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Introduction: Osteosarcoma (OS) is the most common type of primary malignant bone and cartilage tumour. Because of the remarkable developments in technology, remarkable progress has been made in the medical field regarding the diagnosis and management of OS patients. The aim of the study is to describe the clinical and pathological profile of paediatric patients with osteosarcoma and to identify potential prognostic factors for an unfavourable outcome in our country. Methods: We conducted a retrospective study of all children and adolescents with musculoskeletal tumours diagnosed and treated at our tertiary Orthopaedic Department for a period of 10 years. Results: A group of 65 children and adolescents with osteosarcoma who benefited from diagnosis, neoadjuvant, adjuvant and surgical treatment in the Emergency Clinical Hospital for Children "Sfânta Maria" Iasi, România, was analysed. The average age at the time of diagnosis was 12.9 years. The analysis revealed a higher frequency for male patients in the case of femur and tibia locations and a significantly higher frequency of osteosarcoma in the scapula and clavicle in female patients, while OS in the humerus was found only in male patients (χ2 = 19.46, p = 0.0149). The most frequent histopathological subtype was osteoblastic osteosarcoma, but there was no significant correlation with the gender or the age of the patients (χ2 = 0.73, p = 0.863 and χ2 = 0.843, p = 0.839). The results indicated instead a significantly (p = 0.0185) lower age values of patients with undifferentiated osteosarcomas, the average age being 9.4 years ± 2.1 SD. After performing a multivariate logistic regression analysis for the risk of death based on clinical parameters, we found that high tumoural grading increases the risk of death 2.8 times, pleomorphic histological subtype increases the risk of death 3.5 times, and stage IV TNM increases this risk 5.9 times. Conclusions: For the north-eastern geographical part of Romania, the epidemiological and clinical profile of a child with osteosarcoma is a 13-year-old boy with a femoral or tibia tumour or a 12-year-old girl with a femoral, tibia, scapula or clavicle tumour, both coming from a rural area. The tumour has around 12 cm diameter and is a differentiated osteoblastic osteosarcoma. The survival rate at 10 years is 63%. Tumour grading, histological subtype and TNM staging significantly influence the probability of death and could be important prognostic parameters for patients with osteosarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer, age and sex are often studied individually, but the impact of the intersection of these factors on cancer incidence and survival remains unclear. Using the most up-to-date data, we provide an up-to-date analysis of the impact of sex and age on cancer incidence and survival. Using population-based data from the United States Cancer Statistics public use research database and the Centers for Disease Control and Prevention's National Program of Cancer Registries Survival database, we assessed sex and age differences in the incidence and survival of cancers diagnosed from 2001 to 2020. Results demonstrate significant age and sex differences in cancer incidence and survival across the US from 2001 to 2020. Males had a higher cancer incidence compared to females, with notable exceptions for younger age groups among certain types, suggesting age may be a critical component in further understanding the biology of sex differences in cancer. Background: In cancer, age and sex are often studied individually, but the impact of the intersection of these factors on cancer incidence and survival remains unclear. Using population-level data, we provide an up-to-date analysis of the impact of sex and age on cancer incidence and survival. Methods: Using data from the United States Cancer Statistics public use research database and the Centers for Disease Control and Prevention's National Program of Cancer Registries Survival database, we assessed sex and age differences in the incidence and survival of malignant cancers diagnosed from 2001 to 2020. Results: Males experienced higher cancer incidence than females in all sites and age groups, excluding 20–29- and 30–39-year-olds. The highest Male-to-female (M:F) age-adjusted incidence rates (IRR) were observed in mesothelioma within ages 80+ (IRR: 5.48; 95% CI: 5.25–5.71; p < 0.001), and lowest in endocrine cancer within ages 20–29 years (M:F IRR: 0.20; 95% CI: 0.20–0.21; p < 0.001). Among all sites and age groups, excluding 0–9 years, males experienced worse survival than females, particularly within ages 20–29 years (Hazard Ratio (HR): 2.19; 95% CI: 2.15–2.23; p < 0.001). Highest M:F HRs were observed in endocrine system cancers within ages 20–29 (HR: 3.52; 95% CI: 3.15–3.94; p < 0.001), and lowest among lymphomas within ages 0–9 (HR: 0.74; 95% CI: 0.63–0.87; p < 0.001). Conclusions: Significant age and sex differences in cancer incidence and survival were observed across the US from 2001 to 2020. Males had a higher cancer incidence compared to females, with notable exceptions for younger age groups among certain types, suggesting age may be a critical component in further understanding the biology of sex differences in cancer. [ABSTRACT FROM AUTHOR]

