ROAR-A: re-optimization based Online Adaptive Radiotherapy of anal cancer, a prospective phase II trial protocol.

BACKGROUND: Chemo-radiotherapy with curative intent for anal cancer has high complete remission rates, but acute treatment-related gastrointestinal (GI) toxicity is significant. Toxicity occurs due to irradiation of surrounding normal tissue. Current radiotherapy requires the addition of large planning margins to the radiation field to ensure target coverage regardless of the considerable organ motion in the pelvic region. This increases the irradiated volume and radiation dose to the surrounding normal tissue and thereby toxicity. Online adaptive radiotherapy uses artificial intelligence to adjust the treatment to the anatomy of the day. This allows for the reduction of planning margins, minimizing the irradiated volume and thereby radiation to the surrounding normal tissue.This study examines if cone beam computed tomography (CBCT)-guided oART with daily automated treatment re-planning can reduce acute gastrointestinal toxicity in patients with anal cancer. METHODS/DESIGN: The study is a prospective, single-arm, phase II trial conducted at Copenhagen University Hospital, Herlev and Gentofte, Denmark. 205 patients with local only or locally advanced anal cancer, referred for radiotherapy with or without chemotherapy with curative intent, are planned for inclusion. Toxicity and quality of life are reported with Common Terminology Criteria of Adverse Events and patient-reported outcome questionnaires, before, during, and after treatment. The primary endpoint is a reduction in the incidence of acute treatment-related grade ≥ 2 diarrhea from 36 to 25% after daily online adaptive radiotherapy compared to standard radiotherapy. Secondary endpoints include all acute and late toxicity, overall survival, and reduction in treatment interruptions. RESULTS: Accrual began in January 2022 and is expected to finish in January 2026. Primary endpoint results are expected to be available in April 2026. DISCUSSION: This is the first study utilizing online adaptive radiotherapy to treat anal cancer. We hope to determine whether there is a clinical benefit for the patients, with significant reductions in acute GI toxicity without compromising treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05438836. Danish Ethical Committee: H-21028093.

Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer.

Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

Myocardial Ischemia Induced by 5-Fluorouracil: A Prospective Electrocardiographic and Cardiac Biomarker Study.

BACKGROUND: Cardiotoxicity induced by 5-fluorouracil (5-FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5-FU to increase our understanding of the cardiotoxicity. SUBJECTS, MATERIALS, AND METHODS: Patients with colorectal or anal cancer that received first-time treatment with 5-FU-based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12-lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5-FU treatment (intervention). RESULTS: A total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5-FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5-FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5-FU treatment. CONCLUSION: 5-FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5-FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%-6% of the patients developed acute coronary syndromes during treatment with 5-FU. IMPLICATIONS FOR PRACTICE: Symptomatic 5-fluorouracil (5-FU) cardiotoxicity occurs in 0.6%-19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5-FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5-FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5-FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5-FU.

Management of late adverse effects after chemoradiation for anal cancer.

BACKGROUND AND PURPOSE: Significant improvements in the treatment of anal cancer have produced a growing population of anal cancer survivors. These patients often experience late adverse effects related to their treatment. Research has revealed substantial unmet needs because of long-term symptoms and functional impairments after treatment that may negatively affect health-related quality of life. The purpose of the present guidelines is to review the scientific evidence for the management of late adverse effects after (chemo)radiotherapy ([C]RT) for anal cancer and to extrapolate knowledge from other pelvic malignancies treated with pelvic (C)RT so that they may guide the clinical management of late adverse effects. MATERIALS AND METHODS: Relevant studies were systematically searched in four databases from their inception to June 2020 (no language limitation) and guidelines were searched in 16 databases, focussing on bowel dysfunction, psychosocial aspects, pain, and sexual and urinary dysfunction. The guidelines were developed by a panel of experts using the Oxford Centre for Evidence-based Medicine, levels of evidence, and grades of recommendations. SCIENTIFIC EVIDENCE: Late adverse effects after (C)RT for anal cancer are associated with a low overall quality of life among survivors. The most pronounced late adverse effects are bowel dysfunction (present in up to 78%), urinary dysfunction (present in up to 45%), and sexual dysfunction (present in up to 90% of men and up to 100% of women). Only indirect data on adequate treatment options of these late adverse effects for anal cancer are available. CONCLUSION: Quality of life and late adverse effects should be monitored systematically following treatment for anal cancer to identify patients who require further specialist evaluation or support. Increased awareness of the extent of the problem may serve to stimulate and facilitate multidisciplinary collaboration, which is often required.

Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version.

