Training and external validation of pre-treatment FDG PET-CT-based models for outcome prediction in anal squamous cell carcinoma.

OBJECTIVES: The incidence of anal squamous cell carcinoma (ASCC) is increasing worldwide, with a significant proportion of patients treated with curative intent having recurrence. The ability to accurately predict progression-free survival (PFS) and overall survival (OS) would allow for development of personalised treatment strategies. The aim of the study was to train and external test radiomic/clinical feature derived time-to-event prediction models. METHODS: Consecutive patients with ASCC treated with curative intent at two large tertiary referral centres with baseline FDG PET-CT were included. Radiomic feature extraction was performed using LIFEx software on the pre-treatment PET-CT. Two distinct predictive models for PFS and OS were trained and tuned at each of the centres, with the best performing models externally tested on the other centres' patient cohort. RESULTS: A total of 187 patients were included from centre 1 (mean age 61.6 ± 11.5 years, median follow up 30 months, PFS events = 57/187, OS events = 46/187) and 257 patients were included from centre 2 (mean age 62.6 ± 12.3 years, median follow up 35 months, PFS events = 70/257, OS events = 54/257). The best performing model for PFS and OS was achieved using a Cox regression model based on age and metabolic tumour volume (MTV) with a training c-index of 0.7 and an external testing c-index of 0.7 (standard error = 0.4). CONCLUSIONS: A combination of patient age and MTV has been demonstrated using external validation to have the potential to predict OS and PFS in ASCC patients. CLINICAL RELEVANCE STATEMENT: A Cox regression model using patients' age and metabolic tumour volume showed good predictive potential for progression-free survival in external testing. The benefits of a previous radiomics model published by our group could not be confirmed on external testing. KEY POINTS: • A predictive model based on patient age and metabolic tumour volume showed potential to predict overall survival and progression-free survival and was validated on an external test cohort. • The methodology used to create a predictive model from age and metabolic tumour volume was repeatable using external cohort data. • The predictive ability of positron emission tomography-computed tomography-derived radiomic features diminished when the influence of metabolic tumour volume was accounted for.

Comparative evaluation of canal transportation and centering ability of rotary and reciprocating file systems using cone-beam computed tomography: An in vitro study.

Aim: The aim of the study was to evaluate the canal transportation and centering ability of rotary and reciprocating file systems using cone-beam computed tomography. Materials and Methods: Mesiobuccal canals of sixty mandibular molars were selected for the study. Canals of length 19 mm, curvature of 10°-12°, and uncalcified with fully formed apex were selected. Canals were randomly divided into three groups of 20 teeth, and canal preparation with the WaveOne Gold, TruNatomy, and One Curve systems was performed according to the manufacturers' instructions. Cone-beam computed tomographic images were taken before and after instrumentation in the same position for comparative analysis. Statistical Analysis Used: Apical transportation was calculated at the distances of 2, 3, and 4 mm from the apex. Tukey's post hoc test and unpaired "t"-tests were used to statistically analyze the data. Results: WaveOne Gold caused less canal transportation and better-centering ability than TruNatomy and One Curve at all the three levels; there was a significant difference in canal transportation and centering ability among all the groups as well as all the three levels, i.e., 2, 3, and 4 mm from the apex. Conclusion: WaveOne Gold (Reciprocating) reported less canal transportation and better-centering ability than rotary instruments TruNatomy and One Curve (Rotary) at all the three levels.

Radiotherapy-related insufficiency fractures and bone mineral density: what is the connection?

