Shell-by-Shell functionalized nanoparticles as radiosensitizers and radioprotectors in radiation therapy of cancer cells and tumor spheroids.

Shell-by-Shell (SbS)-functionalized NPs can be tailor-made by combining a metal oxide NP core of choice with any desired phosphonic acids and amphiphiles as 1st or 2nd ligand shell building blocks. The complementary composition of such highly hierarchical structures makes them interesting candidates for various biomedical applications, as certain active ingredients can be incorporated into the structure. Here, we used TiO2 and CoFe2O4 NPs as drug delivery tools and coated them with a hexadecylphosphonic acid and with hexadecyl ammonium phenolates (caffeate, p-coumarate, ferulate), that possess anticancer as well as antioxidant properties. These architectures were then incubated in 2D and 3D cell cultures of non-tumorigenic and tumorigenic breast cells and irradiated to study their anticancer effect. It was found that both, the functionalized TiO2 and CoFe2O4 NPs acted as strong protective agents in non-tumorigenic spheroids. In contrast, the functionalized CoFe2O4 NPs induce a higher damage in irradiated tumor spheroids compared to the functionalized TiO2 NPs. CoFe3O4 NPs act additionally as radiosensitizing agents to the tumor spheroids. The radio-enhancement of the CoFe2O4 NPs is due to the generation of highly toxic hydroxyl radicals during X-ray irradiation. The irradiation exposed the CoFe2O4 surface, releasing the anticancer drugs into the cytoplasm and making the surface Co2+ ions accessible. These surface ions catalyze the Fenton reaction. This combination of radiosensitizer and anticancer drug delivery proved to be a very effective nanotherapeutic in 2D and 3D cell cultures of breast cancer cells.

Radiosensitivity in individuals with tuberous sclerosis complex.

Benign tumors, but rarely cancer, are common in patients with tuberous sclerosis complex (TSC). Blood samples from patients undergoing treatment for TSC at our institution were analyzed for their individual sensitivity to ionizing radiation. Blood samples were collected from 13 adult patients with TSC. The samples were irradiated ex vivo and analyzed by 3-color fluorescence in situ hybridization. In each patient, aberrations were analyzed in 200 metaphases of chromosomes 1, 2, and 4 and scored as breaks. Radiosensitivity was determined by mean breaks per metaphase (B/M) and compared to both healthy donors and oncologic patients. The radiosensitivity (B/M) of the TSC patient cohort (n = 13; female: 46.2%, B/M: 0.48 ± 0.11) was clearly increased compared to healthy individuals of similar age (n = 90; female: 54.4%; B/M: 0.40 ± 0.09; p = 0.001). There was no difference compared to age-matched oncological patients (n = 78; female: 67.9%; B/M 0.49 ± 0.14; p = 0.246). Similarly, the proportion of radiosensitive (B/M > 0.5) and distinctly radiosensitive individuals (B/M > 0.6) was increased in the TSC and oncological patient cohorts (TSC: 30.8% and 7.7%, oncological patients: 46.2% and 14.1%) compared to the healthy individuals (11.1% and 2.2%). Although patients with TSC develop mostly benign and rarely malignant tumors, they are similarly sensitive to radiation as patients with malignant tumors.

Tumor-Associated Neutrophils Are a Negative Prognostic Factor in Early Luminal Breast Cancers Lacking Immunosuppressive Macrophage Recruitment.

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.

The Effect of Ionizing Irradiation on the Autotaxin-Lysophasphatidic Acid Axis and Interleukin-6/8 Secretion in Different Breast Cancer Cell Lines.

