Search

Abstract The resistivity scaling of Cu electrical interconnects represents a critical challenge in Si CMOS technology. As interconnect dimensions reach below 10 nm, Cu resistivity increases significantly due to surface scattering. Topological materials have been considered for application in ultra-scaled interconnects (below 5 nm), due to their topologically protected surface states that have reduced electron scattering. Recent theoretical work on the topological chiral semimetal CoSi suggests that this material could offer lower resistivity than Cu at dimensions smaller than 10 nm. Here we investigate the scaling trend of textured and amorphous CoSi thin films, deposited by molecular beam epitaxy in a thickness range between 2 and 82.5 nm. Contrary to predictions of standard resistivity models, we report here a reduction in resistivity for thin amorphous CoSi films, which is instead consistent with surface-dominated transport. Moreover, magnetotransport measurements reveal significant enhancement of the magnetoresistance in scaled films, highlighting the complex transport mechanisms present in these highly disordered films at thicknesses of a few nanometers.

Abstract The chiral anomaly - a hallmark of chiral spin-1/2 Weyl fermions - is an imbalance between left- and right-moving particles that underpins phenomena such as particle decay and negative longitudinal magnetoresistance in Weyl semimetals. The discovery that chiral crystals can host higher-spin generalizations of Weyl quasiparticles without high-energy counterparts, known as multifold fermions, raises the fundamental question of whether the chiral anomaly is a more general phenomenon. Answering this question requires materials with chiral quasiparticles within a sizable energy window around the Fermi level that are unaffected by extrinsic effects such as current jetting. Here, we report the chiral anomaly of multifold fermions in CoSi, which features multifold bands within ~0.85 eV of the Fermi level. By excluding current jetting through the squeezing test, we measure an intrinsic, longitudinal negative magnetoresistance. We develop a semiclassical theory to show that the negative magnetoresistance originates in the chiral anomaly, despite a sizable and detrimental orbital magnetic moment contribution. A concomitant non-linear Hall effect supports the multifold-fermion origin of the magnetotransport. Our work confirms the chiral anomaly of higher-spin generalizations of Weyl fermions, currently inaccessible outside solid-state platforms.

Abstract Semiconductor transistors operate by modulating the charge carrier concentration of a channel material through an electric field coupled by a capacitor. This mechanism is constrained by the fundamental transport physics and material properties of such devices—attenuation of the electric field, and limited mobility and charge carrier density in semiconductor channels. In this work, we demonstrate a new type of transistor that operates through a different mechanism. The channel material is a Weyl semimetal, NbP, whose resistivity is modulated via a magnetic field generated by an integrated superconductor. Due to the exceptionally large electron mobility of this material, which reaches over 1,000,000 cm2/Vs, and the strong magnetoresistive coupling, the transistor can generate significant transconductance amplification at nanowatt levels of power. This type of device can enable new low-power amplifiers, suitable for qubit readout operation in quantum computers.

Abstract The idea of benefitting from the properties of III-V semiconductors and silicon on the same substrate has been occupying the minds of scientists for several years. Although the principle of III-V integration on a silicon-based platform is simple, it is often challenging to perform due to demanding requirements for sample preparation rising from a mismatch in physical properties between those semiconductor groups (e.g. different lattice constants and thermal expansion coefficients), high cost of device-grade materials formation and their post-processing. In this paper, we demonstrate the deposition of group-III metal and III-V semiconductors in microfabricated template structures on silicon as a strategy for heterogeneous device integration on Si. The metal (indium) is selectively electrodeposited in a 2-electrode galvanostatic configuration with the working electrode (WE) located in each template, resulting in well-defined In structures of high purity. The semiconductors InAs and InSb are obtained by vapour phase diffusion of the corresponding group-V element (As, Sb) into the liquified In confined in the template. We discuss in detail the morphological and structural characterization of the synthesized In, InAs and InSb crystals as well as chemical analysis through scanning electron microscopy (SEM), scanning transmission electron microscopy (TEM/STEM), and energy-dispersive X-ray spectroscopy (EDX). The proposed integration path combines the advantage of the mature top-down lithography technology to define device geometries and employs economic electrodeposition (ED) and vapour phase processes to directly integrate difficult-to-process materials on a silicon platform. Graphical abstract

Integrating optically active III-V materials on silicon/insulator platforms is one potential path towards improving the energy efficiency and performance of modern computing. Here we demonstrate the applicability of direct wafer bonding combined with plasma etching to the fabrication of complex nanophotonic systems out of InP layers. We explore and optimise the plasma etching of InP, validating existing processes and developing improved ones. We explore the use of microdisk lasing as a way to evaluate fabrication fidelity, and demonstrate that we can create complex lasing systems of interest to us: coupled disk cavities and random network lasers.

To realize on-chip optical communication schemes based on silicon, the integration of waveguides onto III-V devices must be achieved. Here, the authors report waveguide-coupled III-V heterostructure photodiodes monolithically integrated on silicon waveguides via aligned nanowire.

A good way to identify microscopic conduction regimes where current flow deviates from Ohm’s law is still lacking. Here, the authors identify Sondheimer oscillations as a quantitative probe of the length scale of relaxing electron scattering in studying the non-ohmic electron flow of WP2 crystals.