Background: Radiotherapy-related insufficiency fractures (RRIFs) represent a common, burdensome consequence of pelvic radiotherapy. Their underlying mechanisms remain unclear, and data on the effect of osteoporosis are contradictory, with limited studies assessing bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA). Methods: BMD by DXA (Hologic) scan and fracture risk following pelvic RRIF were retrospectively assessed in 39 patients (median age 68 years) at a tertiary cancer centre. Patient characteristics and treatment history are presented narratively; correlations were explored using univariate regression analyses. Results: Additional cancer treatments included chemotherapy (n = 31), surgery (n = 20) and brachytherapy (n = 19). Median interval between initiation of radiotherapy and RRIF was 11 (7.5-20.8) and that between RRIF and DXA 3 was (1-6) months. Three patients had normal BMD, 16 had osteopenia and 16 osteoporosis, following World Health Organization classification. Four patients were <40 years at the time of DXA (all Z-scores > -2). Median 10-year risk for hip and major osteoporotic fracture was 3.1% (1.5-5.7) and 11.5% (7.1-13.8), respectively. Only 33.3% of patients had high fracture risk (hip fracture >4% and/or major osteoporotic >20%), and 31% fell above the intervention threshold per National Osteoporosis Guidelines Group (NOGG) guidance (2017). Higher BMD was predicted by lower pelvic radiotherapy dose (only in L3 and L4), concomitant chemotherapy and higher body mass index. Conclusion: At the time of RRIF, most patients did not have osteoporosis, some had normal BMD and overall had low fracture risk. Whilst low BMD is a probable risk factor, it is unlikely to be the main mechanism underlying RRIFs, and further studies are required to understand the predictive value of BMD.

RAS Mutation Status Should Not Be Used to Predict Outcome from Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases.

BACKGROUND: Genetic biomarkers guide systemic anti-cancer treatment (SACT) in metastatic colorectal cancer. It has been suggested they have a role in selecting patients with colorectal peritoneal metastases (CRPM) for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). This study aims to quantify the effect of mutation status on overall survival (OS), adjusting for confounders such as pre-operative systemic anticancer treatment (SACT). PATIENTS AND METHODS: Retrospective analysis of patients undergoing CRS/HIPEC for CRPM at a national peritoneal tumour centre (2004-2017) was performed. Demographics, treatment history and operative data were extracted. Known biomarker gene mutation status was noted including: KRAS, NRAS, BRAF, PIK3CA and MMR. Cox regression analysis and Kaplan-Meier curves were used to determine overall survival. RESULTS: One hundred ninety-five patients were included. Median follow-up time was 34.7 months (range 5.4-184.9 months) and median OS was 38.7 months (95% CI 32.4-44.9 months). Biomarker status was as follows: KRAS (n = 114), NRAS (n = 85), BRAF (n = 44), PIK3CA (n = 15) and MMR (n = 21). Mutation rates were 45.6%, 3.5%, 13.6%, 13.3% and 14.3%, respectively. Seventy-four per cent underwent complete cytoreduction (CC = 0), 81% received SACT pre-CRS/HIPEC and 65% post-CRS/HIPEC. RAS (p = 0.21) or BRAF (p = 0.109) mutation status did not predict OS. Nodal involvement, extramural vascular invasion, Peritoneal Cancer Index (PCI) score, CC score, SACT post-HIPEC and NRAS mutation were significant negative predictors of OS in univariate analysis (p < 0.05). Multivariate Cox regression confirmed CC-score > 1 (HR: 7.599, 95% CI 3.402-16.974, p < 0.0001) as a negative predictor of OS. RAS mutation status did not affect outcome (HR: 1.682, 95% CI 0.995-2.843, p = 0.052). CONCLUSIONS: RAS mutation status should not in isolation be used to select patients for CRS/HIPEC.

Patterns and Timing of Recurrence following CRS and HIPEC in Colorectal Cancer Peritoneal Metastasis.