Background: The UICC TNM 7th edition introduced stage groups for anal cancer which in 2019 has not yet come into general use. The new TNM 8th edition from 2016 defines 7 sub-stages. Background data for these changes are lacking. We aimed to investigate whether the new classification for anal cancer reliably predict the prognosis in the different stages.Patients and methods: The Nordic Anal Cancer Group (NOAC) conducted a large retrospective study of all anal cancers in Norway, Sweden and most of Denmark in 2000-2007. From the Nordic cohort 1151 anal cancer patients with follow-up data were classified by the TNM 4th edition which has identical T, N and M definitions as the TNM 7th edition, and therefore also can be classified by the TNM 7th stage groups. We used the Nordic cohort to translate the T, N and M stages into the TNM 8th stages and sub-stages. Overall survival for each stage was assessed.Results: Although the summary stage groups for TNM 8th edition discriminates patients with different prognosis reasonably well, the analyses of the seven sub-stages show overlapping overall survival: HR for stage IIA 1.30 (95%CI 0.80-2.12) is not significantly different from stage I (p = .30) and HR for stage IIB 2.35 (95%CI 1.40-3.95) and IIIA 2.48 (95%CI 1.43-4.31) are also similar as were HRs for stage IIIB 3.41 (95%CI 1.99-5.85) and IIIC 3.22 (95%CI 1.99-5.20). Similar overlapping was shown for local recurrence and distant spread.Conclusion: The results for the sub-stages calls for a revision of the staging system. We propose a modification of the TNM 8th edition for staging of anal cancer into four stages based on the T, N and M definitions of the TNM 8th classification.

Anticipatory coarticulation in non-speeded arm movements can be motor-equivalent, carry-over coarticulation always is.

In a sequence of arm movements, any given segment could be influenced by its predecessors (carry-over coarticulation) and by its successor (anticipatory coarticulation). To study the interdependence of movement segments, we asked participants to move an object from an initial position to a first and then on to a second target location. The task involved ten joint angles controlling the three-dimensional spatial path of the object and hand. We applied the principle of the uncontrolled manifold (UCM) to analyze the difference between joint trajectories that either affect (non-motor equivalent) or do not affect (motor equivalent) the hand's trajectory in space. We found evidence for anticipatory coarticulation that was distributed equally in the two directions in joint space. We also found strong carry-over coarticulation, which showed clear structure in joint space: More of the difference between joint configurations observed for different preceding movements lies in directions in joint space that leaves the hand's path in space invariant than in orthogonal directions in joint space that varies the hand's path in space. We argue that the findings are consistent with anticipatory coarticulation reflecting processes of movement planning that lie at the level of the hand's trajectory in space. Carry-over coarticulation may reflect primarily processes of motor control that are governed by the principle of the UCM, according to which changes that do not affect the hand's trajectory in space are not actively delimited. Two follow-up experiments zoomed in on anticipatory coarticulation. These experiments strengthened evidence for anticipatory coarticulation. Anticipatory coarticulation was motor-equivalent when visual information supported the steering of the object to its first target, but was not motor equivalent when that information was removed. The experiments showed that visual updating of the hand's path in space when the object approaches the first target only affected the component of the joint difference vector orthogonal to the UCM, consistent with the UCM principle.

Individuals with dark eyes and hair exhibit higher pain sensitivity.

Emerging evidence suggests that some phenotypic features, such as eye or hair colour, might predict pain. We investigated if light and dark eye and hair colour would influence pain in 60 healthy subjects divided in groups of 15 according to their eye-hair colour and gender. Pressure pain thresholds (PPTs), cold pressor test (CPT), and quality of the perceived pain were assessed. Findings indicated that dark pigmentation phenotype is more sensitive in response to CPT.

Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer.

BACKGROUND: The majority (90%) of anal cancers are human papillomavirus (HPV)-driven, identified using immunochemistry for p16. Compared with HPV- patients, those with HPV+ disease generally show improved survival, although relapse rates around 25% indicate a need for further stratification of this group. METHODS: Using two cohorts of anal cancer, previously characterised for p16, we assessed the prognostic value of tumour-infiltrating lymphocytes (TILs). RESULTS: Tumour-infiltrating lymphocyte scores were used to stratify p16+ cases, where tumours with absent/low levels of TIL had a relapse-free rate of 63%, as opposed to 92% with high levels of TIL (log rank P=0.006). CONCLUSIONS: Assessment of TIL adds to p16 status in the prognosis of anal cancer following chemo-radiotherapy and provides evidence of the clinical importance of the immune response.

