Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Cell. 2016 Aug 25;166(5):1147-1162.e15

Authors: Zhang X, Chen MH, Wu X, Kodani A, Fan J, Doan R, Ozawa M, Ma J, Yoshida N, Reiter JF, Black DL, Kharchenko PV, Sharp PA, Walsh CA

Abstract
Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

PMID: 27565344 [PubMed - indexed for MEDLINE]

Often seen, rarely recognized: mast cell activation disease--a guide to diagnosis and therapeutic options.

Ann Med. 2016;48(3):190-201

Authors: Afrin LB, Butterfield JH, Raithel M, Molderings GJ

Abstract
Mast cell (MC) disease has long been thought to be just the rare disease of mastocytosis (in various forms, principally cutaneous and systemic), with aberrant MC mediator release at symptomatic levels due to neoplastic MC proliferation. Recent discoveries now show a new view is in order, with mastocytosis capping a metaphorical iceberg now called "MC activation disease" (MCAD, i.e. disease principally manifesting inappropriate MC activation), with the bulk of the iceberg being the recently recognized "MC activation syndrome" (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Given increasing appreciation of a great menagerie of mutations in MC regulatory elements in mastocytosis and MCAS, the great heterogeneity of MCAD's clinical presentation is unsurprising. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme. Preliminary epidemiologic investigation suggests MCAD, while often misrecognized, may be substantially prevalent, making it increasingly important that practitioners of all stripes learn how to recognize its more common forms such as MCAS. We review the diagnostically challenging presentation of MCAD (with an emphasis on MCAS) and current thoughts regarding its biology, epidemiology, natural history, diagnostic evaluation, and treatment.

PMID: 27012973 [PubMed - indexed for MEDLINE]

Liver transplantation for adenomatosis: European experience.

Liver Transpl. 2016 Apr;22(4):516-26

Authors: Chiche L, David A, Adam R, Oliverius MM, Klempnauer J, Vibert E, Colledan M, Lerut J, Mazzafero VV, Di-Sandro S, Laurent C, Scuderi V, Suc B, Troisi R, Bachelier P, Dumortier J, Gugenheim J, Mabrut JY, Gonzalez-Pinto I, Pruvot FR, Le-Treut YP, Navarro F, Ortiz-de-Urbina J, Salamé E, Spada M, Bioulac-Sage P

Abstract
The aim of this study was to collect data from patients who underwent liver transplantation (LT) for adenomatosis; to analyze the symptoms, the characteristics of the disease, and the recipient outcomes; and to better define the role of LT in this rare indication. This retrospective multicenter study, based on data from the European Liver Transplant Registry, encompassed patients who underwent LT for adenomatosis between January 1, 1986, and July 15, 2013, in Europe. Patients with glycogen storage disease (GSD) type IA were not excluded. This study included 49 patients. Sixteen patients had GSD, and 7 had liver vascular abnormalities. The main indications for transplantation were either a suspicion of hepatocellular carcinoma (HCC; 15 patients) or a histologically proven HCC (16 patients), but only 17 had actual malignant transformation (MT) of adenomas. GSD status was similar for the 2 groups, except for age and the presence of HCC on explants (P = 0.030). Three patients with HCC on explant developed recurrence after transplantation. We obtained and studied the pathomolecular characteristics for 23 patients. In conclusion, LT should remain an extremely rare treatment for adenomatosis. Indications for transplantation primarily concern the MT of adenomas. The decision should rely on morphological data and histological evidence of MT. Additional indications should be discussed on a case-by-case basis. In this report, we propose a simplified approach to this decision-making process.

PMID: 26919265 [PubMed - indexed for MEDLINE]

The changing face of liver transplantation for acute liver failure: Assessment of current status and implications for future practice.

Liver Transpl. 2016 Apr;22(4):527-35

Authors: Donnelly MC, Hayes PC, Simpson KJ

Abstract
The etiology and outcomes of acute liver failure (ALF) have changed since the definition of this disease entity in the 1970s. In particular, the role of emergency liver transplantation has evolved over time, with the development of prognostic scoring systems to facilitate listing of appropriate patients, and a better understanding of transplant benefit in patients with ALF. This review examines the changing etiology of ALF, transplant benefit, outcomes following transplantation, and future alternatives to emergency liver transplantation in this devastating condition.

