Rare germline structural variants increase risk for pediatric solid tumors.

Pediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)-an underexplored form of germline variation-in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.

Quantitative measurements of radiation-induced fibrosis for head and neck cancer: A narrative review.

Objectives: To provide a comprehensive summary of the different modalities available to measure soft tissue fibrosis after radiotherapy in head and neck cancer patients. Data Sources: PubMed, Scopus, and Web of Sciences. Review Methods: A search was conducted using a list of medical subject headings and terms related to head and neck oncology, radiation fibrosis, and quantitative measurements, including bioimpedance, MRI, and ultrasound. Original research related to quantitative measurement of neck fibrosis post-radiotherapy was included without time constraints, while reviews, case reports, non-English texts, and inaccessible studies were excluded. Discrepancies during the review were resolved by discussing with the senior author until consensus was reached. Results: A total of 284 articles were identified and underwent title and abstract screening. Seventeen articles had met our criteria for full-text review based on relevance, of which nine had met our inclusion criteria. Young's modulus (YM) and viscoelasticity measures have demonstrated efficacy in quantifying neck fibrosis, with fibrotic tissues displaying significantly higher YM values and altered viscoelastic properties such as increased stiffness rate-sensitivity and prolonged stress-relaxation post-radiation. Intravoxel incoherent motion offers detailed insights into tissue changes by assessing the diffusion of water molecules and blood perfusion, thereby differentiating fibrosed from healthy tissues. Shear wave elastography has proven to be an effective technique for quantifying radiation-induced fibrosis in the head and neck region by measuring shear wave velocity. Conclusion: There are various modalities to measure radiation-induced fibrosis, each with its unique strengths and limitations. Providers should be aware of these implications and decide on methodologies based on their specific clinical workflow. Level of Evidence: Step 5.

Implementation of a Quality Metrics Competition to Improve Panel Management Among Internal Medicine Residents.

Background Panel management is essential for residents to learn, yet challenging to teach. To our knowledge, prior literature has not described curricula utilizing a financially incentivized competition to improve resident primary care metrics. Objective We developed a panel management curriculum, including a financially incentivized quality competition, to improve resident performance on quality metrics. Methods We developed a cancer screening and diabetes metric quality competition for internal medicine residents at Vanderbilt University Medical Center for their primary care clinics for the 2020-2021 (pilot) and 2021-2022 academic years. Residents received several educational tools, including a 1-hour introduction to the health maintenance dashboard within the electronic medical record (EMR) and instructions on how to access the quality dashboard outside the EMR, and were encouraged to discuss panel management with preceptors. Chief residents distributed measures to trainees 3 times annually, so residents were aware of their competition ranking. Residents' composite metrics at year end were compared to baseline to determine top performers. The top 15 performers received $100 gift cards as incentives. We also assessed the curriculum's impact on the residents' metrics in aggregate. Results At curriculum completion, residents (n=100) demonstrated an average improvement of 1.9% from baseline composite metrics for the percent of patients receiving screening. In aggregate, residents improved in every measure except HbA1c testing. Breast cancer screening had the largest improvement from 69.5% (1518 of 2183) to 75.6% (1646 of 2178) of all patients receiving recommended screening. Conclusions The curriculum resulted in more patients receiving recommended cancer and diabetes screenings.

ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination.

