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Simple Summary: Neutrophil granulocytes in the vicinity of malignant tumors are referred to as tumor-associated neutrophils (TANs). Knowledge about the role of TANs in the disease progression of early hormone-receptor-positive breast cancer is limited but essential to the development of new immunotherapies and biomarkers. In this work, we counted immunohistochemically stained TANs in sections of 144 early-stage breast cancer tumors and correlated these results with disease-free survival. Our results indicate that not only intratumoral TANs but also those in adjacent normal tissue and in sentinel lymph nodes were associated with shorter disease-free survival. Combined analysis with other immune cells from previous studies revealed that intratumoral TANs were only associated with prognosis in tumors that did not express an unfavorable macrophage polarization profile, providing a clinical example of the known interactions between different types of immune cells within the tumor microenvironment. This indicates that future research in the field should evaluate the two types of immune cells together. Background: Tumor-associated neutrophils (TANs) are important modulators of the tumor microenvironment with opposing functions that can promote and inhibit tumor progression. The prognostic role of TANs in early luminal breast cancer is unclear. Methods: A total of 144 patients were treated for early-stage hormone-receptor-positive breast cancer as part of an Accelerated Partial Breast Irradiation (APBI) phase II trial. Resection samples from multiple locations were processed into tissue microarrays and sections thereof immunohistochemically stained for CD66b+ neutrophils. CD66b+ neutrophil density was measured separately in the stromal and intraepithelial compartment. Results: High stromal and intraepithelial CD66b+ TAN density was a negative prognostic factor in central tumor samples. In addition, neutrophil density in adjacent normal breast tissue and lymph node samples also correlated with reduced disease-free survival. TAN density correlated with CD163+ M2-like tumor-associated macrophage (TAM) density, which we analyzed in a previous study. TANs were a negative prognostic factor in tumors with an elevated M1/M2 TAM ratio, while this impact on patient outcome was lost in tumors with a low M1/M2 ratio. A combined multivariate analysis of TAM and TAN density revealed that only TAM polarization status was an independent prognostic factor. Conclusions: CD66b+ neutrophils were a negative prognostic factor in early-stage luminal breast cancer in single-marker analysis. Combined analysis with TAMs could be necessary to correctly evaluate their prognostic impact in future studies. TAN recruitment might act as a compensatory mechanism of immunoevasion and disease progression in tumors that are unable to sufficiently attract and polarize TAMs. [ABSTRACT FROM AUTHOR]

Background: Failure mode and effects analysis (FMEA) is a valuable tool for radiotherapy risk assessment, yet its outputs might be unreliable due to failures not being identified or due to a lack of accurate error rates. Purpose: A novel incident reporting system (IRS) linked to an FMEA database was tested and evaluated. The study investigated whether the system was suitable for validating a previously performed analysis and whether it could provide accurate error rates to support the expert occurrence ratings of previously identified failure modes. Methods: Twenty‐three pre‐identified failure modes of our external beam radiotherapy process, covering the process steps from patient admission to treatment delivery, were proffered on dedicated FMEA feedback and incident reporting terminals generated by the IRS. The clinical setting involved a computed tomography scanner, dosimetry, and five linacs. Incoming reports were used as basis to identify additional failure modes or confirm initial ones. The Kruskal–Wallis H test was applied to compare the risk priorities of the retrospective and prospective failure modes. Wald's sequential probability ratio test was used to investigate the correctness of the experts' occurrence ratings by means of the number of incoming reports. Results: Over a 15‐month period, 304 reports were submitted. There were 0.005 (confidence interval [CI], 0.0014–0.0082) reported incidents per imaging study and 0.0006 (CI, 0.0003–0.0009) reported incidents per treatment fraction. Sixteen additional failure modes could be identified, and their risk priorities did not differ from those of the initial failure modes (p = 0.954). One failure mode occurrence rating could be increased, whereas the other 22 occurrence ratings could not be disproved. Conclusions: Our approach is suitable for validating FMEAs and deducing additional failure modes on a continual basis. Accurate error rates can only be provided if a sufficient number of reports is available. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. Methods: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. Results: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40–43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. Discussion: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. Conclusions: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Compared to whole-breast irradiation, partial-breast irradiation uses smaller radiotherapy volumes and usually leads to lower radiation doses to the healthy tissues, such as the heart and lungs. For the first time, the present evaluation offers a complete analysis of the doses to on whole-breast irradiation. The dose reduction to the healthy organs was significant in favor of partial-breast irradiation. Therefore, partial-breast irradiation should be recommended to suitable patients to minimize the risk of secondary tumor induction and the incidence of consecutive major cardiac events. 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. [ABSTRACT FROM AUTHOR]

Cell-in-cell (CIC) structures in breast cancer have so far been studied in a small inhomogeneous patient population, suggesting the prognostic importance of CIC. In the present study, we focused on CIC in early hormone-sensitive breast cancer. With in vitro co-culture experiments, we compared the homotypic phagocytic capacity of two breast cancer cell lines to that of primary human fibroblasts. Afterward, we studied 601 tissue specimens from 147 patients participating in an institutional accelerated partial breast irradiation (APBI) phase II trial. Both breast cancer cell lines performed non-professional phagocytosis at a higher rate than primary human fibroblasts. In this study cohort, 93.2% of the patients had T1 tumours, and 6.8% had T2 tumours. CIC was found in 61.2% of the patients, with a CIC rate ranging from <1/mm2 to 556.5/mm2 with a mean of 30.9/mm2 ± 68.4/mm2. CIC structures were prognostically favourable for local recurrence-free survival and disease-free survival. Regarding metastasis-free survival, CIC-positive patients had an unfavourable prognosis. Subgroup analysis indicated a correlation between a high proliferation index and high CIC rates. CIC had the highest prognostic value in young breast cancer patients (p = 0.004). With this study, we provide further evidence of CIC as a prognostic marker in breast cancer. [ABSTRACT FROM AUTHOR]

The therapy of high-risk soft tissue sarcomas (STS) remains an interdisciplinary challenge. Regional hyperthermia (RHT) sparked interest as it has been shown to improve overall survival when added to perioperative chemotherapy (CTX). However, questions arise on how RHT should be optimally integrated into current multi-modal therapies. We performed a systematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies written in English and focused mainly on radiative RHT and superficial hyperthermia were evaluated and included. Studies including patients below the age of 18, with metastatic disease or review articles, were excluded. We identified 15 clinical reports from 1990 until July 2022. Three articles combined RHT + CTX, and twelve focused on combined RHT + radiotherapy (RT) or neoadjuvant chemoradiotherapy (CRT). Most treatments were based on invasive thermometry, and less on magnetic resonance imaging (MRI)-based, noninvasive thermometry for STS of the extremities. Perioperative chemotherapy was used for the combination of RHT and CTX, mostly Ifosfamide-based. The effectiveness of RT appeared to be increased by RHT, especially with two RHT sessions/week. The trimodal simultaneous approach of neoadjuvant RHT and CRT was also feasible. No significant toxicity of RHT was reported. The gathered data strengthen the beneficial role of RHT in the multimodal setting. Further expert consensus and clinical trials are required to determine the optimal integration of RHT in treating STS. [ABSTRACT FROM AUTHOR]

Simple Summary: Accelerated partial breast irradiation represents a well-established and safe treatment alternative for selected patients with early stage breast cancer after breast-conserving surgery. In a prospective trial on external beam partial breast irradiation, the risk for radiogenic pneumonitis is analyzed. After a median follow-up of 56 (1–129) months, radiogenic pneumonitis grade 2 appeared in only 1/170 (0.6%) patients. Compared to standard whole breast irradiation, the radiation doses applied to the lungs were very low. The patient with the radiogenic pneumonitis was found to have a generally increased radiation susceptibility. Using accelerated partial breast irradiation, the risk of radiogenic pneumonitis appeared quite low and may be limited to very exceptional cases associated with innate risk factors with an increased radiation susceptibility. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyperthermia (HT) is a cancer treatment which locally heats the tumor to supraphysiological temperature, and it is an effective sensitizer for radiotherapy (RT) and chemotherapy. HT is further capable of modulating the immune system. Thus, a better understanding of its effect on the immune phenotype of tumor cells, and particularly when combined with RT, would help to optimize combined anti-cancer treatments. Since in clinics, no standards about the sequence of RT and HT exist, we analyzed whether this differently affects the cell death and immunological phenotype of human breast cancer cells. We revealed that the sequence of HT and RT does not strongly matter from the immunological point of view, however, when HT is combined with RT, it changes the immunophenotype of breast cancer cells and also upregulates immune suppressive immune checkpoint molecules. Thus, the additional application of immune checkpoint inhibitors with RT and HT should be beneficial in clinics. Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39–44 °C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and particularly, how the sequence of HT and RT changes the immune phenotype of breast cancer cells. Therefore, human MDA-MB-231 and MCF-7 breast cancer cells were treated with HT of different temperatures (39, 41 and 44 °C), alone and in combination with RT (2 × 5 Gy) in different sequences, with either RT or HT first, followed by the other. Tumor cell death forms and the expression of immune checkpoint molecules (ICMs) were analyzed by multicolor flow cytometry. Human monocyte-derived dendritic cells (moDCs) were differentiated and co-cultured with the treated cancer cells. In both cell lines, RT was the main stressor for cell death induction, with apoptosis being the prominent cell death form in MCF-7 cells and both apoptosis and necrosis in MDA-MB-231 cells. Here, the sequence of the combined treatments, either RT or HT, did not have a significant impact on the final outcome. The expression of all of the three examined immune suppressive ICMs, namely PD-L1, PD-L2 and HVEM, was significantly increased on MCF-7 cells 120 h after the treatment of RT with HT of any temperature. Of special interest for MDA-MB-231 cells is that only combinations of RT with HT of both 41 and 44 °C induced a significantly increased expression of PD-L2 at all examined time points (24, 48, 72, and 120 h). Generally, high dynamics of ICM expression can be observed after combined RT and HT treatments. There was no significant difference between the different sequences of treatments (either HT + RT or RT + HT) in case of the upregulation of ICMs. Furthermore, the co-culture of moDCs with tumor cells of any treatment had no impact on the expression of activation markers. We conclude that the sequence of HT and RT does not strongly affect the immune phenotype of breast cancer cells. However, when HT is combined with RT, it results in an increased expression of distinct immune suppressive ICMs that should be considered by including immune checkpoint inhibitors in multimodal tumor treatments with RT and HT. Further, combined RT and HT affects the immune system in the effector phase rather than in the priming phase. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease. [ABSTRACT FROM AUTHOR]