The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.

Mimics of Pediatric Small Vessel Primary Angiitis of the Central Nervous System.

OBJECTIVE: Small vessel primary angiitis of the central nervous system is a rare and often severe disease characterized by central nervous system-restricted inflammatory vasculitis on histopathology. Diagnosis requires brain biopsy for confirmation and is suggested prior to starting immunotherapy when feasible. However, emerging evidence suggests that other neuroinflammatory conditions may have a clinical and radiographic phenotype that mimics small vessel primary angiitis, at times with overlapping pathologic features as well. Such diagnoses, including myelin oligodendrocyte glycoprotein antibody-associated disease and central nervous system-restricted hemophagocytic lymphohistiocytosis, can be non-invasively diagnosed with serum antibody or genetic testing that would prompt different monitoring and treatment paradigms. To determine the ultimate diagnosis of patients who were suspected prior to biopsy to have small vessel primary angiitis, we reviewed the clinical, radiographic, and pathological features of a cohort of patients at a single center undergoing brain biopsy for non-oncologic indications. METHODS: Clinical data were retrospectively extracted from the medical record. Pathology and neuroimaging review was conducted. RESULTS: We identified 21 patients over a 19-year time-period, of whom 14 (66.7%) were ultimately diagnosed with entities other than small vessel primary angiitis that would have obviated the need for brain biopsy. Diagnoses included anti-myelin oligodendrocyte glycoprotein antibody associated disease (n = 9), central nervous system-restricted hemophagocytic lymphohistiocytosis (n = 3), anti-GABAA receptor encephalitis (n = 1), and Aicardi-Goutières syndrome (n = 1). INTERPRETATION: This study highlights the importance of pursuing now readily available non-invasive testing for mimicking diagnoses before performing a brain biopsy for suspected small vessel primary angiitis of the central nervous system. ANN NEUROL 2023;93:109-119.

Pediatric nasal chondromesenchymal hamartomas: a case series.

PURPOSE: Nasal chondromesenchymal hamartomas (NCMH) are rare, predominantly benign tumors of the sinonasal tract. The distinction from higher grade malignancy may be challenging based on imaging features alone. To increase the awareness of this entity among radiologists, we present a multi-institutional case series of pediatric NCMH patients showing the varied imaging presentation. METHODS: Descriptive assessment of imaging appearances of the lesions on computed tomography (CT) and magnetic resonance imaging (MRI) was performed. In addition, we reviewed demographic information, clinical data, results of genetic testing, management, and follow-up data. RESULTS: Our case series consisted of 10 patients, with a median age of 0.5 months. Intraorbital and intracranial extensions were both observed in two cases. Common CT findings included bony remodeling, calcifications, and bony erosions. MRI showed heterogeneous expansile lesion with predominantly hyperintense T2 signal and heterogenous post-contrast enhancement in the majority of cases. Most lesions exhibited increased diffusivity on diffusion weighted imaging and showed signal drop-out on susceptibility weighted images in the areas of calcifications. Genetic testing was conducted in 4 patients, revealing the presence of DICER1 pathogenic variant in three cases. Surgery was performed in all cases, with one recurrence in two cases and two recurrences in one case on follow-up. CONCLUSION: NCMHs are predominantly benign tumors of the sinonasal tract, typically associated with DICER1 pathogenic variants and most commonly affecting pediatric population. They may mimic aggressive behavior on imaging; therefore, awareness of this pathology is important. MRI and CT have complementary roles in the diagnosis of this entity.

Imaging panorama of pediatric central nervous system tuberculosis.

Central nervous system tuberculosis (CNS TB) is the most dreaded manifestation of systemic tuberculosis in the pediatric age group. It is associated with high morbidity and mortality due to severe neurological complications and sequelae. Knowledge about the imaging spectrum of CNS TB will help in early presumptive diagnosis and prompt treatment, reducing the development of complications. Imaging also plays a vital role in monitoring the progression of disease after the initiation of antituberculosis therapy. Advanced magnetic resonance imaging (MRI) techniques have recently improved the diagnostic efficacy manifold.In this review, we describe the imaging characteristics, the role of advanced imaging techniques, and follow-up imaging in various types of CNS TB in the pediatric population.

Through the looking glass: attempting to predict future opportunities and challenges in experimental biology.

To celebrate its centenary year, Journal of Experimental Biology (JEB) commissioned a collection of articles examining the past, present and future of experimental biology. This Commentary closes the collection by considering the important research opportunities and challenges that await us in the future. We expect that researchers will harness the power of technological advances, such as '-omics' and gene editing, to probe resistance and resilience to environmental change as well as other organismal responses. The capacity to handle large data sets will allow high-resolution data to be collected for individual animals and to understand population, species and community responses. The availability of large data sets will also place greater emphasis on approaches such as modeling and simulations. Finally, the increasing sophistication of biologgers will allow more comprehensive data to be collected for individual animals in the wild. Collectively, these approaches will provide an unprecedented understanding of 'how animals work' as well as keys to safeguarding animals at a time when anthropogenic activities are degrading the natural environment.

