Concurrent chemoradiotherapy for squamous cell carcinoma of the anus using a shrinking field radiotherapy technique without a boost

Chemoradiotherapy (CRT) is now widely accepted as the primary treatment modality for squamous cell cancer of the anus. While randomised trials have clearly shown CRT to be more effective than radiotherapy alone, there remains uncertainty over the optimal integration of chemotherapy and radiation. We describe a series of 50 patients treated by a site specialist gastrointestinal nonsurgical oncologist with CRT at a single UK centre. Chemotherapy comprised mitomycin C (MMC) (day 1) and 5-fluorouracil (5-FU) (days 1–4, and 29–32), concurrent with 50 Gy in 25 fractions radiation, using a two-phase shrinking field technique. A radiation boost was not planned. At a median follow-up of 48 months, 11 (22%) of the patients have failed locally, of which three have been surgically salvaged. Nine (18%) have died of anal cancer. These results are comparable with those from large randomised studies, and suggest that a two-phase shrinking field radiotherapy technique with no boost, concurrent with MMC/5-FU chemotherapy, is an effective regimen for this disease. The CRT regimen described here provides the basis for the ‘control arm’ of the current UK-randomised CRT trial in anal cancer (ACT2)

Structure of Extreme Correlated Equilibria: a Zero-Sum Example and its Implications

We exhibit the rich structure of the set of correlated equilibria by analyzing the simplest of polynomial games: the mixed extension of matching pennies. We show that while the correlated equilibrium set is convex and compact, the structure of its extreme points can be quite complicated. In finite games the ratio of extreme correlated to extreme Nash equilibria can be greater than exponential in the size of the strategy spaces. In polynomial games there can exist extreme correlated equilibria which are not finitely supported; we construct a large family of examples using techniques from ergodic theory. We show that in general the set of correlated equilibrium distributions of a polynomial game cannot be described by conditions on finitely many moments (means, covariances, etc.), in marked contrast to the set of Nash equilibria which is always expressible in terms of finitely many moments

FDG-PET/CT imaging for staging and target volume delineation in conformal radiotherapy of anal carcinoma

Background: FDG-PET/CT imaging has an emerging role in staging and treatment planning of various tumor locations and a number of literature studies show that also the carcinoma of the anal canal may benefit from this diagnostic approach. We analyzed the potential impact of FDG-PET/CT in stage definition and target volume delineation of patients affected by carcinoma of the anal canal and candidates for curative radiotherapy. Methods: Twenty seven patients with biopsy proven anal carcinoma were enrolled. Pathology was squamous cell carcinoma in 20 cases, cloacogenic carcinoma in 3, adenocarcinoma in 2, and basal cell carcinoma in 2. Simulation was performed by PET/CT imaging with patient in treatment position. Gross Tumor Volume (GTV) and Clinical Target Volume (CTV) were drawn on CT and on PET/CT fused images. PET-GTV and PET-CTV were respectively compared to CT-GTV and CT-CTV by Wilcoxon rank test for paired data. Results: PET/CT fused images led to change the stage in 5/27 cases (18.5%): 3 cases from N0 to N2 and 2 from M0 to M1 leading to change the treatment intent from curative to palliative in a case. Based on PET/CT imaging, GTV and CTV contours changed in 15/27 (55.6%) and in 10/27 cases (37.0%) respectively. PET-GTV and PET-CTV resulted significantly smaller than CT-GTV (p = 1.2 7 10-4) and CT-CTV (p = 2.9 7 10-4). PET/CT-GTV and PET/CT-CTV, that were used for clinical purposes, were significantly greater than CT-GTV (p = 6 7 10-5) and CT-CTV (p = 6 7 10-5). Conclusions: FDG-PET/CT has a potential relevant impact in staging and target volume delineation of the carcinoma of the anal canal. Clinical stage variation occurred in 18.5% of cases with change of treatment intent in 3.7%. The GTV and the CTV changed in shape and in size based on PET/CT imaging

Cross-cultural adaptation and validation of the VISA-A questionnaire for German-speaking Achilles tendinopathy patients

