Cutaneous Metastasis of Alveolar Rhabdomyosarcoma in a Child.

ABSTRACT: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. This lesion is classically included in the generic group of "small round blue cell tumors" along with other entities that share similar microscopic features. Although the head and neck region is a frequent site for primary tumors, cutaneous metastases of RMS involving this anatomical location are rare in the pediatric population. We report a case of a 12-year old girl previously diagnosed with a primary alveolar RMS involving the left maxillary sinus, presenting with a metastatic lesion on the skin of the left temple area. Along with a brief review of the previous case reports on the topic, we highlight the initial immunohistochemistry panel useful for diagnosing this tumor.

Thoracic Sertoli-Leydig cell tumor: An alternative type of pleuropulmonary blastoma associated with DICER1 variation.

A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl.

Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication.

BACKGROUND: The treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects. Consequently, there is an urgent need to identify novel therapies that will improve outcomes for children and adults with Ewing sarcoma tumors while also decreasing treatment-related toxicities. METHODS: We analyzed data from the PRISM drug repurposing screen, which tested the activity of 4518 drugs across 578 cancer cell lines, to identify drugs that selectively inhibit the growth of Ewing sarcoma cell lines. We then tested the effects of a top hit from the screen on cell proliferation, cell cycle progression, and activation of the DNA damage pathway using Ewing sarcoma cell lines. We also used a CRISPR/Cas9 gene knockout approach to investigate the role of Schlafen 11 (SLFN11), a restriction factor for DNA replication stress that is overexpressed in Ewing sarcoma tumors, in mediating the sensitivity of Ewing sarcoma cells to the drug. RESULTS: We found that eltrombopag, an FDA-approved thrombopoietin-receptor agonist (TPO-RA) that is currently being evaluated as a treatment for chemotherapy-induced thrombocytopenia, inhibits the growth of Ewing sarcoma cell lines in vitro in proliferation and colony formation assays. However, from a mechanistic standpoint, the thrombopoietin receptor is not expressed in Ewing sarcoma cells and we show that eltrombopag impairs DNA replication and causes DNA damage in Ewing sarcoma cells by chelating iron, a known "off-target" effect of the drug. We also found that the sensitivity of Ewing sarcoma cells to eltrombopag is mediated, in part, by SLFN11, which regulates the cellular response to DNA replication stress. CONCLUSIONS: Ewing sarcoma cell lines are sensitive to eltrombopag and this drug could improve outcomes for patients with Ewing sarcoma tumors by both targeting the tumor, via chelation of iron and inhibition of DNA replication, and reducing chemotherapy-induced thrombocytopenia, via stimulation of the thrombopoietin receptor.

Novel Use of Porcine Urinary Bladder Matrix in the Exenterated Socket.

The aim of exenteration reconstruction is to stabilize the postsurgical wound bed to promote expeditious healing particularly in patients who are undergoing adjuvant radiation and/or chemotherapy. Porcine urinary bladder matrix has previously been used successfully as a wound-healing scaffold in treatment of burns and in acute, chronic, and surgical wounds, but the use of these products has not previously been reported in the exenterated orbit. The authors present a case of the novel use of porcine urinary bladder matrix in a pediatric patient who underwent exenteration for recurrent embryonal rhabdomyosarcoma, subsequent split-thickness skin grafting, and adjuvant radiation.

Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization.

BACKGROUND: Filaggrin loss-of-function (FLG-LOF) mutations are an established genetic cause of eczema. These mutations have subsequently been reported to increase the risk of aeroallergen sensitization and allergic airway disease. However, it is unclear whether FLG variants require both eczema and aeroallergen sensitization to influence airway disease development long-term outcomes. OBJECTIVE: To examine the effects of FLG-LOF mutations on allergic airway disease outcomes, with eczema and aeroallergen sensitization as intermediate variables, using the Isle of Wight birth cohort. METHODS: Study participants were evaluated at ages 1, 2, 4, 10 and 18 years to ascertain the development of allergic diseases (eczema, asthma and allergic rhinitis) and aeroallergen sensitization (determined by skin prick tests). FLG-LOF mutations were genotyped in 1150 subjects. To understand the complex associations between FLG mutations, intermediate variables (eczema and aeroallergen sensitization) and airway disease, path analysis was performed. RESULTS: There were significant total effects of FLG-LOF mutations on both asthma and allergic rhinitis at all ages as well as on aeroallergen sensitization up till 10 years old. In the filaggrin-asthma analysis, a direct effect of FLG-LOF mutations was observed on early childhood eczema (age 1 and 2 years) (relative risk (RR) 2.01, 95% CI: 1.74-2.31, P < .001), and all significant indirect pathways on asthma outcomes passed through eczema at these ages. In contrast, for the filaggrin-rhinitis model, FLG-LOF mutations exerted significant direct effects on early eczema as well as rhinitis at 10 years (RR 1.99; 95% CI: 1.72-2.29, P = .002). CONCLUSION: FLG-LOF mutations are a significant risk factor for later childhood asthma and rhinitis. However, the pathway to asthma is only through early childhood eczema while a direct effect was observed for childhood rhinitis.

