KCa channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by KCa expression levels.

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that KCa-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

Regional hyperthermia for soft tissue sarcoma - a survey on current practice, controversies and consensus among 12 European centers.

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

Efficacy of a fish hydrolysate supplement on sleep quality: A randomized, double-blind, placebo-controlled, crossover clinical trial.

BACKGROUND & AIMS: Sleep disturbances are widespread in modern societies and linked to a variety of diseases, creating an urgent need for the development of products that help combat sleep difficulties. One suitable nutritional supplement may be a fish hydrolysate composed of low molecular weight peptides. METHODS: This two-arm, double-blind, randomized, placebo-controlled crossover study investigated the effect of a 4-week fish hydrolysate intervention on sleep in a healthy German population reporting poor sleep quality, assessed with the Pittsburgh Sleep Quality Index (PSQI). Further sleep parameters were measured using an online diary and a wrist wearable device. Additionally, questionnaires related to stress, anxiety, depression, and well-being were evaluated and salivary cortisol and product satisfaction were assessed. RESULTS: The 4-week fish hydrolysate supplementation significantly improved subjective sleep quality measured with the PSQI-score (p = .002). Moreover, individuals reported improvements in sleep efficacy and a reduction in sleep disturbances and daytime sleepiness during fish hydrolysate intake (p = .013, p = .046, p = .004 respectively), but not during placebo phase (all p > .05). No significant intra-individual differences were found between fish hydrolysate and placebo supplementation (p > .05). CONCLUSIONS: Although no significant intra-individual differences were found between fish hydrolysate and placebo supplementation, the significant improvement in subjective sleep quality from baseline to treatment phase suggests that fish hydrolysate is a safe nutritional supplement to support individuals with self-reported sleep problems. CLINICAL TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov with the Identifier NCT04983355.

Clinical characteristics, treatment, and outcome of patients with large cell neuroendocrine carcinoma of the lung and brain metastases - data from a tertiary care center.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is an aggressive malignancy, with brain metastases (BM) occurring in approximately 20% of cases. There are currently no therapy guidelines for this population as only few data on the management of LCNEC and BM have been published. For this retrospective single center study, patients with LCNEC and BM were identified from the Vienna Brain Metastasis Registry. Data on clinicopathological features, BM-specific characteristics, treatment, and outcome were extracted. In total, 52/6083 (0.09%) patients in the dataset had a diagnosis of LCNEC and radiologically verified BM. Median age at diagnosis of LCNEC and BM was 59.1 and 60.1 years, respectively. Twenty-seven (51.9%) presented with single BM, while 12 (23%) exhibited > 3 BM initially. Neurologic symptoms due to BM were present in n = 40 (76.9%), encompassing neurologic deficits (n = 24), increased intracranial pressure (n = 18), and seizures (n = 6). Initial treatment of BM was resection (n = 13), whole brain radiation therapy (n = 19), and/or stereotactic radiosurgery (n = 25). Median overall survival (mOS) from LCNEC diagnosis was 16 months, and mOS after BM diagnosis was 7 months. Patients with synchronous BM had reduced mOS from LCNEC diagnosis versus patients with metachronous BM (11 versus 27 months, p = 0.003). Median OS after BM diagnosis did not differ between LCNEC patients and a control group of small cell lung cancer patients with BM (7 versus 6 months, p = 0.17). Patients with LCNEC and BM have a poor prognosis, particularly when synchronous BM are present. Prospective trials are required to define optimal therapeutic algorithms.

Clinical Implementation and Evaluation of Auto-Segmentation Tools for Multi-Site Contouring in Radiotherapy.