Background/Objectives: Both hyperandrogenism (HA) and vitamin D deficiency (VDD) can separately lead to impaired vascular reactivity and ovulatory dysfunction in fertile females. The aim was to examine the early interactions of these states in a rat model of PCOS. Methods: Four-week-old adolescent female rats were divided into four groups: vitamin D (VD)-supplemented (n = 12); VD-supplemented and testosterone-treated (n = 12); VDD- (n = 11) and VDD-and-testosterone-treated (n = 11). Animals underwent transdermal testosterone treatment for 8 weeks. Target VD levels were achieved with oral VD supplementation and a VD-free diet. Estrous cycles were followed by vaginal smear, and quantitative histomorphometric measurements of the ovaries were also taken. In the 8th week, testosterone- and estrogen-induced relaxation of coronary arterioles was examined with pressure angiography. Estrogen receptor (ER) density and oxidative and nitrative stress parameters (Poly-(ADP-Ribose)-Polymerase and 3-nitrotyrosine) in the vessel wall were investigated with immunohistochemistry. Results: VDD caused impaired estrous cycles, and testosterone caused anovulatory cycles (the cycles were stopped at the diestrous phase). VDD combined with testosterone treatment resulted in reduced testosterone and estrogen vasorelaxation, lower ER density, and higher oxidative and nitrative stress in the vessel wall. Conclusions: PCOS with vitamin D deficiency may be associated with increased oxidative–nitrative stress in coronary arterioles. This oxidative and nitrative stress, potentially caused by hyperandrogenism and/or vitamin D deficiency, could impair estrogen-induced relaxation of the coronary arterioles, possibly by decreasing NO bioavailability and disrupting the estrogen-induced relaxation pathway. [ABSTRACT FROM AUTHOR]

Background/Objectives: Renal cell carcinoma is an aggressive form of kidney cancer, contributing to an estimated 138,000 deaths globally in 2017. Traditional treatments like chemotherapy and radiation are generally considered ineffective. Additionally, CD47 has been identified as a crucial tumor antigen involved in the development and progression of various cancers, including renal cell carcinoma. The interaction of CD47 with SIRPα triggers a "don't eat me" signal to the macrophages, inhibiting phagocytosis. Much progress has been made in targeting CD47 for cancer immunotherapy in solid tumors (STs) and hematological malignancies. This study aimed to evaluate CD47 expression in malignant and benign renal cell tumors and compare it with prognostic histopathological parameters. Methods: We included 160 malignant and 26 benign tumors. The malignant tumors consisted of renal cell carcinoma (RCC) subtypes including 37 clear cell, 30 chromophobe, 30 papillary type 1, 29 papillary type 2, and 34 unclassified RCC cases. As for the benign tumors, we included 26 oncocytoma cases. All samples were stained with anti-CD47 antibodies by immunohistochemistry methods. Results: The statistical analysis yielded a significant correlation between CD47 expression and survival, metastasis, and capsule invasion for the unclassified RCC cases. We did not find any further significant correlation between CD47 expression and the studied parameters. Conclusions: To the best of our knowledge, our study is the first to research CD47 expression in benign and malignant renal carcinoma subtypes. Further large-scale studies are needed to determine the expression profile of CD47 in renal cell tumors. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer is a major public health issue, yet risk factors for its occurrence are still insufficiently known. This study aimed to estimate the global burden of esophageal cancer and its risk factors. Methods: This ecological study presented the incidence, mortality, and Disability-Adjusted Life Years (DALYs) of esophageal cancer in the world. This study collected the Global Burden of Disease study data from 1990 to 2019. Trends in esophageal cancer burden were assessed using the joinpoint regression analysis and calculating the average annual percent change (AAPC). Results: Globally, in 2019, in both sexes and all ages, the ASR for the incidence of esophageal cancer was 6.5 per 100,000 and for mortality, 6.1 per 100,000. The global proportion of DALYs for esophageal cancer attributable to selected behavioral, metabolic, and dietary risk factors was similar in males and females: chewing tobacco (3.8% vs. 5.1%), diet low in fruits (10.1% vs. 12.6%), diet low in vegetables (3.3% vs. 4.6%), and high body mass index (18.8% vs. 19.3%). However, the proportion of DALYs for esophageal cancer attributable to smoking and alcohol use was 4–5 times higher in males than in females (50.1% vs. 11.3%, and 29.6% vs. 5.1%, respectively). From 1990 to 2019, a significant decrease in global trends in rates of DALYs for esophageal cancer attributable to smoking (AAPC = −1.6%), chewing tobacco (AAPC = −0.5%), alcohol use (AAPC = −1.0%), a diet low in fruits (AAPC = −3.1%), and a diet low in vegetables (AAPC = −3.6%) was observed, while a significant increase in trends was observed in DALYs rates for esophageal cancer attributable to a high body mass index (AAPC = +0.4%). Conclusions: More epidemiological research is needed to elucidate the relationship between esophageal cancer and certain risk factors and guide prevention efforts. [ABSTRACT FROM AUTHOR]

