Impact of FAPI-46/dual-tracer PET/CT imaging on radiotherapeutic management in esophageal cancer.

BACKGROUND: Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC). METHODS: 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as "minor" (adaption of radiation field) or "major" (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue. RESULTS: Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields ("minor change") in 5/32 patients (16%) and changed treatment regimen ("major change") in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p < 0.001)) with similar results for nuclear medical FTVs. IHC revealed heterogenous FAP-expression in all specimens (mean H-score: 36.3 (SD 24.6)) without correlation between FAP expression in IHC and FAPI tracer uptake in PET/CT. CONCLUSION: We report first data on the use of PET with FAPI-46 for patients with EC, who are scheduled to receive RT. Tumor uptake was high and not depending on FAP expression in TME. Further, FAPI-46/dual-tracer PET had relevant impact on management in this setting. Our data calls for prospective evaluation of FAPI-46/dual-tracer PET to improve clinical outcomes of EC.

Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume.

PURPOSE: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. METHODS: A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. RESULTS: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. CONCLUSION: Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging.

Satisfaction with radiotherapy care among cancer patients treated in Germany-secondary analysis of a large multicenter study.

PURPOSE: Patient satisfaction with healthcare has been linked to clinical outcomes and regulatory agencies demand its regular assessment. Therefore, we aimed to investigate patient satisfaction with radiotherapy care and its determinants. METHODS: This is a secondary analysis of a multicenter prospective cross-sectional study. Eligible cancer patients anonymously completed questionnaires at the end of a course of radiotherapy. The outcome variable was overall patient satisfaction with radiotherapy care measured with a 10-point Likert scaled single-item. Given patient satisfaction was defined for patients scoring ≥ 8 points. Determinants of given patient satisfaction were assessed by univariable and multivariable analyses. A p-value < 0.05 was considered statistically significant. RESULTS: Out of 2341 eligible patients, 1075 participated (participation rate 46%). Data on patient satisfaction was provided by 1054 patients. There was a right-skewed distribution towards more patient satisfaction (mean = 8.8; SD = 1.68). Given patient satisfaction was reported by 85% (899/1054) of the patients. Univariable analyses revealed significant associations of lower patient satisfaction with tumor entity (rectal cancer), concomitant chemotherapy, inpatient care, treating center, lower income, higher costs, and lower quality of life. Rectal cancer as tumor entity, treating center, and higher quality of life remained significant determinants of patient satisfaction in a multivariable logistic regression. CONCLUSION: Overall patient satisfaction with radiotherapy care was high across 11 centers in Germany. Determinants of patient satisfaction were tumor entity, treating center, and quality of life. Although these data are exploratory, they may inform other centers and future efforts to maintain high levels of patient satisfaction with radiotherapy care.

Psychosocial distress in cancer patients undergoing radiotherapy: a prospective national cohort of 1042 patients in Germany.

PURPOSE: Psychosocial distress is common among cancer patients in general, but those undergoing radiotherapy may face specific challenges. Therefore, we investigated the prevalence and risk factors for distress in a large national cohort. METHODS: We performed a secondary analysis of a multicenter prospective cross-sectional study which surveyed cancer patients at the end of a course of radiotherapy using a patient-reported questionnaire. Distress was measured with the distress thermometer (DT), using a cut-off of ≥ 5 points for clinically significant distress. Univariate analyses and multivariate multiple regression were used to assess associations of distress with patient characteristics. A two-sided p-value < 0.05 was considered statistically significant. RESULTS: Out of 2341 potentially eligible patients, 1075 participated in the study, of which 1042 completed the DT. The median age was 65 years and 49% (511/1042) of patients were female. The mean DT score was 5.2 (SD = 2.6). Clinically significant distress was reported by 63% (766/1042) of patients. Of the patient characteristics that were significantly associated with distress in the univariate analysis, a lower level of education, a higher degree of income loss, lower global quality of life, and a longer duration of radiotherapy in days remained significantly associated with higher distress in the multivariate analysis. Yet effect sizes of these associations were small. CONCLUSION: Nearly two in three cancer patients undergoing radiotherapy reported clinically significant distress in a large multicenter cohort. While screening and interventions to reduce distress should be maintained and promoted, the identified risk factors may help to raise awareness in clinical practice. TRIAL REGISTRY IDENTIFIER: DRKS: German Clinical Trial Registry identifier: DRKS00028784.

Financial toxicity in cancer patients undergoing radiotherapy in a universal health care system - A prospective multicenter study of 1075 patients.