The cluster beam route to model catalysts and beyond.

The generation of beams of atomic clusters in the gas phase and their subsequent deposition (in vacuum) onto suitable catalyst supports, possibly after an intermediate mass filtering step, represents a new and attractive approach for the preparation of model catalyst particles. Compared with the colloidal route to the production of pre-formed catalytic nanoparticles, the nanocluster beam approach offers several advantages: the clusters produced in the beam have no ligands, their size can be selected to arbitrarily high precision by the mass filter, and metal particles containing challenging combinations of metals can be readily produced. However, until now the cluster approach has been held back by the extremely low rates of metal particle production, of the order of 1 microgram per hour. This is more than sufficient for surface science studies but several orders of magnitude below what is desirable even for research-level reaction studies under realistic conditions. In this paper we describe solutions to this scaling problem, specifically, the development of two new generations of cluster beam sources, which suggest that cluster beam yields of grams per hour may ultimately be feasible. Moreover, we illustrate the effectiveness of model catalysts prepared by cluster beam deposition onto agitated powders in the selective hydrogenation of 1-pentyne (a gas phase reaction) and 3-hexyn-1-ol (a liquid phase reaction). Our results for elemental Pd and binary PdSn and PdTi cluster catalysts demonstrate favourable combinations of yield and selectivity compared with reference materials synthesised by conventional methods.

Sexual Dysfunction Among Adolescent and Young Adult Men Diagnosed with Cancer.

Purpose: Adolescent and young adult (AYA) cancer patients frequently demonstrate sexual dysfunction; however, there is a lack of data quantifying the severity and frequency. Methods: Males aged 18-39 years, diagnosed with cancer of any kind and who were scheduled to begin, were actively receiving, or had completed cancer treatment within 6 months, were offered validated surveys during their oncology appointment. These surveys included the International Index of Erectile Function (IIEF-6), Masturbation Erection Index (MEI), 36-Item Short Form Survey, and 5-point Likert scales to assess their desire and ability to engage in sex and masturbation. Results: Forty subjects completed the IIEF survey with a mean score of 17.7 ± 11, erectile dysfunction (ED) prevalence accordingly was 58%. Thirty-eight subjects completed the MEI with a mean score of 25.3 ± 5.3, ED prevalence was again 58%. Age and IIEF scores demonstrated a statistically significant (p < 0.05, n = 38) Pearson's correlation coefficient of 0.40, patients younger than 30 years had an ED prevalence of 72% (mean IIEF 13), whereas patients aged 30 years and older had an ED prevalence of 45% (mean IIEF 22). All treatment modalities had ED rates >30%: chemotherapy demonstrated the highest prevalence at 64% (mean IIEF 17), whereas radiation therapy had the lowest prevalence at 33% (mean IIEF 23). Conclusion: This study demonstrates that the prevalence of sexual dysfunction among male AYA patients undergoing treatment for cancer is high. AYA oncologists should discuss potential sexual health concerns when treating this population. The exact cause of ED (non-organic vs. organic) within this group should be explored further.

Low pathogenic avian influenza A (H7N2) virus infection in immunocompromised adult, New York, USA, 2003.

In 2003, infection with low pathogenic avian influenza A (H7N2) virus was identified in an immunocompromised man with fever and community-acquired pneumonia in New York, USA. The patient recovered. Although the source of the virus was not identified, this case indicates the usefulness of virus culture for detecting novel influenza A viruses.

Inhibitor of DNA binding 2 (ID2) regulates the expression of developmental genes and tumorigenesis in ewing sarcoma.

Sarcomas are difficult to treat and the therapy, even when effective, is associated with long-term and life-threatening side effects. In addition, the treatment regimens for many sarcomas, including Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, are relatively unchanged over the past two decades, indicating a critical lack of progress. Although differentiation-based therapies are used for the treatment of some cancers, the application of this approach to sarcomas has proven challenging. Here, using a CRISPR-mediated gene knockout approach, we show that Inhibitor of DNA Binding 2 (ID2) is a critical regulator of developmental-related genes and tumor growth in vitro and in vivo in Ewing sarcoma tumors. We also identified that homoharringtonine, which is an inhibitor of protein translation and FDA-approved for the treatment of leukemia, decreases the level of the ID2 protein and significantly reduces tumor growth and prolongs mouse survival in an Ewing sarcoma xenograft model. Furthermore, in addition to targeting ID2, homoharringtonine also reduces the protein levels of ID1 and ID3, which are additional members of the ID family of proteins with well-described roles in tumorigenesis, in multiple types of cancer. Overall, these results provide insight into developmental regulation in Ewing sarcoma tumors and identify a novel, therapeutic approach to target the ID family of proteins using an FDA-approved drug.

