare, slowly but aggressive malignancy. We reported the case of a 31-year-old woman who was treated by local excision and then hemi-vulvectomy, with positive margins and perineural invasion. Radiation therapy (RT) was then performed delivering 45Gy in 25 fractions in bilateral inguinal lymph nodes and 64.8Gy in 36 fractions on the vulvar area. After 30 months, there was no local relapse (LR) but the patient presented a histologically documented lung recurrence. Genomic profiling of the tumor showed a MYB-NFIB fusion transcript and a somatic mutation of PLCG1. A treatment by Lenvatinib was started. We conducted a literature review of 100 published cases. Patients were mainly treated by radical vulvectomy (30%), hemi-vulvectomy (17%), wide or local excision (21% and 24%, respectively) or other. Forty-four percent of patients received postoperative RT, more frequently in case of positive margin (71.9% versus 29.5%). RT may reduce the risk of LR regardless of margin status, with 15.4% vs. 41.9% of LR with or without RT, respectively, in patients with negative margins, and 13% vs. 33.3% of LR with or without RT, respectively, in patients with positive margins. The risk of relapse of any type was 40.9% in patients who received adjuvant RT vs. 48.2% in patients who did not. Median time to relapse was 24 months (range 6-156 months). The most frequent metastatic sites were lung (76.7%) and bone (26.7%). Optimal treatment for ACCBG is still not clearly defined but pooling the data from published case report help us better understand this rare disease and help in the therapeutic decision.

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The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks.

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Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.

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Multi-drug resistance (MDR) developed in response to chemotherapy is one of the prominent causes of therapeutic failure. The major underlying factors that contribute to such malignancies include tumor microenvironment, genetic alterations, changes at the cellular level and most of all the heterogeneity of tumors. Recent advances in the field of oncology have prompted a mechanistic understanding of the human genome which is responsible for such alterations, upon which the therapy would be designed. Such an approach that administers drugs by targeting the molecular changes is attributed to precision medicine. Precision medicine helps design therapy as per the requirement of patients based on the sharing of similar complex tumor environments. This revolutionized approach would help in early detection, better targeting, improved patient compliance and survival along with much reduced toxicity otherwise evidenced in conventional cancer therapy. This review discusses the cause of MDR, highlighting the role of precision medicine in overcoming such critical events. Major limitations and future prospects are also highlighted.

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Leishmaniosis, endemic to the Mediterranean area and considered to be the most important zoonosis in Europe, is caused by Leishmania infantum, an intracellular protozoan parasite transmitted by sandflies Phlebotomus. On the one hand, the Ibizan hound, a canine breed native of the Mediterranean region has been described to present a great resistance to the leishmaniosis parasitic infection. On the other hand, other breeds, including boxer, present high prevalence, and severity of the infection. In this study, serum levels of cytokines related to immune response together with the genetic variants found in genes encoding these cytokines have been interrogated in dogs of these two canine breeds (Ibizan hound and boxer) living in the Mediterranean region. A total of 59 apparently healthy dogs were sampled with their corresponding epidemiological data. Serum levels of cytokines were interrogated by ELISA commercial kits and the genetic analysis was carried out with the commercial CanineHD BeadChip and subsequent bioinformatic analysis. The results showed higher levels of IFN-γ, IL-2, and IL-18 and lower levels of IL-8 in Ibizan hound dogs compared to boxer ones. Genomic analysis revealed several genetic variants fixed in the Ibizan hound samples, including IFNG, IL2, IL6R, and IL12RB1 genes, which could explain these differences.

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