PMID: 26823231 [PubMed - indexed for MEDLINE]

Coronary artery disease in Eisenmenger's syndrome--Rare but not to be forgotten.

Int J Cardiol. 2016 Jan 15;203:276-7

Authors: Abraham D, Freeman LJ, Lewis C, O'Sullivan M

PMID: 26519685 [PubMed - indexed for MEDLINE]

Putative modifier genes in mevalonate kinase deficiency.

Mol Med Rep. 2016 Apr;13(4):3181-9

Authors: Marcuzzi A, Vozzi D, Girardelli M, Tricarico PM, Knowles A, Crovella S, Vuch J, Tommasini A, Piscianz E, Bianco AM

Abstract
Mevalonate kinase deficiency (MKD) is an autosomal recessive auto‑inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non‑homogeneous genotype‑phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.

PMID: 26935981 [PubMed - indexed for MEDLINE]

Socio-economic burden of rare diseases: A systematic review of cost of illness evidence.

Health Policy. 2015 Jul;119(7):964-79

Authors: Angelis A, Tordrup D, Kanavos P

Abstract
Cost-of-illness studies, the systematic quantification of the economic burden of diseases on the individual and on society, help illustrate direct budgetary consequences of diseases in the health system and indirect costs associated with patient or carer productivity losses. In the context of the BURQOL-RD project ("Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe") we studied the evidence on direct and indirect costs for 10 rare diseases (Cystic Fibrosis [CF], Duchenne Muscular Dystrophy [DMD], Fragile X Syndrome [FXS], Haemophilia, Juvenile Idiopathic Arthritis [JIA], Mucopolysaccharidosis [MPS], Scleroderma [SCL], Prader-Willi Syndrome [PWS], Histiocytosis [HIS] and Epidermolysis Bullosa [EB]). A systematic literature review of cost of illness studies was conducted using a keyword strategy in combination with the names of the 10 selected rare diseases. Available disease prevalence in Europe was found to range between 1 and 2 per 100,000 population (PWS, a sub-type of Histiocytosis, and EB) up to 42 per 100,000 population (Scleroderma). Overall, cost evidence on rare diseases appears to be very scarce (a total of 77 studies were identified across all diseases), with CF (n=29) and Haemophilia (n=22) being relatively well studied, compared to the other conditions, where very limited cost of illness information was available. In terms of data availability, total lifetime cost figures were found only across four diseases, and total annual costs (including indirect costs) across five diseases. Overall, data availability was found to correlate with the existence of a pharmaceutical treatment and indirect costs tended to account for a significant proportion of total costs. Although methodological variations prevent any detailed comparison between conditions and based on the evidence available, most of the rare diseases examined are associated with significant economic burden, both direct and indirect.

PMID: 25661982 [PubMed - indexed for MEDLINE]

[Ophthalmogenetics: Rare Diseases - A Challenge for Diagnostic and Treatment].

Klin Monbl Augenheilkd. 2016 Mar;232(3):242

Authors: Rudolph G

PMID: 27011027 [PubMed - indexed for MEDLINE]

GerOSS (German Obstetric Surveillance System). A Project to Improve the Treatment of Obstetric Rare Diseases and Complications Using a Web Based Documentation and Information Platform.

