Acute and Long-Term Toxicity after Planned Intraoperative Boost and Whole Breast Irradiation in High-Risk Patients with Breast Cancer-Results from the Targeted Intraoperative Radiotherapy Boost Quality Registry (TARGIT BQR).

In the context of breast cancer treatment optimization, this study prospectively examines the feasibility and outcomes of utilizing intraoperative radiotherapy (IORT) as a boost in combination with standard external beam radiotherapy (EBRT) for high-risk patients. Different guidelines recommend such a tumor bed boost in addition to whole breast irradiation with EBRT for patients with risk factors for local breast cancer recurrence. The TARGIT BQR (NCT01440010) is a prospective, multicenter registry study aimed at ensuring the quality of clinical outcomes. It provides, for the first time, data from a large cohort with a detailed assessment of acute and long-term toxicity following an IORT boost using low-energy X-rays. Inclusion criteria encompassed tumors up to 3.5 cm in size and preoperative indications for a boost. The IORT boost, administered immediately after tumor resection, delivered a single dose of 20 Gy. EBRT and systemic therapy adhered to local tumor board recommendations. Follow-up for toxicity assessment (LENT SOMA criteria: fibrosis, teleangiectasia, retraction, pain, breast edema, lymphedema, hyperpigmentation, ulceration) took place before surgery, 6 weeks to 90 days after EBRT, 6 months after IORT, and then annually using standardized case report forms (CRFs). Between 2011 and 2020, 1133 patients from 10 centers were preoperatively enrolled. The planned IORT boost was conducted in 90%, and EBRT in 97% of cases. Median follow-up was 32 months (range 1-120, 20.4% dropped out), with a median age of 61 years (range 30-90). No acute grade 3 or 4 toxicities were observed. Acute side effects included erythema grade 1 or 2 in 4.4%, palpable seroma in 9.1%, punctured seroma in 0.3%, and wound healing disorders in 2.1%. Overall, chronic teleangiectasia of any grade occurred in 16.2%, fibrosis grade ≥ 2 in 14.3%, pain grade ≥ 2 in 3.4%, and hyperpigmentation in 1.1%. In conclusion, a tumor bed boost through IORT using low-energy X-rays is a swift and feasible method that demonstrates low rates in terms of acute or long-term toxicity profiles in combination with whole breast irradiation.

Longitudinal cosmetic outcome after planned IORT boost with low kV X-rays-monocentric results from the TARGIT BQR registry.

Background: Intraoperative radiotherapy can serve as an anticipated boost (IORT boost) in combination with a subsequent external whole breast irradiation in high-risk breast cancer patients and is part of many guidelines. Nevertheless, there are only few prospective data available regarding cosmetic outcome after IORT boost using kV X-rays. The aim of this study was to evaluate the cosmetic outcome of patients treated within the prospective phase IV TARGeted Intraoperative radioTherapy (TARGIT) Boost Quality Registry (BQR) study (NCT01440010) in one center. Methods: In the context of the TARGIT BQR study standardized photos in three positions (arms down, arms up, from the side) were available for different time points. For this analysis a layperson, a radiation oncologist and a gynecologist evaluated available photos at different time points during follow-up with up to 4 years using the Harvard scale (comparison of treated and the untreated breast; rating: excellent, good, fair, poor). Longitudinal results were compared to preoperative results (baseline). Results: Seventy-three patients were available for the analysis. Baseline cosmetic assessment was excellent/good in 98.8% (mean value for all three positions). Postoperative cosmetic outcome (median) was good for all positions and remained constant for 4 years. Around 30% of the patients showed a constant or even improved cosmetic outcome compared to baseline. Only few patients showed a poor result at 4 years. The majority of patients showed an excellent or good cosmetic outcome at all time points. Conclusions: Patients from the prospective TARGIT BQR study treated with IORT boost and additional whole breast irradiation showed good or excellent cosmetic outcomes in most cases during 4 years of follow-up. These results add important information for shared decision making in breast cancer patients.

Prospective Comparison of Hypofractionated Versus Normofractionated Intensity-Modulated Radiotherapy in Breast Cancer: Late Toxicity Results of the Non-Inferiority KOSIMA Trial (ARO2010-3).

Purpose: To compare the late toxicity profile of hypofractionation and normofractionation for whole-breast radiotherapy in breast cancer (BC) patients after conserving surgery. Methods: Sixty-year-old or older patients with pTis-pT3, pN0-pN1a, M0 BC were recruited and stratified to hypofractionated (arm R-HF) or normofractionated (arm L-NF) intensity-modulated radiotherapy (IMRT), for right- and left-sided BC, respectively, in this single-center, non-randomized, non-inferiority trial. A boost was allowed if indicated. The primary outcome was the cumulative percentage of patients developing grade III fibrosis, grade I telangiectasia, and/or grade II hyperpigmentation after 2 years, with a pre-specified non-inferiority margin of 15% increase from an expected 2-year toxicity rate of 20%. Results: The Median follow-up was 4.93 (0.57-8.65) years for R-HF and 5.02 (0.65-8.72) years for L-NF (p=0.236). The median age was 68 (60-83 and 60-80) years, respectively. In total, 226 patients were recruited (107 for R-HF and 119 for L-NF), with 100 and 117 patients suitable for assessment, respectively. A boost was delivered in 51% and 53% of each arm, respectively. Median PTV volumes were 1013.6 (273-2805) cm3 (R-HF) and 1058.28 (315-2709) cm3 (L-NF, p=0.591). The 2-year primary endpoint rate was 6.1% (95% CI 1.3-11.7, n=5 of 82) and 13.3% (95% CI 7-20.2, n=14 of 105), respectively (absolute difference -7.2%, one-sided 95% CI ∞ to -0.26, favoring R-HF). No local recurrence-free- or overall-survival differences were found. Conclusion: In this prospective non-randomized study, hypofractionation did not have higher toxicity than normofractionated whole-breast IMRT.

Long-Term Outcomes of an International Cooperative Study of Intraoperative Radiotherapy Upfront Boost With Low Energy X-Rays in Breast Cancer.

Purpose: The purpose of this study was to assess the effectivity of upfront kilovoltage intraoperative radiotherapy (IORT) as a boost in high-risk early-stage breast cancer patients from an international pooled cohort. Materials/Methods: Patients from four centers in three different countries were retrospectively screened. Those with a minimum 1-year follow-up were included. Cumulative local (LR), regional (RR), and distant metastasis rates (DM) were analyzed. Additionally, the estimated overall survival (OS) was assessed. The Cox regression analysis was performed to identify failure predicting factors. Results: A total of 653 patients from centers in Peru, Spain, and Germany were included. The median follow-up was 55 (12-180) months, and age was 58 (27-86) years. Clinical tumor (T) staging was T1 65.85%, T2 30.17%, and T3 3.98%. Positive margins were found in 7.9% and in-situ component in 20.06%. The median IORT dose was 20 (6-20). The median time from IORT to EBRT was 74.5 (13-364) days. An overall 3.4% (n = 22) of patients developed local recurrence at some point during follow-up. The 12-, 60-, and 120-month cumulative LR were 0.3%, 2.3%, and 7.9%, respectively. After multivariate analysis, only age <50 remained to be a significant prognostic factor for local recurrence (HR 0.19, 95% CI 0.08-0.47; p < 0.05). The 10-year estimated OS was 81.2%. Conclusion: Upfront boost with IORT yields similar local control outcomes to those EBRT-based reports. Results from prospective trials, regarding toxicity, cosmesis, and effectivity are awaited to confirm these findings.

Radiotherapy and newly approved cancer drugs - A quantitative analysis of registered protocols for drugs approved for the treatment of solid tumors.

BACKGROUND/PURPOSE: To evaluate the usage of RT in trial protocols for anti-cancer drugs approved by the US Food and Drug Administration (FDA). METHODS: Drugs which had been granted an FDA approval between 2010 and 2017 for the treatment of solid tumors in adults were identified. Use of RT in relation to each drug's approval date was reviewed on ClinicalTrials.gov. RESULTS: Out of 42 drugs, none was initially approved for an indication which mandates RT. One drug (2.4%) has a post-approval label extension for sequential usage after RT. 5846 records were screened, exclusion of non-cancer trials and duplicates resulted in 4254 protocols out of which 2919 were industry-sponsored (68.6%). RT was tested in 350 (8.2%) studies. Out of 75 drug/RT trials which were initiated prior to approval, fourteen had not yet started recruitment, 45 were recruiting, one was completed, one prematurely terminated and fourteen fully-recruited but ongoing at approval time. Out of the fully-recruited or completed studies, results from four studies on three drugs were already published. In 52.4% of drugs, no patient had been treated with a drug/RT combination at the approval date. Drug/RT studies were less likely industry-sponsored (p < 0.001) and more likely initiated post-approval (p < 0.001) compared to drug-only trials. Despite this imbalance, pre-approval drug/RT trials were still mostly industry-sponsored (65.3%). CONCLUSION: No drug/RT data were publicly available in over 90% of newly approved anti-cancer drugs. These results indicate that clinicians must rely on postmarketing surveillance to identify drug/RT interactions as data from trials are unavailable at approval.

Molecular features of glioblastomas in long-term survivors compared to short-term survivors-a matched-pair analysis.

BACKGROUND: Although glioblastoma (GB) is associated with a devastating prognosis, a small proportion of patients achieve long-term survival rates. We herein present a matched-pair analysis of molecular factors found in long- and short-term survivors (LTS, STS). METHODS: We performed a cross-institutional analysis of 262 patient records and matched a group of 91 LTS (≥ 3 years) with two groups of STS (STS-1, n = 91; STS-2, n = 80). Matching was performed according to age, Karnofsky Performance Status, initial therapy and adjuvant therapy. Molecular factors were compared between LTS (total of 91 patients) v. STS-1, and LTS (subgroup of 80 patients) v. STS-2. We included glial fibrillary acidic protein (GFAP), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase 1 (IDH-1); furthermore, the proliferation index was analyzed (Ki-67/MIB-1). RESULTS: IDH-1 and decreased Ki-67 were numerically associated with LTS but the difference was only significant compared to STS-1 (n.s. v. STS-2). LTS was associated with MGMT promoter hypermethylation (p = 0.013 and p = 0.022) and GFAP expression (p < 0.001 and p = 0.001). Positivity for both factors combined compared to negativity for one factor occurred more often in the LTS group (p = 0.002 and p = 0.006); negativity for both factors combined did not occur in the LTS group. CONCLUSION: In this retrospective analysis, GFAP expression and MGMT promoter methylation were associated with LTS. Given the hypothesis-generating nature of our study, these observations should be confirmed in prospective clinical trials.

Dosimetric benefits of daily treatment plan adaptation for prostate cancer stereotactic body radiotherapy.

BACKGROUND: Hypofractionation is increasingly being applied in radiotherapy for prostate cancer, requiring higher accuracy of daily treatment deliveries than in conventional image-guided radiotherapy (IGRT). Different adaptive radiotherapy (ART) strategies were evaluated with regard to dosimetric benefits. METHODS: Treatments plans for 32 patients were retrospectively generated and analyzed according to the PACE-C trial treatment scheme (40 Gy in 5 fractions). Using a previously trained cycle-generative adversarial network algorithm, synthetic CT (sCT) were generated out of five daily cone-beam CT. Dose calculation on sCT was performed for four different adaptation approaches: IGRT without adaptation, adaptation via segment aperture morphing (SAM) and segment weight optimization (ART1) or additional shape optimization (ART2) as well as a full re-optimization (ART3). Dose distributions were evaluated regarding dose-volume parameters and a penalty score. RESULTS: Compared to the IGRT approach, the ART1, ART2 and ART3 approaches substantially reduced the V37Gy(bladder) and V36Gy(rectum) from a mean of 7.4cm3 and 2.0cm3 to (5.9cm3, 6.1cm3, 5.2cm3) as well as to (1.4cm3, 1.4cm3, 1.0cm3), respectively. Plan adaptation required on average 2.6 min for the ART1 approach and yielded doses to the rectum being insignificantly different from the ART2 approach. Based on an accumulation over the total patient collective, a penalty score revealed dosimetric violations reduced by 79.2%, 75.7% and 93.2% through adaptation. CONCLUSION: Treatment plan adaptation was demonstrated to adequately restore relevant dose criteria on a daily basis. While for SAM adaptation approaches dosimetric benefits were realized through ensuring sufficient target coverage, a full re-optimization mainly improved OAR sparing which helps to guide the decision of when to apply which adaptation strategy.

[Subjective well-being and ability to work of hospital staff after SARS-CoV2 immunization with the mRNA vaccine BNT162b2]. / Subjektives Wohlbefinden und Arbeitsfähigkeit von Krankenhauspersonal nach SARS-CoV-2-Immunisierung mit dem mRNS-Impfstoff BNT162b2 ­ Ergebnisse einer anonymen Umfrage.

BACKGROUND: Since December 27, 2020, employees of the health system in Germany have been vaccinated against the SARS coronavirus-2 with the vaccine BNT162B2. Initial observations show that especially among younger vaccinated people side effects are common. In this study, using the example of clinic employees, the self-perceived well-being after the first and second dose of the vaccine was examined. METHODS: Anonymized online questionnaire to be filled out once by all employees after the second dose of BNT162B2 was offered. The severity of side effects was queried using an ordinal numerical rating scale with values between 0 and 10. Other key data points were age, gender, and occupational group. The ability to work in the days following the injections was recorded by self-reporting. RESULTS: Data from 555 respondents were evaluated. The mean age was 40.25 years (standard deviation 12.35). 56 % of the respondents were female, 44.3 % belonged to the medical service, 42.9 % to the nursing service and 12.8 % were assigned to other professional groups with COVID-19 patient contact. Around 2 % of all employees did not experience any side effects at all. The most common side effect was pain at the injection site. Fatigue, headaches and myalgia followed with decreasing frequency. After the first dose, ¾ of the respondents said they had tolerated the vaccination well overall, after the second dose it was only half. After the first dose, over 90 % of the respondents felt that they were able to work again on the following day, after the second dose one third stated that they were only able to work again on the second day. 2.2 % of all employees had to report that they were unable to work for at least one day after the first dose and 19.5 % after the second dose. CONCLUSIONS: Vaccination with BNT162B2 frequently leads to side effects, especially after the second dose. Perception of side effects resulted in 19 % of those questioned being sick after the second dose. Nevertheless, 95 % of all respondents would choose a coronavirus vaccination again.

Intracellular Delivery of Doxorubicin by Iron Oxide-Based Nano-Constructs Increases Clonogenic Inactivation of Ionizing Radiation in HeLa Cells.

In this study, we determined the potential of polyethylene glycol-encapsulated iron oxide nanoparticles (IONPCO) for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to enhance the cytotoxic effects of ionizing radiation. The biological effects of IONP and X-ray irradiation (50 kV and 6 MV) were determined in HeLa cells using the colony formation assay (CFA) and detection of γH2AX foci. Data are presented as mean ± SEM. IONP were efficiently internalized by HeLa cells. IONPCO radiomodulating effect was dependent on nanoparticle concentration and photon energy. IONPCO did not radiosensitize HeLa cells with 6 MV X-rays, yet moderately enhanced cellular radiosensitivity to 50 kV X-rays (DMFSF0.1 = 1.13 ± 0.05 (p = 0.01)). IONPDOX did enhance the cytotoxicity of 6 MV X-rays (DMFSF0.1 = 1.3 ± 0.1; p = 0.0005). IONP treatment significantly increased γH2AX foci induction without irradiation. Treatment of HeLa cells with IONPCO resulted in a radiosensitizing effect for low-energy X-rays, while exposure to IONPDOX induced radiosensitization compared to IONPCO in cells irradiated with 6 MV X-rays. The effect did not correlate with the induction of γH2AX foci. Given these results, IONP are promising candidates for the controlled delivery of DOX to enhance the cytotoxic effects of ionizing radiation.

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.

BACKGROUND: The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. METHODS: In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. RESULTS: Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091. CONCLUSION: TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. TRIAL REGISTRATION: ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

Gene Expression Profiles Reveal Extracellular Matrix and Inflammatory Signaling in Radiation-Induced Premature Differentiation of Human Fibroblast in vitro.

PURPOSE: Fibroblasts are considered to play a major role in the development of fibrotic reaction after radiotherapy and premature radiation-induced differentiation has been proposed as a cellular basis. The purpose was to relate gene expression profiles to radiation-induced phenotypic changes of human skin fibroblasts relevant for radiogenic fibrosis. MATERIALS AND METHODS: Exponentially growing or confluent human skin fibroblast strains were irradiated in vitro with 1-3 fractions of 4 Gy X-rays. The differentiated phenotype was detected by cytomorphological scoring and immunofluorescence microscopy. Microarray analysis was performed on Human Genome U133 plus2.0 microarrays (Affymetrix) with JMP Genomics software, and pathway analysis with Reactome R-package. The expression levels and kinetics of selected genes were validated with quantitative real-time PCR (qPCR) and Western blotting. RESULTS: Irradiation of exponentially growing fibroblast with 1 × 4 Gy resulted in phenotypic differentiation over a 5-day period. This was accompanied by downregulation of cell cycle-related genes and upregulation of collagen and other extracellular matrix (ECM)-related genes. Pathway analysis confirmed inactivation of proliferation and upregulation of ECM- and glycosaminoglycan (GAG)-related pathways. Furthermore, pathways related to inflammatory reactions were upregulated, and potential induction and signaling mechanisms were identified. Fractionated irradiation (3 × 4 Gy) of confluent cultures according to a previously published protocol for predicting the risk of fibrosis after radiotherapy showed similar downregulation but differences in upregulated genes and pathways. CONCLUSION: Gene expression profiles after irradiation of exponentially growing cells were related to radiation-induced differentiation and inflammatory reactions, and potential signaling mechanisms. Upregulated pathways by different irradiation protocols may reflect different aspects of the fibrogenic process thus providing a model system for further hypothesis-based studies of radiation-induced fibrogenesis.