Background and purpose: Tools for auto-segmentation in radiotherapy are widely available, but guidelines for clinical implementation are missing. The goal was to develop a workflow for performance evaluation of three commercial auto-segmentation tools to select one candidate for clinical implementation. Materials and Methods: One hundred patients with six treatment sites (brain, head-and-neck, thorax, abdomen, and pelvis) were included. Three sets of AI-based contours for organs-at-risk (OAR) generated by three software tools and manually drawn expert contours were blindly rated for contouring accuracy. The dice similarity coefficient (DSC), the Hausdorff distance, and a dose/volume evaluation based on the recalculation of the original treatment plan were assessed. Statistically significant differences were tested using the Kruskal-Wallis test and the post-hoc Dunn Test with Bonferroni correction. Results: The mean DSC scores compared to expert contours for all OARs combined were 0.80 ± 0.10, 0.75 ± 0.10, and 0.74 ± 0.11 for the three software tools. Physicians' rating identified equivalent or superior performance of some AI-based contours in head (eye, lens, optic nerve, brain, chiasm), thorax (e.g., heart and lungs), and pelvis and abdomen (e.g., kidney, femoral head) compared to manual contours. For some OARs, the AI models provided results requiring only minor corrections. Bowel-bag and stomach were not fit for direct use. During the interdisciplinary discussion, the physicians' rating was considered the most relevant. Conclusion: A comprehensive method for evaluation and clinical implementation of commercially available auto-segmentation software was developed. The in-depth analysis yielded clear instructions for clinical use within the radiotherapy department.

Efficacy of combined tumor irradiation and KCa3.1-targeting with TRAM-34 in a syngeneic glioma mouse model.

The intermediate-conductance calcium-activated potassium channel KCa3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and KCa3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560's intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-ß1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3+, CD8+ or FoxP3+ T cells was not impacted by either irradiation or KCa3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model.

Potential of pre-operative MRI features in glioblastoma to predict for molecular stem cell subtype and patient overall survival.

AIM OF THE STUDY: A molecular signature based on 10 mRNA abundances that characterizes the mesenchymal-to-proneural phenotype of glioblastoma stem(like) cells (GSCs) enriched in primary culture has been previously established. As this phenotype has been proposed to be prognostic for disease outcome the present study aims to identify features of the preoperative MR imaging that may predict the GSC phenotype of individual tumors. MATERIAL/METHODS: Molecular mesenchymal-to-proneural mRNA signatures and intrinsic radioresistance (SF4, survival fraction at 4 Gy) of primary GSC-enriched cultures were associated with survival data and pre-operative MR imaging of the corresponding glioblastoma patients of a prospective cohort (n = 24). The analyzed imaging parameters comprised linear vectors derived from tumor volume, necrotic volume and edema as contoured manually. RESULTS: A necrosis/tumor vector ratio and to a weaker extent the product of this ratio and the edema vector were identified to correlate with the mesenchymal-to-proneural mRNA signature and the SF4 of the patient-derived GSC cultures. Importantly, both parameter combinations were predictive for overall survival of the whole patient cohort. Moreover, the combination of necrosis/tumor vector ratio and edema vector differed significantly between uni- and multifocally recurring tumors. CONCLUSION: Features of the preoperative MR images may reflect the molecular signature of the GSC population and might be used in the future as a prognostic factor and for treatment stratification especially in the MGMT promotor-unmethylated sub-cohort of glioblastoma patients.

DNA as the main target in radiotherapy-a historical overview from first isolation to anti-tumour immune response.

DNA damage is one of the foremost mechanisms of irradiation at the biological level. After the first isolation of DNA by Friedrich Miescher in the 19th century, the structure of DNA was described by Watson and Crick. Several Nobel Prizes have been awarded for DNA-related discoveries. This review aims to describe the historical perspective of DNA in radiation biology. Over the decades, DNA damage has been identified and quantified after irradiation. Depending on the type of sensing, different proteins are involved in sensing DNA damage and repairing the damage, if possible. For double-strand breaks, the main repair mechanisms are non-homologous end joining and homologous recombination. Additional mechanisms are the Fanconi anaemia pathway and base excision repair. Different methods have been developed for the detection of DNA double-strand breaks. Several drugs have been developed that interfere with different DNA repair mechanisms, e.g., PARP inhibitors. These drugs have been established in the standard treatment of different tumour entities and are being applied in several clinical trials in combination with radiotherapy. Over the past decades, it has become apparent that DNA damage mechanisms are also directly linked to the immune response in tumours. For example, cytosolic DNA fragments activate the innate immune system via the cGAS STING pathway.

