Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison

We compared concurrent combination chemotherapy and radiotherapy with surgery and adjuvant radiotherapy in patients with stage III/IV nonmetastatic squamous cell head and neck cancer. Patients with non-nasopharyngeal and nonsalivary resectable squamous cell head and neck cancer were randomised to receive either surgery followed by adjuvant radiotherapy (60 Gy over 30 fractions) or concurrent combination chemotherapy and radiotherapy (66 Gy in 33 fractions). Combination chemotherapy comprised two cycles of i.v. cisplatin 20 mg m− 2 day− 1 and i.v. 5-fluorouracil 1000 mg m− 2 day− 1, both to run over 96 h given on days 1 and 28 of the radiotherapy. A total of 119 patients were randomised. At a median follow-up of 6 years, there was no significant difference in the 3-year disease-free survival rate between the surgery and concurrent chemoradiotherapy (50 vs 40% respectively). The overall organ preservation rate or avoidance of surgery to primary site was 45%. Those with laryngeal/hypopharyngeal disease subsite had a higher organ-preservation rate than the rest (68 vs 30%). Combination chemotherapy and concurrent irradiation with salvage surgery was not superior to conventional surgery and postoperative radiotherapy for resectable advanced squamous cell head and neck cancer. However, this form of treatment schedule with a view to organ-preservation can be attempted especially for those with laryngeal/hypopharyngeal and possibly oropharyngeal disease subsites

Molecular characterization of interdigitating dendritic cell sarcoma

Interdigitating dendritic cell sarcoma is an extremely rare cancer that lacks a standard treatment approach. We report on a patient who was surgically resected and remains disease- free. The tumor was assessed for druggable targets using immunohistochemical staining to identify potential agents that could be used in the event of disease recurrence

Effect of the displacement rate and inclination angle in steel fiber pullout tests

This paper summarizes the results obtained in an experimental campaign on the effect of the displacement pullout rate and the inclination angle of the steel fiber pullout tests. For that purpose, specimens were obtained from a self-compacting concrete with a compressive strength of 86 MPa. In the experimental program, hooked-end steel fibers of 0.75 mm diameter and 60 mm length were used. Tests were executed with both hooked-end fibers, and smooth fibers obtained from the former by cutting the hooked end. For both type of fibers, their embedment length into concrete was 20 mm, and the influence of fiber inclination angle toward the load direction was investigated by adopting values of 0∘, 30∘ and 60∘. The tests were performed at displacement rates of 0.01, 0.1 and 1 mm/s. The results have shown that the peak pullout load increased with the inclination angle, in particular for the smooth series. Furthermore, higher displacement rates led to a higher energy absorption capacity for the pullout of the smooth fibers, while the energy absorption remained almost stable for hooked-end fibers.project BIA2015-68678-C2-1-R. M. Tarifa appreciates the financial support from the Department of Applied Mechanics and Project Engineering, UCLM (2018), and from the Programa propio de I+D+i de la Universidad Politécnica de Madrid para realizar estancias de investigación internacional igual o superior a un mes (2019), to do two stays at the University of Minho, Guimarães, Portugal. E. Poveda acknowledges the funding from the International Campus of Excellence CYTEMA and the University of Castilla-La Mancha, throughout Ayudas para estancias en universidades y centros de investigación en el extranjero en 2019 en el ámbito del plan propio de investigación susceptibles de cofinanciación por el Fondo Europeo de Desarrollo Regional (FEDER), Programa 010100021 to fund her stays in the University of Minho during 2018 and 2019, respectively. The authors thank the support of the Department of Civil Engineering and the Laboratory of the Structural Division (LEST), University of Minh

Brezin-Gross-Witten model as "pure gauge" limit of Selberg integrals

The AGT relation identifies the Nekrasov functions for various N=2 SUSY gauge theories with the 2d conformal blocks, which possess explicit Dotsenko-Fateev matrix model (beta-ensemble) representations the latter being polylinear combinations of Selberg integrals. The "pure gauge" limit of these matrix models is, however, a non-trivial multiscaling large-N limit, which requires a separate investigation. We show that in this pure gauge limit the Selberg integrals turn into averages in a Brezin-Gross-Witten (BGW) model. Thus, the Nekrasov function for pure SU(2) theory acquires a form very much reminiscent of the AMM decomposition formula for some model X into a pair of the BGW models. At the same time, X, which still has to be found, is the pure gauge limit of the elliptic Selberg integral. Presumably, it is again a BGW model, only in the Dijkgraaf-Vafa double cut phase.Comment: 21 page

Disease-specific survival for limited-stage small-cell lung cancer affected by statistical method of assessment