Massage therapy for children, adolescents, and young adults: Clinical delivery and effectiveness in hematology and oncology.

BACKGROUND: Children, adolescents, and young adults with hematologic and/or oncologic conditions experience multiple, significant symptoms (e.g., pain, stress, and anxiety), which may be addressed by nonpharmacologic approaches such as massage therapy (MT). The purpose of this study was to describe the clinical delivery of MT provided by a certified pediatric massage therapist and assess effectiveness in two patient groups: those with sickle cell disease (SCD) or hematologic and/or oncologic conditions excluding SCD (HemOnc). METHODS: Investigators conducted a retrospective review of MT sessions provided to patients 0-39 years with hematologic and/or oncologic conditions at a large pediatric academic medical center. RESULTS: Between October 2019 and December 2021, 3015 MT sessions were provided to 243 patients (171 HemOnc; 72 SCD) and documented in the electronic health record. Patients (mean age: 12.21 ± 7.19 years) were generally White (49.4%) or Black/African American (43.2%), non-Hispanic (94.2%), and 52.3% female. Patients in the SCD group (vs. patients in the HemOnc group) reported significantly higher (p < .05) pretreatment pain (6.95 vs. 4.46), stress (6.47 vs. 4.58), and anxiety (6.67 vs. 4.59). All patients reported clinically and statistically significant (p < .001) mean reductions in pain (-2.25 ± 1.87), stress (-2.50 ± 1.73), and anxiety (-2.52 ± 1.69), with patients in the HemOnc group reporting greater mean pain change (-2.54 vs. -1.87) than patients in the SCD group. CONCLUSIONS: This study supports the clinical effectiveness of MT for addressing acute pain, stress, and anxiety among youth with hematologic and/or oncologic conditions. Future research is needed to identify optimal MT utilization.

How to Start a Lymphatic Program.

Many patients are born with lymphatic abnormalities or are susceptible to pathology following cardiac surgery. It therefore becomes important to evaluate and treat lymphatic disorders in centers performing congenital heart surgery. Programs can make strides towards starting a lymphatic branch if appropriately equipped with proper staff, tools, and other capabilities to perform lymphatic system access, imaging, and intervention. In reality, many of these components already exist in most centers, and a successful and comprehensive program can be established by enlisting these already established services.

Bone health in haemophilia carriers and persons with von Willebrand disease: A large database analysis.

INTRODUCTION: Persons with haemophilia(PWH) have been shown to have low bone mineral density likely the result of prolonged immobility, recurrent hemarthrosis, decreased weight bearing, lower physical activity level and obesity. Bone health has been poorly characterized in haemophilia carriers (HC) and persons with von Willebrand disease (PWvWD). AIM: To estimate the prevalence of osteoporosis, osteoarthritis and bone fractures in HC and PWvWD and identify risk factors for poor bone health. METHODS: This is a retrospective study using a population level, commercial database - Explorys (IBM Watson Health, Cleveland, USA). We compared prevalence rates of osteoporosis, osteoarthritis and fractures among cases (HC or PWvWD) and controls (general population without an underlying bleeding disorder) from 1999 to 2020. Prevalence of common risk factors for poor bone health were compared among cases and controls. RESULTS: Among 72,917,850 active persons in the database, we identified 940 women with the diagnosis of HC and 19,580 PWvWD. Among HC and PWvWD, prevalence of osteoporosis, osteoarthritis and fractures were significantly higher in cases, when compared to controls. In HC, the prevalence of vitamin D deficiency, obesity, hypothyroidism, smoking, diabetes mellitus, hypocalcaemia, corticosteroid use, malignancy, renal failure and Nonsteroidal anti-inflammatory drugs (NSAID) use were significantly higher among the cases. In PWvWD, the prevalence of risk factors was significantly higher in cases when compared to controls. CONCLUSION: The prevalence of osteoporosis, osteoarthritis and fractures is significantly higher among HC and PWvWD. This data highlights the importance of screening patients for risk factors for poor bone health and provide education to prevent these complications.

Small-amplitude head oscillations result from a multimodal head stabilization reflex in hawkmoths.