Hyperthermia in the treatment of high-risk soft tissue sarcomas: a systematic review.

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

Increasing Patient Safety and Treatment Quality by Using Intraoperative MRI for Organ-Preserving Tumor Resection and High-Dose Rate Brachytherapy in Children with Bladder/Prostate and Perianal Rhabdomyosarcoma.

In children with bladder/prostate (BP) and perianal rhabdomyosarcoma (RMS), we use a hybrid treatment concept for those suitable, combining organ-preserving tumor resection and high-dose rate brachytherapy (HDR-BT). This treatment concept has been shown to improve outcomes. However, it is associated with specific challenges for the clinicians. The exact position of the tubes for BT is a prerequisite for precise radiotherapy. It can finally be determined only with an MRI or CT scan. We evaluated the use of an intraoperative MRI (iMRI) to control the position of the BT tubes and for radiotherapy planning in all patients with BP and perianal RMS who received the above-mentioned combination therapy in our department since January 2021. iMRI was used in 12 children. All tubes were clearly localized. No adverse events occurred. In all 12 children, radiotherapy could be started on time. In a historical cohort without iMRI, this was not possible in 3 out of 20 children. The use of iMRI in children with BP and perianal RMS improved patient safety and treatment quality. This technology has proven to be successful for the patient population we have defined and has become a standard procedure in our institution.

Prognostic impact of the post-treatment T cell composition and spatial organization in soft tissue sarcoma patients treated with neoadjuvant hyperthermic radio(chemo)therapy.

Soft tissue sarcomas (STS) form a heterogeneous group of tumors sharing a mesenchymal origin. Despite good local control of the disease, the occurrence of distant metastases often limits survival of STS patients with localized, high-risk tumors of the extremities. Accumulating evidence suggests a central role for the tumor immune microenvironment in determining the clinical outcome and response to therapy. Thus, it has been reported that STS patients with a high immune signature and especially presence of B cells and tertiary lymphoid structures display improved overall survival and response to checkpoint inhibitor treatment. Here, we explored the effect of curative multimodal therapy on the T cell landscape of STS using multiplex immunohistochemistry. We analyzed the phenotype, frequency, and spatial distribution of STS-infiltrating CD8+ T cells by staining for CD8, 4-1BB, Granzyme B, Ki67, PD-1, and LAG-3 as well as CD3+ T helper cells using a panel consisting of CD3, T-bet, GATA3, RORγT, FoxP3, and Ki67. All patients received neoadjuvant radiotherapy plus locoregional hyperthermia with or without chemotherapy. While the treatment-naïve biopsy sample allows an analysis of baseline T cell infiltration levels, both intra- and peritumoral areas of the matched resected tissue were analyzed to assess composition and spatial distribution of the T cell compartment and its therapeutic modulation. Generally, post-treatment tissues displayed lower frequencies of CD3+ and CD8+ T cells. Association with clinical data revealed that higher post-treatment frequencies of peritumoral and intratumoral CD3+ T cells and intratumoral PD-1+ CD8+ T cells were significantly associated with improved disease-free survival (DFS), while these densities had no prognostic significance in the biopsy. Upon spatial analysis, a high ratio of intratumoral to peritumoral CD8+ T cells emerged as an independent prognostic marker for longer DFS. These results indicate that the STS T cell landscape is altered by multimodal therapy and may influence the clinical outcome of patients. An enhanced understanding of the STS immune architecture and its modulation by neoadjuvant therapy may pave the way towards novel treatment modalities and improve the long-term clinical outcome of STS patients.

Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer.

PURPOSE: HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non-small cell lung cancer (NSCLC) as the basis for future clinical trial design. EXPERIMENTAL DESIGN: We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. RESULTS: A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. CONCLUSIONS: HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961.