INTRODUCTION: Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is an established treatment of Colorectal Peritoneal Metastases (CRPM). This study aims to determine the timing and patterns of recurrent disease on imaging following complete CRS/HIPEC. METHODS: Retrospective analysis of a national peritoneal tumour service database identified CRPM patients with complete CRS/HIPEC(CC0) from 2005 to-2018. Patients with<2 years follow-up or and those where post-operative histology from the CRS/HIPEC procedure did not confirm CRPM from their original colorectal cancer were excluded. Time to recurrence was measured from surgery to first radiologically illustrated recurrence. CT was the primary modality used, supplemented by PET-CT or MRI if required. Outcomes of interest were survival data (including overall survival (OS), disease-free survival (DFS) and peritoneal-recurrence free survival (PRFS)), timing and patterns of recurrent disease. RESULTS: 146 of the 176 patients identified were eligible for inclusion. Median OS for all study patients was 45.2 months (95% CI 38-53 months), median DFS was 11.7 months (95% CI 9-14 months), and median PRFS was 25.2 months (95% CI 14.7-30 months). Recurrent disease was seen in 112 cases (77%), radiologically classified as intraperitoneal in 50 patients (44%), single site systemic in 21 patients (19%) and multi-site in 41 patients (37%). CT detection rate for disease recurrence was 88%. Subgroup analyses showed that PCI ≥12, positive nodal primary disease and synchronous peritoneal disease were associated with worse outcomes. CONCLUSION: Patients selected for CRS/HIPEC for CRPM have an OS > 45 months, with the majority recurring systemically within a year. Peritoneal recurrence is a later event after several years. Surveillance programs in this group should be most intensive in the first 2 years after surgery, using CT with oral and intravenous contrast.

Prevalence of C-shaped canal and related variations in maxillary and mandibular second molars in the Indian Subpopulation: A cone-beam computed tomography analysis.

Aim: The aim of this study was to evaluate the prevalence and anatomical configuration of the C-shaped canal in permanent maxillary and mandibular second molars in the Greater Noida population by compiling the results of data that used cone-beam computed tomography (CBCT) analysis. Subjects and Methods: CBCT images were taken from the archive in the department of oral medicine and radiology taken for diagnostic purposes referred by other departments in the dental college. Five hundred CBCT records of patients, between the age group of 15-40 years, containing maxillary second molars and mandibular second molars were selected and reviewed. Statistical Analysis: Statistical analysis was done using the Chi-square test to find out the most common configuration of the C-shaped canal between maxillary and mandibular second molars. Results: Hundred and ten out of 500 patients had C-shaped canals (22%). Among them, 58 teeth (52.7%) were continuous C-shaped canals, 41 teeth (37.3%) were semicolon-shaped canals and 11 teeth (10%) had separated canals. (Chi-square test value = 8.26, P = 0.024). Statistically significant difference was found in configuration types. Among the jaw type, 62 maxillary second molar presented with C-shaped canal (25.1%) and 48 mandibular second molar presented with C-shaped canal (18.9%) (Chi-square test value = 3.87, P = 0.276). However, the difference was statistically insignificant in relation to the jaw type. Conclusions: Within the limitation of the study, we can conclude that the overall prevalence of C-shaped canals was 22% and the most common C-shaped canal configuration type was continuous (52.7%). However, no statistically significant difference was found in relation to jaw type.

Development and validation of prognostic models for anal cancer outcomes using distributed learning: protocol for the international multi-centre atomCAT2 study.

BACKGROUND: Anal cancer is a rare cancer with rising incidence. Despite the relatively good outcomes conferred by state-of-the-art chemoradiotherapy, further improving disease control and reducing toxicity has proven challenging. Developing and validating prognostic models using routinely collected data may provide new insights for treatment development and selection. However, due to the rarity of the cancer, it can be difficult to obtain sufficient data, especially from single centres, to develop and validate robust models. Moreover, multi-centre model development is hampered by ethical barriers and data protection regulations that often limit accessibility to patient data. Distributed (or federated) learning allows models to be developed using data from multiple centres without any individual-level patient data leaving the originating centre, therefore preserving patient data privacy. This work builds on the proof-of-concept three-centre atomCAT1 study and describes the protocol for the multi-centre atomCAT2 study, which aims to develop and validate robust prognostic models for three clinically important outcomes in anal cancer following chemoradiotherapy. METHODS: This is a retrospective multi-centre cohort study, investigating overall survival, locoregional control and freedom from distant metastasis after primary chemoradiotherapy for anal squamous cell carcinoma. Patient data will be extracted and organised at each participating radiotherapy centre (n = 18). Candidate prognostic factors have been identified through literature review and expert opinion. Summary statistics will be calculated and exchanged between centres prior to modelling. The primary analysis will involve developing and validating Cox proportional hazards models across centres for each outcome through distributed learning. Outcomes at specific timepoints of interest and factor effect estimates will be reported, allowing for outcome prediction for future patients. DISCUSSION: The atomCAT2 study will analyse one of the largest available cross-institutional cohorts of patients with anal cancer treated with chemoradiotherapy. The analysis aims to provide information on current international clinical practice outcomes and may aid the personalisation and design of future anal cancer clinical trials through contributing to a better understanding of patient risk stratification.

