Outcomes following management of relapsed pediatric posterior fossa ependymoma in the molecular era.

PURPOSE: The overall survival and prognostic factors for children with multiply recurrent posterior fossa ependymoma are not well understood. We aimed to assess prognostic factors associated with survival for relapsed pediatric posterior fossa ependymoma. METHODS: An institutional database was queried for children with a primary diagnosis of posterior fossa ependymoma from 2000 to 2019. Kaplan-Meier survival analysis and Cox-proportional hazard regression were used to assess the relationship between treatment factors and overall survival. RESULTS: There were 60 patients identified; molecular subtype was available for 56, of which 49 (87.5%) were PF-A and 7 (12.5%) were PF-B. Relapse occurred in 29 patients (48%) at a mean time of 24 months following primary resection. Median 50% survival was 12.3 years for all patients and 3.3 years following diagnosis of first relapsed disease. GTR was associated with significantly improved survival following primary resection (HR 0.373, 95% CI 0.14-0.96). Presence of recurrent disease was significantly associated with worse survival (p < 0.0001). At recurrent disease diagnosis, disseminated disease was a negative prognostic factor (HR 11.0 95% CI 2.7-44) while GTR at first relapse was associated with improved survival HR 0.215 (95% CI: 0.048-0.96, p = 0.044). Beyond first relapse, the impact of GTR was not significant on survival, though surgery compared to no surgery was favorable with HR 0.155 (95% CI: 0.04-0.59). CONCLUSIONS: Disseminated disease at recurrence and extent of resection for first relapsed disease were important prognostic factors. Surgery compared to no surgery was associated with improved survival for the multiply recurrent ependymoma cohort.

Time to dismiss boost? Outcomes of children with localized and metastatic germinoma.

PURPOSE: To determine long-term outcomes of a cohort of children with germinoma treated with chemotherapy and radiation therapy without primary tumor boost even in the absence of complete response to chemotherapy METHODS: This retrospective study analyzed the outcome of patients with germinoma consecutively diagnosed and treated at a tertiary care center from January 2000 to December 2021. MRIs were reviewed by two radiologists, blinded to patient data. Tumor location at diagnosis, tumor response to chemotherapy and at completion of radiation therapy and site of relapse were assessed. Tumor response was assessed radiologically by determining the tumor size and response on diffusion-weighted imaging, in addition to biochemical, cytological parameters and neurological status. RESULTS: Of 46 pediatric germinoma patients, 29 children (14 male; median age 12.8 years) received no primary tumor boost. Median follow-up was 63 months (range 9-187 months). Twenty-five children had localized disease and tumor location was suprasellar (n = 11), pineal (n = 10), bifocal (n = 3) and basal ganglia (n = 1) while 4 children had metastatic disease at presentation. All patients completed multi-agent chemotherapy followed by either ventricular irradiation (VI) (23.4 Gy) (n = 23), whole brain (WBI) (23.4 Gy) (n = 5) or craniospinal radiation (CSI) (23.4 Gy) (n = 1). Two children, who had localized disease at presentation and received VI after chemotherapy, relapsed 9 months and 32 months after completion of treatment respectively. No patient had a local relapse. Location of relapse was distant, outside (n = 1) and out- and inside (n = 1) the irradiation field. Five-year progression free survival (PFS) was 91% and overall survival (OS) was 100%. CONCLUSIONS: In this case series, excellent 5-year PFS and OS rates were achieved with chemotherapy followed by radiation therapy of 23.4 Gy delivered without primary tumor boost. No local relapse was observed despite omitting primary tumor boost in patients with localized and metastatic germinoma.

Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children's Oncology Group.

PURPOSE: To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT). METHODS AND MATERIALS: Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Children's Oncology Group study ACNS1123 who received 30.6 Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40). RESULTS: Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. CONCLUSIONS: Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.

Long-term neurocognitive, psychological, and return to work outcomes in meningioma patients.