Ion channels as molecular targets of glioblastoma electrotherapy.

Therapies with weak, non-ionizing electromagnetic fields comprise FDA-approved treatments such as Tumor Treating Fields (TTFields) that are used for adjuvant therapy of glioblastoma. In vitro data and animal models suggest a variety of biological TTFields effects. In particular, effects ranging from direct tumoricidal, radio- or chemotherapy-sensitizing, metastatic spread-inhibiting, up to immunostimulation have been described. Diverse underlying molecular mechanisms, such as dielectrophoresis of cellular compounds during cytokinesis, disturbing the formation of the spindle apparatus during mitosis, and perforating the plasma membrane have been proposed. Little attention, however, has been paid to molecular structures that are predestinated to percept electromagnetic fields-the voltage sensors of voltage-gated ion channels. The present review article briefly summarizes the mode of action of voltage sensing by ion channels. Moreover, it introduces into the perception of ultra-weak electric fields by specific organs of fishes with voltage-gated ion channels as key functional units therein. Finally, this article provides an overview of the published data on modulation of ion channel function by diverse external electromagnetic field protocols. Combined, these data strongly point to a function of voltage-gated ion channels as transducers between electricity and biology and, hence, to voltage-gated ion channels as primary targets of electrotherapy.

Brain metastases from hepatopancreatobiliary malignancies.

While colorectal and gastroesophageal cancer represent the two gastrointestinal (GI) tumor entities with the highest incidence of brain metastatic (BM) disease, data on the clinical course of BM patients from hepatopancreatobiliary malignancies are rare. Patients with cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC) and gastroenteropancreatic neuroendocrine neoplasms (GEP NEN). Treated for BM between 1991 and 2017 at an academic care center were included. Brain metastases-free survival (BMFS) was defined as interval from first diagnosis until BM development. Overall survival (OS) was defined as interval from diagnosis of BM until death or last date of follow-up. Outcome was correlated with clinical and treatment factors. 29 patients from overall 6102 patients (0.6%) included in the Vienna Brain Metastasis Registry presented with BM from hepatopancreatobiliary primaries including 9 (31.0%) with CCA, 10 (34.5%) with HCC, 7 (24.1%) with PDAC and 3 (10.3%) with GEP NEN as primary tumor. Median BMFS was 21, 12, 14 and 7 months and median OS 4, 4, 6 and 4 months, respectively. Karnofsky Performance Status (KPS) below 80% (p = 0.08), age above 60 years (p = 0.10) and leptomeningeal carcinomatosis (LC) (p = 0.09) diagnosed concomitant to solid BM showed an inverse association with median OS (Cox proportional hazards model). In this cohort of patients with BM from hepatopancreatobiliary tumor entities, prognosis was shown to be very limited. Performance status, age and diagnosis of LC were identified as negative prognostic factors.

Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment.

BACKGROUND: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. METHODS: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). RESULTS: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. CONCLUSIONS: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Robotic Esophagectomy Compared With Open Esophagectomy Reduces Sarcopenia within the First Postoperative Year: A Propensity Score-Matched Analysis.

INTRODUCTION: Sarcopenia is a known risk factor for adverse outcomes after esophageal cancer (EC) surgery. Robot-assisted minimally invasive esophagectomy (RAMIE) offers numerous advantages, including reduced morbidity and mortality. However, no evidence exists to date comparing the development of sarcopenia after RAMIE and open esophagectomy (OE). The objective was to evaluate whether the development of sarcopenia within the first postoperative year after esophagectomy is associated with the surgical approach: RAMIE versus OE. METHODS: A total of 168 patients with EC were analyzed who either underwent total robotic or fully open Ivor Lewis esophagectomy in a propensity score-matched analysis. Sarcopenia was assessed using the skeletal muscle index (cm2/m2) and psoas muscle thickness per height (mm/m) on axial computed tomography scans during the first postoperative year; in total 540 computed tomography scans were evaluated. RESULTS: After 1-to-1 propensity score matching for confounders, 67 patients were allocated to RAMIE and OE groups, respectively. Skeletal muscle index in the OE group was significantly lower compared with the RAMIE group at the third (43.2 ± 7.6 cm2/m2 versus 49.1 ± 6.9 cm2/m2, p = 0.001), sixth (42.7 ± 7.8 cm2/m2 versus 51.5 ± 8.2 cm2/m2, p < 0.001) and ninth (43.0 ± 7.0 cm2/m2 versus 49.9 ± 6.6 cm2/m2, p = 0.015) postoperative month. Similar results were recorded for psoas muscle thickness per height. CONCLUSIONS: To our knowledge, this study is the first to suggest a substantial benefit of RAMIE compared with open esophagectomy in terms of postoperative sarcopenia. These results add further evidence to support the implementation of the robotic approach in multimodal therapy of EC.

