Palliative team involvement in end-of-life care for Jewish and Muslim children in Jerusalem: A unique clinical and cultural context.

OBJECTIVES: Pediatric palliative care services improve the quality of life for children with life-limiting and life-threatening diseases, although little has been published about variation based on cultural and religious factors. This article sets out to describe clinical and cultural characteristics of pediatric end-of-life patients in a majority Jewish and Muslim country with religious and legal constraints around end-of-life care. METHODS: We conducted a retrospective chart review of 78 pediatric patients who died during a 5-year period and could potentially have utilized pediatric palliative care services. RESULTS: Patients reflected a range of primary diagnoses, most commonly oncologic diseases and multisystem genetic disorders. Patients followed by the pediatric palliative care team had less invasive therapies, more pain management and advance directives, and more psychosocial support. Patients from different cultural and religious backgrounds had similar levels of pediatric palliative care team follow-up but certain differences in end-of-life care. SIGNIFICANCE OF RESULTS: In a culturally and religiously conservative context that poses constraints on decision-making around end-of-life care, pediatric palliative care services are a feasible and important means of maximizing symptom relief, as well as emotional and spiritual support, for children at the end of life and their families.

Radiological artificial intelligence - predicting personalized immunotherapy outcomes in lung cancer.

Personalized medicine has revolutionized approaches to treatment in the field of lung cancer by enabling therapies to be specific to each patient. However, physicians encounter an immense number of challenges in providing the optimal treatment regimen for the individual given the sheer complexity of clinical aspects such as tumor molecular profile, tumor microenvironment, expected adverse events, acquired or inherent resistance mechanisms, the development of brain metastases, the limited availability of biomarkers and the choice of combination therapy. The integration of innovative next-generation technologies such as deep learning-a subset of machine learning-and radiomics has the potential to transform the field by supporting clinical decision making in cancer treatment and the delivery of precision therapies while integrating numerous clinical considerations. In this review, we present a brief explanation of the available technologies, the benefits of using these technologies in predicting immunotherapy response in lung cancer, and the expected future challenges in the context of precision medicine.

Propofol Inhibits Glioma Stem Cell Growth and Migration and Their Interaction with Microglia via BDNF-AS and Extracellular Vesicles.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration, and recurrence, and are thereby considered important therapeutic targets. Recent clinical studies have suggested that the choice of general anesthetic (GA), particularly propofol, during tumor resection, affects subsequent tumor response to treatments and patient prognosis. In this study, we investigated the molecular mechanisms underlying propofol's anti-tumor effects on GSCs and their interaction with microglia cells. Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers, and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations, propofol induced a large degree of cell death, as demonstrated using microfluid chip technology. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM, and silencing of this lncRNA partially abrogated propofol's effects. Propofol also inhibited the pro-tumorigenic GSC-microglia crosstalk via extracellular vesicles (EVs) and delivery of BDNF-AS. In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized these cells to radiation and TMZ, and inhibited their pro-tumorigenic interactions with microglia via transfer of BDNF-AS by EVs.

Risk of Cancer in Paediatric onset Inflammatory Bowel Diseases: A Nation-wide Study From the epi-IIRN.