INTRODUCTION: This study aimed to investigate long-term neurocognitive, psychological, and return to work (RTW) outcomes in meningioma patients, and to explore whether neurocognitive and psychological factors influence RTW outcomes in this population. METHODS: In this retrospective study, 61 meningioma patients completed in-depth clinical neuropsychological assessments. Of these participants, 42 were of working-age and had RTW information available following neuropsychological assessment. Seventy-one percent and 80% of patients received radiation and surgery, respectively, with 49% receiving both radiation and surgery. Associations between demographic, medical, neurocognitive, psychological, and RTW data were analyzed using multivariable logistic regression analyses. RESULTS: In our sample, 68% of patients exhibited global neurocognitive impairment, with the largest effect sizes found on tests of visual memory (d = 0.73), executive function (d = 0.61), and attention (d = 0.54). Twenty-seven percent exhibited moderate to severe levels of depressive symptoms. In addition, 23% and 30% exhibited clinically significant state and trait anxiety, respectively. Forty-eight percent of patients were unable to RTW. Younger age, faster visuomotor processing speed, and, unexpectedly, higher trait anxiety scores were associated with an increased likelihood of returning to work. CONCLUSIONS: Meningioma patients are at risk of experiencing neurocognitive deficits, psychological symptoms, and difficulties returning to work. Our results suggest that neurocognitive and psychological factors contribute to RTW status in meningioma patients. Prospective research studies are necessary to increase our understanding of the complexity of functional disability in this growing population.

Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma.

BACKGROUND: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. METHODS: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. RESULTS: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. CONCLUSIONS: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

Requirement for the intestinal epithelial insulin-like growth factor-1 receptor in the intestinal responses to glucagon-like peptide-2 and dietary fat.

The intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances the enterocyte chylomicron production. However, GLP-2 is known to require the intestinal-epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) for its other actions to increase intestinal growth and barrier function. The role of the IE-IGF-1R in enterocyte lipid handling was thus tested in the GLP-2 signaling pathway, as well as in response to a Western diet (WD). IE-IGF-1R knockout (KO) and control mice were treated for 11 days with h(GLY2 )GLP-2 or fed a WD for 18 weeks followed by a duodenal fat tolerance test with C14 -labeled triolein. Human Caco-2BBE cells were treated with an IGF-1R antagonist or signaling inhibitors to determine triglyceride-associated protein expression. The IE-IGF-1R was required for GLP-2-induced increases in CD36 and FATP-4 in chow-fed mice, and for expression in vitro; FATP-4 also required PI3K/Akt. Although WD-fed IE-IGF-1R KO mice demonstrated normal CD36 expression, the protein was incorrectly localized 2h post-duodenal fat administration. IE-IGF-1R KO also prevented the WD-induced increase in MTP and decrease in APOC3, increased jejunal mucosal C14 -fat accumulation, and elevated plasma triglyceride and C14 -fat levels. Collectively, these studies elucidate new roles for the IE-IGF-1R in enterocyte lipid handling, under basal conditions and in response to GLP-2 and WD-feeding.

Palliative radiation therapy for children with cancer.

Radiation therapy (RT) is often used as a palliative treatment for children with recurrent malignant disease to ameliorate or prevent symptoms. However, no guidelines exist regarding the clinical indications or dose fractionation for palliative RT. The goal of this report is to provide guidelines for the use of palliative RT in children with cancer. In this guideline, appropriate indications for palliative RT, recommended dose-fractionation schedules, relevant toxicities, and avenues for future research are explored. RT is an effective palliative treatment for bone, brain, liver, lung, abdominopelvic and head-and-neck metastases, spinal cord compression, superior vena cava syndrome, and bleeding. Single-fraction regimens (8 Gy in one fraction) for children with short life expectancy are recommended for simple, uncomplicated bone metastases and can be considered for some patients with lung or liver metastases. A short, hypofractionated regimen (20 Gy in five fractions) may be used for other indications to minimize overall burden of therapy. There are little data supporting use of more prolonged fractionation regimens, though they may be considered for patients with very good performance status. Future research should focus on response and outcomes data collection, and to rigorously evaluate the role of stereotactic body RT in well-designed, prospective studies.

Late effects of radiation therapy in pediatric patients and survivorship.

Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past.

Sinonasal Chondrosarcoma Presenting With Isolated Severe Vision Loss.