Methods Inf Med. 2015;54(5):406-11

Authors: Berlage S, Grüßner S, Lack N, Franz HB

Abstract
BACKGROUND: Severe and very rare obstetric complications (e.g. eclampsia, postpartum haemorrhage or uterine rupture), typically culminate in a chaotic, uncontrollable sequence of events. Outcome for mother and child depends on whether doctors and midwives are able to quickly take correct decisions and initiate optimal treatment.
OBJECTIVES: GerOSS (German Obstetric Surveillance System) aims at generating deeper insight into relevant risk factors to improve diagnosis and treatment of severe complications during pregnancy and delivery. As such it is primarily conceived as a system for quality improvement and less as a register. Another focus is the provision of an information and communication platform for dissemination of these insights. Finally, incidences of selected rare obstetric events may be derived.
METHODS: These rare events are monitored for two to five years in Lower Saxony, Bavaria and Berlin. Quantitative analyses of aggregate data are complemented with in depth case based anonymised evaluations by experts. The temporal sequence of measures taken as well as the management of care is inspected. Participants receive a feedback of comments on the synopsis of individual cases. Aggregate data results are published and made available through the GerOSS platform. A scientific advisory committee ensures the link with the professional scientific bodies. A comparison within INOSS (International Network of Obstetric Survey Systems) allows additional insights into the treatment of obstetric rare diseases and complications. More reliable estimates of the incidence of such events can be computed and compared within a larger database.
RESULTS: Following the implementation in three federal states in Germany in 2010, participation in GerOSS-Project has increased to 100% of all hospitals with a delivery unit in Lower Saxony, 30% in Bavaria and 80% in Berlin. Feasibility of the project is shown by successful implementation of GerOSS. Quantitative analyses enable construction of risk profiles (e.g. for the prevalence of hysterectomies and uterine ruptures) such that tailored treatment algorithms may be derived. Age, body mass index and previous caesarean section are common risk factors when complications occur. Respective recommendations have not always been adhered to in the diagnosis and therapy of such cases. The presentation of initial GerOSS results has paved the path for first changes in obstetric care.
CONCLUSIONS: The envisaged expansion of GerOSS to an interactive platform will allow dissemination of insights such that optimal obstetric care and transferal among all involved medical facilities may see future enhancements via the internet or even through smartphone applications.

PMID: 26065375 [PubMed - indexed for MEDLINE]

Novel Treatments for Rare Cancers: The U.S. Orphan Drug Act Is Delivering-A Cross-Sectional Analysis.

Oncologist. 2016 Apr;21(4):487-93

Authors: Stockklausner C, Lampert A, Hoffmann GF, Ries M

Abstract
BACKGROUND: Rare cancers are a heterogeneous group of conditions with highly unmet medical needs. Although infrequent in individuals, rare cancers affect millions of people who deserve effective treatments. Therefore, we systematically analyzed the impact of the U.S. Orphan Drug Act of 1983 on delivery of novel treatments for rare cancers.
METHODS: Quantitative cross-sectional analysis was conducted on the U.S. Food and Drug Administration Orphan Drug Product database according to Strengthening the Reporting of Observational Studies in Epidemiology Statement criteria between 1983 and 2015.
RESULTS: Since 1983, a total of 177 approvals have originated from 1,391 orphan drug designations to treat rare cancers, which represents 36% of all approvals within the U.S. orphan drug act (n = 492). Two compounds (1%) to treat rare cancer were withdrawn after approval. Median time from designation to approval was 2.49 years (interquartile range 1.13-4.64) and decreased significantly over time (p < .001, linear regression). Over the last decade, rare cancer treatments have been transformed from nonspecific cytotoxic agents toward targeted therapies, such as protein kinase inhibitors and monoclonal antibodies, representing the largest groups of innovative rare cancer treatments today. Most compounds were approved to treat solid tumors and hematological malignancies.
CONCLUSION: The U.S. Orphan Drug Act and associated incentives, such as 7 years of marketing exclusivity, have fostered delivery of novel treatments for rare cancers. More than one-third of all orphan drug approvals address needs of patients suffering from rare cancers. Over the last decade, the understanding of tumorigenesis and genetic driver mutations in different tumor entities has produced innovative treatments, of which many were first approved within the U.S. Orphan Drug Act.
IMPLICATIONS FOR PRACTICE: Over the last 30 years, the U.S. Orphan Drug Act successfully delivered numerous novel treatments for rare cancers, of which some were subsequently used in other, nonorphan indications. The understanding of molecular mechanisms of diseases is directly connected to the search for novel therapies. The constant pursuit to translate basic research findings into clinical practice is a crucial prerequisite to address unmet medical needs in rare cancers, as in other rare diseases. Oncological drug development proves to be a major player in overall orphan drug research, displayed by more than one-third of all U.S. Food and Drug Administration-approved orphan drugs with oncological indications.

PMID: 27022038 [PubMed - indexed for MEDLINE]

[Pathophysiology of systemic sclerosis].

Med Sci (Paris). 2016 Feb;32(2):183-91

Authors: Allanore Y

Abstract
Systemic sclerosis (SSc) is an orphan disease affecting the connective tissue. The cause of SSc remains unknown but is likely to involve environmental factors in a genetically primed individual with SSc belonging to the multigenic disorders. Pathogenesis is dominated by early microvascular changes targeting endothelial cells and with the release of several mediators promoting an inflammatory response and vascular remodelling. Several lines of evidence position autoimmunity as a key perpetuating event with activation of both innate and adaptive immunity and with the production of distinct autoantibodies. The cascade ultimates with the fibrosis defined by accumulation of extra-cellular matrix through an imbalance between synthesis and degradation of several components and mesenchymal cell activation and differentiation controlled by a large number of autocrine and paracrine factors.