Clinical and radiomics prediction of complete response in rectal cancer pre-chemoradiotherapy.

Background and purpose: Patients with rectal cancer could avoid major surgery if they achieve clinical complete response (cCR) post neoadjuvant treatment. Therefore, prediction of treatment outcomes before treatment has become necessary to select the best neo-adjuvant treatment option. This study investigates clinical and radiomics variables' ability to predict cCR in patients pre chemoradiotherapy. Materials and methods: Using the OnCoRe database, we recruited a matched cohort of 304 patients (152 with cCR; 152 without cCR) deriving training (N = 200) and validation (N = 104) sets. We collected pre-treatment MR (magnetic resonance) images, demographics and blood parameters (haemoglobin, neutrophil, lymphocyte, alkaline phosphate and albumin). We segmented the gross tumour volume on T2 Weighted MR Images and extracted 1430 stable radiomics features per patient. We used principal component analysis (PCA) and receiver operating characteristic area under the curve (ROC AUC) to reduce dimensionality and evaluate the models produced. Results: Using Logistic regression analysis, PCA-derived combined model (radiomics plus clinical variables) gave a ROC AUC of 0.76 (95% CI: 0.69-0.83) in the training set and 0.68 (95% CI 0.57-0.79) in the validation set. The clinical only model achieved an AUC of 0.73 (95% CI 0.66-0.80) and 0.62 (95% CI 0.51-0.74) in the training and validation set, respectively. The radiomics model had an AUC of 0.68 (95% CI 0.61-0.75) and 0.66 (95% CI 0.56-0.77) in the training and validation sets. Conclusion: The predictive characteristics of both clinical and radiomics variables for clinical complete response remain modest but radiomics predictability is improved with addition of clinical variables.

RadBone: bone toxicity following pelvic radiotherapy - a prospective randomised controlled feasibility study evaluating a musculoskeletal health package in women with gynaecological cancers undergoing pelvic radiotherapy.

INTRODUCTION: Patients receiving radiotherapy are at risk of developing radiotherapy-related insufficiency fractures, which are associated with increased morbidity and pose a significant burden to patients' quality of life and to the health system. Therefore, effective preventive techniques are urgently required. The RadBone randomised controlled trial (RCT) aims to determine the feasibility and acceptability of a musculoskeletal health package (MHP) intervention in women undergoing pelvic radiotherapy for gynaecological malignancies and to preliminary explore clinical effectiveness of the intervention. METHODS AND ANALYSIS: The RadBone RCT will evaluate the addition to standard care of an MHP consisting of a physical assessment of the musculoskeletal health, a 3-month prehabilitation personalised exercise package, as well as an evaluation of the fracture risk and if required the prescription of appropriate bone treatment including calcium, vitamin D and-for high-risk individuals-bisphosphonates. Forty participants will be randomised in each group (MHP or observation) and will be followed for 18 months. The primary outcome of this RCT will be feasibility, including the eligibility, screening and recruitment rate, intervention fidelity and attrition rates; acceptability and health economics. Clinical effectiveness and bone turnover markers will be evaluated as secondary outcomes. ETHICS AND DISSEMINATION: This study has been approved by the Greater Manchester East Research Ethics Committee (Reference: 20/NW/0410, November 2020). The results will be published in peer-reviewed journals, will be presented in national and international conferences and will be communicated to relevant stakeholders. Moreover, a plain English report will be shared with the study participants, patients' organisations and media. TRIAL REGISTRATION NUMBER: NCT04555317.

A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer (APHRODITE): protocol for a multicentre, open-label randomised controlled trial.