Carry-over coarticulation in joint angles.

Coarticulation indicates a dependence of a movement segment on a preceding segment (carry-over coarticulation) or on the segment that follows (anticipatory coarticulation). Here we study coarticulation in multidegrees of freedom human arm movements. We asked participants to transport a cylinder from a starting position to a center target and on to a final target. In this naturalistic setting, the human arm has ten degrees of freedom and is thus comfortably redundant for the task. We studied coarticulation by comparing movements between the same spatial locations that were either preceded by different end-effector paths (carry-over coarticulation) or followed by different end-effector paths (anticipatory coarticulation). We found no evidence for coarticulation at the level of the end-effector. We found very clear evidence, however, for carry-over, not for anticipatory coarticulation at the joint level. We used the concept of the uncontrolled manifold to systematically establish coarticulation as a form of motor equivalence, in which most of the difference between different movement contexts lies within the uncontrolled manifold that leaves the end-effector invariant. The findings are consistent with movement planning occurring at the level of the end-effector, and those movement plans being transformed to the joint level by a form of inverse kinematics. The observation of massive self-motion excludes an account that is solely based on a kinematic pseudo-inverse.

MR-guided stereotactic radiotherapy of infra-diaphragmatic oligometastases: Evaluation of toxicity and dosimetric parameters.

BACKGROUND AND PURPOSE: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE). MATERIALS AND METHODS: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model. RESULTS: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D0.1cc, D1cc, and D20cc. CONCLUSION: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D0.1cc, D1cc, and D20cc were associated with grade ≥ 2 GI toxicity.

Promising long-term outcome of bladder autoaugmentation in children with neurogenic bladder dysfunction.

PURPOSE: We evaluated the long-term outcome of bladder autoaugmentation in children with neurogenic bladder dysfunction. MATERIALS AND METHODS: Data were compiled from the records of 25 children with a median age of 9.3 years (range 0.9 to 14.2) who underwent detrusor myotomy between 1992 and 2008. All patients were diagnosed with small bladder capacity, low compliance and high end filling pressures, and were unresponsive to clean intermittent catheterization and anticholinergics. RESULTS: Median followup was 6.8 years (range 0.1 to 15.6). Median postoperative bladder capacity was unchanged or decreased to 95 ml (range 25 to 274) during the first 3 months compared to a median preoperative capacity of 103 ml (14 to 250). At 5 months postoperatively median bladder capacity increased significantly to 176 ml (range 70 to 420, p<0.01). This increase remained significant during the rest of followup. Median bladder compliance doubled after 1 year to 10 ml/cm H2O (range 1 to 31, p<0.05) compared to the preoperative level, and further increased to 17 ml/cm H2O (5 to 55) at 5 years (p<0.05). Median maximal detrusor pressure was 43 cm H2O (range 8 to 140) preoperatively. This value decreased significantly postoperatively (p<0.01) and at final followup it was 26 cm H2O (range 6 to 97). Kidney function developed normally in all patients except 1 with persistent uremia. Reflux was alleviated in 7 of 9 cases. Of the patients 18 became continent on clean intermittent catheterization. CONCLUSIONS: Bladder autoaugmentation in children with neurogenic bladder dysfunction offers, after a transient decrease in bladder capacity, a long lasting increase in capacity and compliance, while the end filling pressure decreases.

One-Year Treatment-Related Side Effects and Quality of Life After Chemoradiotherapy in Squamous Cell Carcinoma of the Anus.

PURPOSE: Patient-reported outcome (PRO) and National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) data for patients with squamous cell carcinoma of the anus (SCCA) treated with modern radiation therapy (RT) are lacking. The primary aim of this study was to report bowel and bladder PRO and NCI-CTCAE for patients with SCCA 1 year after RT. METHODS AND MATERIALS: From 2015 to 2020, we included patients in a prospective Danish national study. Data were collected before treatment (PT) and 1 year after treatment (1Y) using NCI-CTCAE version 4.0, as well as European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and CR29. We evaluated the combined PRO scores according to the European Organisation for Research and Treatment of Cancer scoring guidelines, and classified changes according to score difference from PT to 1Y as no change (0-5), minor (5-10), moderate (11-20), and major (>20). Raw scores were reported as frequencies of each of the scores: Not at all, a little, quite a bit, and very much. RESULTS: Of the 270 patients, 81% had complete data sets, including PT and 1Y answers. Functional mean scores were equal to a matched normal population cohort at PT and 1Y. From PT to 1Y, C30 scores were stable despite minor improvements in global health status/quality of life (7.3), emotional functioning (9.3), insomnia (8.0), and appetite loss (7.8). For questionnaire CR29, bowel and bladder symptoms and sore skin improved with minor change (6.2), and buttocks, anal, or rectal pain improved with moderate change (18.3). Flatulence worsened moderately (12.6), and fecal incontinence had minor worsening (7.8). Agreement between PROs and NCI-CTCAE was generally only fair to moderate, especially for quantitative symptoms, such as pain (κ = 0.25). CONCLUSIONS: For patients with SCCA who underwent definitive RT, only a few patients had high scores (indicating quite a bit or very much frequency of bother) regarding bowel and bladder symptoms.

