The predictive and prognostic value of tumour necrosis in muscle invasive bladder cancer patients receiving radiotherapy with or without chemotherapy in the BC2001 trial (CRUK/01/004)

Background: Severe chronic hypoxia is associated with tumour necrosis. In patients with muscle invasive bladder cancer (MIBC), necrosis is prognostic for survival following surgery or radiotherapy and predicts benefit from hypoxia modification of radiotherapy. Adding mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy to radiotherapy improved locoregional control (LRC) compared to radiotherapy alone in the BC2001 trial. We hypothesised that tumour necrosis would not predict benefit for the addition of MMC and 5-FU to radiotherapy, but would be prognostic. Methods: Diagnostic tumour samples were available from 230 BC2001 patients. Tumour necrosis was scored on whole-tissue sections as absent or present, and its predictive and prognostic significance explored using Cox proportional hazards models. Survival estimates were obtained by Kaplan–Meier methods. Results: Tumour necrosis was present in 88/230 (38%) samples. Two-year LRC estimates were 71% (95% CI 61–79%) for the MMC/5-FU chemoradiotherapy group and 49% (95% CI 38–59%) for the radiotherapy alone group. When analysed by tumour necrosis status, the adjusted hazard ratios (HR) for MMC/5-FU vs. no chemotherapy were 0.46 (95% CI: 0.12–0.99; P=0.05, necrosis present) and 0.55 (95% CI: 0.31–0.98; P=0.04, necrosis absent). Multivariable analysis of prognosis for LRC by the presence vs. absence of necrosis yielded a HR=0.89 (95% CI 0.55–1.44, P=0.65). There was no significant association for necrosis as a predictive or prognostic factor with respect to overall survival. Conclusions: Tumour necrosis was neither predictive nor prognostic, and therefore MMC/5-FU is an appropriate radiotherapy-sensitising treatment in MIBC independent of necrosis status

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC

Quasi-normal frequencies: Key analytic results

The study of exact quasi-normal modes [QNMs], and their associated quasi-normal frequencies [QNFs], has had a long and convoluted history - replete with many rediscoveries of previously known results. In this article we shall collect and survey a number of known analytic results, and develop several new analytic results - specifically we shall provide several new QNF results and estimates, in a form amenable for comparison with the extant literature. Apart from their intrinsic interest, these exact and approximate results serve as a backdrop and a consistency check on ongoing efforts to find general model-independent estimates for QNFs, and general model-independent bounds on transmission probabilities. Our calculations also provide yet another physics application of the Lambert W function. These ideas have relevance to fields as diverse as black hole physics, (where they are related to the damped oscillations of astrophysical black holes, to greybody factors for the Hawking radiation, and to more speculative state-counting models for the Bekenstein entropy), to quantum field theory (where they are related to Casimir energies in unbounded systems), through to condensed matter physics, (where one may literally be interested in an electron tunelling through a physical barrier).Comment: V1: 29 pages; V2: Reformatted, 31 pages. Title changed to reflect major additions and revisions. Now describes exact QNFs for the double-delta potential in terms of the Lambert W function. V3: Minor edits for clarity. Four references added. No physics changes. Still 31 page

Effective treatment of anal cancer in the elderly with low-dose chemoradiotherapy

Chemoradiotherapy (CRT) is accepted as the standard initial treatment for squamous cell anal cancer. However, frail elderly patients cannot always tolerate full-dose CRT. This paper reports the results of a modified regimen for this group of patients. In all, 16 patients with biopsy-proven squamous cell carcinoma of the anal canal or margin and performance status or co-morbidity precluding the use of full-dose CRT were included in this protocol. The median age was 81 (range 77–91). Patients received a dose of 30 Gy to the gross tumour volume plus 3 cm margin in all directions. Concurrent chemotherapy comprised 5-fluorouracil 600 mg m−2 given over 24 h on days 1–4 of radiotherapy. The treatment was well tolerated. All 16 patients completed treatment as planned. Only one patient experienced any grade 3 toxicity (skin). The local control at a median follow-up of 16 months was 73% (13 out of 16). The overall survival was 69% and disease-specific survival 86%. This is a well-tolerated regimen for elderly/poor performance patients with anal cancer, which can achieve high rates of local control and survival. Longer follow-up will determine whether these encouraging results are maintained

2:1 for Naturalness at the LHC?

A large enhancement of a factor of 1.5 - 2 in Higgs production and decay in the diphoton channel, with little deviation in the ZZ channel, can only plausibly arise from a loop of new charged particles with large couplings to the Higgs. We show that, allowing only new fermions with marginal interactions at the weak scale, the required Yukawa couplings for a factor of 2 enhancement are so large that the Higgs quartic coupling is pushed to large negative values in the UV, triggering an unacceptable vacuum instability far beneath the 10 TeV scale. An enhancement by a factor of 1.5 can be accommodated if the charged fermions are lighter than 150 GeV, within reach of discovery in almost all cases in the 8 TeV run at the LHC, and in even the most difficult cases at 14 TeV. Thus if the diphoton enhancement survives further scrutiny, and no charged fermions beneath 150 GeV are found, there must be new bosons far beneath the 10 TeV scale. This would unambiguously rule out a large class of fine-tuned theories for physics beyond the Standard Model, including split SUSY and many of its variants, and provide strong circumstantial evidence for a natural theory of electroweak symmetry breaking at the TeV scale. Alternately, theories with only a single fine-tuned Higgs and new fermions at the weak scale, with no additional scalars or gauge bosons up to a cutoff much larger than the 10 TeV scale, unambiguously predict that the hints for a large diphoton enhancement in the current data will disappear.Comment: 18 pages, 6 figures; typos corrected and references adde

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP vs SOC+DocP

Diquark contributions to Top quark charge asymmetry at the Tevatron and LHC

We study contributions of a scalar diquark particle in a color representation of anti-triplet and sextet to the top quark pair production at the Tevatron and the Large hadron collider (LHC). The model can give Forward-Backward (FB) asymmetry at the Tevatron while can avoid the same sign top quark production at the LHC by assuming the top-number conserving diquark couplings. We study compatibility between the large positive FB asymmetry observed at the Tevatron and non-observation of the charge asymmetry at the LHC, by including contributions from the single and pair production of diquarks. We find that the whole parameter space of the models can soon be explored at the LHC by measuring the total t-tbar production cross section and the inclusive charge asymmetry with smaller uncertainties. In addition, we compare the statistical significance of the charge asymmetry measured at the LHC with that of the optimal observable of the subprocess FB asymmetry, and find that they are comparable even when we ignore the uncertainty in the parton distribution functions.Comment: 18 pages,7 figures, 1 table. Accepted version for publication in JHE