Sarcoma

GBD 2019 estimated each epidemiological quantity of interest—incidence, prevalence, mortality, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs)—for 23 age groups; males, females, and both sexes combined; and 204 countries and territories that were grouped into 21 regions and seven super-regions. For GBD 2019, nine countries and territories (Cook Islands, Monaco, San Marino, Nauru, Niue, Palau, Saint Kitts and Nevis, Tokelau, and Tuvalu) were added, such that the GBD location hierarchy now includes all WHO member states. GBD 2019 includes subnational analyses for Italy, Nigeria, Pakistan, the Philippines, and Poland, and 16 countries previously estimated at subnational levels (Brazil, China, Ethiopia, India, Indonesia, Iran, Japan, Kenya, Mexico, New Zealand, Norway, Russia, South Africa, Sweden, the UK, and the USA). All subnational analyses are at the first level of administrative organisation within each country except for New Zealand (by Māori ethnicity), Sweden (by Stockholm and non-Stockholm), the UK (by local government authorities), and the Philippines (by province). In this publication, we present subnational estimates for Brazil, India, Indonesia, Japan, Kenya, Mexico, Sweden, the UK, and the USA; given space constraints, these results are presented in appendix 2. At the most detailed spatial resolution, we generated estimates for 990 locations. The GBD diseases and injuries analytical framework generated estimates for every year from 1990 to 2019.
Diseases and injuries were organised into a levelled cause hierarchy from the three broadest causes of death and disability at Level 1 to the most specific causes at Level 4. Within the three Level 1 causes—communicable, maternal, neonatal, and nutritional diseases; non-communicable diseases; and injuries—there are 22 Level 2 causes, 174 Level 3 causes, and 301 Level 4 causes (including 131 Level 3 causes that are not further disaggregated at Level 4; see appendix 1 sections 3.4 and 4.12 for the full list of causes). 364 total causes are non-fatal and 286 are fatal. For GBD 2019, 12 new causes were added to the modelling framework: pulmonary arterial hypertension, eye cancer, soft tissue and other extraosseous sarcomas, malignant neoplasm of bone and articular cartilage, and neuroblastoma and other peripheral nervous cell tumours at Level 3, and hepatoblastoma, Burkitt lymphoma, other non-Hodgkin lymphoma, retinoblastoma, other eye cancers, and two sites of osteoarthritis (hand and other joints) at Level 4.

Results are based in part upon data generated by TCGA Research Network (http://cancergenome.nih.gov/). We aggregated TCGA transcriptomic and RPPA data from public repositories, listed in the “Data availability” section. RNA-seq expression data were processed by TCGA at the gene level, rather than at the transcript level. Tumors spanned 32 different TCGA projects, each project representing a specific cancer type, listed as follows: LAML, acute myeloid leukemia; ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; LGG, lower grade glioma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; CRC, colorectal adenocarcinoma (combining COAD and READ projects); ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THYM, thymoma; THCA, thyroid carcinoma; UCS, uterine carcinosarcoma; UCEC, uterine corpus endometrial carcinoma; UVM, uveal melanoma. Cancer molecular profiling data were generated through informed consent as part of previously published studies and analyzed per each original study’s data use guidelines and restrictions.

Authorizations for reporting these three cases were granted by the Eastern Ontario Regional Forensic Unit and the Laboratoire de Sciences Judiciaires et de Médecine Légale du Québec.
The sampling followed a relatively standardized protocol for all TBI cases: samples were collected from the cortex and underlying white matter of the pre-frontal gyrus, superior and middle frontal gyri, temporal pole, parietal and occipital lobes, deep frontal white matter, hippocampus, anterior and posterior corpus callosum with the cingula, lenticular nucleus, thalamus with the posterior limb of the internal capsule, midbrain, pons, medulla, cerebellar cortex and dentate nucleus. In some cases, gross pathology (e.g. contusions) mandated further sampling along with the dura and spinal cord if available. The number of available sections for these three cases was 26 for case1, and 24 for cases 2 and 3.
For the detection of ballooned neurons, all HE or HPS sections, including contusions, were screened at 200×.
Representative sections were stained with either hematoxylin–eosin (HE) or hematoxylin-phloxin-saffron (HPS). The following histochemical stains were used: iron, Luxol-periodic acid Schiff (Luxol-PAS) and Bielschowsky. The following antibodies were used for immunohistochemistry: glial fibrillary acidic protein (GFAP) (Leica, PA0026,ready to use), CD-68 (Leica, PA0073, ready to use), neurofilament 200 (NF200) (Leica, PA371, ready to use), beta-amyloid precursor-protein (β-APP) (Chemicon/Millipore, MAB348, 1/5000), αB-crystallin (EMD Millipore, MABN2552 1/1000), ubiquitin (Vector, 1/400), β-amyloid (Dako/Agilent, 1/100), tau protein (Thermo/Fisher, MN1020 1/2500), synaptophysin (Dako/Agilent, ready to use), TAR DNA binding protein 43 (TDP-43) ((Protein Tech, 10,782-2AP, 1/50), fused in sarcoma binding protein (FUS) (Protein tech, 60,160–1-1 g, 1/100), and p62 (BD Transduc, 1/25). In our index cases, the following were used for the evaluation of TAI: β-APP, GFAP, CD68 and NF200; for the neurodegenerative changes: αB-crystallin, NF200, ubiquitin, tau protein, synaptophysin, TDP-43, FUS were used.
For the characterization of the ballooned neurons only, two cases of fronto-temporal lobar degeneration, FTLD-Tau, were used as controls. One was a female aged 72 who presented with speech difficulties followed by neurocognitive decline and eye movement abnormalities raising the possibility of Richardson’s disorder. The other was a male aged 67 who presented with a primary non-fluent aphasia progressing to fronto-temporal demαentia. In both cases, the morphological findings were characteristic of a corticobasal degeneration.

Statistical analysis will be performed at the JCOG Data Center. The primary analysis will be performed 6 months after the end of accrual, when collection of the primary endpoint data for all enrolled patients is expected to be complete. The treatment protocol with the best point estimate of the HR for PFS, which is the primary endpoint of this study, will be the test treatment arm in a subsequent phase III trial. However, the treatment arm for the phase III trial will be decided comprehensively if the following results are obtained, taking into consideration endpoints other than PFS. First, the PFS obtained is substantially lower than expected (insufficient results for promising therapy). Second, the overall survival results differ significantly from those of PFS. Third, the frequency of adverse events among the arms differs significantly from the expected frequency.
For the primary analysis of PFS, the respective HRs of arms A to B and A to C will be calculated using an unstratified Cox proportional-hazards model for all enrolled patients, and the treatment with the best HR will be judged to be the most promising regimen. Since this study does not make judgments based on hypothesis testing, no significance level is set a priori, and no adjustment will be made for multiplicity.
Subgroup analyses based on the factors mentioned below are to be conducted, as necessary. The factors for which subgroup analyses are planned include age group 1 (< 40/ ≥ 40 years), age group 2 (< 70/ ≥ 70 years), sex (male/female), PS (0/1 and 2), histological type (liposarcoma/leiomyosarcoma/translocation-related sarcoma/other), distant metastasis 1 [(M1 and/or N1)/other], distant metastasis 2 [M1/(N1 and M0)/other], and doxorubicin (perioperative chemotherapy/palliative chemotherapy).