INTRODUCTION: The standard of care for patients with localised rectal cancer is radical surgery, often combined with preoperative neoadjuvant (chemo)radiotherapy. While oncologically effective, this treatment strategy is associated with operative mortality risks, significant morbidity and stoma formation. An alternative approach is chemoradiotherapy to try to achieve a sustained clinical complete response (cCR). This non-surgical management can be attractive, particularly for patients at high risk of surgical complications. Modern radiotherapy techniques allow increased treatment conformality, enabling increased radiation dose to the tumour while reducing dose to normal tissue. The objective of this trial is to assess if radiotherapy dose escalation increases the cCR rate, with acceptable toxicity, for treatment of patients with early rectal cancer unsuitable for radical surgery. METHODS AND ANALYSIS: APHRODITE (A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer) is a multicentre, open-label randomised controlled phase II trial aiming to recruit 104 participants from 10 to 12 UK sites. Participants will be allocated with a 2:1 ratio of intervention:control. The intervention is escalated dose radiotherapy (62 Gy to primary tumour, 50.4 Gy to surrounding mesorectum in 28 fractions) using simultaneous integrated boost. The control arm will receive 50.4 Gy to the primary tumour and surrounding mesorectum. Both arms will use intensity-modulated radiotherapy and daily image guidance, combined with concurrent chemotherapy (capecitabine, 5-fluorouracil/leucovorin or omitted). The primary endpoint is the proportion of participants with cCR at 6 months after start of treatment. Secondary outcomes include early and late toxicities, time to stoma formation, overall survival and patient-reported outcomes (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CR29, low anterior resection syndrome (LARS) questionnaire). ETHICS AND DISSEMINATION: The trial obtained ethical approval from North West Greater Manchester East Research Ethics Committee (reference number 19/NW/0565) and is funded by Yorkshire Cancer Research. The final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines. TRIAL REGISTRATION NUMBER: ISRCTN16158514.

Feasibility of a multiparametric MRI protocol for imaging biomarkers associated with neoadjuvant radiotherapy for soft tissue sarcoma.

Objective: Soft tissue sarcoma (STS) is a rare malignancy with a 5 year overall survival rate of 55%. Neoadjuvant radiotherapy is commonly used in preparation for surgery, but methods to assess early response are lacking despite pathological response at surgery being predictive of overall survival, local recurrence and distant metastasis. Multiparametric MR imaging (mpMRI) is used to assess response in a variety of tumours but lacks a robust, standardised method. The overall aim of this study was to develop a feasible imaging protocol to identify imaging biomarkers for further investigation. Methods: 15 patients with biopsy-confirmed STS suitable for pre-operative radiotherapy and radical surgery were imaged throughout treatment. The mpMRI protocol included anatomical, diffusion-weighted and dynamic contrast-enhanced imaging, giving estimates of apparent diffusion coefficient (ADC) and the area under the enhancement curve at 60 s (iAUC60). Histological analysis of resected tumours included detection of CD31, Ki67, hypoxia inducible factor and calculation of a hypoxia score. Results: There was a significant reduction in T1 at visit 2 and in ADC at visit 3. Significant associations were found between hypoxia and pre-treatment iAUC60, pre-treatment ADC and mid-treatment iAUC60. There was also statistically significant association between mid-treatment ADC and Ki67. Conclusion: This work showed that mpMRI throughout treatment is feasible in patients with STS having neoadjuvant radiotherapy. The relationships between imaging parameters, tissue biomarkers and clinical outcomes warrant further investigation. Advances in knowledge: mpMRI-based biomarkers have good correlation with STS tumour biology and are potentially of use for evaluation of radiotherapy response.

Three-dimensional (3D) magnetic resonance volume assessment and loco-regional failure in anal cancer: early evaluation case-control study.

