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Targeted muscle reinnervation (TMR) is an established modality for the surgical management of neuropathic pain. Although the preventive effect of primary (acute) TMR at the time of amputation has been demonstrated previously, it remains unclear how many and which patients benefit most. Therefore, this study investigated the proportion of patients achieving sustained pain prophylaxis following amputation, as well as factors associated with its efficacy. Primary patients who underwent TMR with a minimum follow-up of 6 months between 2018 and 2023 were enrolled. Pain outcomes (numeric rating scale [NRS], 0–10), comorbidities, and surgical factors were collected from chart review. Patients achieving sustained pain prophylaxis (NRS of ≤3 for ≥3 months until final follow-up) were identified. Multilevel mixed-effect models and multivariable regression were used to visualize pain courses and identify associated factors. Seventy-five patients who underwent primary TMR were included (median follow-up: 2.0 years), of whom 57.3% achieved sustained pain prophylaxis whereas 26.7% reported pain disappearance. Distal amputation levels (p = 0.036), a lower Elixhauser Comorbidity Index (p = 0.001), and the absence of psychiatric comorbidities (p = 0.039) were associated with pain prophylaxis. This study demonstrates that more than half of all patients undergoing primary TMR achieved sustained pain prophylaxis, and approximately a quarter of patients achieved sustained pain disappearance. Several factors associated with these favorable outcomes are described. These results will aid in preoperative counseling, managing patient expectations, and selecting patients who may benefit most from primary TMR surgery. IV – Therapeutic [ABSTRACT FROM AUTHOR]

Simple Summary: Radiotherapy is a crucial component in the multimodal treatment of Ewing sarcoma; it can be applied for local disease in addition to surgery or as definitive treatment for inoperable disease. Particularly in pelvic Ewing sarcoma, definitive radiotherapy offers the possibility of avoiding extensive and potentially mutilating resections and preserving crucial neurological functions. Adult patients with primary or locally recurrent pelvic Ewing sarcoma treated with curative intent with protons for primary disease and carbon ions for recurrent disease at the Heidelberg Ion-Beam Therapy Center (HIT) were considered for this retrospective analysis. We report excellent dosimetric characteristics in the treatment with protons in comparison to photon IMRT and promising early clinical outcomes. Particle therapy in adult pelvic Ewing sarcoma is shown to be feasible in a consecutive patient cohort. However, further long-term follow-up is needed to assess late toxicity and clinical outcomes. Purpose: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. Methods: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45–60 Gy (RBE) (1.5–2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan–Meier method. Results: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1–2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. Conclusions: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed. [ABSTRACT FROM AUTHOR]

In image-guided adaptive brachytherapy (IGABT) a quantitative evaluation of the dosimetric changes between fractions due to anatomical variations, can be implemented via rigid registration of images from subsequent fractions based on the applicator as a reference structure. With available treatment planning systems (TPS), this is a manual and time-consuming process. The aim of this retrospective study was to automate this process. A neural network (NN) was trained to predict the applicator structure from MR images. The resulting segmentation was used to automatically register MR-volumes. DICOM images and plans of 56 patients treated for cervical cancer with high dose-rate (HDR) brachytherapy were used in the study. A 2D and a 3D NN were trained to segment applicator structures on clinical T2-weighted MRI datasets. Different rigid registration algorithms were investigated and compared. To evaluate a fully automatic registration workflow, the NN-predicted applicator segmentations (AS) were used for rigid image registration with the best performing algorithm. The DICE coefficient and mean distance error between dwell positions (MDE) were used to evaluate segmentation and registration performance. The mean DICE coefficient for the predicted AS was 0.70 ± 0.07 and 0.58 ± 0.04 for the 3D NN and 2D NN, respectively. Registration algorithms achieved MDE errors from 8.1 ± 3.7 mm (worst) to 0.7 ± 0.5 mm (best), using ground-truth AS. Using the predicted AS from the 3D NN together with the best registration algorithm, an MDE of 2.7 ± 1.4 mm was achieved. Using a combination of deep learning models and state of the art image registration techniques has been demonstrated to be a promising solution for automatic image registration in IGABT. In combination with auto-contouring of organs at risk, the auto-registration workflow from this study could become part of an online-dosimetric interfraction evaluation workflow in the future. [ABSTRACT FROM AUTHOR]