Detailed functional results after bladder-preserving surgery and high-dose-rate brachytherapy in pediatric bladder/prostate rhabdomyosarcoma.

PURPOSE: In pediatric bladder/prostate-rhabdomyosarcoma, the rate of bladder preservation after neoadjuvant chemotherapy is high, with an excellent oncological outcome. Information about functional urological long-term outcomes is rare. METHODS: Data of all patients who had undergone bladder-preserving surgery with or without brachytherapy at our institution between 2009 and 2020 were analyzed retrospectively. Detailed urological function was assessed focusing on age-related continence, bladder capacity and urodynamic findings. RESULTS: We identified 40 patients, median age at surgery of 27 months (range 9-191), and 32 patients additionally received postoperative high-dose-rate brachytherapy. The median follow-up was 32.5 months (range 6-125). The bladder capacity increased from median 66.7% (21.1-180) of expected bladder capacity related to age 3 months after surgery to 87.4% (58.1-181.8) 9 months after surgery. In the group of aged > 6-year-old, continence was 94% (83% with brachytherapy, 100% without brachytherapy). Erectile function was normal in 92% (90% with brachytherapy, 100% without brachytherapy). Bladder capacity was more than 65% expected bladder capacity related to age in 70% (60% with brachytherapy, 86% without brachytherapy). 65% of all patients need neither anticholinergic drugs nor low-dose antibiotics (63% with brachytherapy, 71% without brachytherapy). CONCLUSIONS: Bladder preservation with good functional outcome can be achieved in localized bladder/prostate-rhabdomyosarcoma. In selected cases, supportive brachytherapy additionally contributes to an improvement in the oncological outcome with calculable risks for bladder and erectile function. Careful urological aftercare should be a fixed priority after oncological follow-ups.

Dose-escalated radiotherapy with simultaneous integrated boost for bone metastases in selected patients with assumed favourable prognosis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) concepts for dose escalation are increasingly used for bone metastases in patients with oligometastatic or oligoprogressive disease. For metastases that are not suitable for SBRT-regimens, a treatment with 30/40 Gy with simultaneous integrated boost (SIB) in 10 fractions represents a possible regimen. The aim of this study was to investigate the feasibility of this concept and the acute and subacute toxicities. PATIENTS AND METHODS: Clinical records for dose-escalated radiotherapy of all consecutive patients treated with this regimen were evaluated retrospectively (24 patients with 28 target volumes for oncologic outcomes and 25 patients with 29 target volumes for treatment feasibility and dose parameters analysis). Analysis of radiotherapy plans included size of target volumes and dosimetric parameter for target volumes and organs at risk (OAR). Acute and subacute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) V4.0. RESULTS: The most common localization was the spine (71.4%). The most common histology was prostate cancer (45.8%). Oligometastatic or oligoprogressive disease was the indication for dose-escalated radiotherapy in 19/24 patients (79.2%). Treatment was feasible with all patients completing radiotherapy. Acute toxicity grade 1 was documented in 36.0% of the patients. During follow up, one patient underwent surgery due to bone instability. The 1-year local control and patient-related progression-free survival (PFS) were 90.0 ± 6.7% and 33.3 ± 11.6%, respectively. CONCLUSIONS: Dose-escalated hypofractionated radiotherapy with simultaneous integrated boost for bone metastases resulted in good local control with limited acute toxicities. Only one patient required surgical intervention. The regimen represents an alternative to SBRT in selected patients.