PMID: 26936176 [PubMed - indexed for MEDLINE]

The wide spectrum of cerebrotendinous xanthomatosis: Case report of a rare but treatable disease.

Clin Neurol Neurosurg. 2016 Apr;143:1-3

Authors: Rosafio F, Cavallieri F, Guaraldi P, Taroni F, Nichelli PF, Mandrioli J

Abstract
Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive disorder of lipid storage caused by mutations in the CYP27A1 gene, coding for a sterol 27-hydroxylase, leading to increased deposition of cholesterol in multiple tissues. CTX is characterized by the association of early non-neurological manifestations and adult-onset neurological dysfunctions (spastic ataxia, dementia, psychiatric disorders, peripheral neuropathy). Early and long-term treatment with chenodeoxycholic acid (CDCA) can slow down neurological symptoms progression, but diagnosis usually has a delay of several years. We report two Italian siblings having quite different phenotypes associated to a G-to-A transition in the c-1263 terminal causing a splicing alteration. This mutation has not been described before in Italy, and has been reported once in Japan. This case widens the clinical and genetic spectrum of Cerebrotendinous Xantomatosis in Italy and would like to suggest the importance of genetic testing in patients with autosomal recessive spastic paraparesis associated with typical non-neurological symptoms.

PMID: 26874936 [PubMed - indexed for MEDLINE]

LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency.

Nat Cell Biol. 2016 Dec 19;:

Authors: Tsanov KM, Pearson DS, Wu Z, Han A, Triboulet R, Seligson MT, Powers JT, Osborne JK, Kane S, Gygi SP, Gregory RI, Daley GQ

Abstract
Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation.

PMID: 27992407 [PubMed - as supplied by publisher]

Budget impact of everolimus for the treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic.

J Med Econ. 2016 Dec 16;:1-19

Authors: Rose DB, Nellesen D, Neary MP, Cai B

Abstract
BACKGROUND: Advanced neuroendocrine tumors (NETs) are a rare malignancy with considerable need for effective therapies. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2016 for treatment of adults with progressive, well-differentiated, non-functional NETs of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic.
OBJECTIVE: To assess the 3-year budget impact for a typical US health plan following availability of everolimus for treatment of GI and lung NETs.
METHODS: An economic model was developed that considered two perspectives: an entire health plan and a pharmacy budget. The total budget impact included costs of drug therapies, administration, hospitalizations, physician visits, monitoring, and adverse events (AEs). The pharmacy model only considered drug costs.
RESULTS: In a US health plan with 1 million members, the model estimated 66 patients with well-differentiated, non-functional, and advanced or metastatic GI NETs and 20 with lung NETs undergoing treatment each year. Total budget impact in the first through third year after FDA approval ranged from $0.0568-$0.1443 per member per month (PMPM) for GI NETs and from $0.0181-$0.0355 PMPM for lung NETs. The total budget impact was lower than the pharmacy budget impact because it included cost offsets from administration and AE management for everolimus compared with alternative therapies (e.g., chemotherapies).
LIMITATIONS: Because GI and lung NETs are rare diseases with limited published data, several assumptions were made that may influence interpretation of results.
CONCLUSIONS: The budget impact for everolimus was minimal in this rare disease area with a high unmet need, largely due to low disease prevalence. These results should be considered in the context of significant clinical benefits potentially provided by everolimus, including significantly longer progression-free survival (PFS) for advanced GI and lung NET patients.

PMID: 27981858 [PubMed - as supplied by publisher]

Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate.

Neuron. 2016 Nov 23;92(4):813-828

Authors: Jayaraman D, Kodani A, Gonzalez DM, Mancias JD, Mochida GH, Vagnoni C, Johnson J, Krogan N, Harper JW, Reiter JF, Yu TW, Bae BI, Walsh CA

Abstract
Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.

PMID: 27974163 [PubMed - in process]

Clinical presentation, pathological features, and natural course of metastatic uveal melanoma (MUM) as an orphan and commonly fatal disease.