Background: Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma both portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying LMD are unclear. The Abelson (ABL) tyrosine kinase family members, ABL1 and ABL2, have been implicated in cancer cell migration, invasion, adhesion, metastasis, and chemotherapy resistance, and are upstream mediators of the oncogene c-MYC in fibroblasts and lung cancer cells. However, their role in medulloblastoma has not yet been explored. The purpose of this work was to elucidate the role of ABL1/2 in medulloblastoma LMD. Methods: ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of medulloblastoma LMD. RNA sequencing of ABL1/2 genetic knockdown versus scrambled control medulloblastoma was completed. Results: ABL1/2 mRNA is highly expressed in human medulloblastoma and pharmacologic inhibition of ABL kinases resulted in cytotoxicity. Knockdown of ABL1/2 resulted in decreased adhesion of medulloblastoma cells to the extracellular matrix protein, vitronectin (P = .0013), and significantly decreased tumor burden in a mouse model of medulloblastoma LMD with improved overall survival (P = .0044). Furthermore, both pharmacologic inhibition of ABL1/2 and ABL1/2 knockdown resulted in decreased expression of c-MYC, identifying a putative signaling pathway, and genes/pathways related to oncogenesis and neurodevelopment were differentially expressed between ABL1/2 knockdown and control medulloblastoma cells. Conclusions: ABL1 and ABL2 have potential roles in medulloblastoma LMD upstream of c-MYC expression.

Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue. METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity. FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition. CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research. FUNDING: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.

Choroid plexus-CSF-targeted antioxidant therapy protects the brain from toxicity of cancer chemotherapy.

For many cancer patients, chemotherapy produces untreatable life-long neurologic effects termed chemotherapy-related cognitive impairment (CRCI). We discovered that the chemotherapy methotrexate (MTX) adversely affects oxidative metabolism of non-cancerous choroid plexus (ChP) cells and the cerebrospinal fluid (CSF). We used a ChP-targeted adeno-associated viral (AAV) vector approach in mice to augment CSF levels of the secreted antioxidant SOD3. AAV-SOD3 gene therapy increased oxidative defense capacity of the CSF and prevented MTX-induced lipid peroxidation in the hippocampus. Furthermore, this gene therapy prevented anxiety and deficits in short-term learning and memory caused by MTX. MTX-induced oxidative damage to cultured human cortical neurons and analyses of CSF samples from MTX-treated lymphoma patients demonstrated that MTX diminishes antioxidant capacity of patient CSF. Collectively, our findings motivate the advancement of ChP- and CSF-targeted anti-oxidative prophylactic measures to relieve CRCI.

Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes.

More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 individuals with pediatric sarcoma diagnoses (226 Ewing sarcoma, 438 osteosarcoma, 180 rhabdomyosarcoma, and 303 other sarcoma) relative to identically processed cancer-free control individuals. Findings in Ewing sarcoma were validated with an additional cohort of 430 individuals, and a subset of 301 Ewing sarcoma parent-proband trios was analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals, OR 12.6, 95% CI 3.0-43.2, p = 0.003, FDR = 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals, OR 7.0, 95% CI 1.7-23.6, p = 0.014), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in individuals with Ewing sarcoma. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.

The Utility of Verbal Therapy for Pediatric Cancer Patients and Survivors: Expressive Writing, Video Narratives, and Bibliotherapy Exercises.

Childhood cancer is a stressful experience. No pediatric patient, however, should be made to feel as if their concerns and feelings about their cancer experience must be bottled up inside. Importantly, talking and writing about one's illness has myriad implications for young cancer patients and survivors. The most salient of these may include increased understanding of one's condition as well as improved physical and cognitive symptoms (e.g., lowered depression, decreased anxiety, and an enhanced quality of life overall). This literature review explores three promising avenues for verbal therapy in the pediatric oncology setting: expressive writing, video narratives, and bibliotherapy exercises. Several recent studies, covering verbal therapy methods from illness blogging to book interventions, are referenced and discussed. Ultimately, we conclude that expressive writing, video narratives, and bibliotherapy exercises are valuable, feasible, inexpensive, and acceptable tools for patients and survivors of childhood cancer to facilitate self-expression-and to find meaning in the uncertainty and anxiety that cancer inherently fosters. We recommend that future studies investigate this theme so that we may improve quality of life and mental health for pediatric cancer patients and survivors worldwide.

Using Ultrasound to Evaluate Nasal Septal Cartilage.

Importance: Having a noninvasive tool that quantifies the amount of remaining septal cartilage in the setting of prior septoplasty would be useful for surgical planning and patient counseling. Objective: The objective of this pilot study is to determine if endocavitary ultrasound can be used to evaluate the presence and thickness of septal cartilage in vivo. Design, Setting, and Participants: A small prospective observational study was designed to assess the feasibility of using intranasal ultrasound to verify the presence and measure the thickness of septal cartilage. Imaging was undertaken by the principle investigator using a protocol developed by the research team. Six healthy volunteers were enrolled including three subjects who have had prior septoplasty. Images and measurements of the nasal septum were obtained. Main Outcomes: Confirming the presence of the nasal septum was the main outcome with a secondary outcome of measurement of septum thickness. Results: The endonasal ultrasound probe was able to identify the septum and resected areas. The mean thickness of the septum in subjects without surgery was 1.0 mm and those with prior septoplasty was 0.8 mm. Student's t-test show a statistically significant difference in septum thickness between these two groups with a p-value of 0.0093. Conclusions and Relevance: This study demonstrates a novel method of determining the presence of septal cartilage after septoplasty surgery. This information may be useful for operative planning in revision rhinoplasty.

Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer.

Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5, and ABL-001, are equipped to overcome these issues. Several contemporary studies have demonstrated their potential efficacy in three key areas: primary hematologic and solid malignancies, metastasis, and combination with other small molecules. Further, ongoing clinical trials are investigating the efficacy of ABL-001 for the treatment of CML and recurrent solid tumors. This work reviews the current literature of the preclinical testing of GNF-2 and GNF-5 and the preclinical and clinical testing of ABL-001. Future research will continue to evaluate these promising inhibitors as both first-line therapy for solid tumors and salvage therapy when more traditional drugs such as imatinib fail.

The Limited Usefulness of Ultrasound Surveillance after Radical and Partial Nephrectomy for Renal Cell Carcinoma.

INTRODUCTION: We determined the usefulness of ultrasound compared to cross-sectional imaging in the detection of intra-abdominal recurrences after radical or partial nephrectomy for localized renal cell carcinoma. METHODS: We performed a retrospective review of 800 patients with clinically localized renal cell carcinoma who had undergone radical or partial nephrectomy between 2008 and 2015. Patients had at minimum 1 year of followup at our institution, at least 1 ultrasound during surveillance and no metastases at time of surgery. Our primary outcome was the rate of diagnosis of abdominal recurrence based on modality of surveillance. RESULTS: Median followup for the entire cohort was 37.5 months (range 12 to 166). Overall 396 and 404 patients underwent radical and partial nephrectomy, respectively, for localized renal cell carcinoma. There were 224 (57%) and 234 (58%) patients in the radical and partial nephrectomy cohorts, respectively, who had 2 or more ultrasounds performed during surveillance. In the radical and partial nephrectomy cohorts a total of 149 (19%) abdominal recurrences were detected, with only 8 (19%) initially detected by ultrasound. On the other hand, 15 (10%) recurrences were missed by a prior negative ultrasound. Furthermore, there were 8 false-positive ultrasound studies that cross-sectional imaging later ruled out. CONCLUSIONS: The low yield of ultrasound in the detection of abdominal recurrences after radical or partial nephrectomy for renal cell carcinoma raises questions as to its usefulness in routine surveillance.

MRI findings of absorbable hydrogel spacer for prostate cancer therapy: a pictorial review.

Prior studies have shown that dose-escalated radiation therapy for prostate cancer improves clinical outcomes. However, this is associated with increased rectal toxicity. Hydrogel spacer for prostate cancer therapy is an effective way of decreasing rectal toxicity in the late post-therapeutic stages. In some occasions, the gel spacer may not be placed symmetrically between the rectum and prostate. There are several forms of a malpositioned spacer, including lateral displacement, rectal wall infiltration, and prostate capsule infiltration. This manuscript is aimed at evaluating appropriately positioned and malpositioned gel spacers, primarily via magnetic resonance imaging. There are limited educational imaging guides that address what radiologists should evaluate on post-spacer placement imaging. This pictorial review will specifically evaluate post-injection pitfalls such as asymmetry, rectal wall infiltration, and subcapsular injection.