BACKGROUND: The Autotaxin (ATX)-lysophosphatidic acid (LPA) axis is involved in decreasing radiation sensitivity of breast tumor cells. This study aims to further elucidate the effect of irradiation on the ATX-LPA axis and cytokine secretion in different breast cancer cell lines to identify suitable breast cancer subtypes for targeted therapies. METHODS: Different breast cancer cell lines (MCF-7 (luminal A), BT-474 (luminal B), SKBR-3 (HER2-positive), MDA-MB-231 and MDA-MB-468 (triple-negative)) and the breast epithelial cell line MCF-10A were irradiated. The influence of irradiation on LPA receptor (LPAR) expression, ATX expression, and Interleukin (IL)-6 and IL-8 secretion was analyzed. Further, the effect of IL-6 and IL-8 on ATX expression of adipose-derived stem cells (ADSC) was investigated. RESULTS: Irradiation increased ATX and LPAR2 expression in MDA-MB-231 cells. Additionally, IL-6 secretion was enhanced in MDA-MB-231, and IL-8 secretion in MDA-MB-231 and MDA-MB-468. Stimulation of ADSC with IL-6 and IL-8 increased ATX expression in ADSC. CONCLUSIONS: Targeting ATX or its downstream signaling pathways might enhance the sensitivity of triple-negative breast cancer cells to radiation. Further exploration of the interplay between irradiation, the ATX-LPA axis, and inflammatory cytokines may elucidate novel pathways for overcoming radioresistance and improving individual treatment outcomes.

The course of tumor-related epilepsy in glioblastoma patients: A retrospective analysis.

PURPOSE: Many patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. METHODS: We retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. RESULTS: In the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. CONCLUSION: Tumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.

Application of Stem Cells Shows Antiinflammatory Effect in an Irradiated Random Pattern Flap Model.

BACKGROUND: In reconstructive surgery, local flaps might develop tissue necrosis or partial flap loss especially after previous irradiation, which may be necessary in many tumor entities. The application of stem cells seems promising to improve flap perfusion and might be a possible solution to optimize flap survival. METHODS: Twenty rats received harvesting of bilateral random pattern fasciocutaneous flaps. The right flaps received 20 Gy ionizing radiation 4 weeks prior to the surgery, while the left flaps served as the non-irradiated control. After flap harvest, four different stem cell mixtures (5 × 106 ASC, ASC-HUVEC, MSC, MSC-HUVEC) were applied under both right and left flaps using 1 mL fibrin glue as the delivery vehicle. Flap size and its necrotic area were examined clinically. Two weeks after the surgery, HE staining and immunohistochemical staining for CD68 and ERG, as well as PCR analysis (Interleukin 6, HIF-1α and VEGF), were performed. RESULTS: Application of ASCs, ASCs-HUVECs and MSCs resulted in a lower number of CD68-stained cells compared to the no cell group. The expression of Hif1α was higher in the ASC group compared to those in the MSC and previously treated no cell groups. Treatment with MSCs and MSCs-HUVECs prevented shrinking of the flaps in this series. CONCLUSION: Application of ASCs, MSCs and ASCs-HUVECs was shown to have an antiinflammatory effect. Treatment with MSCs and MSCs-HUVECs can prevent early shrinking of the flaps.

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib.

(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer-Analyses of CD68, CD163, TGF-ß1, GLUT-1 and HIF-1α Expressions.

BACKGROUND: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms. METHODS: A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-ß, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann-Whitney U test. RESULTS: Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status. CONCLUSIONS: Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to "high dose" neoadjuvant RCT, which may be therapeutically desirable.

Neutrophils in HNSCC Can Be Associated with Both a Worse or Favorable Prognosis.

The prognostic significance of tumor-infiltrating neutrophils in head and neck squamous cell carcinoma (HNSCC) is poorly understood. It is unclear how the presence of neutrophils affects prognosis due to their polarization into cytotoxic N1 or immunosuppressive N2. Therefore, we determined the number of CD66b+ neutrophil granulocytes separately in the stromal and epithelial compartments in cancer tissues from 397 patients with HNSCC. Tumor samples from six historical patient groups were processed into tissue microarrays and stained immunohistochemically. In total, 21.9% were HPV positive (p16+). Neutrophil counts were much lower in the stromal compartment (372 ± 812) than in the epithelial cancer compartment (1040 ± 1477) (p < 0.001), with large differences between groups. In three groups with high neutrophil infiltration, high rates were associated with a favorable prognosis, whereas in two groups, high rates were a negative prognostic factor. In p16- oropharyngeal and hypopharyngeal cancer high infiltration was associated with a favorable prognosis. Cancers with an exclusion of neutrophils in the epithelial compartment were associated with improved prognosis. In oropharyngeal and hypopharyngeal HPV-negative cancer high neutrophil infiltration rates were clearly associated with prolonged survival. Neutrophil granulocytes in HNSCC may contribute to a favorable or unfavorable prognosis.