PURPOSE: To establish and confirm prevalence as well as risk factors of financial toxicity in a large national cohort of cancer patients undergoing radiotherapy in a universal health care system. METHODS: We conducted a prospective cross-sectional study offering a patient-reported questionnaire to all eligible cancer patients treated with radiotherapy in 11 centers in Germany during 60 consecutive days. The four-point subjective financial distress question of the EORTC QLQ-C30 was used as a surrogate for financial toxicity. Confirmatory hypothesis testing evaluated the primary study outcomes: overall prevalence of financial toxicity and its association with predefined risk factors. P-values < 0.05 were considered statistically significant. RESULTS: Of 2341 eligible patients, 1075 (46%) participated. The prevalence of subjective financial distress (=any grade higher than not present) was 41% (438/1075) exceeding the hypothesized range of 26.04-36.31%. Subjective financial distress was felt "A little" by 26% (280/1075), "Quite a bit" by 11% (113/1075) and "Very much" by 4% (45/1075) of the patients. Lower household income, lower global health status/ quality of life, higher direct costs and higher loss of income significantly predicted higher subjective financial distress per ordinal regression and confirmed these risk factors. Higher psychosocial distress and lower patient satisfaction were significantly associated with higher subjective financial distress in an exploratory ordinal regression model. CONCLUSION: The overall prevalence of financial toxicity was higher than anticipated, although reported at low or moderate degrees by most affected patients. As we confirmed risk factors associated with financial toxicity, patients at risk should be addressed early for potential support.

First Clinical Experience With [68Ga]Ga-FAPI-46-PET/CT Versus [18F]F-FDG PET/CT for Nodal Staging in Cervical Cancer.

INTRODUCTION: In several solid tumors, fibroblast activation protein (FAP) is overexpressed by cancer-associated fibroblasts in the tumor microenvironment. Preliminary evidence suggests that detection and staging are feasible with PET/CT imaging using [68Ga]-radiolabeled inhibitors of FAP also in cervical cancer (CC). Our study aims to explore the accuracy of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT and [18F]F-FDG PET/CT compared with histopathological results of surgical lymph node (LN) staging before primary chemoradiation. METHODS: Seven consecutive women with treatment-naive and biopsy-proven locally advanced CC underwent both whole-body [68Ga]Ga-FAPI-46- and [18F]F-FDG PET/CT, for imaging nodal staging before systematic laparoscopic lymphadenectomy of the pelvic and para-aortic region. Location and number of suspicious LNs in PET imaging were recorded and compared with the results of histopathological analysis, including immunohistochemical staining for FAP. RESULTS: All 7 patients had focal uptake above background in their tumor lesions in [68Ga]Ga-FAPI-46 PET/CT. [68Ga]Ga-FAPI-46 PET/CT showed a higher tumor-to-background ratio (TBR) in primary tumor as well as in LN metastasis. Median TBRmax values using liver were 32.02 and 5.15 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Median TBRmax using blood pool was 18.45 versus 6.85 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Higher TBR also applies for nodal metastasis: TBRmax was 14.55 versus 1.39 (liver) and 7.97 versus 1.8 (blood pool) for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Overall, [68Ga]Ga-FAPI-46 PET/CT detected more lesions compared with [18F]F-FDG PET/CT. Following surgical staging, a total of 5 metastatic LNs could be pathologically confirmed, of which 2 and 4 were positive by [18F]F-FDG PET/CT and [68Ga]Ga-FAPI-46 PET/CT, respectively. CONCLUSION: [68Ga]Ga-FAPI-46 PET/CT seems useful to improve detection of nodal metastasis in patients with CCs. Future studies should aim to compare [68Ga]Ga-FAPI-46 PET/CT to surgical staging of pelvic and para-aortic LNs in patients with locally advanced CC.

Dose-escalated re-irradiation improves outcome in locally recurrent head and neck cancer - Results of a large multicenter analysis.

