Primary Urothelial Carcinoma of the Ureter: 11-Year Experience in Taipei Veterans General Hospital

BackgroundUrothelial carcinoma of the upper urinary tract is relatively rare, occurring in 5% of all urothelial tumors. Ureteral urothelial carcinoma is even less common than that of the renal pelvis, accounting for about 25% of all upper urinary tract tumors. The aim of this study was to evaluate the clinical behavior, survival, recurrence and prognostic information of primary ureteral urothelial carcinoma from our 11 years of experience at the Taipei Veterans General Hospital.MethodsWe retrospectively reviewed 111 patients with ureteral urothelial carcinoma who had been treated in our hospital between January 1993 and December 2003. Tumor staging was according to the 2002 AJCC TNM classification and stage groupings. Patients with stage 0a and stage 0is were categorized as stage 0a/is, and patients with pathologic T stage pTa and pTis were categorized as pTa/is for statistical analysis. The Kaplan-Meier method was used for survival analysis.ResultsThere were 69 males and 42 females, with a mean age of 70.5 ± 9.4 years at diagnosis. Of the 111 patients, 5 presented with stage 0a/is, 38 with stage I, 23 with stage II, 21 with stage III, and 24 with stage IV. Nephroureterectomy with bladder cuff excision was performed in 78 patients, 12 patients received segmental resection of the ureter, 4 received ureteroscopic laser coagulation, and 17 underwent chemotherapy or radiotherapy or both. Tumors were located on the left side in 53 patients, on the right in 53, and bilaterally in 5. The most frequent initial presenting symptom was gross hematuria (65%). The mean postoperative follow-up period was 49.3 months. Disease recurrence in the nephroureterectomy group occurred in 36 patients (46.2%), with 17 (21.8%) at the urinary bladder, 2 (2.6%) at the retroperitoneum, 1 (1.3%) at the contralateral ureter, 6 (7.7%) with distant metastases to the lung, bone, distant lymph nodes or liver, and 10 (12.8%) at multiple sites. The 5-year cancer-specific survival rate was 100% for pTa/is, 95.2% for pT1, 69.4% for pT2, and 43.8% for pT3. All 3 pT4 cases died of cancer in a median of 12 months. Significant prognostic factors for cancer-specific survival by univariate analysis were pT (p = 0.00001), stage (p = 0.00001), type of treatment (p = 0.00001) and grade (p = 0.0001). On multivariate analysis, only stage (p = 0.0001) and grade (p = 0.014) were significant for cancer-specific and overall survival. Stage (p = 0.0001), pT (p =0.0001) and grade (p = 0.026) were also significant prognostic factors of recurrence in multivariate analysis.ConclusionOur experience showed that patients with pTa/is and pT1 tumors treated with radical surgery have excellent prognoses. Tumor stage and grade are the only significant prognostic factors for both cancer-specific and overall survival

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival