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Abstract Background Total body irradiation (TBI)-based allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for selected patients with acute myeloid leukemia (AML). Yet, secondary malignancies contribute to long-term morbidity and mortality with TBI potentially influencing these risks. Methods This retrospective study analyzed the cumulative incidences of secondary solid malignancies and precancerous lesions of 89 consecutive AML patients after TBI-based conditioning before 1st allo-HSCT between 2000 and 2016. TBI was performed with an average dose rate of 4 cGy/min and a twice-daily fractionation. Cause-specific hazard models analyzed risk factors for secondary malignancies/precancerous lesions and the competing risks of dying before developing secondary malignancies/precancerous lesions. Results The median patient age at TBI was 42.5 years (interquartile range, 32.5–51.2), while the median follow-up was 15.2 years (interquartile range, 13.0-18.2). Most patients received a myeloablative conditioning (MAC) containing 8 Gy (n = 47) and 12 Gy TBI (n = 11). Reduced-intensity regimens (RIC, 4 Gy TBI) were applied in 31 patients. Of note, patients receiving RIC were older than patients receiving MAC. The most common cancer types were non-squamous cell carcinomas (n = 14) after exclusion of a patient diagnosed with sarcoma within less than a year after TBI. The cumulative incidences of secondary malignancies and precancerous lesions were 8% (95%CI, 4–16), 14% (95%CI, 7–23), and 17% (95%CI, 9–27) at 10, 15 and 20 years, while the cumulative incidences of premature deaths were 59% (95%CI, 48–69), 59% (95%CI, 48–69), and 64% (95%CI, 49–76). In multivariate analyses, higher patient age at TBI was associated with lower rates of secondary malignancies/precancerous lesions, while higher patient age translated into a trend towards premature deaths (before patients could develop malignancies). Higher TBI doses, mainly applied in younger patients, translated into lower rates of secondary malignancies/precancerous lesions while lacking associations with mortality. Chronic GVHD requiring systemic immunosuppression was associated with premature deaths. Conclusions Although this study indicates an inverse relationship between TBI doses applied and treatment-related malignancies, confounding by competing risks is present. The age dependency may be explained by the fact that older patients had a lower life expectancy independent of malignancies, illustrating the pitfalls of competing risks. Trial registration The study was retrospectively registered.

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating the Renalase (Rnls) gene. Here, we demonstrate that Rnls loss of function in beta cells shapes autoimmunity by mediating a regulatory natural killer (NK) cell phenotype important for the induction of tolerogenic antigen-presenting cells. Rnls-deficient beta cells mediate cell–cell contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 is markedly elevated on beta cells deficient for Rnls. Altered glucose metabolism in Rnls mutant beta cells is involved in the upregulation of CD47 surface expression. These findings are crucial to better understand how genetically engineered beta cells shape autoimmunity, giving valuable insights for future therapeutic advancements to treat and cure T1D.

Abstract Background Single-fraction stereotactic radiosurgery (SRS) is an established standard for radiation therapy of brain metastases although recent developments indicate that multi-fractionated stereotactic radiotherapy (FSRT) results in lower radiation necrosis especially for larger metastases, and the same or even better local control in comparison to SRS. Methods Seventy-two patients with 111 brain metastases received SRS with a single dose of 18 Gy between September 2014 and December 2021. The dose prescription was either 18 Gy given to the enclosing 80% isodose with a normalization to Dmax = 100% of 22.5 Gy (part I) or 18 Gy = D98, while D0.03 cc of 21.6–22.5 Gy was accepted (part II). The study retrospectively evaluated local progression-free survival (LPFS), response on the first follow-up magnetic resonance imaging (MRI), and radiation necrosis. Results Melanoma brain metastases (n = 44) were the most frequent metastases. The median gross tumor volume (GTV) was 0.30 cm³ (IQR, 0.17–0.61). The median follow-up time of all patients was 50.8 months (IQR, 30.4–64.6). Median LPFS was 23.5 months (95%CI 17.2, 29.8). The overall LPFS rates at 12-, 18-, 24- and 30 months were 65.3%, 56.3%, 46.5%, and 38.8%. Brain metastases with radioresistant histology (melanoma, renal cell cancer, and sarcoma) showed a 12-month LPFS of 60.2%, whereas brain metastases with other histology had a 12-month LPFS of 70.1%. The response of brain metastases on first follow-up MRIs performed after a median time of 47 days (IQR, 40–63) was crucial for long-term local control and survival. Eight brain metastases (7.2%) developed radiation necrosis after a median time of 18.4 months (IQR, 9.4–26.5). In multivariate analyses, a GTV > 0.3 cm³ negatively affected LPFS (HR 2.229, 95%CI 1.172, 4.239). Melanoma, renal cell cancers, and sarcoma had a lower chance of LPFS in comparison to other cancer types (HR 2.330, 95%CI 1.155, 4.699). Conclusions Our results indicate a reasonable 1-year local control of brain metastases with radiosensitive histology. Radioresistant metastases show a comparatively poor local control. Treatment refinements merit exploration to improve local control of brain metastases. Trial registration This study is retrospectively registered (ethics approval number 23-3451-104).

Abstract Background Lasting local control of brain metastases following stereotactic radiotherapy is becoming increasingly relevant since systemic treatment constantly improves the prognosis of patients with extracranial metastases. Methods 73 patients with 103 brain metastases received hypofractionated stereotactic radiotherapy (FSRT) in 6 fractions of 5 Gy between January 2017 and December 2021 at the University Hospital Regensburg, Germany. The study retrospectively evaluated local progression free survival (LPFS), overall survival (OS) and distant brain progression free survival (DPFS) of patients without prior radiotherapy of the brain. Response rate and brain radiation necrosis were reported. Cox proportional hazard models evaluated prognostic factors of OS and LPFS. Results The median patient age was 61.0 years (Interquartile range, IQR 51.0, 67.5). The most common tumor types were malignant melanoma (34.2%) and non-small cell lung adenocarcinoma (26.0%). The median gross tumor volume (GTV) was 0.9 cm³ (IQR 0.4, 3.6). The median follow-up time of all patients was 36.3 months (95%CI 29.1, 43.4). The median OS was 17.4 months (95%CI 9.9, 24.9). Overall survival rates at 6-, 12-, 18-, 24-, and 30 months were 81.9%, 59.1%, 49.0%, 41.3%, and 37.2%, retrospectively. The mean LPFS was 38.1 months (95%CI 31.4, 44.9), while the median LPFS has not been reached. LPFS rates at 6-, 12-, 18-, 24- and 30 months were 78.9%, 68.7%, 64.3%, 61.6% and 58.7%, retrospectively. Median DPFS of all patients was 7.7 months (95%CI 6.1, 9.3). Six, 12-, 18-, 24- and 30 months DPFS rates were 62.1%, 36.3%, 31.1%, 24.8% and 21.7%. Five brain metastases (4.8%) developed brain radiation necrosis. In multivariate analysis, the number of brain metastases negatively affected LPFS. Non-melanoma and non-renal cell cancer was associated with a higher chance of LPFS in comparison to other cancer. A GTV > 1.5 cm³ translated into a higher risk of death compared to a GTV ≤ 1.5 cm³ and Karnofsky performance score was predictive of OS. Conclusions FSRT in 6 fractions of 5 Gy seems to be an effective treatment with an acceptable local control for patients with brain metastases although melanoma and renal cell cancer seem to have a worse local control in comparison to other cancer. Trial registration This study is retrospectively registered.

Abstract Background Total body irradiation (TBI)-based-conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is standard of care in patients with acute myeloid leukemia (AML) but can cause long-term morbidity. Data on the impact of chronic Graft-versus-host disease (cGvHD) on cognitive function (CF) and quality of life (QoL) of long-term transplant survivors are sparse. Methods We analyzed patient-reported outcomes focusing on progression-free AML patients and 1st allo-HSCT applying a standardized TBI-technique with an average dose rate of 4 cGy/min to the total body and lung shielding in case of doses > 8 Gy. Instruments included the Functional Assessment of Cancer Therapy-Bone marrow transplant (FACT-BMT, version 4), the FACT-Cognition Function (FACT-Cog, version 3) and the Patient Health Questionaire-4 (PHQ-4). We put focus on the impact of cGvHD and compared the results to normative data derived from the general population. Results Out of 41 eligible patients contacted, 32 (78.0%) patients with a medium follow-up of 154 months (Interquartile range 113, 191 months) participated in the study. Eleven patients (34.4%) had active cGvHD, 11 (34.4%) resolved cGvHD and 10 (31.3%) never had cGvHD. Patients with active cGvHD had poorer FACT-BMT, FACT-Cog and higher PHQ-4 scores compared to patients with resolved cGvHD or who never had cGvHD. Outcomes were similar in patients with resolved cGvHD and those who never had cGvHD. Patients with active cGvHD had similar FACT-Cog, but lower FACT-BMT in comparison to normative data. However, the overall patient sample had similar FACT-BMT and FACT-Cog in comparison to normative data. Conclusion Our data indicate that CF of long-term survivors upon TBI-based allo-HSCT is not impaired, even in the presence of active cGvHD. However, active cGvHD has a negative impact on QoL. Trial registration The local Ethics Board of the University of Regensburg approved this study (Number 20-1810_1-101).

Abstract Background Patients with large cutaneous squamous cell carcinoma of the scalp are a treatment challenge. We report a case of dramatic radiotherapy response of a patient with a giant cutaneous squamous cell carcinoma of the scalp with extensive skull destruction and suspected infiltration of the dura mater and superior sagittal sinus. This case is the first report of this kind in the literature that shows that large bone defects can heal with the resolution of tumor and inflammation by secondary intention without surgical reconstruction. We want to put an end to concerns about radiocurability of tumors with extensive bone involvement, and show sustained complete response after definitive radiotherapy and programmed cell death protein-1 inhibiting antibody therapy. Case presentation A 74-year-old White man presented with a 7.2 × 6.8 × 5.5 cm painless tumor on the right parietal region of the scalp. Medical imaging revealed widespread destruction of the skull and suspected infiltration of the dura mater and superior sagittal sinus. Biopsies showed cutaneous squamous cell carcinoma (cT4a cN0 cM0, stage IVA). The patient was treated with a total dose of 60 Gy, at 2 Gy per daily fraction with volumetric modulated arc therapy using 6 megavoltage photons. The biologically effective dose (alpha/beta 10 Gy) was 72 Gy. The tumor response correlated with dose received. The patient had a massive tumor necrosis secondary to tumor shrinkage after 18 fractions (36 Gy, biologically effective dose 43.2 Gy). Leakage of cerebrospinal fluid did not occur. Radiotherapy did not hamper the patient’s quality of life. The patient had a clear regression of the initial tumor on the final day of radiotherapy. The bone defect healed by secondary intention without surgical interventions. The patient achieved a complete response with a good cosmetic result after 82 days follow-up. He started a programmed cell death protein-1 inhibiting antibody therapy with cemiplimab 2 months after radiotherapy, and is now at 10 months follow-up without evidence of recurrence. Conclusion Definitive radiotherapy is a safe and highly effective therapy for giant tumors of the scalp with extensive bone destruction. We report a sustained complete response with a good cosmetic result after secondary wound healing.

Abstract Definitive radiotherapy is a curative and noninvasive treatment modality for cutaneous squamous cell carcinomas of the midface when surgery has an impact on function and cosmetics. Volumetric modulated arc therapy provides optimal dose coverage for complex‐shaped tumors without compromising adjacent organs at risk.

The development, support and recognition of plurilingual competence, in other words a person´s ability to perform successfully in a plurilingual setting, required school curricula to include not only the instruction of at least two foreign languages (e.g. Italian and English as foreign languages) within one course but also a corresponding exam format. We will outline the guidelines for and challenges of a plurilingual syllabus, explore the concepts of bilingualism, plurilingualism and multilingualism and give clear examples of what we believe an oral plurilingual examination should look like. Guidelines for teachers on how to develop competence-oriented plurilingual tasks will also be accompanied by the necessary test specifications. In addition, 14 possible situations for examinations are provided. An assessment grid and examples of test papers complete the document on bilingual competences and their simultaneous evaluation in two foreign languages. Dall’insegnamento plurilingue all’esame plurilingue Lo sviluppo, il supporto e il riconoscimento della competenza plurilingue, in altre parole della capacità di una persona di muoversi con successo in un ambiente plurilingue, ha richiesto che i programmi scolastici includessero non solo l’insegnamento di almeno due lingue straniere (ad es. italiano e inglese come lingue straniere) all’interno del curricolo di studi, ma anche un corrispondente formato d’esame. In questo contributo descriveremo le linee guida e le sfide di un programma plurilingue, esploreremo i concetti di bilinguismo, plurilinguismo e multilinguismo e forniremo esempi chiari di come crediamo che dovrebbe essere un esame plurilingue orale. Le linee guida per gli insegnanti su come sviluppare compiti plurilinguistici orientati alle competenze saranno inoltre accompagnate dalle necessarie specifiche indicazioni per l’esame. Inoltre, sono previste 14 possibili situazioni per gli esami. Una griglia di valutazione ed esempi di prove d’esame completano il documento sulle competenze bilingui e la loro valutazione simultanea in due lingue straniere.

The hippocampal formation (HF) is a relevant brain structure that is involved in several neurological and psychiatric diseases. In cats, structural changes of the HF are associated with epilepsy. The knowledge of a detailed anatomy of this brain region may lead to the accurate diagnosis and development of better therapies. There are, however, discrepancies among the research findings, which may be due to different definitions being used, according to anatomical guidelines and boundaries, as well as different magnetic resonance (MR) protocols. The aim of this study is to evaluate the anatomical borders of the HF on transverse MR images and the correlated anatomic sections in three cats. The boundaries of the HF were mostly visible in the formalin fixed anatomic sections, except in the areas where the hippocampus proper exchanges into the subicular complex. Also, the delineation of the anteroventral part and the latero-caudal borders of the HF were not clearly defined. Based on our preliminary results these problems are reinforced on MR images, and further histological and anatomical research must be done to find a way to delineate these neurological structures accurately.