High-performance electronics would greatly benefit from a versatile III-V integration process on silicon. Unfortunately, integration using hetero epitaxy is hampered by polarity, lattice, and thermal expansion mismatch. This work proposes an alternative concept of III-V integration combining advantages of pulse electrodeposition, template-assisted selective epitaxy, and recrystallization from a melt. Efficient electrodeposition of nano-crystalline and stochiometric InSb in planar templates on Si (001) is achieved. The InSb deposits are analysed by high resolution scanning transmission electron microscopy (HR-STEM) and energy-dispersive X-ray spectroscopy (EDX) before and after melting and recrystallization. The results show that InSb can crystallise epitaxially on Si with the formation of stacking faults. Furthermore, X-ray photoelectron (XPS) and Auger electron (AE) spectroscopy analysis indicate that the InSb crystal size is limited by the impurity concentration resulting from the electrodeposition process.

In this work, we report a novel Indium Arsenide-on-insulator (InAsOI) FinFET platform designed with record high aspect ratio that favors the use of the devices as charge sensors. InAs has very high mobility among III-V semiconductors and an intrinsic surface accumulation layer yielding good ohmic contacts thus making it an interesting choice for chemical and biological sensing platforms. Template Assisted Selective Epitaxy (TASE) enables the integration of III-V highly scaled devices, monolithically integrated on Silicon, within a fully CMOS compatible fabrication scheme hence without any catalyst-induced growth. With a new geometry, high-aspect-ratio (HAR) InAs fins and a new application of pH sensing the versatility of TASE is exhibited. HAR InAs fins, fin height to fin width in excess of 4 for fin width down to 30 nm are fabricated on a Si substrate. The HAR InAs-on-insulator fins are characterized as pH sensors. A sensitivity of 38.8 mV per pH is extracted at $6~\mu \text{A}$ drain current from a 40 nm wide 20 multi-finger array.

Thermometry using scanning probe techniques allows for the thermal imaging and characterization of devices with nanoscale resolution, however can be hindered by contact-related artefacts. Here, the authors demonstrate a thermal scanning probe approach which eliminates contact-resistance effects.

It is a long-standing goal to leverage silicon photonics through the combination of a low-cost advanced silicon platform with III-V-based active gain material. The monolithic integration of the III-V material is ultimately desirable for scalable integrated circuits but inherently challenging due to the large lattice and thermal mismatch with Si. Here, we briefly review different approaches to monolithic III-V integration while focusing on discussing the results achieved using an integration technique called template-assisted selective epitaxy (TASE), which provides some unique opportunities compared to existing state-of-the-art approaches. This method relies on the selective replacement of a prepatterned silicon structure with III-V material and thereby achieves the self-aligned in-plane monolithic integration of III-Vs on silicon. In our group, we have realized several embodiments of TASE for different applications; here, we will focus specifically on in-plane integrated photonic structures due to the ease with which these can be coupled to SOI waveguides and the inherent in-plane doping orientation, which is beneficial to waveguide-coupled architectures. In particular, we will discuss light emitters based on hybrid III-V/Si photonic crystal structures and high-speed InGaAs detectors, both covering the entire telecom wavelength spectral range. This opens a new path towards the realization of fully integrated, densely packed, and scalable photonic integrated circuits.

In this paper, we introduce p-channel InAs-Si tunnel field-effect transistors (TFETs) fabricated using selective epitaxy in nanotube templates. We demonstrate the versatility of this approach, which enables III-V nanowire integration on Si substrates of any crystalline orientation. Electrical characterization of diodes and of TFETs fabricated using this method is presented; the TFETs exhibit a good overall performance with on-currents, Ion of 6 μA/μm (|VGS| = |VDS| = 1 V) and a room-temperature subthreshold swing (SS) of ~160 mV/dec over at least three orders of magnitude in current. Temperature-dependent measurements indicate that SS is limited by traps. We demonstrate improved TFET Ion performance by 1-2 orders of magnitude by scaling the equivalent oxide thickness from 2.7 to 1.5 nm. Furthermore, a novel benchmarking scheme is proposed to allow the comparison of different TFET data found in literature despite the different measurement conditions used.

We are developing a high-resolution printing technique based on transferring a pattern from an elastomeric stamp to a solid substrate by conformal contact. This is an attempt to enhance the accuracy of classical printing to a precision comparable with optical lithography, creating a low-cost, large-area, high-resolution patterning process. First, we introduce the components of this technique, called soft lithography, and review its evolution. Topics described in detail are the stamp material, stamp architecture, pattern design rules, and printing tools. The accuracy of the prints made by thin patterned elastomeric layers supported on a stiff and flexible backplane is then assessed, and defects are characterized using a new electrical metrology approach. This is followed by a discussion of various printing processes used in our laboratory: (1) thiol printing for high-resolution patterns of noble metals that may also be used as sacrificial masks; (2) confined contact processing with liquids in cavities or channels to chemically convert a substrate or deposit layers of materials or biomolecules; (3) printing of catalysts to mediate patterned deposition of metals; and (4) structured, light-guiding stamps for transferring high-resolution patterns into photoresists. Finally, we compare classical and high-resolution printing approaches, and describe their potential for emerging micro- and nanoscale patterning technologies.

Abstract Background To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction. Methods This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65–92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated. Results Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%). Conclusions In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.

The growth pattern of oropharyngeal squamous cell carcinomas (OPSCC) varies from compact tumor cell aggregates to diffusely infiltrating tumor cell-clusters. The influence of the growth pattern on local tumor control and survival has been studied mainly for surgically treated oral cavity carcinomas on a visual basis. In this study, we used multiplex immunofluorescence staining (mIF) to examine the antigens pan-cytokeratin, p16INK4a, Ki67, CD271, PD-L1, and CD8 in pretherapeutic biopsies from 86 OPSCC. We introduce Tumor-stroma contact ratio (TSC), a novel parameter, to quantify the relationship between tumor cells in contact with the stromal surface and the total number of epithelial tumor cells. mIF tumor cores were analyzed at the single-cell level, and tumor-stromal contact area was quantified using the R package ''Spatstat''. TSC was correlated with the visually assessed invasion pattern by two independent investigators. Furthermore, TSC was analyzed in relation to clinical parameters and patient survival data to evaluate its potential prognostic significance.Higher TSC correlated with poor response to (chemo-)radiotherapy (r = 0.3, p < 0.01), and shorter overall (OS) and progression-free (PFS) survival (median OS: 13 vs 136 months, p < 0.0001; median PFS: 5 vs 85 months, p < 0.0001). Visual categorization of growth pattern according to established criteria of tumor aggressiveness showed interobserver variability increasing with more nuanced categories (2 categories: k = 0.7, 95 %-CI: 0.55 - 0.85; 4 categories k = 0.48, 95 %-CI: 0.35 - 0.61).In conclusion, TSC is an objective and reproducible computer-based parameter to quantify tumor-stroma contact area. We demonstrate its relevance for the response of oropharyngeal carcinomas to primary (chemo-)radiotherapy.

Background and Purpose: Squamous cell carcinoma of unknown primary (SCC-CUP) of the head and neck region remains a clinical challenge, with uncertainty surrounding the necessity of contralateral irradiation of cervical lymphatic drainage in cases of unilateral involvement. Materials and Methods: A retrospective study was conducted at the Department of Radiation Oncology, University Medical Center Mainz, on a cohort of 50 patients with unilateral SCC-CUP of the head and neck region treated between 2005 and 2019. 30 patients received bilateral and 20 received unilateral cervical radiotherapy. The majority (n = 38, 76 %) were treated with modern IMRT/ VMAT (Intensity-modulated Radiation Therapy/ Volumetric Modulated Arc Therapy) techniques. Results: After a median follow-up of 64.5 months, locoregional recurrences occurred in 26 % of cases (n = 13/50), all of which were ipsilateral and predominantly within the volume of the previous irradiated CTV (clinical target volume) (85 %, n = 11/13). No patient treated unilaterally developed a contralateral recurrence in the neck. After 3 years, we observed 7 locoregional recurrences in the bilateral irradiated group (n = 7/30, 23 %), and 5 locoregional recurrences in the unilateral irradiated group (n = 5/20, 25 %). After 3 years, 12 patients had died in the bilateral irradiated group (n = 12/30, 40 %), and 7 in the unilateral irradiated group (n = 7/20, 35 %). 7 Patients showed distant metastases after 3 years in the bilateral irradiated group (n = 7/30, 23 %), and 2 in the unilateral irradiated group (n = 2/20, 10 %). Locoregional control (LRC) at 5 years was 66.2 % in the bilaterally irradiated group, and 70.0 % in the unilaterally irradiated group. Overall survival (OS) was 52.6 % (bilateral) and 64.0 % (unilateral). Distant metastasis-free survival (DMFS) was 74.7 % (bilateral) and 84.4 % (unilateral). No significant differences were observed in OS (p = 0.37), LRC (p = 0.91), and DMFS (p = 0.91) between the groups.Acute toxicity ≥ °2 accordingly CTCAE (Common Terminology Criteria of Adverse Events) was high with 97% while late toxicity ≥ °2 was moderate with 31%. There was no statistically significant difference between the group of unilateral and bilateral irradiated patients. Conclusion: These data suggest that contralateral cervical irradiation may be of limited benefit in patients with SCC-CUP, as recurrences occured ipsilaterally, and predominantly within the area of prior irradiation. Unilateral irradiation seems to be adequate for carefully selected patients.

Abstract Background Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. Methods Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case–control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. Results We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. Conclusion N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well.

Background: Previous studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT. Methods: In a cohort of 11,982 BC patients diagnosed in 1998–2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events. Results: Mean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94–1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98–1.01, P = .68). Conclusions: Contrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.

Abstract Background The etiology and most risk factors for a sporadic first primary neoplasm in childhood or subsequent second primary neoplasms are still unknown. One established causal factor for therapy-associated second primary neoplasms is the exposure to ionizing radiation during radiation therapy as a mainstay of cancer treatment. Second primary neoplasms occur in 8% of all cancer survivors within 30 years after the first diagnosis in Germany, but the underlying factors for intrinsic susceptibilities have not yet been clarified. Thus, the purpose of this nested case–control study was the investigation and comparison of gene expression and affected pathways in primary fibroblasts of childhood cancer survivors with a first primary neoplasm only or with at least one subsequent second primary neoplasm, and controls without neoplasms after exposure to a low and a high dose of ionizing radiation. Methods Primary fibroblasts were obtained from skin biopsies from 52 adult donors with a first primary neoplasm in childhood (N1), 52 with at least one additional primary neoplasm (N2+), as well as 52 without cancer (N0) from the KiKme study. Cultured fibroblasts were exposed to a high [2 Gray (Gy)] and a low dose (0.05 Gy) of X-rays. Messenger ribonucleic acid was extracted 4 h after exposure and Illumina-sequenced. Differentially expressed genes (DEGs) were computed using limma for R, selected at a false discovery rate level of 0.05, and further analyzed for pathway enrichment (right-tailed Fisher’s Exact Test) and (in-) activation (z ≥|2|) using Ingenuity Pathway Analysis. Results After 0.05 Gy, least DEGs were found in N0 (n = 236), compared to N1 (n = 653) and N2+ (n = 694). The top DEGs with regard to the adjusted p-value were upregulated in fibroblasts across all donor groups (SESN1, MDM2, CDKN1A, TIGAR, BTG2, BLOC1S2, PPM1D, PHLDB3, FBXO22, AEN, TRIAP1, and POLH). Here, we observed activation of p53 Signaling in N0 and to a lesser extent in N1, but not in N2+. Only in N0, DNA (excision-) repair (involved genes: CDKN1A, PPM1D, and DDB2) was predicted to be a downstream function, while molecular networks in N2+ were associated with cancer, as well as injury and abnormalities (among others, downregulation of MSH6, CCNE2, and CHUK). After 2 Gy, the number of DEGs was similar in fibroblasts of all donor groups and genes with the highest absolute log2 fold-change were upregulated throughout (CDKN1A, TIGAR, HSPA4L, MDM2, BLOC1SD2, PPM1D, SESN1, BTG2, FBXO22, PCNA, and TRIAP1). Here, the p53 Signaling -Pathway was activated in fibroblasts of all donor groups. The Mitotic Roles of Polo Like Kinase -Pathway was inactivated in N1 and N2+. Molecular Mechanisms of Cancer were affected in fibroblasts of all donor groups. P53 was predicted to be an upstream regulator in fibroblasts of all donor groups and E2F1 in N1 and N2+. Results of the downstream analysis were senescence in N0 and N2+, transformation of cells in N0, and no significant effects in N1. Seven genes were differentially expressed in reaction to 2 Gy dependent on the donor group (LINC00601, COBLL1, SESN2, BIN3, TNFRSF10A, EEF1AKNMT, and BTG2). Conclusion Our results show dose-dependent differences in the radiation response between N1/N2+ and N0. While mechanisms against genotoxic stress were activated to the same extent after a high dose in all groups, the radiation response was impaired after a low dose in N1/N2+, suggesting an increased risk for adverse effects including carcinogenesis, particularly in N2+.

UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18–60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).

Purpose: Radiation therapy (RT) is an integral part of treatment concepts for early-stage Hodgkin lymphoma. This analysis reports on RT quality in the recent HD16 and 17 trials of the German Hodgkin Study Group (GHSG). Methods and Materials: All RT plans of involved-node radiation therapy (INRT) in HD 17 were requested for analysis, along with 100 and 50 involved-field radiation therapy (IFRT) plans in HD 16 and 17, respectively. A structured assessment regarding field design and protocol adherence was performed by the reference radiation oncology panel of the GHSG. Results: Overall, 100 (HD 16) and 176 (HD 17) patients were eligible for analysis. In HD 16, 84% of RT series were evaluated as correct, with significant improvement compared with the predecessor studies (P < .001). In HD 17, 76.1% of INRT cases revealed a correct RT design compared with 69.0% of IFRT-cases, which was superior to previous studies (P < .001). Comparing INRT and IFRT, we found no significant differences in the percentage of any deviation (P = .418) or major deviations (P = .466). Regarding dosimetry, INRT was accompanied by an improvement in thyroid doses. Comparing different RT techniques, we found that intensity-modulated RT showed a reduction of high doses in the lung at the expense of an increased low-dose exposure in HD 17. Conclusions: The latest study generation of the GHSG demonstrates an improved quality in RT. A modern INRT design could be established without deterioration in quality. On a conceptual level, an individual consideration of the appropriate RT technique has to be performed.

BackgroundChildhood cancer survivors (CCS) are at particularly high risk for therapy-related late sequelae, with secondary primary neoplasms (SPN) being the most detrimental. Since there is no standardized questionnaire for retrospective assessment of associations between prior cancer treatments and late health effects, we developed a self-administered questionnaire and validated it in a cohort of CCS.MethodsCCS of a first primary neoplasm (FPN, N=340) only or with a subsequent SPN (N=101) were asked whether they had received cancer therapies. Self-reports were compared to participants’ medical records on cancer therapies from hospitals and clinical studies (N=242). Cohen’s Kappa (κ) was used to measure their agreement and logistic regression was used to identify factors influencing the concordance. Associations between exposure to cancer therapies and late health effects (overweight/obesity, diseases of the lipid metabolism and the thyroid gland, cardiovascular diseases, occurrence of SPN) were analyzed in all participants by applying generalized linear mixed models to calculate odds ratios (OR) and 95% confidence intervals (95%CI).ResultsFor CCS of SPN, a perfect agreement was found between self-reports and medical records for chemotherapy (CT, κ=1.0) while the accordance for radiotherapy (RT) was lower but still substantial (κ=0.8). For the CCS of FPN the accordance was less precise (CT: κ=0.7, RT: κ=0.3). Cancer status, tumors of the central nervous system, sex, age at recruitment, vocational training, follow-up time, and comorbidities had no impact on agreement. CCS with exposure to CT were found to be less often overweight or obese compared to those without CT (OR=0.6 (95%CI 0.39; 0.91)). However, they were found to suffer more likely from thyroid diseases excluding thyroid cancers (OR=9.91 (95%CI 4.0; 24.57)) and hypercholesterolemia (OR=4.45 (95%CI 1.5; 13.23)). All other analyses did not show an association.ConclusionOur new questionnaire proved reliable for retrospective assessment of exposure to CT and RT in CCS of SPN. For the CCS of FPN, self-reported RT was very imprecise and should not be used for further analyses. We revealed an association between late health outcomes occurring as hypercholesterolemia and thyroid diseases, excluding thyroid cancer, and the use of CT for the treatment of childhood cancer.

IntroductionLong non-coding ribonucleic acids (lncRNAs) are involved in the cellular damage response following exposure to ionizing radiation as applied in radiotherapy. However, the role of lncRNAs in radiation response concerning intrinsic susceptibility to late effects of radiation exposure has not been examined in general or in long-term survivors of childhood cancer with and without potentially radiotherapy-related second primary cancers, in particular.MethodsPrimary skin fibroblasts (n=52 each) of long-term childhood cancer survivors with a first primary cancer only (N1), at least one second primary neoplasm (N2+), as well as tumor-free controls (N0) from the KiKme case-control study were matched by sex, age, and additionally by year of diagnosis and entity of the first primary cancer. Fibroblasts were exposed to 0.05 and 2 Gray (Gy) X-rays. Differentially expressed lncRNAs were identified with and without interaction terms for donor group and dose. Weighted co-expression networks of lncRNA and mRNA were constructed using WGCNA. Resulting gene sets (modules) were correlated to the radiation doses and analyzed for biological function.ResultsAfter irradiation with 0.05Gy, few lncRNAs were differentially expressed (N0: AC004801.4; N1: PCCA-DT, AF129075.3, LINC00691, AL158206.1; N2+: LINC02315). In reaction to 2 Gy, the number of differentially expressed lncRNAs was higher (N0: 152, N1: 169, N2+: 146). After 2 Gy, AL109976.1 and AL158206.1 were prominently upregulated in all donor groups. The co-expression analysis identified two modules containing lncRNAs that were associated with 2 Gy (module1: 102 mRNAs and 4 lncRNAs: AL158206.1, AL109976.1, AC092171.5, TYMSOS, associated with p53-mediated reaction to DNA damage; module2: 390 mRNAs, 7 lncRNAs: AC004943.2, AC012073.1, AC026401.3, AC092718.4, MIR31HG, STXBP5-AS1, TMPO-AS1, associated with cell cycle regulation).DiscussionFor the first time, we identified the lncRNAs AL158206.1 and AL109976.1 as involved in the radiation response in primary fibroblasts by differential expression analysis. The co-expression analysis revealed a role of these lncRNAs in the DNA damage response and cell cycle regulation post-IR. These transcripts may be targets in cancer therapy against radiosensitivity, as well as provide grounds for the identification of at-risk patients for immediate adverse reactions in healthy tissues. With this work we deliver a broad basis and new leads for the examination of lncRNAs in the radiation response.

BackgroundEffective anti-tumor immune responses are mediated by T cells and require organized, spatially coordinated interactions within the tumor microenvironment (TME). Understanding coordinated T-cell-behavior and deciphering mechanisms of radiotherapy resistance mediated by tumor stem cells will advance risk stratification of oropharyngeal cancer (OPSCC) patients treated with primary chemoradiotherapy (RCTx).MethodsTo determine the role of CD8 T cells (CTL) and tumor stem cells for response to RCTx, we employed multiplex immunofluorescence stains on pre-treatment biopsy specimens from 86 advanced OPSCC patients and correlated these quantitative data with clinical parameters. Multiplex stains were analyzed at the single-cell level using QuPath and spatial coordination of immune cells within the TME was explored using the R-package Spatstat.ResultsOur observations demonstrate that a strong CTL-infiltration into the epithelial tumor compartment (HR for overall survival, OS: 0.35; p

Background and purposeTo evaluate the tolerability and outcomes of chemoradiation in elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC).Materials and methodsThis multi-center retrospective analysis included 161 patients with SCC of the esophagus with a median age of 73 years (range 65-89 years) treated with definitive or neoadjuvant (chemo)radiotherapy between 2010 and 2019 at 3 large comprehensive cancer centers in Germany. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities were analyzed, and parameters determining patient outcomes and treatment tolerance were assessed.ResultsThe delivery of radiotherapy without dose reduction was possible in 149 patients (93%). In 134 patients (83%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 41% of these patients (n = 55) required chemotherapy de-escalation due to treatment-related toxicities. Fifty-two patients (32%) experienced higher-grade acute toxicities, and 22 patients (14%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS rates amounted to 67.5%, 33.8%, 31.4%, and 40.4%, respectively. Upon multivariate analysis, full-dose concomitant chemotherapy (vs. no or modified chemotherapy) was associated with significantly better DMFS (p=0.005), PFS (p=0.005) and OS (p=0.001). Furthermore, neoadjuvant chemoradiotherapy followed by tumor resection (vs. definitive chemoradiotherapy or definitive radiotherapy alone) significantly improved PFS (p=0.043) and OS (p=0.049). We could not identify any clinico-pathological factor that was significantly associated with LRC. Furthermore, definitive (chemo)radiotherapy, brachytherapy boost and stent implantation were significantly associated with higher-grade acute toxicities (p

Most childhood cancers occur sporadically and cannot be explained by an inherited mutation or an unhealthy lifestyle. However, risk factors might trigger the oncogenic transformation of cells. Among other regulatory signals, hypermethylation of RAD9A intron 2 is responsible for the increased expression of RAD9A protein, which may play a role in oncogenic transformation. Here, we analyzed the RAD9A intron 2 methylation in primary fibroblasts of 20 patients with primary cancer in childhood and second primary cancer (2N) later in life, 20 matched patients with only one primary cancer in childhood (1N) and 20 matched cancer-free controls (0N), using bisulfite pyrosequencing and deep bisulfite sequencing (DBS). Four 1N patients and one 2N patient displayed elevated mean methylation levels (³10 %) of RAD9A. DBS revealed ³2 % hypermethylated alleles of RAD9A, indicative for constitutive mosaic epimutations. Bone marrow samples of NHL and AML tumor patients (n=74), EBV (Epstein Barr Virus) lymphoblasts (n=6), tumor cell lines (n=5) and FaDu subclones (n=13) were analyzed to substantiate our findings. We find a broad spectrum of tumor entities with an aberrant methylation of RAD9A. We detected a significant difference in mean methylation of RAD9A for NHL versus AML patients (p ≤0.025). Molecular karyotyping of AML samples during therapy with hypermethylated RAD9A showed an evolving duplication of 1.8 kb on Chr16p13.3 including the PKD1 gene. Radiation, colony formation assays, cell proliferation, PCR and molecular karyotyping SNP-array experiments using generated FaDu subclones suggest that hypermethylation of RAD9A intron 2 is associated with genomic imbalances in regions with tumor-relevant genes and survival of the cells. In conclusion, this is the very first study of RAD9A intron 2 methylation in childhood cancer and Leukemia. RAD9A epimutations may have an impact on leukemia and tumorigenesis and can potentially serve as a biomarker.

Abstract Purpose Cardiac effects after breast cancer radiation therapy potentially affect more patients as survival improves. The heart’s heterogeneous radiation exposure and composition of functional structures call for establishing individual relationships between structure dose and specific late effects. However, valid dosimetry requires reliable contouring which is challenging for small volumes based on older, lower-quality computed tomography imaging. We developed a heart atlas for robust heart contouring in retrospective epidemiologic studies. Methods and materials The atlas defined the complete heart and geometric surrogate volumes for six cardiac structures: aortic valve, pulmonary valve, all deeper structures combined, myocardium, left anterior myocardium, and right anterior myocardium. We collected treatment planning records from 16 patients from 4 hospitals including dose calculations for 3D conformal tangential field radiation therapy for left-sided breast cancer. Six observers each contoured all patients. We assessed spatial contouring agreement and corresponding dosimetric variability. Results Contouring agreement for the complete heart was high with a mean Jaccard similarity coefficient (JSC) of 89%, a volume coefficient of variation (CV) of 5.2%, and a mean dose CV of 4.2%. The left (right) anterior myocardium had acceptable agreement with 63% (58%) JSC, 9.8% (11.5%) volume CV, and 11.9% (8.0%) mean dose CV. Dosimetric agreement for the deep structures and aortic valve was good despite higher spatial variation. Low spatial agreement for the pulmonary valve translated to poor dosimetric agreement. Conclusions For the purpose of retrospective dosimetry based on older imaging, geometric surrogate volumes for cardiac organs at risk can yield better contouring agreement than anatomical definitions, but retain limitations for small structures like the pulmonary valve.

Use of historical data in clinical trial design and analysis has shown various advantages such as reduction of number of subjects and increase of study power. The metaanalytic-predictive (MAP) approach accounts with a hierarchical model for between-trial heterogeneity in order to derive an informative prior from historical data. In this paper, we introduce the package RBesT (R Bayesian evidence synthesis tools) which implements the MAP approach with normal (known sampling standard deviation), binomial and Poisson endpoints. The hierarchical MAP model is evaluated by Markov chain Monte Carlo (MCMC). The MCMC samples representing the MAP prior are approximated with parametric mixture densities which are obtained with the expectation maximization algorithm. The parametric mixture density representation facilitates easy communication of the MAP prior and enables fast and accurate analytical procedures to evaluate properties of trial designs with informative MAP priors. The paper first introduces the framework of robust Bayesian evidence synthesis in this setting and then explains how RBesT facilitates the derivation and evaluation of an informative MAP prior from historical control data. In addition we describe how the meta-analytic framework relates to further applications including probability of success calculations.

BackgroundImproved treatments for childhood cancer result in a growing number of long-term childhood cancer survivors (CCS). The diagnosis and the prevalence of comorbidities may, however, influence their lifestyle later in life. Nonetheless, little is known about differences in late effects between CCS of a first primary neoplasm (FPN) in childhood and subsequent second primary neoplasms (SPN) and their impact on lifestyle. Therefore, we aim to investigate associations between the occurrence of FPN or SPN and various diseases and lifestyle in the later life of CCS.MethodsCCS of SPN (n=101) or FPN (n=340) and cancer-free controls (n=150) were matched by age and sex, and CCS additionally by year and entity of FPN. All participants completed a self-administered questionnaire on anthropometric and socio-economic factors, medical history, health status, and lifestyle. Mean time between FPN diagnosis and interview was 27.3 years for SPN and 26.2 years for FPN CCS. To confirm results from others and to generate new hypotheses on late effects of childhood cancer as well as CCS´ lifestyles, generalized linear mixed models were applied.ResultsCCS were found to suffer more likely from diseases compared to cancer-free controls. In detail, associations with cancer status were observed for hypercholesterinemia and thyroid diseases. Moreover, CCS were more likely to take regular medication compared to controls. A similar association was observed for CCS of SPN compared to CCS of FPN. In contrast to controls, CCS rarely exercise more than 5 hours per week, consumed fewer soft and alcoholic drinks, and were less likely to be current, former, or passive smokers. Additionally, they were less likely overweight or obese. All other exploratory analyses performed on cardiovascular, chronic lung, inflammatory bone, allergic, and infectious diseases, as well as on a calculated health-score revealed no association with tumor status.ConclusionCCS were more affected by pathologic conditions and may consequently take more medication, particularly among CCS of SPN. The observed higher disease burden is likely related to the received cancer therapy. To reduce the burden of long-term adverse health effects in CCS, improving cancer therapies should therefore be in focus of research in this area.

Abstract Background This study aimed to contrast four different irradiation methods for pediatric medulloblastoma tumors in a dosimetric comparison regarding planning target volume (PTV) coverage and sparing of organs at risk (OARs). Methods In sum 24 treatment plans for 6 pediatric patients were realized. Besides the clinical standard of a 3D-conformal radiotherapy (3D-CRT) treatment plan taken as a reference, volumetric modulated arc therapy (VMAT) treatment plans (“VMAT_AVD” vs. “noAVD” vs. “FullArc”) were optimized and calculated for each patient. For the thoracic and abdominal region, the short partial-arc VMAT_AVD technique uses an arc setup with reduced arc-length by 100°, using posterior and lateral beam entries. The noAVD uses a half 180° (posterior to lateral directions) and the FullArc uses a full 360° arc setup arrangement. The prescription dose was set to 35.2 Gy. Results We identified a more conformal dose coverage for PTVs and a better sparing of OARs with used VMAT methods. For VMAT_AVD mean dose reductions in organs at risk can be realized, from 16 to 6.6 Gy, from 27.1 to 8.7 Gy and from 8.0 to 1.9 Gy for the heart, the thyroid and the gonads respectively, compared to the 3D-CRT treatment method. In addition we have found out a superiority of VMAT_AVD compared to the noAVD and FullArc trials with lower exposure to low-dose radiation to the lungs and breasts. Conclusions With the short partial-arc VMAT_AVD technique, dose exposures to radiosensitive OARS like the heart, the thyroid or the gonads can be reduced and therefore, maybe the occurrence of late sequelae is less likely. Furthermore the PTV conformity is increased. The advantages of the VMAT_AVD have to be weighed against the potentially risks induced by an increased low dose exposure compared to the 3D-CRT method.

Abstract Background Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. Methods Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p-value

Background: To support innovative trial designs in a regulatory setting for pediatric-onset multiple sclerosis (MS), the study aimed to perform a systematic literature review and meta-analysis of relapse rates with interferon β (IFN β), fingolimod, and natalizumab and thereby demonstrate potential benefits of Bayesian and non-inferiority designs in this population. Methods: We conducted a literature search in MEDLINE and EMBASE from inception until 17 June 2020 of all studies reporting annualized relapse rates (ARR) in IFN β-, fingolimod-, or natalizumab-treated patients with pediatric-onset relapsing–remitting MS. These interventions were chosen because the literature was mainly available for these treatments, and they are currently used for the treatment of pediatric MS. Two researchers independently extracted data and assessed study quality using the Cochrane Effective Practice and Organization of Care – Quality Assessment Tool. The meta-analysis estimates were obtained by Bayesian random effects model. Data were summarized as ARR point estimates and 95% credible intervals. Results: We found 19 articles, including 2 randomized controlled trials. The baseline ARR reported was between 1.4 and 3.7. The meta-analysis-based ARR was significantly higher in IFN β-treated patients (0.69, 95% credible interval: 0.51–0.91) versus fingolimod (0.11, 0.04–0.27) and natalizumab (0.17, 0.09–0.31). Based on the meta-analysis results, an appropriate non-inferiority margin versus fingolimod could be in the range of 2.29–2.67 and for natalizumab 1.72–2.29 on the ARR ratio scale. A Bayesian design, which uses historical information for a fingolimod or natalizumab control arm, could reduce the sample size of a new trial by 18 or 14 patients, respectively. Conclusion: This meta-analysis provides evidence that relapse rates are considerably higher with IFNs versus fingolimod or natalizumab. The results support the use of innovative Bayesian or non-inferiority designs to avoid exposing patients to less effective comparators in trials and bringing new medications to patients more efficiently.

BackgroundTherapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development. ObjectiveTherefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls. MethodsWe conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation). ResultsSince 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510). ConclusionsThis molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify genetic predispositions related to ionizing radiation in childhood and SPNs. In the future, fibroblasts of the participants will be used for standardized irradiation experiments, which will inform analysis of the case-control study and vice versa. Differences between participants will be identified using several molecular markers. With its innovative combination of experimental and observational components, this new study will provide valuable data to forward research on radiation-related risk factors in childhood cancer and SPNs. International Registered Report Identifier (IRRID)DERR1-10.2196/32395

Background and PurposeTo compare two validated spinal instability scores regarding the stabilizing effects and skeletal-related events (SREs) of palliative radiotherapy (RT) in patients with spinal bone metastases (SBM).Materials and MethodsTwo hundred eighty-two osteolytic SBM of lung or breast cancer patients were analyzed for stability before and following RT based on the Spinal Instability Neoplastic Score (SINS) or the Taneichi score. Score concordance was quantified by absolute agreement and Cohen’s kappa coefficient. SREs were defined as fractures or local progression after RT. OS was quantified as the time between the start of RT and death from any cause.ResultsAt 3 and 6 months after RT, 35 and 50% of initially unstable SBM were re-stabilized according to SINS in patients still alive. Corresponding Taneichi score-based stabilization proportions were 25 and 46%, respectively. Comparison of both stability scores showed high absolute agreement for all time-points (range 71–78%, kappa range 0.35–0.44). SRE occurred more frequently in initially unstable SBM compared to stable SBM according to SINS (14 vs. 5%), but no such association could be shown for the Taneichi-based instability criterion. Poor general condition of patients was negatively associated with SINS-measured re-stabilization after 6 months, but no predictive factor for re-stabilization could be found for the Taneichi score.ConclusionsDespite the relatively high agreement between both stabilization scores, the SINS should be considered the standard for future studies on the stabilization effects of RT in SBM.