Late-onset renal vein thrombosis: A case report and review of the literature.

INTRODUCTION: Renal vein thrombosis, a rare complication of renal transplantation, often causes graft loss. Diagnosis includes ultrasound with Doppler, and it is often treated with anticoagulation or mechanical thrombectomy. Success is improved with early diagnosis and institution of treatment. PRESENTATION OF CASE: We report here the case of a 29 year-old female with sudden development of very late-onset renal vein thrombosis after simultaneous kidney pancreas transplant. This resolved initially with thrombectomy, stenting and anticoagulation, but thrombosis recurred, necessitating operative intervention. Intraoperatively the renal vein was discovered to be compressed by a large ovarian cyst. DISCUSSION: Compression of the renal vein by a lymphocele or hematoma is a known cause of thrombosis, but this is the first documented case of compression and thrombosis due to an ovarian cyst. CONCLUSION: Early detection and treatment of renal vein thrombosis is paramount to restoring renal allograft function. Any woman of childbearing age may have thrombosis due to compression by an ovarian cyst, and screening for this possibility may improve long-term graft function in this population.

Father to father: focus groups of fathers of children with cancer.

Caring for a child with cancer is a demanding experience for both parents, yet most research focuses on mothers. In this paper, we present the findings of a secondary analysis of data from a study in which the care-giving experience of fathers is investigated. In two focus groups, ten fathers provided first-hand information about caring for a child with cancer and its impact on their families. In addition, the findings demonstrate how these men through sharing a deeply meaningful and challenging experience offered mutual support and caring. This paper describes the fathers' remarkable and unexpected exchange. Social work implications are also addressed.

Renal cortical adenoma incidentally found during living donor nephrectomy.

We report a living related kidney donor incidentally found to have a renal cortical adenoma at nephrectomy. The patient is a 53-year-old man accepted for living related kidney donation. Predonation workup revealed a solitary left renal artery and, on the right kidney, a main artery with a small accessory artery in theupper pole. No other abnormalities were found in the medical history, physical examination, or laboratory and radiological studies. A left laparoscopic nephrectomy was planned. However, during dissection of the upper pole, a 5-mm mass was noted. The nephrectomy was completed, and the organ was preserved in cold University of Wisconsin solution. Permanent section histology showed that the lesion was mostly likely a renal cortical adenoma. As the risk of malignant transformation with immunosuppression could not be adequately determined, the kidney was not transplanted into the recipient. The donor elected not to have the kidney replaced, and the organ was discarded.

Father-to-father support: fathers of children with cancer share their experience.

Fathers are important to the stability of the family and to the coping of mothers and their children when there is a child in treatment with cancer. The vulnerability they experience is stupefying and causes self-doubt, general worry, and frustration with the medical care they receive. Fathers' experiences are relatively unreported in the literature, and even less so, the experiences of fathers with children who have cancer. This research is based on two focus groups of five men each who spoke unabashedly for more than 2 hours about their grief, their struggle to come to terms with the diagnosis and the role strain, and role confusion they experienced as fathers and husbands. The findings could be described as reflecting the following themes: (1) impact on the provider role, (2) the emotional impact: I cry privately, (3) it's the fight of our lives, (4) tag-team parenting, (5) hypervigilance, (6) that place is scary!, and (7) what happens next--coping and moving on. The group format was powerful in terms of what these men were willing to share of themselves and their experience. These groups could be characterized as the coming together of strangers, bound by the common experience of "cancer," who actively supported each other and each other's process. Implications for holistic nursing practice are provided.