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP variants associated with breast cancer risk show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity and penetrance of the disease. However, there are gaps in translating how individual genomic variation affects phenotypic presentation. The expansion of criteria for genetic testing and the increasing utilization of comprehensive genetic panels may enhance the identification of individuals carrying P/LP variants linked to hereditary breast cancer. Individualized risk assessment could facilitate the implementation of personalized risk-reduction strategies for these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through breast imaging, and risk-reducing surgeries. This review addresses the current literature's inconsistencies and limitations, particularly regarding risk factors and the intensity of preventive strategies for women with P/LP variants in moderate- and high-penetrance genes. In addition, it synthesizes the latest evidence on risk assessment and primary and secondary prevention in women at high risk of breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric intestinal metaplasia (GIM) is regarded as "the point of no return" in the gastric cancerogenesis sequence. Helicobacter pylori infection remains the leading etiologic factor for non-cardia gastric cancer in adults. On the other hand, the causes and evolution of GIM in children remain poorly understood. The aim of this study was to evaluate the long-term outcome of GIM once children reached adulthood, after a mean follow-up of a decade between both esophagogastroduodenoscopies with gastric sampling. Furthermore, the results of our study provide valuable insights into the risk factors and surveillance considerations of GIM, diagnosed in children. The results suggest the possibility of discontinuing surveillance for limited complete-type GIM diagnosed in childhood, in patients without additional risk factors for gastric adenocarcinoma. Background/Objectives: Gastric intestinal metaplasia (GIM) is considered an irreversible preneoplastic precursor for gastric adenocarcinoma in adults. However, its significance in children and the long-term outcome remain poorly understood. Methods: All children diagnosed with GIM between 2000 and 2020 were identified at a large tertiary referral centre. Upon reaching adulthood (≥18 years), the patients were invited to undergo follow-up esophagogastroduodenoscopy (using narrow-band imaging additionally to high-definition white light endoscopy), with gastric biopsies obtained according to the updated Sydney protocol. Childhood and adulthood gastric biopsies were re-evaluated by two experienced gastrointestinal pathologists using Kreyberg staining. Results: Paediatric GIM was diagnosed in 178/14,409 (1.2%) esophagogastroduodenoscopies performed during the study period. Fifty adult patients with childhood GIM agreed to participate in the study. The mean age at childhood and adulthood endoscopies were 14.3 years (median 15) and 25.2 years (median 24), respectively. The mean follow-up interval was 10.5 years. All childhood GIM cases were classified as complete-type. Notably, GIM completely resolved in 41/50 of patients (82%) by the time of adulthood follow-up. No dysplasia or carcinoma was detected in any patient. Childhood Helicobacter pylori infection, similar to other evaluated host-related factors, was not significantly associated with the persistence of GIM into adulthood (11.2% vs. 29.3%, p = 0.41). Conclusions: Childhood GIM was a rare finding but demonstrated a high rate of reversibility by adulthood regardless of Helicobacter pylori status, with no cases of dysplasia or carcinoma observed during long-term follow-up. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer (EC) is the sixth leading cause of cancer-related mortality worldwide, continuing to be a significant public health concern. The purpose of this study is to assess the impact of staging and histopathology of EC on associated mortality. The study also aims to further investigate clinical characteristics, prognostic factors, and survival outcomes in patients diagnosed with EC between 2010 and 2017. Furthermore, we analyzed the interaction between tumor histology and staging and the risk of mortality. Methods: A total of 24,011 patients diagnosed with EC between 2010 and 2017 in the United States were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Demographic parameters, tumor stage, and histologic subtypes were analyzed and associated overall mortality (OM) and cancer-specific mortality (CSM) were measured across all subgroups. Covariates reaching the level of statistical significance, demonstrable by a p-value equal to or less than 0.01, were incorporated into a multivariate Cox proportional hazards model. A hazard ratio greater than 1 was indicative of an increased risk of mortality in the presence of the variable under discussion. Additionally, the study explores the interaction between histology and tumor stage on outcomes. Results: The majority of patients were male (80.13%) and non-Hispanic white (77.87%), with a predominant age at diagnosis of between 60 and 79 years (59.86%). Adenocarcinoma was the most common tumor subtype (68.17%), and most patients were diagnosed at a distant stage (41.29%). Multivariate analysis revealed higher mortality risks for males, older patients, unmarried individuals, and those with advanced-stage tumors. Higher income, receiving radiation or chemotherapy, and undergoing surgery were associated with lower mortality. Tumor subtype significantly influenced mortality, with squamous cell carcinoma and neuroendocrine tumors showing higher hazard ratios compared to adenocarcinoma. Adenocarcinoma is linked to a poorer prognosis at advanced stages, whereas the opposite trend is observed for SCC. Conclusions: The study identifies significant demographic and clinicopathologic factors influencing mortality in esophageal cancer patients, highlighting the importance of early diagnosis and treatment intervention. Future research should focus on tailored treatment strategies to improve survival outcomes in high-risk groups and to understand the interaction between tumor histology and tumor stage. [ABSTRACT FROM AUTHOR]