Purpose: Clinical drawings are integral part of image-guided adaptive brachytherapy (IGABT) of cervical cancer. It was used in EMBRACE study protocol as a useful tool. In our study clinical drawings from EMBRACE study were modified to include scales in all the dimensions for more accurate representation of various tumor related volumes. The aim of the present study was to understand patterns of tumor regression and relationship between gross tumor at diagnosis (GTVD) and high-risk clinical target volume (CTV-THR)/intermediate-risk clinical target volume (CTV-TIR) in brachytherapy (BRT), using modified clinical drawings. Material and methods: 42 cervical cancer patients, staged as FIGO IIB-IIIB according to EMBRACE study, were enrolled. Advanced schematic 3D mapping diagram (3D-MD) in axial, coronal, and sagittal orientations, with a measurement scale (grid with 10 mm distance) for precise assessment and documentation was applied (through MRI at diagnosis and during brachytherapy). Dimensions, including height, width, and thickness as well as volumes (GTVD, CTV-THR and CTV-TIR) were compared both qualitatively and quantitatively. Results and conclusions: We found qualitative and quantitative correlation of the dimensions of final CTV-THR with initial GTVD. Meticulous mapping of tumor volumes can provide useful insights to CTV-THR volume during brachytherapy. [ABSTRACT FROM AUTHOR]

Abstract Background To date, there is no consensus on the utility of screening procedures for the early detection of endometrial cancer. The value of transvaginal ultrasound for screening of asymptomatic endometrial cancer has been discussed controversially. This study was conducted to evaluate whether asymptomatic patients with endometrial cancer have a better prognosis than symptomatic patients with endometrial cancer diagnosed after postmenopausal bleeding. Methods In the present multi-center study, the effect of the presence of postmenopausal bleeding on prognosis was evaluated retrospectively in 605 patients with endometrial cancer using patients' files. 543 patients (133 patients were asymptomatic, 410 patients were symptomatic) with endometrioid endometrial cancer were enrolled in all further analysis. Student's t-test, Cox regression analysis and Kaplan-Meier analysis were used were appropriate. Results Presence/absence of a postmenopausal bleeding was not associated with tumor stage (p = 0.2) and age at diagnosis (p = 0.5). Asymptomatic patients with endometrial cancer had a significantly higher rate of well and moderate-differentiated tumors compared to symptomatic patients (p = 0.008). In univariable and multivariable survival analysis, tumor stage, tumor grade, and patients' age at diagnosis, but not presence/absence of a postmenopausal bleeding, were associated with disease free and overall survival. Conclusion Asymptomatic patients with endometrial cancer have a higher rate of well differentiated tumors compared to patients with a postmenopausal bleeding prior to diagnosis. The prognosis of both groups of patients was similar.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk. [ABSTRACT FROM AUTHOR]