Plasma sICAM-1 correlates with tumor volume before primary radiochemotherapy of head and neck squamous cell carcinoma patients.

BACKGROUND: Biomarkers are of major interest to optimize diagnosis, prognosis and to guide treatment in head and neck cancer patients. Especially blood-based biomarkers appear promising as they can be easily collected and repeatedly analyzed during the course of radiochemotherapy. PATIENTS AND METHODS: At first, for a broad overview, multiple immune markers were evaluated in six plasma samples of three head and neck squamous cell carcinoma (HNSCC) patients at the beginning and the end of radio-chemotherapy. In this pre-selection, the soluble Intercellular Adhesion Molecule 1 (sICAM-1) appeared most promising. Thus, this marker was measured in multiple samples (n = 86) during treatment and follow-up in a cohort of eleven patients and correlated with tumor features and clinical data. RESULTS: We found a strong correlation between the initial levels of sICAM-1 in the plasma and the gross tumor volumes of the primary tumor and the involved lymph nodes. However, during the course of treatment no systematic dynamics could be identified. Toxicity or infections did not seem to influence sICAM-1 concentrations. CONCLUSIONS: sICAM-1 appears to reflect the pre-treatment total tumor burden (primary tumor and involved lymph nodes) in head and neck tumor patients. However, it does not seem to be a dynamic marker reflecting response during radiochemotherapy. Thus, if our findings are confirmed in future, sICAM-1 could be used as a staging marker: if high sICAM-1 levels but low tumor burden are found it might be reasonable to intensify staging investigations to rule out further, yet undetected, tumor sites.

Postoperative complications and oncologic outcomes after multimodal therapy of localized high risk soft tissue sarcoma.

BACKGROUND: Standard therapy for localized high-risk soft tissue sarcoma includes surgical resection and neoadjuvant or adjuvant radiation therapy (± chemotherapy and locoregional hyperthermia). No difference in oncologic outcomes for patients treated with neoadjuvant and adjuvant radiation therapy was reported, whereas side effect profiles differ. The aim of this analysis was to analyse oncologic outcomes and postoperative complications in patients treated with multimodal treatment. METHODS: Oncologic outcomes and major wound complications (MWC, subclassified as wound healing disorder, infection, abscess, fistula, seroma and hematoma) were evaluated in 74 patients with localized high-risk soft tissue sarcoma of extremities and trunk undergoing multimodal treatment, and also separately for the subgroup of lower extremity tumors. Clinical factors and treatment modalities (especially neoadjuvant vs. adjuvant radiotherapy) were evaluated regarding their prognostic value and impact on postoperative wound complications. RESULTS: Oncologic outcomes were dependent on number of high risk features (tumor size, depth to superficial fascia and grading), but not on therapy sequencing (however with higher risk patients in the neoadjuvant group). Different risk factors influenced different subclasses of wound healing complications. Slightly higher MWC-rates were observed in patients treated with neoadjuvant therapy, compared to adjuvant radiotherapy, although only with a trend to statistical significance (31.8% vs. 13.3%, p = 0.059). However, except for wound infections, no significant difference for other subclasses of postoperative complications was observed between neoadjuvant and adjuvant therapy. Diabetes was confirmed as a major risk factor for immune-related wound complications. CONCLUSION: Rates of major wound complications in this cohort are comparable to published data, higher rates of wound infections were observed after neoadjuvant radiotherapy. Tumor localization, patient age and diabetes seem to be major risk factors. The number of risk factors for high risk soft tissue sarcoma seem to influence DMFS. Neoadjuvant treatment increases the risk only for wound infection treated with oral or intravenous antibiotic therapy and appears to be a safe option at an experienced tertiary center in absence of other risk factors.