In flying insects, head stabilization is an essential reflex that helps to reduce motion blur during fast aerial manoeuvres. This reflex is multimodal and requires the integration of visual and antennal mechanosensory feedback in hawkmoths, each operating as a negative-feedback-control loop. As in any negative-feedback system, the head stabilization system possesses inherent oscillatory dynamics that depend on the rate at which the sensorimotor components of the reflex operate. Consistent with this expectation, we observed small-amplitude oscillations in the head motion (or head wobble) of the oleander hawkmoth, Daphnis nerii, which are accentuated when sensory feedback is aberrant. Here, we show that these oscillations emerge from the inherent dynamics of the multimodal reflex underlying gaze stabilization, and that the amplitude of head wobble is a function of both the visual feedback and antennal mechanosensory feedback from the Johnston's organs. Our data support the hypothesis that head wobble results from a multimodal, dynamically stabilized reflex loop that mediates head positioning.

Artificial Intelligence Algorithm Improves Radiologist Performance in Skeletal Age Assessment: A Prospective Multicenter Randomized Controlled Trial.

Background Previous studies suggest that use of artificial intelligence (AI) algorithms as diagnostic aids may improve the quality of skeletal age assessment, though these studies lack evidence from clinical practice. Purpose To compare the accuracy and interpretation time of skeletal age assessment on hand radiograph examinations with and without the use of an AI algorithm as a diagnostic aid. Materials and Methods In this prospective randomized controlled trial, the accuracy of skeletal age assessment on hand radiograph examinations was performed with (n = 792) and without (n = 739) the AI algorithm as a diagnostic aid. For examinations with the AI algorithm, the radiologist was shown the AI interpretation as part of their routine clinical work and was permitted to accept or modify it. Hand radiographs were interpreted by 93 radiologists from six centers. The primary efficacy outcome was the mean absolute difference between the skeletal age dictated into the radiologists' signed report and the average interpretation of a panel of four radiologists not using a diagnostic aid. The secondary outcome was the interpretation time. A linear mixed-effects regression model with random center- and radiologist-level effects was used to compare the two experimental groups. Results Overall mean absolute difference was lower when radiologists used the AI algorithm compared with when they did not (5.36 months vs 5.95 months; P = .04). The proportions at which the absolute difference exceeded 12 months (9.3% vs 13.0%, P = .02) and 24 months (0.5% vs 1.8%, P = .02) were lower with the AI algorithm than without it. Median radiologist interpretation time was lower with the AI algorithm than without it (102 seconds vs 142 seconds, P = .001). Conclusion Use of an artificial intelligence algorithm improved skeletal age assessment accuracy and reduced interpretation times for radiologists, although differences were observed between centers. Clinical trial registration no. NCT03530098 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Rubin in this issue.

Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes. METHODS: Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis. RESULTS: A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.

Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG).

BACKGROUND: This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking. METHODS: Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used. RESULTS: The 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p < 0.001) and worse overall survival (OS) (p = 0.010). However, having a major complication was not associated with a worse OS or a higher incidence of local recurrence or distant metastasis. CONCLUSIONS: A surgical approach to recurrent RPS is relatively safe and comparable with primary RPS in terms of complications and postoperative mortality when performed at specialized sarcoma centers. Because alternative effective therapies still are lacking, when indicated, resection of a recurrent RPS is a reasonable option. Every effort should be made to minimize the need for blood transfusions.

Morbidity and Outcomes After Distal Pancreatectomy for Primary Retroperitoneal Sarcoma: An Analysis by the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Multi-visceral resection often is used in the treatment of retroperitoneal sarcoma (RPS). The morbidity after distal pancreatectomy for primary pancreatic cancer is well-documented, but the outcomes after distal pancreatectomy for primary RPS are not. This study aimed to evaluate morbidity and oncologic outcomes after distal pancreatectomy for primary RPS. METHODS: In this study, 26 sarcoma centers that are members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) retrospectively identified consecutive patients who underwent distal pancreatectomy for primary RPS from 2008 to 2017. The outcomes measured were 90-day severe complications (Clavien-Dindo ≥ 3), postoperative pancreatic fistula (POPF) rate, and oncologic outcomes. RESULTS: Between 2008 and 2017, 280 patients underwent distal pancreatectomy for primary RPS. The median tumor size was 25 cm, and the median number of organs resected, including the pancreas, was three. In 96% of the operations, R0/R1 resection was achieved. The 90-day severe complication rate was 40 %. The grades B and C POPF complication rates were respectively 19% and 5% and not associated with worse overall survival. Administration of preoperative radiation and factors to mitigate POPF did not have an impact on the risk for the development of a POPF. The RPS invaded the pancreas in 38% of the patients, and local recurrence was doubled for the patients who had a microscopic, positive pancreas margin (hazard ratio, 2.0; p = 0.042). CONCLUSION: Distal pancreatectomy for primary RPS has acceptable morbidity and oncologic outcomes and is a reasonable approach to facilitate complete tumor resection.

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

Mechanical properties of low-diameter balloon expandable covered stents.