• Adaptive target volume concept for EBRT and brachytherapy in primary vaginal cancer. • MRI is the imaging modality of choice for target volume delineation in brachytherapy. • Common terminology will facilitate multicenter research. External beam radiotherapy (EBRT) combined with brachytherapy has an essential role in the curative treatment of primary vaginal cancer. EBRT is associated with significant tumour shrinkage, making primary vaginal cancer suitable for image guided adaptive brachytherapy (IGABT). The aim of these recommendations is to introduce an adaptive target volume concept for IGABT of primary vaginal cancer. In December 2013, a task group was initiated within GYN GEC-ESTRO with the purpose to introduce an IGABT target concept for primary vaginal cancer. All participants have broad experience in IGABT and vaginal cancer brachytherapy. The target concept was elaborated as consensus agreement based on an iterative process including target delineation and dose planning comparison, retrospective analysis of clinical data and expert opinions. Gynaecological examination and MR imaging are the modalities of choice for local tumour assessment. A specific template for standardised documentation with clinical drawings for vaginal cancer was developed. The adaptive target volume concept comprises different response-related target volumes. For EBRT these are related to the primary tumour and the lymph nodes, while for IGABT these are related to the primary tumour and are consisting of the residual gross tumour volume (GTV-T res) and the high-, and intermediate risk clinical target volumes (CTV-T HR , CTV-T IR). This target concept for IGABT of primary vaginal cancer defines adaptive target volumes for volumetric dose prescription and should improve comparability of different radiotherapy schedules of this rare disease. A prospective evaluation of the target volume concept within a multicentre study is planned. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the dosimetric results and first clinical experiences with a new designed balloon applicator with adjustable catheters for endoluminal brachytherapy for patients with locally advanced rectal cancer not undergoing surgery. Material and methods: The applicator consists of an inflatable rectal balloon with six attached Foley catheters used as guidance for the inserted brachytherapy plastic needles. The construction of the applicator and the dosimetric profile in terms of representative dose points in 0, 2, 5, 10 mm ipsilaterally and in 0 mm contralaterally are described. The first clinical outcomes in three patients are reported. Results: For all three patients, a reproducible dose gradient was achieved. The surface dose on the target side was 204 ± 19% of the normalized dose in 5 mm (100%) tissue depth, and 143 ± 8% in 2 mm and 64 ± 3% in 10 mm tissue depth, while the surface dose on the contra-lateral side was 20 ± 8%. After radiochemotherapy with 50 Gy external beam radiotherapy and concomitant administration of capecitabine, a HDR brachytherapy boost in 2-3 fractions of 7-10 Gy each was delivered. All patients achieved a clinical complete response 3 month after the treatment, and no major toxicity was observed. Conclusion: The use of the applicator was clinically feasible, and resulted in a stable and reproducible dose distribution. First clinical results are promising. [ABSTRACT FROM AUTHOR]

Summary Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha low ) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2 –/– γc – / – mice, lacking lymphocytes and NK cells, and in Ifng –/– mice, Ldha low and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape. [ABSTRACT FROM AUTHOR]

Purpose To investigate the feasibility of a treatment planning workflow for three-dimensional image-guided cervix cancer brachytherapy, combining volumetric transrectal ultrasound (TRUS) for target definition with CT for dose optimization to organs at risk (OARs), for settings with no access to MRI. Methods and Materials A workflow for TRUS/CT-based volumetric treatment planning was developed, based on a customized system including ultrasound probe, stepper unit, and software for image volume acquisition. A full TRUS/CT-based workflow was simulated in a clinical case and compared with MR- or CT-only delineation. High-risk clinical target volume was delineated on TRUS, and OARs were delineated on CT. Manually defined tandem/ring applicator positions on TRUS and CT were used as a reference for rigid registration of the image volumes. Treatment plan optimization for TRUS target and CT organ volumes was performed and compared to MRI and CT target contours. Results TRUS/CT-based contouring, applicator reconstruction, image fusion, and treatment planning were feasible, and the full workflow could be successfully demonstrated. The TRUS/CT plan fulfilled all clinical planning aims. Dose-volume histogram evaluation of the TRUS/CT-optimized plan (high-risk clinical target volume D 90 , OARs D 2cm³ for) on different image modalities showed good agreement between dose values reported for TRUS/CT and MRI-only reference contours and large deviations for CT-only target parameters. Conclusions A TRUS/CT-based workflow for full three-dimensional image-guided cervix brachytherapy treatment planning seems feasible and may be clinically comparable to MRI-based treatment planning. Further development to solve challenges with applicator definition in the TRUS volume is required before systematic applicability of this workflow. [ABSTRACT FROM AUTHOR]