FEN1 Inhibition as a Potential Novel Targeted Therapy against Breast Cancer and the Prognostic Relevance of FEN1.

To improve breast cancer treatment and to enable new strategies for therapeutic resistance, therapeutic targets are constantly being studied. Potential targets are proteins of DNA repair and replication and genomic integrity, such as Flap Endonuclease 1 (FEN1). This study investigated the effects of FEN1 inhibitor FEN1-IN-4 in combination with ionizing radiation on cell death, clonogenic survival, the cell cycle, senescence, doubling time, DNA double-strand breaks and micronuclei in breast cancer cells, breast cells and healthy skin fibroblasts. Furthermore, the variation in the baseline FEN1 level and its influence on treatment prognosis was investigated. The cell lines show specific response patterns in the aspects studied and have heterogeneous baseline FEN1 levels. FEN1-IN-4 has cytotoxic, cytostatic and radiosensitizing effects, expressed through increasing cell death by apoptosis and necrosis, G2M share, senescence, double-strand breaks and a reduced survival fraction. Nevertheless, some cells are less affected by the cytotoxicity and fibroblasts show a rather limited response. In vivo, high FEN1 mRNA expression worsens the prognosis of breast cancer patients. Due to the increased expression in breast cancer tissue, FEN1 could represent a new tumor and prognosis marker and FEN1-IN-4 may serve as a new potent agent in personalized medicine and targeted breast cancer therapy.

Different Impacts of DNA-PK and mTOR Kinase Inhibitors in Combination with Ionizing Radiation on HNSCC and Normal Tissue Cells.

Despite substantial advancements in understanding the pathomechanisms of head and neck squamous cell carcinoma (HNSCC), effective therapy remains challenging. The application of kinase inhibitors (KIs) in HNSCC, specifically mTOR and DNA-PK inhibitors, can increase radiosensitivity and therefore presents a promising strategy when used simultaneously with ionizing radiation (IR) in cancer treatment. Our study focused on the selective DNA-PK-inhibitor AZD7648; the selective mTOR-inhibitor Sapanisertib; and CC-115, a dual inhibitor targeting both mTOR and DNA-PK. The impact of these KIs on HNSCC and normal tissue cells was assessed using various analytical methods including cell death studies, cell cycle analysis, real-time microscopy, colony-forming assays and immunohistochemical staining for γH2AX and downstream mTOR protein p-S6. We detected a strong inhibition of IR-induced DNA double-strand break (DSB) repair, particularly in AZD7648-treated HNSCC, whereas normal tissue cells repaired DNA DSB more efficiently. Additionally, AZD7648 + IR treatment showed a synergistic decline in cell proliferation and clonogenicity, along with an elevated G2/M arrest and cell death in the majority of HNSCC cell lines. CC-115 + IR treatment led to an elevation in G2/M arrest, increased cell death, and a synergistic reduction in cell proliferation, though the effect was notably lower compared to the AZD7648 + IR- treated group. Sapanisertib led to a high cellular toxicity in both HNSCC and normal tissue cells, even in non-irradiated cells. Regarding cell proliferation and the induction of apoptosis and necrosis, Sapanisertib + IR was beneficial only in HPV+ HNSCC. Overall, this study highlights the potential of AZD7648 as a radiosensitizing agent in advanced-stage HPV-positive and negative HNSCC, offering a promising therapeutic strategy. However, the dual mTOR/DNA-PK-I CC-115 did not provide a distinct advantage over the use of selective KIs in our investigations, suggesting limited benefits for its application in KI + IR therapy. Notably, the selective mTOR-inhibitor Sapanisertib was only beneficial in HPV+ HNSCC and should not be applied in HPV- cases.

Radiochemotherapy and interstitial brachytherapy for cervical cancer: clinical results and patient-reported outcome measures.