Introduction: Invasive aspergillosis (IA) is an opportunistic fungal infection that typically occurs in the immunocompromised host and is associated with severe morbidity and mortality. Myocardial abscess formation is seldomly described. Detailed Case Description: We present a case of IA with purulent myocarditis. The patient was on long-term high-dose corticosteroid and mycophenolate mofetil therapy for severe lupus nephritis. After multiple visits to his general practitioner and nephrologist for general malaise, he was admitted to our hospital with visual complaints. Within several days, he developed atrial fibrillation, respiratory insufficiency, and, finally, a decreased level of consciousness. After admission to the intensive care unit, the broncho alveolar lavage (BAL) fluid galactomannan (GM) index was normal, but the serum GM index was severely elevated. Despite initiation of antifungal therapy, the patient passed away shortly thereafter. Autopsy revealed massive intracranial hemorrhage and disseminated IA affecting the lungs, brain, and myocardium, with macroscopic myocardial abscess formation. Discussion: This classic case of diagnostic uncertainty illustrates how invasive fungal infections can progress to disseminated disease while showing nonspecific symptoms only. It emphasizes the importance of vigilance for opportunistic fungal infections in a growing category of immunocompromised patients. Conclusion: Clinicians should have a low threshold of suspicion for fungal infections in patients on combination immunosuppressive medication, such as high-dose corticosteroid therapy in combination with T-cell inhibitors like MMF. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma is a kidney cancer with high incidence rates in the western world. There is an increasing research base fueling the modern application of therapy to treat this cancer. Despite the traditional surgical interventions available for treatment, more is now understood about its metastases and optimal treatment strategies. The treatment of clear cell renal cell carcinoma is quickly advancing to ensure that patients receive personalized cancer therapy specific to their solid tumor. While surgical interventions remain the dominant treatment modality, adjuvant drug therapies have shown promising results, especially for patients with advanced disease. Clear cell renal cell carcinoma is the most common form of kidney cancer, accounting for 75% of malignant kidney tumors, and is generally associated with poor patient outcomes. With risk factors including smoking, obesity, and hypertension, all of which have a high prevalence in the United States and Europe, as well as genetic factors including tuberous sclerosis complex and Von Hippel–Lindau syndrome, there is an increasing need to expand our present understanding. The current clear cell renal cell carcinoma knowledge is outdated, with obsolete diagnostic criteria and moderately invasive surgical treatments still prevailing, partially ascribed to its resistance to chemotherapy and radiation therapy. The standard of treatment relies on surgical intervention, including radical nephrectomy and partial nephrectomy, while more recent treatments target neoplastic growth pathways and immune regulation checkpoints. [ABSTRACT FROM AUTHOR]

Simple Summary: Adrenocortical tumors (ACTs) are rare in children and can be benign (adrenocortical adenoma or ACA) or malignant (adrenocortical carcinoma or ACC). Children with Beckwith–Wiedemann spectrum (BWSp) are at an increased risk of developing ACTs, but there is uncertainty around the prognosis, management, and molecular characteristics associated with these tumors. In this study, we provide a literature review of data from 54 published patients with BWSp-ACT and report on one additional new patient, totaling 55 cases: 19 ACA, 33 ACC, and 3 uncertain malignant potential (umACT). Almost half of the ACC patients were clinically diagnosed with BWSp after ACC onset, suggesting that the BWSp clinical diagnostic score has limited value for early diagnosis in this setting. Two patients with metastatic ACC had a low histopathological Wieneke score, confirming limitations of the current histopathological classification, as previously documented. Ultrasound screening failed to identify ACC before metastasis in two cases, indicating a need for new screening strategies for ACTs in children with BWSp. Notably, in some cases, metastatic ACC exhibited unexpectedly indolent behavior, despite their malignancy. Background/Objectives: Adrenocortical tumors (ACTs), including adrenocortical adenoma (ACA) and carcinoma (ACC), represent 0.3–0.4% of pediatric tumors. Beckwith–Wiedemann spectrum (BWSp) confer an increased risk of ACTs, but prognosis, management, and associated molecular characteristics are unclear. Methods: This paper combines a literature review of 54 published cases of BWSp-ACT with a report of one newly identified patient, totaling 55 cases with a confirmed BWSp clinical and/or molecular diagnosis. Results: Nineteen patients with ACA, 33 with ACC, and 3 with ACT of uncertain malignant potential (umACT) were included. Twenty patients had uniparental disomy of chromosome 11p15.5 (patUPD11), 11imprinting Center 2 Loss-of-methylation (IC2-LoM), and had 2 11p15 locus duplication. Eleven patients were diagnosed during cancer screening procedures, including two metastatic at diagnosis ACC. Conclusions: Almost half of ACC patients reached the minimum score for clinical BWSp diagnosis only after ACC onset, suggesting that the BWSp score has limited value for the early diagnosis in such a setting. Two patients with metastatic ACC had a histopathological Wieneke score ≤2, not correlating with clinical malignancy and confirming limitations of the current histopathological classification, as previously documented. Ultrasound screening failed identifying the ACC before metastasis in two cases, indicating an urgent need to develop new strategies for screening of ACTs in BWSp. Furthermore, some cases of metastatic ACC exhibited unexpectedly indolent behavior despite being malignant. [ABSTRACT FROM AUTHOR]