OBJECTIVES: To determine over-dilation potential of commercially available covered stents. BACKGROUND: Covered stents including the Atrium iCast, Gore VBX, and Lifestream stents (LS) can treat ruptures, dissections, and aneurysms in small vessels. Especially in growing patients, stents often require serial dilations beyond their implant or nominal diameters. Tolerance of serial dilations is clinically important information for interventionalists. METHODS: Serial dilations of 5-12 mm iCast, VBX, and LS covered stents were performed in 1-2 mm increments (up to 20 mm). With each dilation, foreshortening and recoil were measured, and stent strut and covering integrity were assessed. High-pressure balloons were used to expand the stents until they fractured or could not be further expanded. RESULTS: The 5-8 mm LS tolerated dilation to 14.5-16 mm. The 10-12 mm LS stents tolerated dilation to 18 mm and fractured on the 20 mm balloon. LS stents foreshortened 35%-45% on average after 8 mm of over-dilation and had 5%-10% recoil on <6 mm over-dilation. All iCast stents tolerated dilation to 12-13 mm and required fracture for dilation to >14 mm. ICast stents foreshortened 19%-29% at maximum dilation, with 3-6% recoil on <2 mm over-dilation, and < 3% thereafter. VBX stents over-dilated to 2.9-4.7 mm above nominal, foreshortening 40%-50% after 4-6 mm of over-dilation before collapsing into a ring. VBX stent recoil was <2.5% on all dilations. CONCLUSIONS: LS stents had the greatest over-dilation potential. VBX stents had the least recoil but tended to foreshorten significantly 3-4 mm above nominal. Regardless of nominal size, all iCast stents (including the 5 mm) tolerated dilation to a maximum of 12-13 mm.

Clinicopathologic Characteristics and Prognosis of Invasive Papillary Carcinoma of the Breast.

BACKGROUND: Invasive papillary carcinoma (IPC) of the breast is thought to carry a more favorable prognosis than invasive ductal carcinoma (IDC). The aim of this study is to investigate the clinicopathological characteristics between IPC and IDC and their prognosis using a large nationwide data set. METHODS: Female patients diagnosed with malignant IPC and IDC between 2005 and 2014 were analyzed. Patients with incomplete survival data, stage 0/IV, unknown stage, or recurrent disease were excluded. Five-year overall survival was compared between IPC and IDC. RESULTS: Among 308,426 patients, 1147 had IPC and 307,279 had IDC. IPC presented more in older postmenopausal women, black Americans, and people who had government insurance. IPC had larger tumor size, lower-grade, and earlier-stage disease, less node-positive disease, higher hormone positivity, and lower human epidermal growth factor receptor 2 amplification. Adjuvant radiation and chemotherapy rates were lower in IPC than those in IDC. IPC had a similar 5-year overall survival as compared with IDC overall (86.8% versus 88.7%) (P = 0.06). Age, pathologic stage, and radiation treatment were shown to be independent prognostic factors of IPC. CONCLUSIONS: IPC has a similar prognosis as IDC, suggesting that these patients should follow the same treatment protocols.

Primary mesenteric sarcomas: Collaborative experience from the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Primary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function. OBJECTIVES: To determine the overall survival (OS) and recurrence-free survival (RFS) for patients undergoing primary resection for mesenteric STS. METHODS: The Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019. RESULTS: Fifty-six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher-grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery. CONCLUSION: Primary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

Visual outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

Outcomes of patients with invasive mucinous and tubular carcinomas of the breast.

Invasive tubular carcinoma (ITC) and invasive mucinous carcinoma (IMC) of the breast are rare histologic subtypes of breast cancer associated with favorable prognoses. The aim of our study was to investigate the outcomes for these rare subtypes using the National Cancer Database. Female patients diagnosed with ITC or IMC between 2005 and 2014 were analyzed. The primary outcome was overall survival (OS), and we analyzed its association with adjuvant therapy. 2735 patients with ITC and 5602 patients with IMC were identified. ITC presented in younger patients (57 vs. 67 years), had smaller tumors (size <1 cm, 63.1% vs. 25.4%), earlier stage, and less node-positive disease (5% vs. 8.6%), compared with IMC. Older age, government insurance, lower income, treatment in a community cancer program, large tumor size, positive nodal status, and without endocrine therapy were associated with worse OS with either subtype on multivariate analysis. No OS benefit was found for node-positive ITC that received adjuvant chemotherapy compared with those who did not. (5-year OS of 96.0% vs. 91.3%, p = 0.17).OS was improved for IMC that received adjuvant chemotherapy (10-year OS: 82.5% vs. 60.1%, p = 0.008) and endocrine therapy (10-year OS: 86.6% vs. 81.2%, p < 0.001). We concluded that ITC has favorable clinicopathological characteristics and prognosis, even with node-positive disease. ITC and IMC may need to be evaluated independently when administering adjuvant treatment plans.