ABSTRACT: A 24-year-old man presented with a 2-month history of progressive, painless vision loss in the right eye, with no history of headache, nasal congestion, rhinorrhea, or epistaxis. His visual acuity was counting fingers at 1 ft in the right eye and 20 of 20 in the left eye with a right relative afferent pupillary defect and mild temporal optic disc pallor. MRI of the brain and orbits showed a mass involving bilateral ethmoid and sphenoid sinuses and right nasal cavity. He underwent urgent extended endoscopic endonasal transsphenoidal approach for resection of the sinonasal skull base tumor and photon radiation therapy. Pathology revealed a well-differentiated cartilaginous neoplasm with focal areas of entrapped native bone, consistent with a chondrosarcoma WHO grade I/III. At 6-month follow-up after surgery, he had a visual acuity of 20/40 in the right eye and 20/20 in the left eye. Malignant tumors from the sinonasal area should be kept in the differential diagnosis for compressive optic neuropathies and may present with vision loss even in the absence of nasal or sinus symptoms.

Quantification of bronchoalveolar neutrophil extracellular traps and phagocytosis in murine pneumonia.

The past two decades have witnessed a resurgence in neutrophil research, inspired in part by the discovery of neutrophil extracellular traps (NETs) and their myriad roles in health and disease. Within the lung, dysregulation of neutrophils and NETosis have been linked to an array of diseases including pneumonia, cystic fibrosis, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and severe asthma. However, our understanding of pathologic neutrophil responses in the lung remains incomplete. Two methodologic issues have contributed to this gap: first, an emphasis on studying neutrophils from blood rather than the lung and second, the technical difficulties of interrogating neutrophil responses in mice, which has largely restricted basic murine research to specialized laboratories. To address these limitations, we have developed a suite of techniques for studying neutrophil effector functions specifically in the mouse lung. These include ex vivo assays for phagocytosis and NETosis using bronchoalveolar neutrophils and in situ evaluation of NETosis in a murine model of pneumonia. Throughout, we have prioritized technical ease and robust, quantitative readouts. We hope these assays will help to standardize research on lung neutrophils and improve accessibility to this burgeoning field.

Efficacy of stereotactic radiosurgery for radiation-induced meningiomas.

PURPOSE: Stereotactic radiosurgery is an established treatment option for sporadic meningiomas, though limited data exists for radiation-induced lesions. METHODS: Patients treated with cobalt-60 radiosurgery between October 2005 and December 2018 in an institutional registry were reviewed. Single fraction treatments were prescribed to the 50% isodose line. Lesions were deemed to be radiation-induced according to standard criteria previously established by Cahan et al. RESULTS: A total of 37 patients with 72 lesions were analysed. Median follow up per patient was 44 months (range, 1.4-150.7 months). Median age at initial radiotherapy was 5 years (4 months-48 years), and at radiosurgery was 38 years. Of the 72 lesions, 62 were grade 1 (n = 4) or radiologically-diagnosed (n = 58), six were grade 2 and four were grade 3. Median lesion volume was 2.13 cc (0.04-13.8 cc), while the median radiosurgery margin dose was 13 Gy. Local control, on a per lesion basis, was 88.6% at 5 years (95% confidence interval [CI] 72.3-95.6). For grade 1 or radiologically-diagnosed lesions, local control was 96.6% at 5 years (95% CI 77.9-99.5), whereas those with grade 2 or higher lesions had a local control of 40% at 5 years (95% CI 5.2-75.3, p = 0.005). Radiologic oedema developed in 17 lesions (23.6%) and was symptomatic in 12 patients (16.7%). Doses above 12 Gy were not associated with local control probability (p = 0.292). CONCLUSION: Radiosurgery is an effective treatment option for grade 1 or radiologically-diagnosed radiation-induced meningiomas, with 12 Gy appearing to be a sufficient dose.

Hyperbaric Oxygen for Radiation Necrosis of the Brain.