Background.To assess planning aims (PAs) and dose prescription in image-guided adaptive brachytherapy (IGABT) of cervical cancer and investigate potential impact on clinical outcome. Material and methods.Our study population consists of 225 consecutive cervical cancer patients (FIGO stages IB–IVA) treated between 1998 and 2008 at the Medical University of Vienna by external beam radiotherapy (EBRT) ± chemotherapy and IGABT. For this retrospective study, patients were stratified into two treatment groups: PA+ group, all dose constraints fulfilled for prescription; PA-, one or more dose constraints not fulfilled for prescription. The following dose constraints (EBRT+ IGABT) were applied: clinical target volume (CTV)HRD90≥ 85 Gy, D2cm3Rectum < 70 Gy, D2cm3Bladder < 90 Gy. Differences in patient, tumor and treatment characteristics and clinical outcome (event: local failure or grade 3 + 4 toxicity) were compared between Group 1 and 2. Further, the impact of learning period (1998–2000) and protocol period (2001–2008) on the fulfillment of PAs for dose prescription and clinical outcome was analyzed. Results. In the PA+ group there were 77 (34%) and in the PA- group 148 (66%) patients. In the PA- group, CTVHRD90< 85 Gy was prescribed in 82 patients, D2cm3bladder > 90 Gy was prescribed in 80 patients and D2cm3Rectum > 70 Gy in 60 patients. Fulfillment of the PA for dose prescription improved from 4% in the learning period to 48% in the protocol period. The five-year event-free interval was 64% in the learning period and 84% in the protocol period (p = 0.008). Conclusion.Fulfillment of all PAs for dose prescription is challenging – especially in patients with more advanced tumors. However, with growing experience fulfillment of PA for dose prescription can be significantly increased (learning and protocol period). Such increase in fulfilling PA for dose prescription is followed by a significant improvement in clinical outcome. [ABSTRACT FROM PUBLISHER]

Purpose. To investigate the impact of magnetic resonance imaging (MRI)-morphologic differences in parametrial infiltration on tumour response during primary radiochemotherapy in cervical cancer. Material and methods. Eighty-five consecutive cervical cancer patients with FIGO stages IIB (n = 59) and IIIB (n = 26), treated by external beam radiotherapy (± chemotherapy) and image-guided adaptive brachytherapy, underwent T2-weighted MRI at the time of diagnosis and at the time of brachytherapy. MRI patterns of parametrial tumour infiltration at the time of diagnosis were assessed with regard to predominant morphology and maximum extent of parametrial tumour infiltration and were stratified into five tumour groups (TG): 1) expansive with spiculae; 2) expansive with spiculae and infiltrating parts; 3) infiltrative into the inner third of the parametrial space (PM); 4) infiltrative into the middle third of the PM; and 5) infiltrative into the outer third of the PM. MRI at the time of brachytherapy was used for identifying presence (residual vs. no residual disease) and signal intensity (high vs. intermediate) of residual disease within the PM. Left and right PM of each patient were evaluated separately at both time points. The impact of the TG on tumour remission status within the PM was analysed using χ2-test and logistic regression analysis. Results. In total, 170 PM were analysed. The TG 1, 2, 3, 4, 5 were present in 12%, 11%, 35%, 25% and 12% of the cases, respectively. Five percent of the PM were tumour-free. Residual tumour in the PM was identified in 19%, 68%, 88%, 90% and 85% of the PM for the TG 1, 2, 3, 4, and 5, respectively. The TG 3-5 had significantly higher rates of residual tumour in the PM in comparison to TG 1 + 2 (88% vs. 43%, p < 0.01). Conclusion. MRI-morphologic features of PM infiltration appear to allow for prediction of tumour response during external beam radiotherapy and chemotherapy. A predominantly infiltrative tumour spread at the time of diagnosis resulted in a significantly higher rate of residual tumour in the PM at the time of brachytherapy in comparison to a predominantly expansive tumour spread. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: In general late side-effects after prostate cancer radiotherapy are presented by the use of actuarial incidence rates. The aim of this analysis was to describe additional relevant aspects of late side effects after prostate cancer radiotherapy. Materials and methods: All 178 primary prostate-cancer patients were treated within the Austrian–German multicenter trial by three-dimensional radiotherapy up to a local dose of 70Gy (low/intermediate-risk) or 74Gy (high-risk), respectively. Late gastrointestinal/urogenital (GI/GU) side-effects were prospectively assessed by the use of EORTC/RTOG score. Maximum side-effects, actuarial incidence rate and prevalence rates, initial appearance and duration of ⩾grade 2 toxicity were evaluated. Results: Median follow-up was 74months. Late GI/GU side-effects ⩾grade 2 were detected in 15% (27/178) and 22% (40/178). The corresponding 5-year actuarial incidence rates for GI/GU side-effects were 19% and 23%, whereas the prevalence was 1–2% and 2–7% after 5years, respectively. Late side effects ⩾grade 2 appeared within 5years after radiotherapy in all patients with GI side-effects (27/27) and in 85% (34/40) of the patients with GU side-effects, respectively and lasted for less than 3years in 90% (GI) and 98% (GU). Conclusions: This study demonstrates that the majority of late GI and GU side effects after primary external beam radiotherapy for prostate cancer are transient. Using only actuarial incidence rates for reporting side effects may lead to misinterpretation or overestimation. The combination of incidence and prevalence rates provides a more comprehensive view on the complex issue of late side effects. [Copyright &y& Elsevier]