BACKGROUND: Paediatric onset IBD [PIBD] is characterised by a more extensive phenotype than adult-onset IBD and a higher utilisation of immunosuppressive medications; both may be associated with malignancy. We aimed to assess the risk of cancer in a nationwide cohort of PIBD and to explore the risks associated with medical treatments. METHODS: PIBD patients [<18 years old] were included from the epi-IIRN cohort, covering 98% of the Israeli population from 2005, linked to the national cancer registry. We matched PIBD children to non-IBD children for calculating the cumulative incidence of cancer. RESULTS: In all, 3944 PIBD cases were included (2642 [67%] Crohn's disease, 1302 [33%] ulcerative colitis) translating into 23 635 person-years of follow-up, individually matched to 13 005 non-IBD children. By 30 years of age, 14 IBD patients [0.35%, 5.9/10 000 patient-years] were diagnosed with cancer and one [0.03%] with haemophagocytic-lymphohistiocytosis [HLH], compared with 14 [0.11%, 1.9/10 000 patient-years] cases of cancer {relative risk (RR) 2.5 (95% confidence interval [CI] 1.05-6.2); p = 0.04} and no HLH in the comparison-group. There were no cases of hepatosplenic T cell lymphoma, adenocarcinoma, or cholangiocarcinoma. Cancer risk was 15.6 cases/10 000 person-years in those treated with thiopurines alone (RR compared with IBD patients never exposed to either thiopurines or anti-tumuor necrosis factor [TNF] 1.8 [95% CI 0.6-6.1]; p = 0.2), 11.1/10 000 in those treated with anti-TNF alone (RR 1.3 [95% CI 0.3-6.6]; p = 0.5), and 23.1/10 000 treated with combination therapy of anti-TNF and thiopurines (RR 2.8 [95% CI 0.6-13.8]; p = 0.2). CONCLUSIONS: PIBD confers an increased risk for malignancy compared with non-IBD in children. However, the absolute risk is very low and no differences in risk with specific therapies were apparent in our data.

A mutation in POLR3E impairs antiviral immune response and RNA polymerase III.

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Prevalence, Characteristics, and Long-Term Prognosis of Epilepsy Associated with Pediatric Brain Tumors.

OBJECTIVE: We investigated the prevalence, onset, characteristics, and long-term course of epilepsy disease in children who underwent surgical intervention for diagnosed brain tumors. METHODS: We reviewed the medical records of children with diagnosed brain tumors who underwent surgery during 2004-2014 at the Hadassah Medical Center. All patients with epilepsy were invited to a clinical visit that included a neurologic examination. The primary outcome measures were neurologic status according to the Glasgow outcome score (GOS) and postoperative seizure outcome according to the Engel system. We compared clinical characteristics according to the timing of epilepsy onset. RESULTS: The mean follow-up was 49 months. Of 128 patients included in the study, 44 (34%) had seizures; 23 (18%) developed epilepsy after surgery. Of the 30 patients with epilepsy who survived, 21 (70%) are in Engel class I and 13% Engel are in class II. Forty-five percent of the children are classified as GOS 5. Children who developed epilepsy after surgery were more likely to be in GOS 1-2 than were those who had seizures before surgery (P = 0.0173). Children with seizures were more likely to have cortical tumors and less likely to have tumors of the posterior fossa (P < 0.001). Children who underwent gross total resection were less likely to have epilepsy (P < 0.001). CONCLUSIONS: We show a high incidence of epilepsy in the late course of pediatric brain tumor disease. In the long term, seizure outcome was excellent. However, postsurgical onset of epilepsy was associated with a less favorable neurologic outcome.

Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2-16) were applied. The main side effects were neutropenia (CTCAE grade 1-3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8-24) and the median overall survival is 15.6 months (range 6.9-28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.

Treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients.

Molecular portraits of numerous tumors have flooded oncologists with vast amounts of data. In parallel, effective inhibitors of central pathways have shown great clinical benefit. Together, this promises potential clinical benefits to otherwise end-stage cancer patients. Here, we report a clinical service offering mutation detection of archived samples using the ion Ampliseq cancer panel coupled with clinical consultation.A multidisciplinary think tank consisting of oncologists, molecular-biologists, genetic counselors, and pathologists discussed 67 heavily pretreated, advanced cancer patient cases, taking into account mutations identified using ion Ampliseq cancer panel, medical history, and relevant literature.The team generated a treatment plan, targeting specific mutations, for 41 out of 64 cases. Three patients died before results were available. For 32 patients, the treating oncologists chose not to include the panel recommendation in the treatment plan for various reasons. Nine patients were treated as recommended by the panel, 5 with clinical benefit, and 4 with disease progression.This study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team-based decision making. Administration of personalized based therapies at an earlier stage of disease, expansion of genetic alterations examined, and increased availability of targeted therapies may lead to further improvement in the clinical outcome of metastatic cancer patients.

Preferential sites of metastatic relapse on MRI of initially localized ependymoma in children.