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) shows promising results in treating radionecrosis (RN) but there is limited evidence for its use in brain RN. The purpose of this study is to report the outcomes of using HBOT for symptomatic brain RN at a single institution. METHODS: This was a retrospective review of patients with symptomatic brain RN between 2008 and 2018 and was treated with HBOT. Demographic data, steroid use, clinical response, radiologic response and toxicities were collected. The index time for analysis was the first day of HBOT. The primary endpoint was clinical improvement of a presenting symptom, including steroid dose reduction. RESULTS: Thirteen patients who received HBOT for symptomatic RN were included. The median time from last brain radiation therapy to presenting symptoms of brain RN was 6 months. Twelve patients (92%) had clinical improvement with median time to symptom improvement of 33 days (range 1-109 days). One patient had transient improvement after HBOT but had recurrent symptomatic RN at 12 months. Of the eight patients with evaluable follow-up MRI, four patients had radiological improvement while four had stable necrosis appearance. Two patients had subsequent deterioration in MRI appearances, one each in the background of initial radiologic improvement and stability. Median survival was 15 months with median follow-up of 10 months. Seven patients reported side effects attributable to HBOT (54%), four of which were otologic in origin. CONCLUSIONS: HBOT is a safe and effective treatment for brain RN. HBOT showed clinical and radiologic improvement or stability in most patients. Prospective studies to further evaluate the effectiveness and side effects of HBOT are needed.

Utilisation de l'oxygénothérapie hyperbare à la suite de séances de radiothérapie entraînant la mort du tissu cérébral. Introduction: Si l'oxygénothérapie hyperbare (OHB) laisse entrevoir des résultats prometteurs dans le traitement des radionécroses (RN), les preuves demeurent limitées quant à son utilisation dans le cas de RN du cerveau. L'objectif de cette étude est de présenter des résultats de recherche liés, dans un seul établissement de santé, à l'utilisation de l'OHB dans le cas de RN symptomatiques du cerveau. Méthodes: Pour ce faire, nous avons effectué une analyse rétrospective des dossiers de patients atteints de RN symptomatiques du cerveau entre 2008 et 2018 et ayant été traités lors de séances d'OHB. Nous avons aussi recueilli des données de nature démographique et d'autres portant sur l'utilisation de stéroïdes, sur la réponse clinique et radiologique des patients et sur les toxicités. Le point de départ (index time) de notre étude a été la première séance d'OHB alors que son principal indicateur de résultat a été l'amélioration sur le plan clinique d'un symptôme particulier, ce qui a inclus une réduction des doses de stéroïdes. Résultats: Au total, treize patients atteints de RN symptomatiques ont été inclus dans cette étude. Le temps médian entre une ultime séance de radiothérapie et l'apparition de symptômes de RN a été de 6 mois. Douze patients (92 %) ont donné à voir une amélioration de leur état médical, la période médiane d'amélioration de leurs symptômes étant de 33 jours (étendue : 1­109 jours). On a observé chez un seul patient une amélioration transitoire à la suite de séances d'OHB, les symptômes de RN étant réapparus au douzième mois. Sur les huit patients ayant subi un examen d'imagerie de suivi, quatre d'entre eux ont montré des signes d'amélioration sur le plan radiologique tandis que quatre autres ont donné à voir une RN stable. Fait à noter, deux patients chez qui l'on avait observé une amélioration radiologique initiale ou une stabilité de leur état ont montré une détérioration ultérieure à la suite d'un examen d'IRM. Le taux de survie médian de ces patients et leur suivi médian ont été respectivement de 15 mois et de 10 mois. Enfin, sept d'entre eux ont signalé des effets secondaires attribuables à l'OHB, dont quatre d'origine otologique. Conclusions: L'OHB demeure un traitement efficace et sécuritaire dans le cas des RN du cerveau. Elle a permis d'observer chez la plupart des patients une amélioration clinique et radiologique ou à tout le moins une stabilité de leurs symptômes. Cela dit, des études prospectives sont nécessaires afin de pouvoir évaluer plus en profondeur son efficacité et ses effets secondaires.

Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost.

BACKGROUND: Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years. METHODS: Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3). RESULTS: A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042). CONCLUSIONS: Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

Re-irradiation for children with recurrent medulloblastoma in Toronto, Canada: a 20-year experience.