BACKGROUND: The primary aim was to test the hypothesis that deriving pre-treatment 3D magnetic resonance tumour volume (mrTV) quantification improves performance characteristics for the prediction of loco-regional failure compared with standard maximal tumour diameter (1D) assessment in patients with squamous cell carcinoma of the anus undergoing chemoradiotherapy. METHODS: We performed an early evaluation case-control study at two UK centres (2007-2014) in 39 patients with loco-regional failure (cases), and 41 patients disease-free at 3 years (controls). mrTV was determined using the summation of areas method (Volsum). Reproducibility was assessed using intraclass concordance correlation (ICC) and Bland-Altman limits of agreements. We derived receiver operating curves using logistic regression models and expressed accuracy as area under the curve (ROCAUC). RESULTS: The median time per patient for Volsum quantification was 7.00 (inter-quartile range, IQR: 0.57-12.48) minutes. Intra and inter-observer reproducibilities were generally good (ICCs from 0.79 to 0.89) but with wide limits of agreement (intra-observer: - 28 to 31%; inter-observer: - 28 to 46%). Median mrTVs were greater for cases (32.6 IQR: 21.5-53.1 cm3) than controls (9.9 IQR: 5.7-18.1 cm3, p < 0.0001). The ROCAUC for mrT-size predicting loco-regional failure was 0.74 (95% CI: 0.63-0.85) improving to 0.82 (95% CI: 0.72-0.92) when replaced with mrTV (test for ROC differences, p = 0.024). CONCLUSION: Preliminary results suggest that the replacement of mrTV for mrT-size improves prediction of loco-regional failure after chemoradiotherapy for squamous cell carcinoma of the anus. However, mrTV calculation is time consuming and variation in its reproducibility are drawbacks with the current technology.

Temporal improvements in loco-regional failure and survival in patients with anal cancer treated with chemo-radiotherapy: treatment cohort study (1990-2014).

BACKGROUND: We evaluated oncological changes in patients with squamous cell carcinoma of the anus (SCCA) treated by chemoradiotherapy (CRT) from a large UK institute, to derive estimates of contemporary outcomes. METHODS: We performed a treatment-cohort analysis in 560 patients with non-metastatic SCCA treated with CRT over 25 years. The primary outcomes were 3-year loco-regional failure (LRF), 5-year overall survival (OS), and 5-year cancer-specific survival (CSS). We developed prediction models; and overlaid estimates on published results from historic trials. RESULTS: Age distributions, proportions by gender and cT stage remained stable over time. The median follow-up was 61 (IQR: 36-79) months. Comparing the first period (1990-1994) with the last period (2010-2014), 3-year LRF declined from 33 to 16% (Ptrends < 0.001); 5-year OS increased from 60% to 76% (Ptrends = 0.001); and 5-year CCS increased from 62% in to 80% (Ptrends = 0.001). For 2020, the models predicted a 3-year LRF of 14.7% (95% CIs: 0-31.3); 5-year OS of 74.7% (95% CIs: 54.6-94.9); and 5-year CSS of 85.7% (95% CIs: 75.3-96.0). Reported oncological outcomes from historic trials generally underestimated contemporary outcomes. CONCLUSIONS: Current and predicted rates for 3-year LRF and 5-year survivals are considerably improved compared with those in historic trials.

A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus.

Chemoradiotherapy is the primary treatment for patients with squamous cell carcinoma of the anus, but variations in the reported outcomes have restricted between-study comparisons. Treatment-related morbidity is considerable; however, no trial has comprehensively quantified long-term side-effects or quality of life. Therefore, we established the first international health-care professional and patient consensus to develop a core outcome set, using the Core Outcome Measures in Effectiveness Trials method. We used the results from our previous systematic review and combined them in this Review with patient interviews to derive a comprehensive list of outcomes, followed by a two-round Delphi survey completed by 149 participants (55 patients and 94 health-care professionals) from 11 countries. The Delphi results were discussed at a consensus meeting of health-care professionals and patients. Agreement was reached on 19 outcomes across four domains: disease activity, survival, toxicity, and life impact. Implementation of the Core Outcome Research Measures in Anal Cancer (CORMAC) set in future trials will serve as a framework to achieve standardisation, facilitate selection of health-area-specific evaluation tools, reduce redundancy of outcome lists, allow between-study comparisons, and ultimately enhance the relevance of trial findings to health-care professionals, trialists, and patients.

Nodal stage migration and prognosis in anal cancer: a systematic review, meta-regression, and simulation study.