Simple Summary: This research aims to better understand the causes of Mycosis fungoides (MF)—a disease where a type of immune cell, the T cell, malignantly transforms into cancer. It is not yet fully understood what triggers MF or how it progresses, partly because it varies so much between patients and because there is debate about whether the disease begins in immature T cells (thymocytes) or in more mature T cells (memory T cells). Recent findings suggest that bacteria living on the skin, particularly a harmful strain of Staphylococcus aureus, may aggravate MF by triggering specific pathways in T cells. To investigate this hypothesis, we explored the gene expression and microbial abundance of MF patients' skin with advanced statistical methods. We found that varied microbial skin colonization between patients may explain why the skin gene expression is so different from patient to patient. We also observed additional evidence that S. aureus might indeed trigger pathways in mature T cells that fuel cancer progression. Further, our statistical model suggested that certain viruses, like Epstein–Barr virus, could play a role in starting the disease by disrupting thymocytes (immature T cells). Based on these results, we speculate that both perspectives on the origin of MF could be correct, immature (thymocytes) and mature T cells: Thymocytes undergo malignant transformation, possibly caused by viruses, and bacteria like S. aureus fuel the malignant T cells to become prominent cancer cells. Our research could help uncover the complex interplay between bacteria, viruses, and T cells in MF. The findings may pave the way for new treatments targeting the skin microbiome or T cell pathways, offering hope for better management of this challenging disease. Background: Mycosis fungoides (MF) represents the most prevalent entity of cutaneous T cell lymphoma (CTCL). The MF aetiopathogenesis is incompletely understood, due to significant transcriptomic heterogeneity and conflicting views on whether oncologic transformation originates in early thymocytes or mature effector memory T cells. Recently, using clinical specimens, our group showed that the skin microbiome aggravates disease course, mainly driven by an outgrowing, pathogenic S. aureus strain carrying the virulence factor spa, which was shown by others to activate the T cell signalling pathway NF-κB. Methods: To explore the role of the skin microbiome in MF aetiopathogenesis, we here performed RNA sequencing, multi-omic data integration of the skin microbiome and skin transcriptome using Multi-Omic Factor Analysis (MOFA), virome profiling, and T cell receptor (TCR) sequencing in 10 MF patients from our previous study group. Results: We observed that inter-patient transcriptional heterogeneity may be largely attributed to differential activation of T cell signalling pathways. Notably, the MOFA model resolved the heterogenous activation pattern of T cell signalling after denoising the transcriptome from microbial influence. The MOFA model suggested that the outgrowing S. aureus strain evoked signalling by non-canonical NF-κB and IL-1B, which in turn may have fuelled the aggravated disease course. Further, the MOFA model indicated aberrant pathways of early thymopoiesis alongside enrichment of antiviral innate immunity. In line with this, viral prevalence, particularly of Epstein–Barr virus (EBV), trended higher in both lesional skin and the blood compared to nonlesional skin. Additionally, TCRs in both MF skin lesions and the blood were significantly more likely to recognize EBV peptides involved in latent infection. Conclusions: First, our findings suggest that S. aureus with its virulence factor spa fuels MF progression through non-canonical NF-κB and IL-1B signalling. Second, our data provide insights into the potential role of viruses in MF aetiology. Last, we propose a model of microbiome-driven MF aetiopathogenesis: Thymocytes undergo initial oncologic transformation, potentially caused by viruses. After maturation and skin infiltration, an outgrowing, pathogenic S. aureus strain evokes activation and maturation into effector memory T cells, resulting in aggressive disease. Further studies are warranted to verify and extend our data, which are based on computational analyses. [ABSTRACT FROM AUTHOR]

Background/Objectives: One of the most important diagnostic tools in bone tumors is X-rays. Preliminary and, in the case of some benign lesions, definitive diagnoses are formed using this basic tool. Part of the decision making in this stage is based on statistical probability using the patient's age, as well as the incidence and predilection sites of different entities. The information used today is based on older and fragmented data. To verify the underlying principles, we retrospectively evaluated all bone tumors in children and adolescents treated by our tertiary center in the last 20 years. Methods: For this retrospective study, patients under the age of 18 years suffering from histopathologically verified bone tumors were evaluated. Data were retrieved from our local musculoskeletal tumor database. Results: We were able to include 420 children treated for bone tumors in our tertiary center. The cohort consisted of 335 benign and 85 malignant lesions. The most common lesions were 137 osteochondromas; the malignant tumors consisted mainly of osteosarcomas (53) and Ewing's sarcomas (28). The primary predilection sites were the metaphyses of long bones. Conclusions: We were able to confirm and supplement the fragmentary data of these rare diseases using our own cohort. [ABSTRACT FROM AUTHOR]