Abstract: Purpose: It has been shown that a cumulative dose of ⩾87Gy (EQD2) of external beam radiotherapy (EBRT) and image guided adaptive brachytherapy (IGABT) to the high risk clinical target volume (HR CTV) confer a local control rate >95% in locally advanced cervical cancer. This study examines the dose distribution within the HR CTV and intermediate (IR) CTV in patients with cervical cancer treated with definitive EBRT +/− concomitant chemotherapy and MRI-based IGABT between patients with local recurrence (LR) and patients in continuous complete local remission (CCLR). Material and methods: From 1998 to 2010, 265 patients were treated with definitive EBRT +/− concomitant chemotherapy and IGABT. Twenty-four LRs were documented. For the statistical analysis all patients with LR were matched to patients in CCLR from our database according to the following criteria: FIGO stage, histology, lymph node status, tumour size and chemotherapy. DVH parameters (D50, D90, D98, D100) were reported for HR CTV and IR CTV. In order to report the minimum dose in the region where the recurrence occurred, the HR CTV/IR CTV were divided into four quadrants on transversal planes. The minimum dose at the HR CTV/IR CTV contour was measured (within the corresponding quadrant closest to the LR) in the treatment planning system. A mean minimum point dose (MPD) was calculated by averaging these measurements on four consecutive slices at the level of the recurrence for each of the 4 brachytherapy fractions. EQD2 doses were calculated by summation of all BT and external beam therapy fractions. For each matched patient in the control group the measurements were performed on the same quadrant and at the same level. Results: Sufficient image data were available for 21 LRs. Eight central failures and 13 non-central failures were observed. The mean D90 and D100 for HR CTV were 77Gy and 61Gy for patients with LR and 95Gy and 71Gy for patients in CCLR, respectively (p <0.01). The MPD for HR CTV was 72Gy for patients in the LR arm and 99Gy for patients in the CCLR arm (p <0.01). In the LR arm seven patients had a D90 for HR CTV ⩾87Gy, however, in only three patients the MPD was ⩾87Gy. Conclusion: This study demonstrated significant differences in local outcome according to the delivered dose. In 85% of the LRs systematic low dose regions with less than 87Gy were found at HR CTV contour. Systematic low dose regions leading to local recurrence could be detected even if a D90 HR CTV ⩾87Gy was applied. In addition to DVH parameters, inspection of the spatial dose distribution remains a key point in dose prescription. [Copyright &y& Elsevier]

Background. The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer 18F-fluoroazomycin-arabinoside (18FAZA ). Material and methods. Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm3 (+/− 67, SD). Dynamic and static 18FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/− concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. Results. Five patients had visually identifiable tumours on 18FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five 18FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten 18FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/−12, SD). Conclusion. PET imaging with 18FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of 18FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary vaginal cancer is a rare disease and, consequently, evidence about the outcome of treatment is scarce. The aim of our retrospective, observational multicenter study was to assess the oncological outcome of the nowadays standing treatment for vaginal cancer, namely radio(chemo)therapy, followed by image-guided adaptive brachytherapy (IGABT). Our study confirms the results of the earlier published small monocentric IGABT studies, showing a high local control with acceptable morbidity. Notably, patients with large (T3/T4) tumors especially seem to benefit from volumetric (3D) image-guided brachytherapy, as compared to two-dimensional-based radiotherapy. In addition, although interpreted with caution, as for cervical cancer, a higher dose seems to lead to better local control. These results should, however, be further investigated in a prospective trial. Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if >80 Gy EQD2α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Acinic cell carcinoma is a rare disease treated usually by surgery. The role of radiotherapy is controversially discussed. In this retrospective analysis based on 15 patients undergoing postoperative or definitive radiotherapy (intensity-modulated radiotherapy, IMRT) with carbon ion radiotherapy boost leads to excellent results after R1-resection, and is a promising treatment modality in inoperable patients. G1-2 xerostomia, dysgeusia, and trismus were the main reported morbidity symptoms after radiotherapy. Confirmation of the results with larger patient cohorts is needed. Aim: to report clinical outcome in patients with acinic cell carcinoma of the salivary glands treated with intensity-modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) boost. Materials and Methods: all patients with acinic cell carcinoma of the salivary glands treated at the Heidelberg Ion-Beam Therapy Center were considered for this retrospective analysis. All patients received a CIRT boost with 18–24 Gy radiobiologic effectiveness (RBE)-weighted dose in 3 Gy RBE-weighted dose per fraction followed by IMRT, with 50–54 Gy in 2 Gy per fraction. Disease outcome was evaluated for local (LR), nodal (NR), distant recurrence (DR), and disease-free (DFS) and overall survival (OS). Morbidity was scored based on Common Terminology Criteria for Adverse Events (CTCAE) version 5. Descriptive statistics and the Kaplan-Meier method were used for analysis. Results: fifteen patients were available for analysis. Median follow-up after radiotherapy was 43 months. Six patients were treated for primary disease and nine for recurrent disease. Eight patients were treated with radiotherapy for macroscopic disease. Disease recurrence was observed in four patients: 1 LR, 2 NR, and 2 DR; 5-year local control, DFS, and OS were 80%, 52%, and 80%, respectively. No radiotherapy-related G3-5 morbidity was observed. Conclusion: In acinic cell carcinoma, IMRT with carbon ion radiotherapy boost leads to excellent results after R1-resection and is a promising treatment modality for definitive treatment in inoperable patients. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to assess the use of mean, lowest, and highest pulsatility index (PI) of the uterine arteries to screen for adverse pregnany outcome in twin pregnancies. Study Design: This was a screening study of 423 twin pregnancies. Relationship between PI at 20-22 weeks and adverse pregnancy outcome was evaluated. Results: Mean, lowest, and highest PI above the 95th centile were significant risk factors for preeclampsia and adverse pregnancy outcome in monochorionic and dichorionic twins. We calculated a sensitivity for preeclampsia for mean, highest, and lowest PI of 35%, 29%, and 27%, respectively. Conclusion: Increased mean, lowest, and highest PI is associated with a higher risk of preeclampsia and adverse pregnancy outcome in twins. We observed the highest sensitivity and specificity by using highest PI. The high incidence of preeclampsia in twins makes it attractive to use the PI of the uterine artery for risk stratification in twins. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate patient-reported sexual outcomes after chemoradiation therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer in the observational, prospective, multicenter EMBRACE-I study.Methods and Materials: Sexual outcomes were assessed prospectively with the European Organization for Research and Treatment of Cancer Qualify of Life Questionnaire (EORTC-QLQ-CX24) at baseline and follow-up. Crude incidence and prevalence rates of sexual activity, vaginal functioning problems (dryness, shortening, tightening, pain during intercourse), and sexual enjoyment were evaluated. Associations between pain during intercourse and vaginal functioning problems or sexual enjoyment were calculated, pooling observations over all follow-ups (Spearman correlation coefficient). In patients who were frequently sexually active (≥50% of follow-ups), the effects of regular hormonal replacement therapy (HRT) on vaginal functioning problems were evaluated (Pearson χ2).Results: The analysis involved 1045 patients with a median follow-up of 50 months. Sexual activity was reported by 22% of patients at baseline and by 40% to 47% of patients during follow-up (prevalence rates). Vaginal functioning problems in follow-up were dryness (18%-21%), shortening (15%-22%), tightening (16%-22%), pain during intercourse (9%-21%), and compromised enjoyment (37%-47%). Pain during intercourse was significantly associated with vaginal tightening (r = 0.544), shortening (r = 0.532), and dryness (r = 0.408) and negatively correlated with sexual enjoyment (r = -0.407). Regular HRT was associated with significantly less vaginal dryness (P = .015), shortening (P = .024), pain during intercourse (P = .003), and borderline higher sexual enjoyment (P = .062).Conclusions: Vaginal functioning problems are associated with pain and compromised sexual enjoyment. Further effort is required for the primary prevention of vaginal morbidity with dose optimization and adaptation. Secondary prevention strategies, including HRT for vaginal and sexual health after radiation therapy in locally advanced cervical cancer, should be considered and sexual rehabilitation programs should be developed further. [ABSTRACT FROM AUTHOR]

• Urinary morbidity after treatment of locally advanced cervical cancer is prevalent. • Bladder dose constraints based on a high level clinical evidence are not available. • EMBRACE I provides prospective morbidity data for analysis in a large cohort. • Individual physician and patient reported urinary endpoints were analysed in EMBRACE I. • Bladder fistula, bleeding and cystitis showed dose–effect with bladder D 2cm3. To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3–120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D 2cm3 correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D 2cm3 resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis. Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose–effect was established with bladder D 2cm3 , reinforcing the importance of continued optimization during individualized IGABT planning. [ABSTRACT FROM AUTHOR]

• Urinary side effects after radiotherapy can rely on different bladder substructures. • EMBRACE I provides prospective morbidity data to study individual urinary symptoms. • Frequency and incontinence are frequent side effects in cervix cancer radiotherapy. • Limited clinical evidence supports the predictive value of ICRU Bladder point dose. • This analysis showed correlation of ICRU Bladder point dose with incontinence. To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups. Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D 2cm3. The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose. ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose–effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes. [ABSTRACT FROM AUTHOR]

• Local and pelvic control in FIGO 1994 stage IB were ≥95% with acceptable morbidity. • We found no isolated local relapse. Pelvic failure occurred in 3%. Most relapses were systemic. • Results of modern brachytherapy in early cervical cancer parallel those of modern surgery. Multiple treatment options are used in early local-stage cervical cancer, including combinations of surgery with neoadjuvant/adjuvant radiotherapy and chemotherapy. Our aim was to determine the outcome for definitive chemoradiation with image guided brachytherapy (IGBT). FIGO 1994 staging system was used in our study. We included 123 patients with stage IB cervical cancer, treated at 12 centers with external beam radiotherapy (EBRT) ± Chemotherapy and IGBT. Three- and 5-year actuarial local control (LC), pelvic control (PC), overall survival (OS), cancer-specific survival (CSS) and late morbidity (CTCAE v 3.0) were computed. Median age was 48 (23–82) years. FIGO 1994 stage distribution was: IB1 68% and IB2 32%; 41% of the entire cohort had nodal metastases and 73% squamous-cell carcinoma. MRI-based tumor size was >40 mm in 63%. Median EBRT dose was 45 (40–50) Gy; 84% received chemotherapy. At IGBT, mean CTV-HR D90 was 93 ± 17 Gy (EQD2 10). D2cc for bladder was 76 ± 14 Gy, rectum 66 ± 11 Gy, sigmoid 66 ± 10 Gy, bowel 67 ± 7 Gy (EQD2 3). At 43-months median follow-up, 9% of patients had systemic, 6% paraaortic, 3% pelvic-nodal and 2% local failure. Five-year LC was 98%, PC 96%, CSS 90%, OS 83%. Intestinal G3-–4 morbidity was 8%, urinary 7% and vaginal 0%. Chemoradiation with IGBT for FIGO 1994 stage IB cervical cancer leads to excellent loco-regional control with limited morbidity. In IB node-negative disease, it can be regarded equivalent to surgery in terms of oncologic outcome. In tumors with unfavorable pre-treatment characteristics, chemoradiation is the first choice to avoid combining surgery with adjuvant therapy. [ABSTRACT FROM AUTHOR]

• The survey results described in the manuscript captures the heterogeneity in the clinical practice of oligometastatic and oligorecurrent cervical cancer. • This survey will help to define the role of radiation therapy in oligometastatic and oligorecurrent cervical cancer. • This survey highlights the desire of radiation oncologists over the globe to practice stereotactic radiation therapy in oligometastatic disease and will help to plan future clinical trials. In the metastatic or recurrent cervical cancer, systemic chemotherapy constitutes the main treatment. Though there is an increasing use of high dose external radiation and brachytherapy in the metastatic setting, no consensus exists. A 17-item survey was designed with additional case-based questions to explore present management of oligo-metastatic and oligo-recurrent cervix cancer within EMBRACE research group participating sites. The questions were designed to elicit prevailing practices in the management of de-novo oligo-metastasis and oligo-recurrent setting after completing the primary treatment of cervix cancer. The survey was sent electronically with two rounds of email reminders to respond over a 2-week survey period. The online survey was designed such that it was mandatory to complete all questions. The responses were recorded and results were summarized as proportions and summary statistics were generated. Twenty-two centers responded to this survey. A majority (90%) of respondents reported a low incidence of de-novo oligo-metastatic cervical cancer in their practice (<5%), with a higher proportion of patients with oligo-recurrence after completing primary treatment (5–10%). All responding sites preferred to treat pelvic disease in the de-novo oligo-metastatic setting albeit with different fractionation regimens. While 68.2% of respondents recommended chemo-radiation and brachytherapy, 31.8% considered additional systemic therapy. Overall 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis. For out-of-field nodal recurrences, 63.7% of respondents considered treating with curative intent, while 59% preferred treating in-field recurrence with palliative intent. A vast majority of the participating centers (90%) have stereotactic radiation therapy capacity and would consider a clinical trial addressing oligo-metastatic and oligo-recurrent cervical cancer. Although contemporary practice is variable, a substantial proportion of EMBRACE centers consider high dose radiation in de-novo metastatic and oligo-recurrence settings. However, there is clear need for a joint clinical protocol and prospective studies to address the role of high dose radiation within oligo-recurrent and oligo-metastatic scenarios. [ABSTRACT FROM AUTHOR]

Cervical cancer, IGABT, Urinary morbidity, Risk factors, Dose-effect relationship, Clinical study. [Extracted from the article]

Abstract: Purpose: Aim of this analysis was to compare biochemical no evidence of disease (bNED) rates in intermediate-risk prostate-cancer patients treated at two centres of excellence using different approaches: permanent interstitial brachytherapy (BT) and external beam radiotherapy (EBRT). Materials and methods: A total of 890 intermediate-risk prostate-cancer patients, who were treated from 1998 to 2008, were identified in the two local databases. In Utrecht 601 patients received I-125 BT applying a dose of 144Gy. In Vienna 289 patients were treated by EBRT, applying a local dose of 70Gy in 105 patients and 74Gy in 184 patients. bNED-rates (Phoenix-definition) were assessed. Results: Median follow-up was 48months (1–150). 5-Year actuarial bNED-rates were 81% for BT-patients and 75% for EBRT-patients (67% for 70Gy and 82% for 74Gy), respectively. In univariate analysis no difference between BT and EBRT could be detected. In multivariate analysis including tumour-stage, GleasonScore, initial PSA, hormonal therapy and treatment-centre (BT vs. EBRT) only T-stage, GleasonScore and PSA were found to be significant. Additional analysis including radiation dose showed the same outcome. Conclusions: Intermediate-risk prostate cancer patients treated by permanent interstitial brachytherapy show biochemical tumour-control-rates which are comparable to EBRT of 74Gy. [Copyright &y& Elsevier]

Abstract: Background: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT). Methods: Treatment schedule was EBRT with 45–50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings: One hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D2cc 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2–5cm, and 92% for tumours >5cm (p =0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2–5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2–5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n =32/3, for rectum n =14/5, for bowel (including sigmoid) n =3/0, for vagina n =128/2, respectively. Interpretation: 3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings. [Copyright &y& Elsevier]