OBJECTIVE: To evaluate clinical results and long-term patient-reported outcome measures (PROMs) on quality of life in cervical cancer patients following radiochemotherapy (RCT) and brachytherapy (BT) as definitive treatment. MATERIALS AND METHODS: Between 2003 and 2023, a total of 132 patients with advanced cervical cancer were evaluated for possible treatment. Patients treated by postoperative RCT, palliative radiotherapy, and those treated for recurrent disease were excluded. Thus, 46 patients receiving standard RCT and BT as their curative treatment were included in this study. PROMs were assessed prospectively by patients' self-completion of the EORTC-QLQ-C30 and EORTC-QLQ-CX24 questionnaires. RESULTS: Five-year overall survival (OS), distant metastases-free survival (DMFS), and pelvic tumor-free survival rates (PTFS) were 53%, 54%, and 83%, respectively. A significant impact on OS was seen for FIGO (International Federation of Gynecologic Oncology) stage (IIB-IIIA: 79% vs. IIIB-IVA: 33%, p = 0.015), for overall treatment time (OTT; 50-65 d: 64% vs. > 65 d: 38%, p = 0.004), and for rectal D2cc (≤ 73 Gy: 50% vs. > 73 Gy: 38%, p = 0.046). The identical parameters were significantly associated with DMFS (FIGO stage: p = 0.012, OTT: p = 0.008, D2cc: p = 0.024). No parameters with a significant influence on PTFS were seen. In multivariate analysis, an impact of FIGO stage on OS (p = 0.05) and DMFS (p = 0.014) was detected, and of rectal D2cc on DMFS (p = 0.031). The overall QoL score was 63/100. Cognitive function was the least impaired (84/100), while role functioning was the worst (67/100). On the symptom scale, insomnia (46/100), fatigue (41/100), dyspnea (32/100), pain (26/100), and financial difficulties (25/100) were scored the worst. According to EORTC-QLQ-CX24, peripheral neuropathy (36/100) and lymphedema (32/100) occurred most frequently. Impaired sexual/vaginal functioning (32/100) and body image (22/100) were also frequently recorded. CONCLUSION: In patients with advanced cervical cancer, a combination of RCT and BT remains an excellent treatment option. In terms of patient-reported long-term quality of life, specific support is needed to alleviate symptoms including lymphedema, peripheral neuropathy, and impaired sexual activity.

Benchmarking ChatGPT-4 on a radiation oncology in-training exam and Red Journal Gray Zone cases: potentials and challenges for ai-assisted medical education and decision making in radiation oncology.

Purpose: The potential of large language models in medicine for education and decision-making purposes has been demonstrated as they have achieved decent scores on medical exams such as the United States Medical Licensing Exam (USMLE) and the MedQA exam. This work aims to evaluate the performance of ChatGPT-4 in the specialized field of radiation oncology. Methods: The 38th American College of Radiology (ACR) radiation oncology in-training (TXIT) exam and the 2022 Red Journal Gray Zone cases are used to benchmark the performance of ChatGPT-4. The TXIT exam contains 300 questions covering various topics of radiation oncology. The 2022 Gray Zone collection contains 15 complex clinical cases. Results: For the TXIT exam, ChatGPT-3.5 and ChatGPT-4 have achieved the scores of 62.05% and 78.77%, respectively, highlighting the advantage of the latest ChatGPT-4 model. Based on the TXIT exam, ChatGPT-4's strong and weak areas in radiation oncology are identified to some extent. Specifically, ChatGPT-4 demonstrates better knowledge of statistics, CNS & eye, pediatrics, biology, and physics than knowledge of bone & soft tissue and gynecology, as per the ACR knowledge domain. Regarding clinical care paths, ChatGPT-4 performs better in diagnosis, prognosis, and toxicity than brachytherapy and dosimetry. It lacks proficiency in in-depth details of clinical trials. For the Gray Zone cases, ChatGPT-4 is able to suggest a personalized treatment approach to each case with high correctness and comprehensiveness. Importantly, it provides novel treatment aspects for many cases, which are not suggested by any human experts. Conclusion: Both evaluations demonstrate the potential of ChatGPT-4 in medical education for the general public and cancer patients, as well as the potential to aid clinical decision-making, while acknowledging its limitations in certain domains. Owing to the risk of hallucinations, it is essential to verify the content generated by models such as ChatGPT for accuracy.

The Influence of Different Irradiation Regimens on Inflammation and Vascularization in a Random-Pattern Flap Model.