PURPOSE: Children with recurrent medulloblastoma have a poor prognosis. Re-irradiation is an option for some patients, but has not been well-studied in the era of molecular characterization for pediatric medulloblastoma. METHODS: This was a retrospective cohort study of 14 children age 18 years and younger at initial diagnosis with recurrent medulloblastoma, who received two or more courses of radiation therapy (RT). Molecular subgrouping was performed using nanoString and was available for nine patients. The primary study endpoint was overall survival. RESULTS: Re-irradiation (RT2) was directed at the supratentorial brain in six patients, infratentorial brain in one patient, and spine in seven patients. In addition, six patients received stem cell transplant as part of salvage therapy. Median OS for all patients was 12.4 months. One patient with recurrent Wnt-activated medulloblastoma remains alive with 154 months' survival; median survival was not reached for four patients with Group 4 disease, while three with Shh-activated disease had median survival of 2.2 months. A single patient with Group 3 disease died 4.3 months after RT2. Patients treated with RT2 to the spine for diffuse disease had poorer OS (p = 0.02), as compared to focal RT2 for intracranial recurrence. Distant failure, outside RT2 volumes, was the predominant pattern of recurrence after RT2. CONCLUSIONS: Re-irradiation for recurrent pediatric medulloblastoma can offer some patients disease control, particularly those with focally recurrent disease in the brain. Prospective studies are needed to confirm subgroups of patients who may benefit most from RT2.

Repeat irradiation for children with supratentorial high-grade glioma.

BACKGROUND: There are very few studies about the role of repeat irradiation (RT2) for children with recurrent supratentorial high-grade glioma (HGG). It was the aim of this study to assess the effectiveness and safety of RT2 in this population. PROCEDURE: This was a retrospective cohort study of 40 children age 18 years and under with recurrent supratentorial HGG who had received at least one course of RT. In-field reirradiation volumes included focal or whole brain RT, with doses ranging from 30 to 54 Gy. The primary endpoint was overall survival (OS) from the first day of RT2. RESULTS: Fourteen patients underwent RT2. The median survival of these patients was 6.5 months. Patients with ≥12 months elapsed time between RT1 and RT2 experienced longer OS than patients who had < 12 months (P = 0.009). There was no difference in OS between patients with or without germline mutations (e.g., Lynch, Li-Fraumeni, or constitutional mismatch-repair deficiency, P = 0.20). Ten patients received RT2 that overlapped with RT1 volumes for locally recurrent disease. Of this group, 80% experienced clinical benefit from in-field RT2, defined as clinical/radiologic response or stable disease. Ninety-three percent completed the prescribed course of RT2, with one patient developing grade 3 radiation necrosis four months after RT2. When compared with 26 patients who were not offered reirradiation, those selected for RT2 had improved median survival from the time of first disease progression (9.4 vs 3.8 months, P = 0.005). CONCLUSIONS: Reirradiation for children with recurrent supratentorial HGG is a safe, effective treatment that provides short-term disease control.

Insulin-like growth factor-binding protein-4 inhibits epithelial growth and proliferation in the rodent intestine.

Insulin-like growth factor-binding protein-4 (IGFBP-4) is a binding protein that modulates the action of insulin-like growth factor-1 (IGF-1), a growth factor whose presence is required for the intestinotrophic effects of glucagon-like peptide-2 (GLP-2). GLP-2 is a gut hormone that uses both IGF-1 and epidermal growth factor (EGF) as intermediary factors to promote intestinal growth. Therefore, to elucidate the mechanism through which IGFBP-4 regulates IGF-1 activity in the intestine, proliferation assays were conducted using rat intestinal epithelial cells (IEC-6). IGF-1 and EGF synergistically enhanced proliferation, an effect that was dose-dependently decreased by IGFBP-4 ( P < 0.05-0.001) in an IGF-1 receptor (R)- and MEK1/2- but not a phosphatidylinositol 3-kinase-dependent manner ( P > 0.05 for IGFBP-4 effects with IGF-1R and MEK1/2 inhibitors). Intestinal organoids derived from IGFBP-4 knockout mice demonstrated significantly greater Ki-67 expression and an enhanced surface area increase in response to IGF-1 treatment, compared with organoids from control mice ( P < 0.05-0.01). GLP-2 is also known to increase the mucosal expression of IGFBP-4 mRNA. To investigate whether this occurs through the actions of its intermediaries, IGF-1 and EGF, inducible intestinal epithelial-IGF-1R knockout and control mice were treated for 10 days with and without the pan-ErbB inhibitor, CI-1033. However, no differences in mucosal IGFBP-4 mRNA expression were found for any of the treatment groups ( P > 0.05). Consistently, IEC-6 cells treated with IGF-1 and/or EGF displayed no alteration in IGFBP-4 mRNA or in cellular and secreted IGFBP-4 protein ( P > 0.05). Overall, this study establishes that endogenous IGFBP-4 plays an important role in inhibiting IGF-1-induced intestinal epithelial proliferation and that mucosal IGFBP-4 expression is independent of IGF-1 and EGF. NEW & NOTEWORTHY This study demonstrates, for the first time, the inhibitory role of locally expressed insulin-like growth factor-binding protein-4 (IGFBP-4) on the intestinal proliferative actions of IGF-1 and supports the notion of the synergistic roles of IGF-1 and EGF in promoting intestinal epithelial growth. In turn, intestinal IGFBP-4 expression was not found to be regulated by IGF-1 and/or EGF.