Hypertensive disorders of pregnancy among women with a history of leukemia or lymphoma.

OBJECTIVE: Hypertension during pregnancy can adversely affect maternal and fetal health. This study assessed whether diagnosis of leukemia or lymphoma prior to pregnancy is associated with hypertensive disorders of pregnancy including gestational hypertension, preeclampsia and eclampsia. STUDY DESIGN: A cross-sectional study used two statewide population-based datasets that linked birth certificates with sources of maternal medical history: hospital discharges in California and Surveillance, Epidemiology, and End Results (SEER) cancer registry data in Iowa. Birth years included 2007-2012 in California and 1989-2018 in Iowa. MAIN OUTCOME MEASURES: Primary outcome measure was hypertension in pregnancy measured from combined birth certificate and hospital diagnoses in California (for gestational hypertension, preeclampsia, or eclampsia) and birth certificate information (gestational hypertension or eclampsia) in Iowa. RESULTS: After adjusting for maternal age, race, education, smoking, and plurality, those with a history of leukemia/lymphoma were at increased risk of hypertensive disorders of pregnancy in Iowa (odds ratio (OR) = 1.86; 95% CI 1.07-3.23), but not in California (OR = 1.12; 95% CI 0.87-1.43). In sensitivity analysis restricting to more severe forms of hypertension in pregnancy (preeclampsia and eclampsia) in the California cohort, the effect estimate increased (OR = 1.29; 95% CI 0.96-1.74). CONCLUSION: In a population-based linked cancer registry-birth certificate study, an increased risk of hypertensive disorders of pregnancy was observed among leukemia or lymphoma survivors. Findings were consistent but non-significant in a second, more ethnically diverse study population with less precise cancer history data. Improved monitoring and surveillance may be warranted for leukemia or lymphoma survivors throughout their pregnancies.

The risk of preterm birth among women with a history of leukemia or lymphoma.

OBJECTIVE: Leukemia and lymphoma are top cancers affecting children, adolescents and young adults with high five-year survival rates. Late effects of these cancers are a concern in reproductive-age patients, including pregnancy outcomes such as preterm birth. Our study aimed to evaluate whether diagnosis of leukemia or lymphoma prior to pregnancy was associated with preterm birth (<37 weeks gestation). METHODS: We conducted a cross-sectional study using a population-based dataset from California with linked birth certificates to hospital discharge records and an Iowa-based sample that linked birth certificates to Surveillance, Epidemiology, and End Results (SEER) cancer registry data. Preterm birth was defined using birth certificates. We ascertained history of leukemia and lymphoma using discharge diagnosis data in California and SEER registry in Iowa. RESULTS: Prevalence of preterm birth in California and Iowa was 14.6% and 12.0%, respectively, in women with a history of leukemia/lymphoma compared to 7.8% and 8.2%, respectively, in women without a cancer history. After adjusting for maternal age, race, education, smoking, and plurality, Women with history of leukemia/lymphoma were at an increased risk of having a preterm birth in California (odds ratio (OR) 1.89; 95% confidence interval (CI) 1.56-2.28) and Iowa (OR 1.61; 95% CI 1.10-2.37) compared to those with no cancer history. CONCLUSION: In both California and Iowa, women with a history of leukemia or lymphoma were at increased risk for preterm birth. This suggests the importance of counseling with a history of leukemia/lymphoma prior to pregnancy and increased monitoring of women during pregnancy.

Metabolic differences among newborns born to mothers with a history of leukemia or lymphoma.

BACKGROUND: Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers. METHODS: A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program. RESULTS: A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (p < .001 - based on Bonferroni correction for multiple testing) higher compared to newborns of mothers without cancer history: C3-DC (mean difference (MD) = 0.006), C5-DC (MD = 0.009), C8:1 (MD = 0.008), C14 (MD = 0.010), and C16:1 (MD = 0.011), whereas citrulline levels were significantly lower (MD = -0.581) among newborns born to mothers with history of leukemia or lymphoma compared to newborns of mothers without a history of cancer. CONCLUSION: The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

A unique presentation of a rare renal cancer: Appearance of bone metaplasia in tubulocystic renal cell carcinoma.