BACKGROUND: Irradiation plays an important role in the oncological treatment of various tumor entities. The aim of the study was to investigate the influence of different irradiation regimens on random-pattern flaps at the molecular and histopathological levels. METHODS: Twenty-five rats underwent harvesting of bilateral random-pattern fasciocutaneous flaps. The right flaps received irradiation, while the left flaps served as non-irradiated intraindividual controls. Five rats served as a non-irradiated control group. Four different irradiation regimens with give rats each were tested: 20 Gy postoperatively, 3 × 12 Gy postoperatively, 20 Gy preoperatively, and 3 × 12 Gy preoperatively. Two weeks after surgery, HE staining and immunohistochemical staining for CD68 and ERG, as well as PCR analysis to detect Interleukin 6, HIF-1α, and VEGF, were performed. RESULTS: A postoperative cumulative higher dose of irradiation appeared to result in an increase in necrosis, especially in the superficial layers of the flap compared to preoperative or single-stage irradiation. In addition, we observed increased expression of VEGF and HIF-1α in all irradiation groups. CONCLUSION: Even though no statistically significant differences were found between the different groups, there was a tendency for fractional postoperative irradiation with a higher total dose to have a more harmful effect compared to preoperative or single-dose irradiation.

Status epilepticus in patients with glioblastoma: Clinical characteristics, risk factors, and epileptological outcome.

PURPOSE: Epilepsy is a common comorbidity in patients with glioblastoma, however, clinical data on status epilepticus (SE) in these patients is sparse. We aimed to investigate the risk factors associated with the occurrence and adverse outcomes of SE in glioblastoma patients. METHODS: We retrospectively analysed electronic medical records of patients with de-novo glioblastoma treated at our institution between 01/2006 and 01/2020 and collected data on patient, tumour, and SE characteristics. RESULTS: In the final cohort, 292/520 (56.2 %) patients developed seizures, with 48 (9.4 % of the entire cohort and 16.4 % of patients with epilepsy, PWE) experiencing SE at some point during the course of their disease. SE was the first symptom of the tumour in 6 cases (1.2 %) and the first manifestation of epilepsy in 18 PWE (6.2 %). Most SE episodes occurred postoperatively (n = 37, 77.1 %). SE occurrence in PWE was associated with postoperative seizures and drug-resistant epilepsy. Adverse outcome (in-house mortality or admission to palliative care, 10/48 patients, 20.8 %), was independently associated with higher status epilepticus severity score (STESS) and Charlson Comorbidity Index (CCI), but not tumour progression. 32/48 SE patients (66.7 %) were successfully treated with first- and second-line agents, while escalation to third-line agents was successful in 6 (12.5 %) cases. CONCLUSION: Our data suggests a link between the occurrence of SE, postoperative seizures, and drug-resistant epilepsy. Despite the dismal oncological prognosis, SE was successfully treated in 79.2 % of the cases. Higher STESS and CCI were associated with adverse SE outcomes.

Deep Learning and Registration-Based Mapping for Analyzing the Distribution of Nodal Metastases in Head and Neck Cancer Cohorts: Informing Optimal Radiotherapy Target Volume Design.

We introduce a deep-learning- and a registration-based method for automatically analyzing the spatial distribution of nodal metastases (LNs) in head and neck (H/N) cancer cohorts to inform radiotherapy (RT) target volume design. The two methods are evaluated in a cohort of 193 H/N patients/planning CTs with a total of 449 LNs. In the deep learning method, a previously developed nnU-Net 3D/2D ensemble model is used to autosegment 20 H/N levels, with each LN subsequently being algorithmically assigned to the closest-level autosegmentation. In the nonrigid-registration-based mapping method, LNs are mapped into a calculated template CT representing the cohort-average patient anatomy, and kernel density estimation is employed to estimate the underlying average 3D-LN probability distribution allowing for analysis and visualization without prespecified level definitions. Multireader assessment by three radio-oncologists with majority voting was used to evaluate the deep learning method and obtain the ground-truth distribution. For the mapping technique, the proportion of LNs predicted by the 3D probability distribution for each level was calculated and compared to the deep learning and ground-truth distributions. As determined by a multireader review with majority voting, the deep learning method correctly categorized all 449 LNs to their respective levels. Level 2 showed the highest LN involvement (59.0%). The level involvement predicted by the mapping technique was consistent with the ground-truth distribution (p for difference 0.915). Application of the proposed methods to multicenter cohorts with selected H/N tumor subtypes for informing optimal RT target volume design is promising.