Cone Beam CT-Based Daily Adaptive Planning or Defined-Filling Protocol for Neoadjuvant Gastric Cancer Radiation Therapy: A Comparison.

PURPOSE: This study aimed to investigate, in the setting of neoadjuvant gastric irradiation with integrated boost, whether cone beam computed tomography (CBCT)-based adaptive radiation therapy compared with a defined-filling protocol would be beneficial in terms of feasibility and achieving daily reproducible dose volume indexes of the planning target volume (PTV) and organs at risk (OARs) and workflow. METHODS AND MATERIALS: Planning computed tomography (PCT) and 25 CBCT scans of a previously treated patient were used, and neoadjuvant therapy of gastric carcinoma was simulated offline. PTVs and OARs were defined per the TOPGEAR protocol (PTV: 45 Gy/1.8 Gy), and an integrated boost (gross tumor volume [GTV]: 50.4 Gy/2.016 Gy) was added. The patient followed a filling regimen consisting of 12-hour fasting followed by 200 mL of water intake (2 glasses of water) immediately before irradiation. OARs and PTVs were newly contoured on each CBCT. Nonrigid registration of PCT and CBCT scans was performed. Nonadapted plans were recalculated on each CBCT (R-CBCT). Furthermore, an adapted plan was created for the new anatomy (A-CBCT). Dose parameters and comparison of R-CBCT and A-CBCT for the kidneys, liver, and heart were analyzed using a paired t test. RESULTS: A total of 200 plans for R-CBCT and A-CBCT were obtained. Mean gastric volumes were 277.32 cm3 (±54.40 cm3) in CBCT scans and 519.2 cm3 in PCT. Mean doses to the PTV did not differ meaningfully within the CBCT scans, with an average of 1.54%. The D95 improved in GTV coverage by 5.26% compared with the R-CBCT plan. Mean heart, liver, and right kidney doses were reduced with the A-CBCT plan by 35.74%, 10.71% and 29.47%, respectively. The R- and A-CBCT comparison for GTV and OARs was significantly different in all cases (P < .0001). CONCLUSIONS: Adaptive radiation therapy through deformable registration represents an important tool in neoadjuvant gastric irradiation, encompassing daily variability and organ motion, compared with the defined-filling protocol while improving OAR sparing.

Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma.

Background Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.

Navigating hospitals safely through the COVID-19 epidemic tide: Predicting case load for adjusting bed capacity.

BACKGROUND: The pressures exerted by the coronavirus disease 2019 (COVID-19) pandemic pose an unprecedented demand on healthcare services. Hospitals become rapidly overwhelmed when patients requiring life-saving support outpace available capacities. OBJECTIVE: We describe methods used by a university hospital to forecast case loads and time to peak incidence. METHODS: We developed a set of models to forecast incidence among the hospital catchment population and to describe the COVID-19 patient hospital-care pathway. The first forecast utilized data from antecedent allopatric epidemics and parameterized the care-pathway model according to expert opinion (ie, the static model). Once sufficient local data were available, trends for the time-dependent effective reproduction number were fitted, and the care pathway was reparameterized using hazards for real patient admission, referrals, and discharge (ie, the dynamic model). RESULTS: The static model, deployed before the epidemic, exaggerated the bed occupancy for general wards (116 forecasted vs 66 observed), ICUs (47 forecasted vs 34 observed), and predicted the peak too late: general ward forecast April 9 and observed April 8 and ICU forecast April 19 and observed April 8. After April 5, the dynamic model could be run daily, and its precision improved with increasing availability of empirical local data. CONCLUSIONS: The models provided data-based guidance for the preparation and allocation of critical resources of a university hospital well in advance of the epidemic surge, despite overestimating the service demand. Overestimates should resolve when the population contact pattern before and during restrictions can be taken into account, but for now they may provide an acceptable safety margin for preparing during times of uncertainty.