Abundance and signaling of the epidermal growth factor receptor (EGFR) and programmed cell death protein ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC) are not only genetically determined but are also subject to the traits of the tumor microenvironment, which has hitherto not been clarified completely. We investigated the impact of hypoxia on the EGFR system and on PD-L1 in six HPV negative HNSCC cell lines in vitro and in FaDu xenografts in vivo. Protein levels of EGFR, AKT, pAKT, ERK1/2, pERK1/2, CA IX, cleaved PARP (apoptosis), LC3B (autophagy), and PD-L1 were quantified by western blot after oxygen deprivation or CoCl2, staurosporine, and erlotinib treatment. In FaDu xenograft tumors the expression of EGFR, CA IX andCD34 staining were analyzed. Reduced oxygen supply strongly downregulated EGFR protein levels and signaling in FaDu cells in vitro and in vivo, and a transient downregulation of EGFR signaling was found in three other HNSCC cell lines. PD-L1 was affected by oxygen deprivation in only one HNSCC cell line showing increased protein amounts. The results of this study indicate a significant impact of the traits of the tumor microenvironment on crucial molecular targets of cancer therapies with high clinical relevance for therapy resistance and response in HNSCC.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic led to far-reaching restrictions of social and professional life, affecting societies all over the world. To contain the virus, medical schools had to restructure their curriculum by switching to online learning. However, only few medical schools had implemented such novel learning concepts. We aimed to evaluate students' attitudes to online learning to provide a broad scientific basis to guide future development of medical education.MethodsOverall, 3286 medical students from 12 different countries participated in this cross-sectional, web-based study investigating various aspects of online learning in medical education. On a 7-point Likert scale, participants rated the online learning situation during the pandemic at their medical schools, technical and social aspects, and the current and future role of online learning in medical education.ResultsThe majority of medical schools managed the rapid switch to online learning (78%) and most students were satisfied with the quantity (67%) and quality (62%) of the courses. Online learning provided greater flexibility (84%) and led to unchanged or even higher attendance of courses (70%). Possible downsides included motivational problems (42%), insufficient possibilities for interaction with fellow students (67%) and thus the risk of social isolation (64%). The vast majority felt comfortable using the software solutions (80%). Most were convinced that medical education lags behind current capabilities regarding online learning (78%) and estimated the proportion of online learning before the pandemic at only 14%. In order to improve the current curriculum, they wish for a more balanced ratio with at least 40% of online teaching compared to on-site teaching.ConclusionThis study demonstrates the positive attitude of medical students towards online learning. Furthermore, it reveals a considerable discrepancy between what students demand and what the curriculum offers. Thus, the COVID-19 pandemic might be the long-awaited catalyst for a new "online era" in medical education.

IntrodutionWe aimed to evaluate treatment outcome of combined radiotherapy (RT) including photon intensity modulated radiotherapy (IMRT) and carbon ion boost for adenoid cystic carcinomas (ACCs) of the major salivary glands, the currently available largest German collective for this cohort.Materials and MethodsOverall, 207 patients who were irradiated with combined RT between 2009 and 2019 at Heidelberg University Hospital were analyzed retrospectively for local control (LC), progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimates. The majority of patients received postoperative RT (n=176/207, 85%) after previous surgery in large German hospitals mainly Mainz, Freiburg, Mannheim and Heidelberg University Hospitals and 15% received primary RT (n=31/207).ResultsAfter a median follow-up time of 50 months, 84% of the patients were still alive (n=174/207). Disease progression occurred in 32% of the patients (n=66/207) while local recurrence was diagnosed in 12% (n=25/207), and distant relapse in 27% (n=56/207). Estimated 5-year LC, PFS and OS rates were 84%, 56% and 83% for OS, respectively. In multivariate analysis, we could identify two prognostic subgroups: one subgroup resulting in decreased LC, PFS and OS rates and another subgroup having an additional survival disadvantage in PFS and OS. Patients with a macroscopic tumor disease (yes vs. no; p

The purpose of the present study was to investigate whether former childhood cancer patients who developed a subsequent secondary primary neoplasm (SPN) are characterized by elevated spontaneous chromosomal instability or cellular and chromosomal radiation sensitivity as surrogate markers of compromised DNA repair compared to childhood cancer patients with a first primary neoplasm (FPN) only or tumor-free controls. Primary skin fibroblasts were obtained in a nested case-control study including 23 patients with a pediatric FPN, 22 matched patients with a pediatric FPN and an SPN, and 22 matched tumor-free donors. Clonogenic cell survival and cytogenetic aberrations in Giemsa-stained first metaphases were assessed after X-irradiation in G1 or on prematurely condensed chromosomes of cells irradiated and analyzed in G2. Fluorescence in situ hybridization was applied to investigate spontaneous transmissible aberrations in selected donors. No significant difference in clonogenic survival or the average yield of spontaneous or radiation-induced aberrations was found between the study populations. However, two donors with an SPN showed striking spontaneous chromosomal instability occurring as high rates of numerical and structural aberrations or non-clonal and clonal translocations. No correlation was found between radiation sensitivity and a susceptibility to a pediatric FPN or a treatment-associated SPN. Together, the results of this unique case-control study show genomic stability and normal radiation sensitivity in normal somatic cells of donors with an early and high intrinsic or therapy-associated tumor risk. These findings provide valuable information for future studies on the etiology of sporadic childhood cancer and therapy-related SPN as well as for the establishment of predictive biomarkers based on altered DNA repair processes.