Non-Professional Phagocytosis Increases in Melanoma Cells and Tissues with Increasing E-Cadherin Expression.

Non-professional phagocytosis in cancer has been increasingly studied in recent decades. In malignant melanoma metastasis, cell-in-cell structures have been described as a sign of cell cannibalism. To date, only low rates of cell-in-cell structures have been described in patients with malignant melanoma. To investigate these findings further, we examined twelve primary melanoma cell lines in both adherent and suspended co-incubation for evidence of engulfment. In addition, 88 malignant melanoma biopsies and 16 healthy tissue samples were evaluated. E-cadherin levels were determined in the cell lines and tissues. All primary melanoma cell lines were capable of phagocytosis, and phagocytosis increased when cells were in suspension during co-incubation. Cell-in-cell structures were also detected in most of the tissue samples. Early T stages and increasingly advanced N and M stages have correspondingly lower rates of cell-in-cell structures. Non-professional phagocytosis was also present in normal skin tissue. Non-professional phagocytosis appears to be a ubiquitous mechanism in malignant melanoma. The absence of phagocytosis in metastases may be one reason for the high rate of metastasis in malignant melanoma.

Ex Vivo Chromosomal Radiosensitivity Testing in Patients with Pathological Germline Variants in Breast Cancer High-Susceptibility Genes BReast CAncer 1 and BReast CAncer 2.

BACKGROUND: Individual radiosensitivity is an important factor in the occurrence of undesirable consequences of radiotherapy. The potential for increased radiosensitivity has been linked to highly penetrant heterozygous mutations in DNA repair genes such as BRCA1 and BRCA2. By studying the chromosomal radiosensitivity of BRCA1/2 mutation carriers compared to the general population, we study whether increased chromosomal radiation sensitivity is observed in patients with BRCA1/2 variants. METHODS: Three-color-fluorescence in situ hybridization was performed on ex vivo-irradiated peripheral blood lymphocytes from 64 female patients with a heterozygous germline BRCA1 or BRCA2 mutation. Aberrations in chromosomes #1, #2 and #4 were analyzed. Mean breaks per metaphase (B/M) served as the parameter for chromosomal radiosensitivity. The results were compared with chromosomal radiosensitivity in a cohort of generally healthy individuals and patients with rectal cancer or breast cancer. RESULTS: Patients with BRCA1/2 mutations (n = 64; B/M 0.47) overall showed a significantly higher chromosomal radiosensitivity than general healthy individuals (n = 211; B/M 0.41) and patients with rectal cancer (n = 379; B/M 0.44) and breast cancer (n = 147; B/M 0.45) without proven germline mutations. Chromosomal radiosensitivity varied depending on the locus of the BRCA1/2 mutation. CONCLUSIONS: BRCA1/2 mutations result in slightly increased chromosomal sensitivity to radiation. A few individual patients have a marked increase in radiation sensitivity. Therefore, these patients are at a higher risk for adverse therapeutic consequences.

Acriflavine-Functionalized Silica@Manganese Ferrite Nanostructures for Synergistic Radiation and Hypoxia Therapies.

Mesoporous and nonmesoporous SiO2@MnFe2O4 nanostructures were loaded with the hypoxia-inducible factor-1 inhibitor acriflavine for combined radiation and hypoxia therapies. The X-ray irradiation of the drug-loaded nanostructures not only triggered the release of the acriflavine inside the cells but also initiated an energy transfer from the nanostructures to surface-adsorbed oxygen to generate singlet oxygen. While the drug-loaded mesoporous nanostructures showed an initial drug release before the irradiation, the drug was primarily released upon X-ray radiation in the case of the nonmesoporous nanostructures. However, the drug loading capacity was less efficient for the nonmesoporous nanostructures. Both drug-loaded nanostructures proved to be very efficient in irradiated MCF-7 multicellular tumor spheroids. The damage of these nanostructures toward the nontumorigenic MCF-10A multicellular spheroids was very limited because of the small number of nanostructures that entered the MCF-10A spheroids, while similar concentrations of acriflavine without nanostructures were toxic for the MCF-10A spheroids.

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

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