Osimertinib,Surgery, and Radiation Therapy in Treating Patients with Stage IIIB or IV Non-Small Cell Lung Cancer with EGFR Mutations (NORTHSTAR)

Annals of Surgical Oncology -     

Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer

Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations.     

Magnetic resonance imaging of perineural spread of head and neck malignancies

Perineural invasion is a common mechanism of spread of head and neck cancers. Imaging plays an important role in detection of this condition because a large number of patients with perineural spread (PNS) are clinically asymptomatic. Accurate detection of PNS requires an understanding of anatomy of commonly involved neural pathways. High level of suspicion on the part of the radiologist, awareness of common imaging signs of PNS and careful attention to imaging technique can aid in earlier detection of this condition.     

Comparative outcomes and cost-utility after surgical treatment of focal lumbar spinal stenosis compared with osteoarthritis of the hip or knee—part 1: long-term change in health-related quality of life

Background contextIt is well accepted that total hip and knee arthroplasty (THA/TKA) for osteoarthritis (OA) is associated with reliable and sustained improvements in postoperative health-related quality of life (HRQoL). Although several studies have demonstrated comparable outcomes with THA/TKA after surgical intervention for lumbar spinal stenosis (LSS), the sustainability of the outcome after LSS surgery compared with THA/TKA remains uncertain.PurposeThe primary purpose of this study is to assess whether improvements in HRQoL after surgical management of focal lumbar spinal stenosis (FLSS) with or without spondylolisthesis are sustainable over the long term compared with that of THA/TKA for OA.Study designSingle-center, retrospective, longitudinal matched cohort study of prospectively collected outcomes, with a minimum of 5-year follow-up (FU).Patient samplePatients who had primary one- to two-level spinal decompression with or without instrumented fusion for FLSS and THA/TKA for primary OA.Outcome measuresPostoperative change from baseline to last FU in Short-Form 36 physical component summary (PCS) and mental component summary (MCS) scores among groups was used as the primary outcome measure.MethodsAn age, sex-matched inception cohort of primary one- to two-level spinal decompression with or without instrumented fusion for FLSS (n=99) was compared with a cohort of primary THA (n=99) and TKA (n=99) for OA and followed for a minimum of 5 years. Linear regression was used for the primary analysis.ResultsMean (percent) FUs in months were 80.5+16.04 (79%), 94.6+16.62 (92%), and 80.6+16.84 (85%) for the FLSS, THA, and TKA cohorts, respectively, with a range of 5 to 10 years for all three cohorts. The number of patients who have undergone revision including those lost to FU for the FLSS, THA, and TKA cohorts were n=20 (20.2%, same site [n=7] and adjacent segment [n=13]) requiring 27 operations, n=3 (3%, same site) requiring 5 operations, and n=8 (8.1%, same site) requiring 12 operations, respectively (p<.01). The average time to first revision was 56/65/43 months, respectively. Mean postoperative PCS (p<.0001) and MCS (p<.02) scores improved significantly and were durable for all groups at the last FU. The mean changes from baseline PCS/MCS scores to last FU were 8.5/6.4, 12.3/7.0, and 8.3/4.9 for FLSS, THA, and TKA, respectively. Adjusting for baseline age, sex, body mass index, PCS score, and MCS score, there was a strong trend in favor of greater sustained change in the PCS score of THA over FLSS (p=.07) and TKA (p=.08). No difference was noted for change in PCS score between FLSS and TKA (p=.95). No differences were noted for change in MCS score among all three cohorts (p>.1).ConclusionsSignificant improvements in HRQoL after surgical treatment of FLSS with or without spondylolisthesis and hip and knee OA are sustained for a mean of 7 to 8 years, with a minimum of 5-year FU. Despite a higher revision rate, patients undergoing surgery for FLSS can expect a comparable long-term average improvement in HRQoL from baseline compared with their peers undergoing TKA and to a lesser extent THA.     

Unravelling mitochondrial pathways to Parkinson's disease

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson''s disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson''s disease models. However, identification of the recessive genes implicated in Parkinson''s disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson''s disease.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions.     

Early- and late-onset pancreatic adenocarcinoma: A population-based comparative study

BackgroundPancreatic cancer is projected to become the second leading cause of cancer related death in the US. We aim to investigate the demographics, clinical outcomes and survival outcomes of patients diagnosed with early-onset (<40 years) and late-onset (>40 years) pancreatic adenocarcinoma (PAC).MethodsData on PAC between 1975 and 2016 were extracted from the Surveillance, Epidemiology, and End Results Registry.ResultsWithin the study period, 136,100 patients were identified which included 1181 patients with early-onset PAC and 134,919 patients with late-onset PAC. Both cohorts tend to present with distant metastasis (70.3% vs 57.9%). Both groups also showed an exponential rise in incidence (early-onset 3.69% annual change vs late-onset 6.25% annual change). When stratified by anatomical location, there was a trend of increasing cancer in the head of the pancreas for patients <40 years (3.63% annual change). While late PAC showed increasing cancer in all anatomical locations, the largest increase was observed in the tail of the pancreas (8.62% annual change). Overall, there was a mild difference in survival for early- and late-onset PAC (7 months vs 6 months, respectively, log rank p = 0.004). Both age groups showed the worse prognosis when cancer occurred in the tail of the pancreas (6 months vs 4 months, respectively). On cox proportion analysis, patients with late-onset PAC had twice the risk of mortality compared to early-onset PAC (HR 2.06, CI: 1.788–2.370, P = 0.001).ConclusionsOur study showed that both early- and late-onset PAC are increasing and while prognosis remains poor. Tumor anatomy showed a growing incidence of early-onset PAC in the head of the pancreas while late-onset PAC showed a rising incidence in the body and tail of the pancreas.