BACKGROUND: In patients with squamous cell carcinoma of the anus (SCCA), lymph node positivity (LNP) indicates poor prognosis for survival and is central to radiotherapy planning. Over the past three decades, LNP proportion has increased, mainly reflecting enhanced detection with newer imaging modalities; a process known as nodal stage migration. If accompanied by constant T stage distributions, prognosis for both lymph node-positive and lymph node-negative groups may improve without any increase in overall survival for individual patients; a paradox termed the Will Rogers phenomenon. Here, we aim to systematically evaluate the impact of nodal stage migration on survival in SCCA and address a novel hypothesis that this phenomenon results in reduced prognostic discrimination. METHODS: We did a systematic review and meta-regression to quantify changes in LNP over time and the impact of this change on survival and prognostic discrimination. We searched MEDLINE, Embase, and the Cochrane Library to identify randomised trials and observational studies in patients with SCCA published between Jan 1, 1970, and Oct 11, 2016. Studies were eligible if patients received chemoradiotherapy or radiotherapy as the main treatment, reported LNP proportions (all studies), and reported overall survival (not necessarily present in all studies). We excluded studies with fewer than 50 patients. We extracted study-level data with a standardised, piloted form. The primary outcome measure was 5-year overall survival. To investigate scenarios in which reduced prognostic discrimination might occur, we simulated varying true LNP proportions and true overall survival, and compared these with expected observed outcomes for varying levels of misclassification of true nodal state. FINDINGS: We identified 62 studies reporting LNP proportions, which included 10 569 patients. From these, we included 45 studies (6302 patients) with whole cohort 5-year overall survival, 11 studies with 5-year survival stratified by nodal status, and 20 studies with hazard ratios in our analyses of temporal changes. In 62 studies, the LNP proportions increased from a mean estimate of 15·3% (95% CI 10·5-20·1) in 1980 to 37·1% (34·0-41·3) in 2012 (p<0·0001). In 11 studies with prognostic data, increasing LNP was associated with improved overall survival in both lymph node-positive and lymph node-negative categories, whereas the proportions with combined tumour stage T3 and T4 remained constant. In 20 studies, across a range of LNP proportions from 15% to 40%, the hazard ratios for overall survival of lymph node-positive versus lymph node-negative patients decreased significantly from 2·5 (95% CI 1·8-3·3) at 15% LNP to 1·3 (1·2-1·9; p=0·014) at 40% LNP. The simulated scenarios reproduced this effect if the true LNP proportions were 20% or 25%, but not if the true LNP proportions were 30% or greater. INTERPRETATION: We describe a consequence of staging misclassification in anal cancer that we have termed reduced prognostic discrimination. We used this new observation to infer that the LNP proportions of more than 30% seen in modern clinical series (11 out of 15 studies with a median year since 2007) are higher than the true LNP proportion. The introduction of new staging technologies in oncology might misclassify true disease stage, spuriously informing disease management and ultimately increasing the risk of overtreatment. FUNDING: Bowel Disease Research Foundation.

The assessment of local response using magnetic resonance imaging at 3- and 6-month post chemoradiotherapy in patients with anal cancer.

OBJECTIVES: To assess the use of MRI-determined tumour regression grading (TRG) in local response assessment and detection of salvageable early local relapse after chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC). METHODS: From a prospective database of patients with ASCC managed through a centralised multidisciplinary team, 74 patients who completed routine post-CRT 3- and 6-month MRIs (2009-2012) were reviewed. Two radiologists blinded to the outcomes consensus read and retrospectively assigned TRG scores [1 (complete response) to 5 (no response)] and related these to early local relapse (within 12 months) and disease-free survival (DFS). RESULTS: Seven patients had early local relapse. TRG 1/2 scores at 3 and 6 months had a 100 % negative predictive value; TRG 4/5 scores at 6 months had a 100 % positive predictive value. All seven patients underwent salvage R0 resections. We identified a novel 'tram-track' sign on MRI in over half of patients, with an NPV for early local relapse of 83 % at 6 months. No imaging characteristic or TRG score independently prognosticated for late relapse or 3-year DFS. CONCLUSIONS: Post-CRT 3- and 6-month MRI-determined TRG scores predicted salvageable R0 early local relapses in patients with ASCC, challenging current clinical guidelines. KEY POINTS: • Post-chemoradiotherapy MRI (3 and 6 months) helps local response assessment in ASCC. • The MRI-TRG system can be used reproducibly in patients with ASCC. • The TRG system facilitates patient selection for examination under anaesthesia and biopsy. • The use of MRI-TRG predicts for detection of salvageable early local relapses. • The TRG system allows for a standardised follow-up pathway.