<p>Abstract</p> <p>Background</p> <p>Achilles tendinopathy is the predominant overuse injury in runners. To further investigate this overload injury in transverse and longitudinal studies a valid, responsive and reliable outcome measure is demanded. Most questionnaires have been developed for English-speaking populations. This is also true for the VISA-A score, so far representing the only valid, reliable, and disease specific questionnaire for Achilles tendinopathy. To internationally compare research results, to perform multinational studies or to exclude bias originating from subpopulations speaking different languages within one country an equivalent instrument is demanded in different languages. The aim of this study was therefore to cross-cultural adapt and validate the VISA-A questionnaire for German-speaking Achilles tendinopathy patients.</p> <p>Methods</p> <p>According to the "guidelines for the process of cross-cultural adaptation of self-report measures" the VISA-A score was cross-culturally adapted into German (VISA-A-G) using six steps: Translation, synthesis, back translation, expert committee review, pretesting (n = 77), and appraisal of the adaptation process by an advisory committee determining the adequacy of the cross-cultural adaptation. The resulting VISA-A-G was then subjected to an analysis of reliability, validity, and internal consistency in 30 Achilles tendinopathy patients and 79 asymptomatic people. Concurrent validity was tested against a generic tendon grading system (Percy and Conochie) and against a classification system for the effect of pain on athletic performance (Curwin and Stanish).</p> <p>Results</p> <p>The "advisory committee" determined the VISA-A-G questionnaire as been translated "acceptable". The VISA-A-G questionnaire showed moderate to excellent test-retest reliability (ICC = 0.60 to 0.97). Concurrent validity showed good coherence when correlated with the grading system of Curwin and Stanish (rho = -0.95) and for the Percy and Conochie grade of severity (rho 0.95). Internal consistency (Cronbach's alpha) for the total VISA-A-G scores of the patients was calculated to be 0.737.</p> <p>Conclusion</p> <p>The VISA-A questionnaire was successfully cross-cultural adapted and validated for use in German speaking populations. The psychometric properties of the VISA-A-G questionnaire are similar to those of the original English version. It therefore can be recommended as a sufficiently robust tool for future measuring clinical severity of Achilles tendinopathy in German speaking patients.</p

Voting power measurement: a story of misreinvention

In this account of the history of voting-power measurement, we confine ourselves to the concept of a priori voting power. We show how the concept was re-invented several times and how the circumstances in which it was reinvented led to conceptual confusion as to the true meaning of what is being measured. In particular, power-as-influence was conflated with value in the sense of transferable utility cooperative game theory (power as share in constant total payoff). Influence was treated, improperly, as though it were transferable utility, and hence an additive and distributive quantity. We provide examples of the resulting misunderstanding and mis-directed criticism

Concurrent cisplatin, continuous infusion fluorouracil and radiotherapy followed by tailored consolidation treatment in non metastatic anal squamous cell carcinoma

BACKGROUND: To evaluate efficacy and feasibility of chemo-radiotherapy in patients with non-metastatic anal squamous-cell-cancer. METHODS: TNM staged anal squamous-cell cancer patients were treated with pelvic radiotherapy concomitant to continuous infusion fluorouracil plus cisplatin for at least 2 cycles. In T3-T4 or any T - N+ tumours or in "slow-responder" cases, 1-2 chemotherapy courses were subsequently administered. Tumour assessment was performed at baseline and 6-8 weeks after radiotherapy to evaluate response. RESULTS: 29 patients were enrolled: 4 males, 25 females; median age 57 years; baseline T1/T2/T3/T4 2/12/7/8; N involvement 17. Median dose pelvic radiotherapy was 59.4 Gy (range: 54-74). In 5 patients 2 chemotherapy courses, in 12 patients three and in 12 patients four courses were performed. At first evaluation, 27 CR (93.1%; 95% CI: 78% - 98%) and 2 SD were observed. Main grade (G) 3 toxic events were neutropenia (8%), diarrhoea (8%) and dermatitis (62%). Most frequent late events G3-G4 occurred in 14 patients: proctitis (5), dermatitis (4), bladder dysfunctions (2), sexual dysfunctions (9), lower extremity venous thromboses (2), dysuria (1), stenosis (1) and tenesmus (1). Five patients reported G1 leucopoenia. The rate of colostomy was 14%. After a median follow up of 42 months (range: 4-81), 20 patients are still alive without relapse and 3 died due to PD. The estimated 7-year DFS was 83.4% (C.I.: 68.3%-98.5%) and the estimated 7-year OS was 85.7% (C.I.: 70% - 100%). The 1-year and the estimated 7-year colostomy-free survivals were 85.9% (C.I.: 73.1% - 98.7%). CONCLUSIONS: Concurrent cisplatin plus fluorouracil and radiotherapy is associated with favourable local control rates and acute toxicity. Future investigations will be directed towards research into molecular biomarkers related to disease progression and resistance to chemo-radiotherapy and to the evaluation of new cytotoxic agents or targeted drugs, such as anti-epidermal growth factor receptor, concomitant to RT and to determining the role of intensity-modulated radiotherap

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis

Background: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. Objectives: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. Methods: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years’ follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. Results: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. Conclusions: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR