Initial needle tracking with the first standalone combined infrared camera - CT system for brachytherapy-analysis of tracking accuracy and uncertainties.

PURPOSE: A prototype infrared camera - cone-beam computed tomography (CBCT) system for tracking in brachytherapy has recently been developed. We evaluated for the first time the corresponding tracking accuracy and uncertainties, and implemented a tracking-based prediction of needles on CBCT scans. METHODS: A marker tool rigidly attached to needles was 3D printed. The precision and accuracy of tool tracking was then evaluated for both static and dynamic scenarios. Euclidean distances between the tracked and CBCT-derived markers were assessed as well. To implement needle tracking, ground truth models of the tool attached to 200 mm and 160 mm needles were matched to the tracked positions in order to project the needles into CBCT scans. Deviations between projected and actual needle tips were measured. Finally, we put our results into perspective with simulations of the system's tracking uncertainties. RESULTS: For the stationary scenario and dynamic movements, we achieved tool-tracking precision and accuracy of 0.04 ± 0.06 mm and 0.16 ± 0.18 mm, respectively. The tracked marker positions differed by 0.52 ± 0.18 mm from the positions determined via CBCT. In addition, the predicted needle tips in air deviated from the actual tip positions by only 1.62 ± 0.68 mm (200 mm needle) and 1.49 ± 0.62 mm (160 mm needle). The simulated tracking uncertainties resulted in tip variations of 1.58 ± 0.91 mm and 1.31 ± 0.69 mm for the 200 mm and 160 mm needles, respectively. CONCLUSION: With the innovative system it was possible to achieve a high tracking and prediction accuracy of marker tool and needles. The system shows high potential for applicator tracking in brachytherapy.

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. METHODS: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. RESULTS: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. CONCLUSION: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.

C1-C2 posterior screw fixation in atlantoaxial fractures revisited: technical update based on 127 cases.

INTRODUCTION: Posterior fusion of traumatic odontoid fractures by C1 lateral mass and C2 isthmic screws (modified Harms-Goel technique) is a viable alternative to transarticular screw fixation due to its universal applicability. This retrospective study reports on a series of 127 patients. MATERIAL AND METHODS: Our clinical database was screened for patients with fractures of the upper cervical spine incorporating a C2 fracture, operated on between 2007 and 2015. Patients were included if fused by internal fixation via C1 lateral mass screws, C2 isthmic screws in freehand technique under lateral fluoroscopy. Screw placement was controlled postoperatively by computed tomography and rated using the Gertzbein & Robbins classification. Surgery-related complications, consecutive treatment, revision surgeries and duration of surgeries were registered. RESULTS: In total, 127 patients were identified with altogether 572 screws. Correct screw positions of grade A and B according to Gertzbein & Robbins were achieved in a total of 539 (94.2%) screws (grade A: 453 (79.2%); grade B: 86 (15%)), grade C screw malpositions noted in 21 (3.7%), grade D in 10 (1.7%) and grade E in 2 (0.3%) screws. Vertebral artery canal breaches occurred in 29 screws (5.1%), with vertebral artery occlusion in 4 patients. Coiling of injured vertebral artery had to be performed in one patient. None of these patients suffered clinically apparent cerebrovascular complications. Revision surgery was performed in 8 patients (6%). CONCLUSION: Posterior fixation of atlantoaxial fractures by C1 lateral mass and C2 isthmic screws with fluoroscopy without navigation is a safe and feasible method but not free of risk of vertebral artery injuries. These slides can be retrieved under Electronic Supplementary Material.

Inter-observer effects in needle reconstruction for temporary prostate brachytherapy: Dosimetric implications and adaptive CBCT-TRUS registration solutions.

PURPOSE: To investigate geometric and dosimetric inter-observer variability in needle reconstruction for temporary prostate brachytherapy. To assess the potential of registrations between transrectal ultrasound (TRUS) and cone-beam computed tomography (CBCT) to support implant reconstructions. METHODS AND MATERIALS: The needles implanted in 28 patients were reconstructed on TRUS by three physicists. Corresponding geometric deviations and associated dosimetric variations to prostate and organs at risk (urethra, bladder, rectum) were analyzed. To account for the found inter-observer variability, various approaches (template-based, probe-based, marker-based) for registrations of CBCT to TRUS were investigated regarding the respective needle transfer accuracy in a phantom study. Three patient cases were examined to assess registration accuracy in-vivo. RESULTS: Geometric inter-observer deviations >1 mm and >3 mm were found for 34.9% and 3.5% of all needles, respectively. Prostate dose coverage (changes up to 7.2%) and urethra dose (partly exceeding given dose constraints) were most affected by associated dosimetric changes. Marker-based and probe-based registrations resulted in the phantom study in high mean needle transfer accuracies of 0.73 mm and 0.12 mm, respectively. In the patient cases, the marker-based approach was the superior technique for CBCT-TRUS fusions. CONCLUSION: Inter-observer variability in needle reconstruction can substantially affect dosimetry for individual patients. Especially marker-based CBCT-TRUS registrations can help to ensure accurate reconstructions for improved treatment planning.

Seed-displacements in the immediate post-implant phase in permanent prostate brachytherapy.

PURPOSE: To investigate differences in seed-displacements between the immediate post-implant phase (day 0-1) and the time to post-plan computed tomography (CT) (day 1-30) in seed prostate brachytherapy. MATERIALS AND METHODS: Seed positions were identified on the intra-operatively created ultrasound-based treatment plan (day 0) and CT scans of day 1 and 30 for 33 patients. The day 1 (30) seed arrangement was registered onto the day 0 (1) arrangement using a seed-only approach. Based on a 1:1 assignment of seeds via the Kuhn-Munkres algorithm, seed-displacements were analyzed. Displacements were evaluated depending on strand-length and anatomical implant location. Resulting dosimetric effects were calculated. RESULTS: Seed-displacements in the immediate post-implant phase (median displacements: 3.8 ± 3.6 mm) were stronger than in the time to post-plan CT (2.1 ± 2.6 mm) and enhanced along the superior-inferior direction. From day 0 to 1, strands containing one (7.3 ± 5.4 mm) or two (8.1 ± 5.8 mm) seeds showed larger displacements than strands of higher lengths (up to 4.2 ± 7.0 mm), whereas no length-dependency was found to day 30. Seeds implanted in base and apex tended to move towards the prostate midzone during both time periods. D90 (dose that 90% of prostate receives) was with variations of 2 ± 15 Gy more stable from day 1 to 30 than in the immediate post-implant phase (-18 ± 11 Gy). CONCLUSION: Seed-displacements in the immediate post-implant phase was enhanced compared to day 1-30. This may result from uncertainties in the gold-standard ultrasound-based treatment planning and implantation. Adaptive implantation workflows appear useful for ensuring high implant stability from the beginning.

Impact of COVID-19 on Quality of Life in Long-Term Advanced Rectal Cancer Survivors.

Colorectal cancer remains one of the most commonly diagnosed cancers. Advanced rectal cancer patients receive neoadjuvant radiochemotherapy as well as surgery and suffer from reduced health-related quality of life due to various side effects. We were interested in the role of the COVID-19 pandemic and how it affected those patients' quality of life. A total of 489 advanced rectal cancer patients from the University Hospital Erlangen in Germany were surveyed between May 2010 and March 2022 and asked to fill out the EORTC QLQ-C30 and QLQ-CR38 questionnaires over eight different time points: at the beginning, during and after radiochemotherapy, right before surgery, and in yearly intervals after surgery for up to four years. Answers were converted to scores to compare the COVID-19 period to the time before March 2020, focusing on the follow-ups, the developments over time-including by sex and age-and the influence of the TNM cT-stage. Overall, a trend of impaired functional and symptom scores was found across all surveys with few significances (body image -10.6 percentage points (pp) after one year; defecation problems +13.5 pp, insomnia +10.2 pp and weight loss +9.8 pp after three years; defecation problems +11.3 pp after four years). cT4-stage patients lost significantly more weight than their cT1-3-stage counterparts (+10.7 to 13.7 pp). Further studies should be conducted to find possible causes and develop countermeasures for future major infectious diseases.

External-Beam-Accelerated Partial-Breast Irradiation Reduces Organ-at-Risk Doses Compared to Whole-Breast Irradiation after Breast-Conserving Surgery.

In order to evaluate organ-at-risk (OAR) doses in external-beam-accelerated partial-breast irradiation (APBI) compared to standard whole-breast irradiation (WBI) after breast-conserving surgery. Between 2011 and 2021, 170 patients with early breast cancer received APBI within a prospective institutional single-arm trial. The prescribed dose to the planning treatment volume was 38 Gy in 10 fractions on 10 consecutive working days. OAR doses for the contralateral breast, the ipsilateral, contralateral, and whole lung, the whole heart, left ventricle (LV), and the left anterior descending coronary artery (LAD), and for the spinal cord and the skin were assessed and compared to a control group with real-world data from 116 patients who underwent WBI. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Compared to WBI, APBI led to reduced OAR doses for the contralateral breast (0.4 ± 0.6 vs. 0.8 ± 0.9 Gy, p = 0.000), the ipsilateral (4.3 ± 1.4 vs. 9.2 ± 2.5 Gy, p = 0.000) and whole mean lung dose (2.5 ± 0.8 vs. 4.9 ± 1.5 Gy, p = 0.000), the mean heart dose (1.6 ± 1.6 vs. 1.7 ± 1.4 Gy, p = 0.007), the LV V23 (0.1 ± 0.4 vs. 1.4 ± 2.6%, p < 0.001), the mean LAD dose (2.5 ± 3.4 vs. 4.8 ± 5.5 Gy, p < 0.001), the maximum spinal cord dose (1.5 ± 1.1 vs. 4.5 ± 5.7 Gy, p = 0.016), and the maximum skin dose (39.6 ± 1.8 vs. 49.1 ± 5.8 Gy, p = 0.000). APBI should be recommended to suitable patients to minimize the risk of secondary tumor induction and the incidence of consecutive major cardiac events.

Substantial Impairment of Quality of Life during COVID-19 Pandemic in Patients with Advanced Rectal Cancer.

The aim of this study was to analyze the quality of life of patients with advanced rectal cancer before and during the COVID-19 pandemic and to determine whether the pandemic affected patients' quality of life. The study included 389 patients and was performed from May 2010 to June 2021. The fifteen months from March 2020 to June 2021 were categorized as the COVID-19 period. Patients were surveyed using the QLQ-C30 and QLQ-CR38 questionnaires. The questionnaires were used at different phases of radiochemotherapy: prior to RCT (day 1), during RCT (day 14), at the end of RCT (day 35), and prior to mesorectal surgery (day 70). Scores were formed from the questions. In addition, scores were analyzed for different age groups (<64 and >64) and sexes (female and male). Overall, patients reported lower functional scores and higher symptom scores during the pandemic than before the pandemic. Although it had been expected that older and younger patients would differ clearly, there were only minor differences. The comparison between the two sexes showed very different scores, with female patients having lower functional scores and higher symptom scores than male patients before and especially during COVID-19. In conclusion, age does not play a major role in quality of life, but sex does play an important role in perception of functioning and symptoms. COVID-19 also had a major impact on patients' lives, as it was a very isolating and stressful time for everyone, especially cancer patients, which was reflected in worsening scores.

External Beam Accelerated Partial Breast Irradiation in Early Breast Cancer and the Risk for Radiogenic Pneumonitis.

In order to evaluate the risk for radiation-associated symptomatic pneumonitis in a prospective external beam accelerated partial breast irradiation (APBI) trial, between 2011 and 2021, 170 patients with early stage breast cancer were enclosed in the trial. Patients were eligible for study participation if they had a histologically confirmed breast cancer or an exclusive ductal carcinoma in situ (DCIS), a tumor size ≤3 cm, free safety margins ≥2 mm, no involved axillary lymph nodes, tumor bed clips, and were ≥50 years old. Patients received APBI with 38 Gy with 10 fractions in 10 consecutive working days. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Median follow-up was 56 (1−129) months. Ipsilateral lung MLD, V20, and V30 were 4.3 ± 1.4 Gy, 3.0 ± 2.0%, and 1.0 ± 1.0%, respectively. Radiogenic pneumonitis grade 2 appeared in 1/170 (0.6%) patients two months after radiotherapy. Ipsilateral MLD, V20, and V30 were 6.1 Gy, 7, and 3% in this patient. Additionally, individual radiosensitivity was increased in this specific patient. Compared to WBI, APBI leads to lower lung doses. Using APBI, the risk of symptomatic radiogenic pneumonitis is very low and may be limited, with an ipsilateral V20 < 3% to very exceptional cases associated with innate risk factors with an increased radiation susceptibility.

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors.

BACKGROUND: The predictive power of novel biological markers for treatment response to immune checkpoint inhibitors (ICI) is still not satisfactory for the majority of patients with cancer. One should identify valid predictive markers in the peripheral blood, as this is easily available before and during treatment. The current interim analysis of patients of the ST-ICI cohort therefore focuses on the development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with metastatic cancer to ICI targeting the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. METHODS: A total of 104 patients were prospectively enrolled. 54 immune cell subsets were prospectively analyzed in patients' peripheral blood by multicolor flow cytometry before treatment with ICI (pre-ICI; n=89), and after the first application of ICI (n=65). Pre-ICI, patients were randomly allocated to a training (n=56) and a validation cohort (n=33). Univariate Cox proportional hazards regression analysis and least absolute shrinkage and selection operator Cox model were used to create a predictive immune signature, which was also checked after the first ICI, to consider the dynamics of changes in the immune status. RESULTS: Whole blood samples were provided by 89 patients pre-ICI and by 65 patients after the first ICI. We identified a LIPS which is based on five immune cell subtypes: CD14high monocytes, CD8+/PD-1+ T cells, plasmacytoid dendritic cells, neutrophils, and CD3+/CD56+/CD16+ natural killer (NK)T cells. The signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting overall survival (OS) benefit in both the training and the validation cohort. In both cohorts, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI 0.12 to 0.56, p=0.00025; HR 0.30, 95% CI 0.10 to 0.91, p=0.024, respectively). Regarding the whole cohort, LIPS also predicted progression-free survival (PFS). The identified LIPS was not affected by clinicopathological features with the exception of brain metastases. NKT cells and neutrophils of the LIPS can be used as dynamic predictive biomarkers for OS and PFS after first administration of the ICI. CONCLUSION: Our study identified a predictive LIPS for survival of patients with cancer treated with PD-1/PD-L1 ICI, which is based on immune cell subsets in the peripheral whole blood. TRIAL REGISTRATION NUMBER: NCT03453892.

Prospective Evaluation of All-lesion Versus Single-lesion Radiotherapy in Combination With PD-1/PD-L1 Immune Checkpoint Inhibitors.

BACKGROUND: Local ablative treatments improve survival in patients with oligometastatic disease in addition to chemotherapy. The application of immune checkpoint inhibitors prolonged patients' survival in different tumor entities. This raises the question if patients still benefit from intensified local treatments in combination with a more efficient systemic treatment with immune checkpoint inhibitors. METHODS: The prospective non-interventional ST-ICI trial investigates treatment with PD-1/PD-L1 (Programmed cell death protein 1/Programmed cell death 1 ligand 1) immune checkpoint inhibitors and radiotherapy in different tumor entities. Patients who started radiotherapy and immunotherapy concomitantly were included in this interim analysis. In this cohort patients with all-lesion radiotherapy (all tumor lesions irradiated, al-RT) were compared to patients with radiotherapy to only a single of their tumor lesions (single-lesion radiotherapy, sl-RT). Endpoints of the interim analysis were progression-free survival (PFS), overall survival (OS) and time to progression (TTP). RESULTS: A total of 104 patients were registered between April 2017 and August 2019. Fifty patients started immune checkpoint inhibitor treatment and radiotherapy concomitantly and were included. Most frequent tumor entities were non-small cell lung cancer (62%) followed by head and neck squamous cell cancer (26%). Most frequent location of radiotherapy was lung (34%) and central nervous system (20%). Median duration of follow-up was 8.6 months beginning with first administration of the immune-checkpoint-inhibitor. Median PFS was 9.2 months (95% CI, 5.8 - 12.6) in the al-RT group and 3.0 months (95% CI, 2.5 - 3.5) in the sl-RT group (p<0.001). Median OS was 11.6 months (95% CI, 8.1 - 15.1) in the al-RT group and 4.2 months (95% CI, 3.0 - 5.4) in the sl-RT group (p=0.007). Median TTP was not reached in the al-RT group compared to 4.6 months (95% CI, 1.1-8.0) in the sl-RT group (p=0.028). Univariate Cox regression analyses computed tumor entity, histology, central nervous system metastases, immunotherapy drug and al-RT as predictors of OS (with an effect p-value of ≤ 0.1). In the multivariable analysis only tumor entity and al-RT remained prognostic factors for OS. CONCLUSION: Patients with PD-1/PD-L1 immune checkpoint inhibitor therapy benefit from local radiotherapy to all known lesions compared to single-lesion radiotherapy regarding PFS and OS.

Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy.

