Immune profiling of pediatric solid tumors

Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably

Enhancing the potential of immunotherapy in paediatric sarcomas: Breaking the immunosuppressive barrier with receptor tyrosine kinase inhibitors

Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma

Mass spectrometry detection of inhaled drug in distal fibrotic lung

BACKGROUND: Currently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease. METHODS: Patients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography—tandem Mass Spectrometry. RESULTS: Drug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants. CONCLUSIONS: In this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route

Chimeric antigen receptor t cell therapy and the immunosuppressive tumor microenvironment in pediatric sarcoma

Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or meta-static disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive ben-efit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY‐ ESO, GD2, EGFR, GPC3, B7‐H3, and MAGE‐A4. We also outline promising new CAR T cells that are in pre‐clinical development. Finally, we discuss strategies that are being used to overcome tu-mor‐mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma

Delayed intrathyroidal hematoma causing respiratory distress after a seemingly benign fall: a case report

A rare event of a fall causing delayed intrathyroidal hematoma and respiratory distress is reported here. A 75-year-old woman with symptoms of vertigo causing syncope and fall 24 h earlier was seen and discharged from our emergency department after an unremarkable physical exam and 6-h observation period. Within 3 h of discharge, the patient was transported back by Emergency Medical Services with an enlarging neck mass and subjective respiratory distress. CT scan demonstrated a large, expanding hematoma, and the patient underwent an emergency hemithyroidectomy. Hürtle cell adenoma was found on pathologic specimen examination. A review of the literature of similar cases is presented, emphasizing the notion that concurrent thyroid pathology is a risk factor for airway compromise after seemingly benign trauma and that airway compromise can present in a delayed fashion

Social media policies at US medical schools

Background/Purpose: Today's medical students are learning in a social media era in which patient confidentiality is at risk yet schools’ social media policies have not been elucidated. The purpose of this study is to describe the presence of medical schools on top social media sites and to identify whether student policies for these schools explicitly address social media use. Method: Websites of all 132 accredited US medical schools were independently assessed by two investigators for their presence (as of March 31, 2010) on the most common social networking and microblogging sites (Facebook and Twitter) and their publicly available policies addressing online social networking. Key features from these policies are described. Results: 100% (n=132) of US medical schools had websites and 95.45% (126/132) had any Facebook presence. 25.76% (34/132) had official medical school pages, 71.21% (94/132) had student groups, and 54.55% (72/132) had alumni groups on Facebook. 10.6% of medical schools (14/132) had Twitter accounts. 128 of 132 medical schools (96.97%) had student guidelines or policies publicly available online. 13 of these 128 schools (10.16%) had guidelines/policies explicitly mentioning social media. 38.46% (5/13) of these guidelines included statements that defined what is forbidden, inappropriate, or impermissible under any circumstances, or mentioned strongly discouraged online behaviors. 53.85% (7/13) encouraged thoughtful and responsible social media use. Conclusions: Medical schools and their students are using social media. Almost all US medical schools have a Facebook presence, yet most do not have policies addressing student online social networking behavior. While social media use rises, policy informing appropriate conduct in medical schools lags behind. Established policies at some medical schools can provide a blueprint for others to adopt and adapt

Association of tamoxifen use and reduced risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers

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