J Clin Oncol. 2009 May 20;27(15_suppl):e20005

Authors: Cerbone L, Van Ginderdeuren R, Van den Oord J, Fieuws S, Spileers W, Van Eenoo L, Wozniak A, Sternberg CN, Schöffski P

Abstract
e20005 Background: Uveal melanoma (UM) is a rare disease characterized by an unpredictable course and variable outcome ranging from cure by local treatment to the occurrence of untreatable metastasis. The current project analyzed patients with the metastatic phenotype.
METHODS: We performed data collection in 76 pts with MUM treated in Leuven between 1957-2008. Statistical analysis involved nonparametric tests, Kaplan Meyer and log rank test.
RESULTS: The med. age at diagnosis of UM was 58 yrs (range 30-94). Common initial treatments were surgery (71%), brachytherapy (20%) and external beam RT (7%). MUM was more common in women (F:M ratio 48:28) and independent from the side of the primary tumor (left vs. right eye). Synchronous metastasis was found in 9% of cases, all others had metachronous disease after a med. interval of 40 mos (range, 7-420). Statistical analysis failed to identify predisposing factors for MUM with the exception of a significant negative correlation between age at diagnosis of UM and time until metastatic disease (Spearman ρ = -0.4, p<0.001). Metastasis in >1 organ, usually liver plus another site, was seen in 47% of cases. The most frequent sites were liver (96%), lung (23%), subcutaneous (13%), bone (11%) and brain (3%).The med. OS from diagnosis of UM was 46 mos (range, 2-182), and 4,5 mos after diagnosis of metastasis (range, 1-128). 65% of MUM pts qualified for further treatment, including systemic therapy (60%), radiotherapy (7%) and surgery (7%). Systemic therapy (45 pts) included mainly chemo- (50%), chemo- plus hormones (12%), immuno- (3%) or hormonal therapy (3%). The most common drugs given were DTIC (43%), cisplatin (27%), tamoxifen (10%) or phase I agents (8%). Patient benefit (PR+SD) was seen in 16/45 pts (36%), including 2 PR.
CONCLUSIONS: In this orphan disease with female predominance metastasis occurs late, is mainly found but not confined to the liver, and is associated with high morbidity, as >1/3 of pts do not qualify for further therapy. Advances in MUM can only be achieved by networking of sites interested in this tumor with systematic collection of data and tissue to improve our understanding of the molecular biology of the disease. No significant financial relationships to disclose.

PMID: 27962598 [PubMed - in process]

Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany.

Eur J Endocrinol. 2016 Dec;175(6):521-529

Authors: Wendler J, Kroiss M, Gast K, Kreissl MC, Allelein S, Lichtenauer U, Blaser R, Spitzweg C, Fassnacht M, Schott M, Führer D, Tiedje V

Abstract
CONTEXT: Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established.
OBJECTIVE: The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis.
DESIGN: Retrospective cohort study at five German tertiary care centers.
PATIENTS AND METHODS: Totally 100 ATC patients diagnosed between 2000 and 2015 were included in the analysis. Disease-specific overall survival (OS) was compared with the Kaplan-Meier method and log-rank test; Cox proportional hazard model was used to identify risk factors.
RESULTS: The 6-month, 1-year and 5-year disease-specific OS rates were 37, 28 and 5%, respectively. Stage-dependent OS at 6 months was 78, 54 and 18% for stage IVA, B and C, respectively. 29% patients survived >1 year. Multivariate analysis of OS identified age ≥70 years, incomplete local resection status and the presence of distant metastasis as significant risk factors associated with shorter survival. Radical surgery (hazard ratio [HR] 2.20, 95% confidence interval (CI) 1.19-4.09, P = 0.012), external beam radiation therapy (EBRT) ≥40 Gy (HR = 0.34, 0.15-0.76, P = 0.008) and any kind of chemotherapy (CTX) (HR = 11.64, 2.42-60.39, P = 0.003) were associated with longer survival in multivariate analyses adjusted for age and tumor stage. A multimodal treatment regimen was significantly associated with a survival benefit (HR = 1.04, 1.01-1.08, P < 0.0001) only in IVC patients.
CONCLUSION: Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

PMID: 27926471 [PubMed - in process]

25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases"

These pubmed results were generated on 2016/12/21

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases"

These pubmed results were generated on 2016/12/20

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases"

These pubmed results were generated on 2016/12/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.