BACKGROUND: Prospective data about the prognostic value of immune-related adverse events (irAEs) in non-melanoma solid tumours are rare. The prognostic value of irAEs in patients treated with combined radiotherapy and immunotherapy is currently unknown. PATIENTS AND METHODS: The prospective non-interventional ST-ICI trial investigates treatment response of tumour patients to anti-programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors alone and in combination with radiotherapy and possible predictive markers. Patients undergoing immunotherapy or immunoradiotherapy were surveyed for irAEs. RESULTS: A total of 104 patients were included of whom 29 patients (28%) developed irAEs. Additional radiotherapy was performed in 50 patients (48%). Main tumour entities within the entire cohort were non-small cell lung cancer (NSCLC) (44%) and head and neck squamous cell carcinoma (42%). The rate of irAEs did not differ in patients with and without radiotherapy (p = 0.668). Patients who developed irAEs had longer overall survival (OS) (median: 22.8 months versus 9.0 months without irAEs, p = 0.001) and progression-free survival (PFS) (median: 7.8 months versus 3.2 months without irAEs, p = 0.002). In the subgroup with combined radiotherapy, patients with irAEs also had longer OS (median: 22.8 months versus 7.1 months without irAEs, p = 0.005) and PFS (median: 8.8 months versus 3.0 months without irAEs, p = 0.005). On multivariate analysis only PD-L1 on tumour cells (p = 0.049) and irAEs (p = 0.001) remained independent predictors of OS. CONCLUSION: The development of irAEs represents a favourable prognostic parameter in patients undergoing immunotherapy and immunoradiotherapy for solid tumours.

Osteoporosis Is the Most Important Risk Factor for Odontoid Fractures in the Elderly.

Traumatic odontoid fractures (TOFs) have been described as the most common injury affecting the C-spine in the elderly. Previous studies have identified degenerative changes and bone loss as important predisposing factors. However, their interaction and respective age-adjusted impact needs further clarification. We conducted a retrospective analysis of 5303 patients (aged ≥60 years) admitted to a level I trauma center between January 2008 and January 2016 who underwent CT imaging of the C-spine. Ninety-two patients with TOF and 80 patients with other cervical spine fractures (OCSF) were identified and a respective 3:1 age- and sex-matched control group without fractures after trauma was built. In all groups, cervical bone mineral density (cBMD) was determined using phantom calibration, and degenerative changes were evaluated in a qualitative manner. In all groups, the severity of degenerative changes of the C-spine increased with age (all p < 0.05) and was inversely correlated with cBMD (all p < 0.05). cBMD was the only significant predictor of a TOF in a multivariate logistic regression model (adjusted odds ratio [OR] = 3.066, 95% confidence interval [CI] 1.432-6.563 for cervical osteoporosis). An association between odontoid cysts and TOF reached significance only in Anderson and D'Alonzo (A&D) type II TOFs (aOR = 1.383; 95% CI 1.012-1.890). Patients with OCSFs, compared with patients with TOFs, were younger (median 74 versus 83 years) and had a higher cBMD (median 208 mg/mL versus 172 mg/mL). No differences were observable when comparing cBMD and grades of degenerative changes between OCSFs and their control group (all p >0.1). Decreased cBMD is the major predisposing factor for the occurrence of TOF but not for OCSF in the elderly. The severity of odontoid cysts was found to be a cBMD-independent factor associated with A&D type II TOFs. However, degenerative changes in the odontoid neighboring joints seem to be an epiphenomenon of bone loss and older age but do not independently predispose for TOF. © 2017 American Society for Bone and Mineral Research.

[Turkey fattening under extensive rearing conditions--selected parameters concerning health, performance and behavior]. / Putenmast unter extensiven Haltungsbedingungen--Ausgewählte Parameter hinsichtlich Gesundheit, Leistung und Verhalten.

Within two consecutive studies (study I and study II), each involving a summer (su) and a winter mast (wi), 36 male turkeys per B.U.T. Big 6 (BUT) and Kelly Bronze (KB) origin were set on two seperated areas in free range and fatted over a period of 20 (winter mast in study II) and 22 weeks respectively. Aim of both studies was to analyze the effects of extensive rearing conditions on these two turkey origins concerning health, performance and behavior and whether seasonal climatic differences had any additional influence. Besides the aim in study II was to detect how intensely environmental enrichment (plateau and perches) was accepted by the turkeys and if co-housing of BUT and KB turkeys was possible. The occurence of skin lesions in the breast area (breast blisters and/or breast buttons) was significantly influenced by season (su > wi) and origin (BUT > KB). Malposition of the hind extremities was found significantly more often in the BUT origin, whereas the X-leg position was the most common observed leg abnormality. The mortality rate remained beneath 6% during three of the four fattening periods. Due to their genetical determination, the BUT constantly gained higher weights than the KB (wi > su).The intensity of acceptance of the structural elements was influenced by season (su > wi), forage (ecological > commercial) and time of day (night > day).The results of the studies lead to the conclusion that turkeys of the BUT origin can certainly be fattened under extensive rearing conditions alongside the KB origin, while providing good performance.