Tubulocystic renal cell carcinoma is a rare cancer that was not defined as a distinct entity until the early 2000s. Due to the recency of its classification, it remains poorly understood and leaves much room for future research. This report looks at a unique case of this rare subtype of renal cancer. This specific case is unique due to both the demographics of the affected patient and the finding of bone metaplasia within the tumor. We believe this is the first ever reported incidence of this phenomenon.

Testosterone deficiency in men receiving immunotherapy for malignant melanoma.

Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.

Juxtaglomerular Cell Tumor: A Rare Presentation of a Surgically Curable Cause of Secondary Hypertension in the Pediatric Population.

Hypertension is often the primary presenting symptom of multiple renal pathologies. Overactivity of the Renin-Angiotensin-Aldosterone-System (RAAS) is a common cause and usually results from an induced physiologic response. However, conditions do exist that involve autonomous renin production. Juxtaglomerular cell tumors (JGCT), or reninomas, are renal lesions that cause refractory hypertension via this mechanism. Symptoms and lab abnormalities usually subside with surgical resection of these tumors. Here, we present a case of a 13-year old female with uncontrolled hypertension secondary to reninoma treated with partial nephrectomy, with focus on initial presentation, diagnostic evaluation, and surgical management of this uncommon tumor.

The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors.

Ribonucleotide reductase (RNR), which is a heterodimeric tetramer composed of RRM1 and RRM2 subunits, is the rate-limiting enzyme in the synthesis of deoxyribonucleoside triphosphates (dNTPs) and essential for both DNA replication and the repair of DNA damage. The activity of RNR is coordinated with the cell cycle and regulated by fluctuations in the level of the RRM2 subunit. Multiple cancer types, including Ewing sarcoma tumors, are sensitive to inhibitors of RNR or a reduction in the levels of either the RRM1 or RRM2 subunits of RNR. Here, we show that the expression of the RRM2 protein is dependent on active protein synthesis and that 4E-BP1, a repressor of cap-dependent protein translation, specifically regulates the level of the RRM2 protein. Furthermore, inhibition of mTORC1/2, but not mTORC1, activates 4E-BP1, inhibits protein synthesis, and reduces the level of the RRM2 protein in multiple sarcoma cell lines. This effect of mTORC1/2 inhibitors on protein synthesis and RRM2 levels was rescued in cell lines with the CRISPR/Cas9-mediated knockout of 4E-BP1. In addition, the inducible expression of a mutant 4E-BP1 protein that cannot be phosphorylated by mTOR blocked protein synthesis and inhibited the growth of Ewing sarcoma cells in vitro and in vivo in a xenograft. Overall, these results provide insight into the multifaceted regulation of RRM2 protein levels and identify a regulatory link between protein translation and DNA replication.

Factors Impacting Fertility Preservation in Adolescents and Young Adults with Cancer: A Retrospective Study.

Purpose: Fertility preservation before therapy is underutilized for those diagnosed with cancer as an adolescent or young adult (AYA). The purpose of this study was to describe factors impacting utilization of fertility preservation consultations and procedures among AYAs at the University of Iowa Health Care (UIHC). Methods: Patients were identified by the oncology registry at UIHC. Disease site, histology, date of diagnosis, sex, race, ethnicity, insurance, and zip code data were gathered by the registrars. UIHC's electronic medical record was queried for fertility preservation consultation. The Reproductive Endocrinology and Infertility clinical database captured information about patients who underwent fertility preservation. Rural-urban commuting area codes measured rurality. Descriptive statistics and multivariate linear probability models were used to predict the probability of fertility preservation consultation and procedure. Results: From 2008 to 2017, 2932 AYAs were treated for an invasive malignancy at UIHC. Of the 440 (15%) who received a fertility preservation consultation, 156 (5%) underwent a fertility preservation procedure. Multivariate analyses showed that AYAs with public insurance coverage, those diagnosed with central nervous system (CNS) disease or melanoma, and those >30 years old at diagnosis had a significant decrease in the percentage point probability of having a consultation. The percentage point probability of undergoing a procedure was decreased for female patients, those with melanoma or carcinoma, those seen by a pediatric-based provider, and those diagnosed after 25 years of age. Conclusion: This study has important implications for practice and policy, particularly regarding insurance coverage and patient and provider characteristics leading to fertility preservation consultations and procedures for AYAs with cancer.

Inhibition of the ATR-CHK1 Pathway in Ewing Sarcoma Cells Causes DNA Damage and Apoptosis via the CDK2-Mediated Degradation of RRM2.

Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with RNR inhibitors, toward cancer cells. Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. Moreover, we show that the concurrent inhibition of ATR and WEE1 has a synergistic effect in Ewing sarcoma cells. Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. IMPLICATIONS: Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2.