BACKGROUND: In general, prognosis and impact of prognostic/predictive factors are assessed with Kaplan-Meier plots and/or the Cox proportional hazard model. There might be substantive differences from the results using these models for the same patients, if different statistical methods were used, for example, Boag log-normal (cure-rate model), or log-normal survival analysis. METHODS: Cohort of 244 limited-stage small-cell lung cancer patients, were accrued between 1981 and 1998, and followed to the end of 2005. The endpoint was death with or from lung cancer, for disease-specific survival (DSS). DSS at 1-, 3- and 5-years, with 95% confidence limits, are reported for all patients using the Boag, Kaplan-Meier, Cox, and log-normal survival analysis methods. Factors with significant effects on DSS were identified with step-wise forward multivariate Cox and log-normal survival analyses. Then, DSS was ascertained for patients with specific characteristics defined by these factors. RESULTS: The median follow-up of those alive was 9.5 years. The lack of events after 1966 days precluded comparison after 5 years. DSS assessed by the four methods in the full cohort differed by 0–2% at 1 year, 0–12% at 3 years, and 0–1% at 5 years. Log-normal survival analysis indicated DSS of 38% at 3 years, 10–12% higher than with other methods; univariate 95% confidence limits were non-overlapping. Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction significantly impacted DSS. DSS assessed by the Cox and log-normal survival analysis methods for four clinical risk groups differed by 1–6% at 1 year, 15–26% at 3 years, and 0–12% at 5 years; multivariate 95% confidence limits were overlapping in all instances. CONCLUSION: Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction all significantly impacted DSS. Apparent DSS for patients was influenced by the statistical methods of assessment. This would be clinically relevant in the development or improvement of clinical management strategies

Effect of expression of adenine phosphoribosyltransferase on the in vivo anti-tumor activity of prodrugs activated by E. coli purine nucleoside phosphorylase

The use of E. coli purine nucleoside phosphorylase (PNP) to activate prodrugs has demonstrated excellent activity in the treatment of various human tumor xenografts in mice. E. coli PNP cleaves purine nucleoside analogs to generate toxic adenine analogs, which are activated by adenine phosphoribosyl transferase (APRT) to metabolites that inhibit RNA and protein synthesis. We created tumor cell lines that encode both E. coli PNP and excess levels of human APRT, and have used these new cell models to test the hypothesis that treatment of otherwise refractory human tumors could be enhanced by overexpression of APRT. In vivo studies with 6-methylpurine-2′-deoxyriboside (MeP-dR), 2-F-2′-deoxyadenosine (F-dAdo) or 9-β-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate (F-araAMP) indicated that increased APRT in human tumor cells coexpressing E. coli PNP did not enhance either the activation or the anti-tumor activity of any of the three prodrugs. Interestingly, expression of excess APRT in bystander cells improved the activity of MeP-dR, but diminished the activity of F-araAMP. In vitro studies indicated that increasing the expression of APRT in the cells did not significantly increase the activation of MeP. These results provide insight into the mechanism of bystander killing of the E. coli PNP strategy, and suggest ways to enhance the approach that are independent of APRT

A Bayesian re-assessment of two Phase II trials of gemcitabine in metastatic nasopharyngeal cancer

The Simon two-stage minimax design is a popular statistical design used in Phase II clinical trials. The analysis of the data arising from the design typically involves the use of frequentist statistics. This paper presents an alternative, Bayesian, approach to the design and analysis of Phase II clinical trials. In particular, we consider how a Bayesian approach could have affected the design, analysis and interpretation of two parallel Phase II trials of the National Cancer Centre Singapore, on the activity of gemcitabine in chemotherapy-naïve and in previously treated patients with metastatic nasopharyngeal carcinoma. We begin by explaining the Bayesian methodology and contrasting it with the frequentist approach. We then carry out a Bayesian analysis of the trial results. The conclusions drawn using the Bayesian approach were in general agreement with those obtained from the frequentist analysis. However they had the advantage of allowing for different and potentially more useful interpretations to be made regarding the trial results, as well as for the incorporation of external sources of information. In particular, using a Bayesian trial design, we were able to take into account the results of the parallel trial results when deciding whether to continue each trial beyond the interim stage

Unexpected Role of α-Fetoprotein in Spermatogenesis

BACKGROUND: Heat shock severely affects sperm production (spermatogenesis) and results in a rapid loss of haploid germ cells, or in other words, sperm formation (spermiogenesis) is inhibited. However, the mechanisms behind the effects of heat shock on spermatogenesis are obscure. METHODOLOGY/PRINCIPAL FINDINGS: To identify the inhibitory factor of spermiogenesis, experimental cryptorchid (EC) mice were used in this study. Here we show that α-fetoprotein (AFP) is specifically expressed in the testes of EC mice by proteome analysis. AFP was also specifically localized spermatocytes by immunohistochemical analysis and was secreted into the circulation system of EC mice by immunoblot analysis. Since spermatogenesis of an advanced mammal cannot be reproduced with in vitro, we performed the microinjection of AFP into the seminiferous tubules of normal mice to determine whether AFP inhibits spermiogenesis in vivo. AFP was directly responsible for the block in spermiogenesis of normal mice. To investigate whether AFP inhibits cell differentiation in other models, using EC mice we performed a partial hepatectomy (PH) that triggers a rapid regenerative response in the remnant liver tissue. We also found that liver regeneration is inhibited in EC mice with PH. The result suggests that AFP released into the blood of EC mice regulates liver regeneration by inhibiting the cell division of hepatocytes. CONCLUSIONS/SIGNIFICANCE: AFP is a well-known cancer-specific marker, but AFP has no known function in healthy human beings. Our findings indicate that AFP expressed under EC conditions plays a role as a regulatory factor in spermatogenesis and in hepatic generation