Variants in the RB1 gene are associated with retinoblastoma (RB) development, and their presence in germline cells considerably increases the risk of subsequent malignant neoplasms (SMNs) in RB survivors. We report a female patient with bilateral RB who developed two SMNs in less than ten years, with a de novo pathogenic nonsense variant in RB1 [NM_000321.3:c.306T>A, p.(Cys102*)] in heterozygosity. The updated literature review of similar cases of SMN in patients with a previous diagnosis of RB reveals a wide range in both the type of subsequent malignancy and the age at which these SMNs develop. In addition, we identified only three cases with two SMNs following RB diagnosis, with at least one of these being an EWS. This case broadens the clinical and genetic landscape of RB, demonstrates the importance of a multidisciplinary approach in these patients, and highlights genetic diagnosis as a mandatory feature for management. [ABSTRACT FROM AUTHOR]

Disturbances in carbohydrate metabolism are suggested to be the early symptoms of pancreatic ductal adenocarcinoma (PDAC). The accumulated data suggests that endocrine function-related biomarkers may represent a breakthrough in the early detection of PDAC. Factors which may predispose one to the development of PDAC are insulin resistance and hyperinsulinemia. Elevated insulin levels induce the onset of carcinogenesis by altering the differentiation and function of islet cells through stimulating growth factors, including insulin-like growth factors (IGFs). Impaired β cell function, along with the impact of PDAC-released factors (e.g., adrenomedullin (ADM), IGF-1, and macrophage inhibitory factor (MIF) on pancreatic islets, may contribute to the induction of diabetes associated with PDAC. Recently, exosomes have attracted worldwide attention due to their role in varied features of cell function, particularly in cancer progression. Exosomes comprise of small extracellular vesicles produced by almost all cells. These vesicles contain a vast array of biomolecules, including proteins and microRNAs. Exosomes participate in cancer growth and promote angiogenesis. They promote tumorigenesis and metastasis, and are associated with the acquisition of cancer cells resistant to chemotherapy. Data have been accumulating recently on the role of exosomes in the rapid recognition, prognosis and potential therapy of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumors in soft tissue and bones are rare, and there is limited knowledge about how they occur. Better knowledge about inherited predisposition to tumor syndromes increases the chance for the medical community to detect cancer early through targeted screening programs and to choose the most appropriate cancer treatment. In our study, we show that some inherited mutations can increase the risk for these tumors. We applied a novel approach, in which we analyzed a blood sample in tandem with a tumor sample from participants, and we found especially interesting inherited mutations. Some of the mutations we found were already known to increase the risk of cancer, although not proven to be connected to soft tissue and bone tumors before. Other mutations we present have not been shown to be connected to tumors at all before. Our findings can guide further genetic investigations of soft tissue and bone tumors. Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1, RB1, TP53, EXT2, and SDHC) and without (ATM, CDC73, MLH1, MSH6, POLG, and KCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the three CHEK2 carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: The purpose of this pediatric cancer research investigation was to assess how radiation therpay in the first primary malignannt neoplasm predispose to Second Primary Thyroid Maligancy (SPTM), as well as therapeutics and mortality associated with SPTM. This study applied a retrospective cohort design, as non-experiment translational epidemiologic investigation, utilizing the USA National Cancer Institute, Surveillance Epidemiology and End Results (SEER) data in the assessment of risk determinants and predisposing factors in SPTM, as well as racial differentials in SPTM cumulative incidence and mortality. Specifically, radiation utilization in first primary malignancy among children predisposed to SPTM, indicative of the need to assess exposure effect of other carcinogens prior to radiation therapy in first primary malignant neoplasm, hence SPTM marginilaization. Objective: To assess racial and sex variances in second primary thyroid malignancy (SPTM) cumulative incidence and temporal trends and the radiation exposure effect in pediatric SPTM. Materials and Methods: A retrospective cohort study, a non-experimental epidemiologic design, was used to assess the cumulative incidence (CmI) and temporal trends as well as the exposure effect of radiation in SPTM among children, 0–19 years, in the Surveillance, Epidemiology, and End Results (SEER) registry, National Cancer Institute (NCI), USA. Percent change (PC) and annual percent change (APC) were used to examine CmI rates and temporal trends, while chi-square statistics and binomial regression models were used to examine variable distribution by race and to determine the exposure effect of radiation on SPTM as well as mortality, respectively. Results: The frequency of pediatric thyroid cancer was (n = 3457) between 1973 and 2013/14, while the PC was 151.2 for all races but 99.8 among whites. Of all pediatric thyroid cancers diagnosed during this period, SPTM accounted for 3% (n = 99). Compared to whites, blacks/AA were 60% less likely to present with SPTM, adjusted risk ratio, aRR = 0.40, 99% CI 0.06–2.47, while other races were 18% more likely to develop SPTM, aRR = 1.18, 99% CI 0.48–2.87. Additionally, females relative to males were 63% less likely to be diagnosed with SPTM, aRR = 0.37, 99% CI 0.22–0.61. With respect to urbanicity, compared to children in rural areas, those in urban areas were 21% less likely to develop SPTM, aRR = 0.79, 99% CI, 0.12–5.35, while children in metropolitan areas were 40% less likely to develop SPTM, aRR = 0.60, 99% CI, 0.10–3.59. Although imprecise, there was a 5% increased risk of SPTM, with radiation as an exposure effect, aRR = 1.05, 99% CI 1.01–1.75. Conclusions: There are increasing temporal trends in pediatric SPTM with blacks relative to whites having observed lower incidence, despite an increasing percent change among blacks/AA, indicative of the disproportionate burden of this malignant neoplasm. SPTM risk was higher among males and in rural areas, while radiation as a risk for SPTM was clinically and biologically meaningful, albeit an observed statistically insignificant inference due to sampling variability, requiring intervention mapping in radiation exposure margination among children. [ABSTRACT FROM AUTHOR]

A hereditary component of breast (BC) and colorectal cancer (CRC) has been described in approximately one-third of these tumor types. BC patients have an increased risk of developing CRC as a second primary tumor and vice versa. Germline genomic variants (NextSeq550, Illumina) were investigated in 24 unrelated BC and/or CRC patients and 7 relatives from 3 index patients. Fifty-six pathogenic or likely pathogenic variants were identified in 19 of 24 patients. We detected single-nucleotide variants (SNVs) in CRC predisposition genes (MLH1 and MUTYH) and other promising candidates (CDK5RAP3, MAD1L1, NOS3, and POLM). Eighteen patients presented SNVs or copy number variants (CNVs) in DNA damage repair genes. We also identified SNVs recently associated with BC or CRC predisposition (PABPC1, TYRO3, MAP3K1, SLC15A4, and LAMA1). The PABPC1c.1255C>T variant was detected in nine unrelated patients. Each patient presented at least one SNV/CNV in a candidate gene, and most had alterations in more than one gene, reinforcing a polygenic model for BC/CRC predisposition. A significant fraction of BC/CRC patients with a family history of these tumors harbored deleterious germline variants in DNA repair genes. Our findings can lead to strategies to improve the diagnosis, genetic counseling, and treatment of patients and their relatives. [ABSTRACT FROM AUTHOR]

Background: Fertilizers are widely used to supply nutrients to crops, thereby increasing yields and soil fertility. However, the effects of their production and application on human health through occupational, residential, and environmental exposure remain unclear. Objective: To conduct a systematic review of epidemiological studies on the association between exposure to fertilizers and health-related outcomes. Methods: We searched in PubMed, Scopus, and Web of Science for cohort, case-control, cross-sectional, and ecological studies (up to May 2024) related to exposure to fertilizers and any reported human health endpoints across all age groups, without language or geographical limitations. Data were extracted for population and study characteristics, type of fertilizer used, exposure assessment, sample size, outcome and its definition, effect estimate, and quality characteristics from the eligible studies, and they were descriptively synthesized. Results: We found 65 eligible publications, with 407 postulated associations. Forty-six publications (321 associations) assessed exposure to inorganic fertilizers, and nineteen studies (93 associations) assessed organic fertilizers. Exposure assessed was related to occupation, residence, and/or proximity. The assessed outcomes were diverse, with considerable harmonization challenges. Inorganic fertilizers have been associated with an increased risk of cancerous outcomes in a small number of studies with methodological limitations and low replication validity, while organic fertilizers have been associated with infections and diarrhea. Conclusions: The epidemiological evidence suggests possible associations between inorganic fertilizers with solid organ tumors and hematological malignancies and organic fertilizers with infections and diarrhea. However, the available evidence is limited, and heterogeneity prevails. Further research is needed to enlarge the evidence base and increase the replication validity and robustness of the results. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is an asymptomatic malignancy in early stages, with an invasive and cost-ineffective diagnostic toolbox that contributes to severe global mortality rates on an annual basis. Ectopic expression of the lineage survival transcription factors (LS-TFs) GATA4 and 6 promotes stomach oncogenesis. However, LS-TFs also govern important physiological roles, hindering their direct therapeutic targeting. Therefore, their downstream target genes are particularly interesting for developing cancer-specific molecular biomarkers or therapeutic agents. In this work, we couple inducible knockdown systems with chromatin immunoprecipitation and RNA-seq to thoroughly detect and characterize direct targets of GATA-mediated transcriptional regulation in gastric cancer cells. Our experimental and computational strategy provides evidence that both factors regulate the expression of several coding and non-coding RNAs that in turn mediate for their cancer-promoting phenotypes, including but not limited to cell cycle, apoptosis, ferroptosis, and oxidative stress response. Finally, the diagnostic and prognostic potential of four metagene signatures consisting of selected GATA4/6 target transcripts is evaluated in a multi-cancer panel of ~7000 biopsies from nineteen tumor types, revealing elevated specificity for gastrointestinal tumors. In conclusion, our integrated strategy uncovers the landscape of GATA-mediated coding and non-coding transcriptional regulation, providing insights regarding their molecular and clinical function in gastric cancer. [ABSTRACT FROM AUTHOR]