Regulatory Considerations Toward Orphan Drug Designation and Orphan Drug Exclusivity in the United States and European Union: Structural Similarity, Clinical Superiority/Significant Benefit, and Case Studies.

The U.S. Food and Drug Administration and European Commission have developed successful orphan drug legislation to promote the research, development, and marketing approval of drugs to treat rare diseases. Central to these regulations are the concepts of structural similarity and clinical superiority/significant benefit to achieve orphan drug exclusivity. However, differences in health authority expectations remain regarding the qualification for an orphan drug designation, defining structural similarity, and demonstrating clinical superiority/significant benefit. These differences can create sponsor company uncertainty regarding the approvability of products (e.g., blocking risk by an existing orphan product) and divergent orphan drug decisions among health authorities. A comprehensive assessment of current regulations, case studies in exclusivities, and recommendations for improvement are presented.

Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology.

AIM: The aim of this study was to investigate the role of congenital cytomegalovirus (CMV) infection as a cause of various types of sensorineural hearing loss (SNHL) in a group of nonsyndromic children with otherwise unknown aetiology of hearing loss. Furthermore, the occurrence of combined congenital CMV infection and connexin 26 (Cx26) mutations was investigated. METHODS: The dried blood spot (DBS) cards of 45 children with various degrees of hearing deficits and 46 children with severe/profound hearing loss were tested for CMV DNA with polymerase chain reaction (PCR) technique. The DBS cards of the 46 children with severe/profound hearing loss were also analysed for Cx26 mutations. RESULTS: Of the 45 children with various degrees of hearing loss, nine were positive for CMV DNA (20%). The nine children represented severe/profound, mild and unilateral hearing loss. From the 46 children with severe/profound hearing loss, nine of 46 (20%) were positive for CMV DNA. In addition, three of the CMV DNA-positive children were carriers of mutations of Cx26. CONCLUSION: Congenital CMV infection is a high risk factor in hearing impairment among children.

Online adaptive radiotherapy of anal cancer: Normal tissue sparing, target propagation methods, and first clinical experience.

BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially spares OARs as PTV margins are reduced. This study evaluates dosimetric benefits, compared to standard non-adaptive radiotherapy (non-ART), target propagation methods, and first clinical treatments of CBCT-guided oART of anal cancer. MATERIALS AND METHODS: Treatment plans with standard non-ART and reduced oART PTV margins were retrospectively generated for 23 consecutive patients with anal cancer. For five patients randomly selected among the 23 patients, weekly CBCT-guided oART sessions were simulated, where the targets were either deformed or rigidly propagated. Preferred target propagation method and dose to OARs were evaluated. Ten consecutive patients with anal cancer were treated with CBCT-guided oART. Target propagation methods and oART procedure time were evaluated. RESULTS: For the retrospective treatment plans, oART resulted in median reductions in bowel bag V45Gy of 11.4 % and bladder V35Gy of 16.1%. Corresponding values for the simulated sessions were 7.5% and 27.1%. In the simulated sessions, 35% of all targets were deformed while 65% were rigidly propagated. Manual editing and rigid propagation were necessary to obtain acceptable target coverage. In the clinical treatments, the primary and some elective targets were rigidly propagated, while other targets were deformed. The median oART procedure time, measured from CBCT acquisition to completion of plan review and QA, was 23 min. CONCLUSIONS: Simulated oART reduced the dose to OARs, indicating potential reduction in toxicity. Rigid propagation of targets was necessary to reduce the need for manual edit. Clinical treatments demonstrated that oART of anal cancer is feasible but time-consuming.

Online adaptive radiotherapy of urinary bladder cancer with full re-optimization to the anatomy of the day: Initial experience and dosimetric benefits.

BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially reduces the dose to organs at risk (OARs) as the planning target volume (PTV) margins are reduced compared to a non-adaptive approach (non-ART). This study evaluates the feasibility and dosimetric impact of cone-beam computed tomography (CBCT)-guided oART of urinary bladder cancer for the first patients treated, using patient-specific margins. MATERIALS AND METHODS: Sixteen consecutive patients with muscle-invasive bladder cancer received two or more (median = 23) fractions as oART, and remaining fractions as non-ART. The non-ART fractions were delivered with standard population-based margins, while reduced patient-specific margins based on intra-fractional variations extracted from 2-4 fractions were applied to the primary PTV (PTV-T) during the oART fractions. Target volume and coverage, and dose to OARs were compared between non-ART and oART plans, and the oART procedure time was recorded. RESULTS: In total, 297/512 fractions were delivered as oART with full re-optimization to the anatomy of the day. The median (interquartile range, IQR) oART procedure time, measured from the end of CBCT generation to completion of plan review, and quality assurance was 13.9 (11.9;16.6) min. The median (IQR) volume reduction in PTV-T volume was 33.9 (24.2;45.0)%, comparing oART and non-ART plans, resulting in median (IQR) reductions in bowel bag V45Gy of 18.8 (12.7;27.9)% and rectum V50Gy of 70.7 (35.9;94.8)%. By re-optimizing the plan to the daily anatomy, full target coverage was achieved at all oART fractions. CONCLUSIONS: oART resulted in large reductions in treatment volumes and doses to OARs, compared to non-ART, while ensuring target coverage. This indicates potential reductions in gastrointestinal toxicity.

Evaluation of an automated template-based treatment planning system for radiotherapy of anal, rectal and prostate cancer.

Background and purpose: The Ethos system has enabled online adaptive radiotherapy (oART) by implementing an automated treatment planning system (aTPS) for both intensity-modulated radiotherapy (IMRT) and volumetric modulated arc radiotherapy (VMAT) plan creation. The purpose of this study is to evaluate the quality of aTPS plans in the pelvic region. Material and Methods: Sixty patients with anal (n = 20), rectal (n = 20) or prostate (n = 20) cancer were retrospectively re-planned with the aTPS. Three IMRT (7-, 9- and 12-field) and two VMAT (2 and 3 arc) automatically generated plans (APs) were created per patient. The duration of the automated plan generation was registered. The best IMRT-AP and VMAT-AP for each patient were selected based on target coverage and dose to organs at risk (OARs). The AP quality was analyzed and compared to corresponding clinically accepted and manually generated VMAT plans (MPs) using several clinically relevant dose metrics. Calculation-based pre-treatment plan quality assurance (QA) was performed for all plans. Results: The median total duration to generate the five APs with the aTPS was 55 min, 39 min and 35 min for anal, prostate and rectal plans, respectively. The target coverage and the OAR sparing were equivalent for IMRT-APs and VMAT-MPs, while VMAT-Aps.demonstrated lower target dose homogeneity and higher dose to some OARs. Both conformity and homogeneity index were equivalent (rectal) or better (anal and prostate) for IMRT-APs compared to VMAT-MPs. All plans passed the patient-specific QA tolerance limit. Conclusions: The aTPS generates plans comparable to MPs within a short time-frame which is highly relevant for oART treatments.

[Acute compartment syndrome].

This review summarises the present knowledge of acute compartment syndrome, which is a time-critical diagnosis threatening both life and limb of the affected patients. Acute compartment syndrome is a clinical diagnosis, which in equivocal cases can be supported by direct intra-compartmental pressure measurement and laboratory values. Imaging can detect fractures; and non-invasive monitoring is under investigation but has not yet found clinical use. The treatment is a surgical fasciotomy, and this should be performed acutely. If diagnosis is made more than 24-48 hours after onset of symptoms, non-operative treatment should be considered.

Nonplatinum-based therapy with Paclitaxel and Capecitabine for advanced squamous cell carcinomas of the anal canal: A population-based Danish anal cancer group study.

BACKGROUND: First-line platinum-based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second-line treatment options are limited. Paclitaxel and Capecitabine are a well-known regimen with a moderate toxicity profile, but its efficacy has not been evaluated. METHODS: We conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018. RESULTS: A total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42-83). Efficacy was observed, with an overall response rate in patients receiving first-line (N = 28) and second-line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression-free survival (PFS) was 4.5 months (95% CI 3.3-5.9) and 3.8 months (95% CI 2.4-5.5) with OS of 6.7 months (95% CI 5.9-8.5) and 5.9 months (95% CI 3.9-14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS. CONCLUSION: This study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first-line therapy is not feasible or as a potential second-line treatment after failure of platinum-based chemotherapy.