OBJECTIVE: Relapse of ependymoma in childhood portends a grave prognosis. While the detection of local recurrence is usually simple, spotting leptomeningeal metastasis might be challenging. We aimed to evaluate possible "hotspots" where metastasis tend to appear. MATERIALS AND METHODS: Medical records and Magnetic Resonance (MR) studies of all patients diagnosed with brain ependymomas between the years 2000-2015 were reviewed. RESULTS: Leptomeningeal spread was detected among 42% of relapsed patients. The most common sites were spine and hypothalamic area (26% each). CONCLUSION: A meticulous assessment of the brain and spine including a thorough evaluation of the hypothalamic area is recommended.

Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.

BACKGROUND: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. METHODS: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTS: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONS: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.

New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

Ewing Sarcoma: A 15-Year Experience of a Single Center With the MSKCC P6 Treatment Protocol.

INTRODUCTION: Ewing sarcoma (ES) is the second most common bone tumor in children. Current chemotherapeutic regimens include high-dose anthracyclines and alkylating agents with significant variation in treatment length. The Memorial Sloan Kettering Cancer Center P6 regimen (MSKCC P6) treatment protocol is a highly aggressive regimen given over 21 weeks only. We present the outcome of ES patients treated in our center with this protocol over the last 15 years. PROCEDURE: We retrospectively analyzed data on the presentation, patient characteristics, treatment, and outcome of all ES patients treated according to the MSKCC P6 regimen from 1999 to 2014. RESULTS: Of 48 patients, 37 (77%) presented with a nonmetastatic disease and 26 (54%) with tumor located in the extremities. The 5-year overall survival (OS) of the entire cohort was 55.9% ± 8%. Nonmetastatic disease conferred a better prognosis with a 5-year OS of 68.4% ± 8.5%. Patients with a nonmetastatic extremity tumor had the most favorable outcome with 5-year OS of 72.2% ± 9.8%. CONCLUSION: The outcome of ES patients after a short aggressive course of chemotherapy (the MSKCC P6 protocol), is comparable to that following other first-line treatment regimens in use, with potentially fewer long-term adverse events.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

An infant with a diagnostically challenging hepatic teratoma, hypofibrinogenemia, and adrenal neuroblastoma: case report.

Teratomas of the liver are exceedingly rare. Neuroblastoma is the most common, extracranial solid tumor of infancy. We describe the case of a 2-month-old, female infant who presented with an abdominal mass arising in the right lobe of the liver, and a severe coagulopathy, which necessitated cryoprecipitate infusion. Biopsy was interpreted as hepatoblastoma. Following resection, difficulty classifying the mass led to several consultations, and an eventual diagnosis of teratoma. During follow-up, the patient was diagnosed with right adrenal neuroblastoma, which, in retrospect, had been present before the hepatic resection. To our knowledge, these 2 tumors have never been reported together, or in combination with isolated hypofibrinogenemia.

TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current study, we used the SK-N-BE (2) cell line to generate orthotopic NB tumors in order to study the combinational therapeutic potential of TL-118 with either Gemcitabine (40 mg/kg; IP) or Retinoic acid (40 mg/kg; IP). We show that TL-118 treatment (n = 9) significantly inhibited tumor growth, increased cell apoptosis, reduced proliferation and extended mouse survival. Moreover, the reciprocal effect of TL-118 and Gemcitabine treatment (n = 10) demonstrated improved anti-tumor activity. The synergistic effect of these drugs in combination was more effective than either TL or Gemcitabine alone (n = 9), via significantly reduced cell proliferation (p<0.005), increased apoptosis (p<0.05) and significantly prolonged survival (2-fold; p<0.00001). To conclude, we demonstrate that the novel drug combination TL-118 has the ability to suppress the growth of an aggressive NB tumor. The promising results with TL-118 in this aggressive animal model may imply that this drug combination has therapeutic potential in the clinical setting.

Chronic residual lesions in metastatic medulloblastoma patients.