Mining activities, particularly in large excavations like the Bingham Canyon Copper Mine in Utah, have been increasingly linked to respiratory conditions due to heavy-metal-enriched waste and dust. Operating continuously since 1906, the Bingham Canyon Copper Mine contributes 4.4% of the Salt Lake Valley PM2.5 pollution. However, the extent of its contributions to larger-sized particulate matter (PM10) dust, soil and water contamination, and human health impacts is largely unknown. Aerosol optical depth data from Sentinel-2 imagery revealed discernible dust clouds downwind of the mine and smelter on non-prevailing-wind days, suggesting potential heavy metal dispersion from this fugitive dust and subsequent deposition to nearby surface soils. Our analysis of topsoils from across the western Salt Lake Valley found mean arsenic, copper, lead, and zinc concentrations to be well above global background concentrations. Also, the minimum values for arsenic and maximum values for lead were well above the US EPA regional screening levels for residential soils. Thus, arsenic is the metal of greatest concern for impacts on human health. Elevated concentrations of all metals were most notable near the mine, smelter, and tailings pond. Our study linked these elevated heavy metal levels to regional asthma outcomes through cluster analysis and distance-related comparison tests. Significant clusters of high asthma rates were observed in regions with elevated topsoil heavy metal concentrations, impacting both low- and high-income neighborhoods. The findings of this preliminary study suggest that the mine, smelter, and recent construction activities, especially on lands reclaimed from former tailings ponds, could be contributing to atmospheric dust containing high levels of heavy metals and exacerbating asthma outcomes for residents. However, the methods used in the study with aggregated health outcome data cannot determine causal links between the heavy metal contents of soil and health outcomes; they can only point to potential links and a need for further investigation. Such further investigation should involve individual-level data and control for potential confounding factors, such as socioeconomic status, access to healthcare, and lifestyle factors, to isolate the effect of metal exposures on asthma outcomes. This study focused on atmospheric deposition as a source of heavy metal enrichment of topsoil. However, future research is also essential to assess levels of heavy metals in subsoil parent materials and local surface and groundwaters to be able to assess the links between the sources or methods of soil contamination and health outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer of the upper digestive system is associated with poor survival due to difficulties in diagnosing the disease early, before it has spread around the body. Previous research has shown that the healthy bacteria within the body changes in response to medications, diet and infection. Some of these changes are associated with a greater risk of developing cancers of the oesophagus (gullet) and stomach. This occurs, at least in part, through inflammation. This process is the body's natural response to infection, injury and exposure to potentially harmful substances, which, if uncontrolled can lead to diseases including cancer. This review article aims to explain the ways in which this happens. By developing a deeper understanding of these processes, advances in early diagnosis of this disease can be made, which may lead to better survival. Introduction: The upper gastrointestinal microbiome is a dynamic entity that is involved in numerous processes including digestion, production of vitamins and protection against pathogens. Many external and intrinsic factors may cause changes in the proportions of bacteria within the microbial community, termed 'dysbiosis'. A number of these have been identified as risk factors for a range of diseases, including oesophago-gastric carcinoma. Materials and Methods: A narrative review was conducted to elucidate the current evidence on the role of the microbiome in promoting oesophago-gastric tumourigenesis. Significant causes of dysbiosis including age, medications and GORD were examined and key pro-inflammatory pathways implicated in tumourigenesis and their interaction with the microbiome were described. Results and Discussion: An association between microbial dysbiosis and development of oesophago-gastric cancer may be mediated via activation of pro-inflammatory pathways, the inflammasome and the innate immune system. Advances in sequencing technology allow microbial communities to be fingerprinted by sequencing the 16S rRNA gene, enabling a deeper understanding of the genera that may be implicated in driving tumourigenesis. Conclusions: Developing a greater understanding of the influence of the microbiota on oesophago-gastric tumourigenesis may enable advances to be made in the early detection of malignancy and in the development of novel systemic therapies, leading to improved rates of survival. [ABSTRACT FROM AUTHOR]