Comparative evaluation of fracture resistance of root canals obturated with four different obturating systems.

AIM AND OBJECTIVES: The aim of this study is to evaluate and compare the fracture resistance of root canals obturated with four different obturating systems in endodontically treated teeth. MATERIALS AND METHODS: One hundred and twenty single-rooted teeth were selected and decoronated at cementoenamel junction. Instrumentation of teeth (except control group) was done with Mtwo rotary files up to size 25/0.06 using a step-back technique. All teeth were divided into four experimental groups (n = 25) and two control groups (n = 10). In Group I (negative control), teeth were neither instrumented nor obturated, in Group II (positive control), instrumentation was done, but no obturation was performed, in Group III, obturation was done with cold lateral compaction technique, in Group IV, obturation was done with cold free-flow compaction technique, in Group V, obturation was done with warm vertical compaction technique, and in Group VI, obturation was done with injection-molded thermoplasticized technique. All prepared teeth were embedded in an acrylic resin block, and their fracture strength was measured using Universal Testing Machine. Statistical data were analyzed using one-way analysis of variance and Tukey's honestly significant difference test. RESULTS: Negative control Group I showed highest fracture resistance and positive control Group II had lowest fracture resistance. Among experimental groups, cold free-flow compaction technique with GuttaFlow2 (Group IV) showed higher fracture resistance as compared to the Group III, Group V, and Group VI. CONCLUSION: GuttaFlow2 has the potential to strengthen the endodontically treated roots to a level that is similar to that of intact teeth.

Utility of 18-fluorodeoxyglucose positron emission/computed tomography in the management of recurrent colorectal cancer.

BACKGROUND: This study aimed to evaluate the utility of 18-fluorodeoxyglucose positron emission/computed tomography (PET/CT) in the management of colorectal cancer (CRC) patients with suspected recurrence. METHODS: Clinical and imaging histories of CRC patients who underwent PET/CT at our institution between 1 April 2007 and 31 August 2008 for evaluation of recurrent disease were retrospectively reviewed. Patients were divided into two groups - (A) patients evaluated for suspected local recurrence (based on conventional imaging) and (B) patients with carcinoembryonic antigen (CEA) levels in excess of 5 ng/mL; in whom conventional imaging was either normal or equivocal. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were derived using either histopathology or follow-up imaging as the standard of reference. RESULTS: In group A (n = 44), the sensitivity, specificity, PPV, NPV and accuracy of PET/CT were 100% (95% confidence interval (CI): 86.7-100), 84.2% (95% CI: 62.4-94.5), 89.3% (95% CI: 72.8-96.3), 100% (95% CI: 80.6-100) and 93.2%, respectively. In group B (n = 18), the sensitivity, specificity, PPV and NPV of PET/CT were 76.9% (95% CI: 49.7-91.8), 60.0%, (95% CI: 23.1-88.2), 83.3% (95% CI: 55.2-95.3) and 50% (95% CI: 18.8-81.2), respectively. CONCLUSION: PET/CT has high accuracy in the assessment of local recurrence, particularly with regard to its NPV. PET/CT is useful for problem solving in cases of unexplained elevated CEA levels.

Imaging of anal carcinoma.

OBJECTIVE: The purpose of this article is to review the role of imaging in the management of patients with anal cancer. The relevant anatomy, imaging techniques, and interpretation of images of patients before and after therapy will be discussed. CONCLUSION: Anal carcinomas are uncommon but increasing in frequency. Radiologists must recognize typical patterns of disease at initial evaluation, posttherapy appearances, and when to suspect residual or recurrent disease to guide clinicians and achieve optimal patient outcome.