In a retrospective review of 24 metastatic medulloblastoma patients whose treatment included craniospinal irradiation, 5 patients presented with gross residual abnormalities at completion of therapy. This report describes 2 medulloblastoma patients with persistent residual abnormalities on serial follow-up imaging studies. The patients aged 2 and 2.5 years old at the time of diagnosis underwent surgery followed by multiagent chemotherapy. One patient progressed on therapy and underwent salvage craniospinal radiation. The second showed residual tumor on end of treatment imaging and received low-dose craniospinal irradiation. Despite persistent magnetic resonance imaging findings, the patients are alive and well 13 and 7 years after diagnosis with no further treatment applied. The nature of these residual abnormalities is discussed.

Optic pathway gliomas: a review.

Optic pathway gliomas account for 3-5% of all pediatric CNS tumors and represent the most common intrinsic optic nerve tumors. These tumors occur preferentially during the first decade of life and are particularly frequent in children with neurofibromatosis type 1. Although optic pathway gliomas are low-grade tumors, their behavior can be aggressive, and their management is often challenging. Their management includes observation, surgery, chemotherapy and radiation. The role of each modality is discussed as well as current and future developments in treatment, in particular targeted therapies that are currently being investigated.

Favorable outcome with conservative treatment for children with low grade brainstem tumors.

BACKGROUND: Pediatric brainstem tumors (BST) comprise a heterogeneous group of entities. Data regarding treatment options and outcome of BST, specifically brainstem low grade tumors (BSLGT) are limited. In order to better define risk groups and evaluate treatment options for pediatric BST, we performed a comprehensive analysis of all BST patients treated in our hospital during the MRI era. PROCEDURES: We retrospectively analyzed clinical, imaging, and pathology data at presentation, treatment, and outcome of all BST patients followed at the Hospital for Sick Children in Toronto over the last 25 years. RESULTS: Of 1,801 children with brain tumors, 223 (12%) had a brainstem primary location. Tumors without pontine involvement were BSLGT in 98.3%, whereas 75% of tumors involving the pons were high grade (P = 0.0001). Patients with BSLGT had 5-year progression-free survival (PFS) and overall survival (OS) of 57 ± 3% and 89 ± 5%, respectively. Upfront observation of tumor residual conferred no survival disadvantage with 5-year PFS and OS of 57 ± 5% and 93 ± 3%, respectively. In the group of patients requiring further treatment, 5-year PFS and OS were comparable between chemotherapy and radiotherapy with 53 ± 12% and 93 ± 4% and 66 ± 11% and 83 ± 6%, respectively (P = 0.26 and 0.3, respectively). CONCLUSION: BST without pontine involvement are almost invariably BSLGT. Children with BSLGT have an excellent outcome even with careful initial observation. No clear benefit was observed for radiotherapy over chemotherapy when adjuvant treatment was needed. A conservative approach may be warranted for children with non-pontine brainstem lesions.

BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma.

PURPOSE: Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor the BRAF-KIAA1549 (B-K) fusion gene resulting in constitutive activation of the RAS/MAPK pathway. However, the clinical significance of this genetic alteration is yet to be determined. We aimed to test the prognostic role of the B-K fusion in progression of incompletely resected PLGA. EXPERIMENTAL DESIGN: We retrospectively identified 70 consecutive patients with incompletely resected "clinically relevant" PLGA. We added 76 tumors diagnosed at our institution between 1985 and 2010 as controls. We examined BRAF alterations by reverse transcriptase PCR, FISH, and single-nucleotide polymorphism array analysis and correlated that with progression-free survival (PFS). RESULTS: Overall, 60% of tumors were B-K fusion positive. All patients with B-K fused PLGA are still alive. Five-year PFS was 61% ± 8% and 18% ± 8% for fusion positive and negative patients, respectively (P = 0.0004). B-K fusion resulted in similarly significant favorable PFS for patients who received chemotherapy. Multivariate analysis revealed that B-K fusion was the most significant favorable prognostic factor in incompletely resected PLGA and was independent of location, pathology, and age. In vitro, BRAF overexpression resulted in growth arrest associated with DNA damage (γH2AX expression). Five-year PFS was 68% ± 15% and 0% for patients with B-K fused and γH2AX-expressing PLGA versus negative tumors (P = 0.001). CONCLUSION: These data suggest that B-K fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. Combined analysis of B-K fusion and γH2AX expression can determine prognosis and may be a powerful tool to tailor therapy for these patients.