Healthy Bones Study: can a prescription coupled with education improve bone health for patients receiving androgen deprivation therapy?-a before/after study.

PURPOSE: To evaluate the ability of a multimodal patient education initiative to improve adherence to healthy bone behaviors (HBBs) in men with prostate cancer receiving androgen deprivation therapy (ADT). METHODS: This was a pilot prospective, single-site, before-and-after clinical trial. The control arm (n = 51) received routine care. The intervention arm (n = 52) received multimodal HBB education which included a healthy bones prescription (BoneRx), focused face-to-face education with an oncology nurse or physician, and customized educational materials. The primary endpoints were feasibility of study methods and self-reported adherence to HBBs (vitamin D intake ≥ 1000 IU/day, calcium intake 1000-1500 mg/day, and exercise ≥ 150 min/week) at 3-month follow-up. Secondary endpoints included receipt of bone mineral density (BMD) testing. RESULTS: Patients were satisfied with the study intervention, found educational materials easy to understand, and felt that it increased their knowledge about osteoporosis. Although the intervention appeared to be associated with trends toward improved levels of vitamin D intake (adjusted odds ratio [OR] 1.8, 95% confidence interval [CI] 0.74-4.5), calcium intake (OR 1.5, 95% CI 0.63-3.4), and exercise (OR 1.7, 0.75-3.9) as compared to the control arm, none of these were statistically significant. Patients who received the study intervention were more likely to receive BMD testing (OR 3.3, 95% CI 1.3-8.8). CONCLUSIONS: Although a brief, tailored educational intervention was feasible to implement and improve BMD test utilization, it did not increase HBB participation. Larger, well-designed trials are needed to clarify the effect of patient education interventions on HBB adherence. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01973673 ).

Monte Carlo-driven predictions of neurocognitive and hearing impairments following proton and photon radiotherapy for pediatric brain-tumor patients.

As proton radiotherapy (RT) remains a limited resource, predictive estimates of the potential reduction in adverse treatment-related outcomes compared to photon RT could potentially help improve treatment selection. The aim of this study was to predict the magnitude of the neurocognitive and hearing deficits associated with proton and photon RT for children with brain tumors. The existing RT plans for 50 children treated with photon intensity modulated RT were compared with generated intensity modulated proton RT plans. The proton and photon RT dose distribution was used to estimate the Full Scale Intelligence Quotient (IQ) via a Monte Carlo model and the probability of hearing loss per ear, based on previously published dose-risk relationships. Compared to photon plans, the mean brain dose was found to be reduced in all proton plans, translating into a gain of [Formula: see text] IQ points for the whole cohort at 5 years post-RT for dose regimens of 54 Gy, or [Formula: see text] IQ points for dose regimens of 59.4 Gy, where the errors shown represent statistical and systematic uncertainties. The probability of hearing loss ≥20 dB per ear was less for proton versus photon RT: overall (9 ± 4) versus (17 ± 6)%, respectively, based on dose regimens of 54 Gy, and (13 ± 5) versus (23 ± 9)% for dose regimens of 59.4 Gy. Proton RT is thus expected to reduce the detrimental effect of RT upon IQ and hearing as compared to photon RT for pediatric brain tumors.

Pseudoprogression in pediatric low-grade glioma after irradiation.

This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0-35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5-11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.