To determine efficacy and prognostic parameters of definitive re-irradiation of locoregionally recurrent squamous cell carcinoma of the head and neck (HNSCC). MATERIALS AND METHODS: Patients with locoregionally recurrent or second primary HNSCC undergoing re-irradiation with modern radiotherapy technique were eligible for this multicentric retrospective analysis. Main endpoints were overall survival (OS), progression-free survival (PFS) and locoregional control (LC). Univariate analyses were performed using the Kaplan Meier Method (log-rank). For multivariable analysis, Cox regression was used. RESULTS: A total of 253 patients treated between 2009 and 2020 at 16 university hospitals in Germany were included. The median follow up was 27.4 months (range 0.5-130). The median OS and PFS were 13.2 (CI: 10.7 - 15.7) months and 7.9 (CI: 6.7 - 9.1) months, respectively, corresponding to two-year OS and PFS rates of 29 % and 19 %. Rates of locoregional progression and "in-field-failure" were 62 % and 51 % after two years. Multivariable Cox regression analysis identified good ECOG performance status and high radiation dose as independent prognostic parameters for OS. Doses above 50 Gy (EQD2) achieved longer median OS of 17.8 months (vs 11.7 months, p < 0.01) and longer PFS of 9.6 months (vs 6.8 months, p < 0.01). In addition, there was a trend for worse survival in patients with tracheostomy (multivariable, p = 0.061). Concomitant systemic therapy did not significantly impact PFS or OS. CONCLUSION: Re-irradiation of locally recurrent or second primary HNSCC is efficient, especially if doses above 50 Gy (EQD2) are delivered. ECOG performance score was the strongest prognostic parameter for OS and PFS.

Teaching in radiation oncology: now and 2025-results of a focus group with medical students.

PURPOSE: In Germany, the new Licensing Regulations for Physicians 2025 (Ärztliche Approbationsordnung, ÄApprO) define a binding legal framework on the basis of which medical faculties modernize their curricula. Since 2015, the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) formulates competencies and learning objectives to be achieved in the course of studies as curriculum orientation for the medical faculties. In addition, about 80% of the areas of a new core curriculum are to be made compulsory. A needs analysis in the target group of students has not yet taken place for the subject of radiation therapy (RT) or radiation oncology (RO). This study therefore surveys the experiences and requirements of students regarding medical education in RT. METHODS: Qualitative single-center study using a semistructured in-depth focus group with 11 medical students (20-26 years; 6 female, 5 male) was conducted. Brainstorming sessions were conducted in small groups and individually; oral contributions were recorded, transcribed, and analyzed using qualitative content analysis according to Mayring. Results were compared with the content of the future curriculum and reviewed for congruence with current expert recommendations of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). RESULTS: The plans to develop a longitudinal and practice-oriented curriculum was positively received by students. Specifically, students wanted to introduce the basics of RT as an early link to practice in preclinical teaching units. The necessary acquisition of communicative skills should also be taught by lecturers in RO. Methodologically, regular digital survey tools for self-monitoring, discussion rooms, and problem-based learning were named. In the perception of students, the subject appears underrepresented in relation to its relevance in the multimodal therapy of oncological diseases. CONCLUSION: Results of the needs analysis for the subject of RT are consistent with ÄApprO, NKLM, and DEGRO. Moreover, they complement them and should be considered in the curriculum development of Masterplan Medical Education 2020 (Masterplan Medizinstudium 2020). The results contribute to high-quality and target-group-oriented medical training in the subject of RT, increased visibility, and thus early bonding of future physicians to RO in Germany.

Chemoradiation for elderly patients (≥ 65 years) with esophageal cancer: a retrospective single-center analysis.

BACKGROUND: Present studies on the efficacy and safety of curative chemoradiation therapy (CRT) with esophageal cancer reflect heterogenous results especially in elderly patients. The aim of this study was to evaluate the toxicity and efficacy of CRT in patients ≥ 65 years. In a cohort, the focus centered around treatment-related toxicity (CTCAE Grade > 3), overall survival as well as progression free survival, comparing these rates in-between patients older than 70 years to those younger than 70 years. METHODS: A total of 67 patients older than 65 years (34 (50.7%) were older than 70 years) met the inclusion criteria for retrospective analysis (period from January 2013 to October 2017). Treatment consisted of radiotherapy and chemotherapy with carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. A sum of 67 patients received CRT (44 (65.6%) patients in neoadjuvant, 23 (34.4%) in definite intent). Of these, 22 and 12 patients were older than 70 years (50% and 52.2% in both treatment groups, respectively). Median age was 71 years and patients had a good physical performance status (ECOG 0: 57.6%, ECOG 1: 27.3%). Median follow-up was 24 months. Most patients had advanced tumour stages (T3 stage: n = 51, 79.7%) and nodal metastasis (N1 stage: n = 54, 88.5%). A subgroup comparison was conducted between patients aged ≤ 70 years and > 70 years. RESULTS: In severe (CTCAE Grade 3-5) toxicities (acute and late), no significant differences were observed between both patient groups (< 70 years vs. > 70 years). 21% had acute grade 3 events, 4 patients (4%) had grade 4 events, and two patients (3%) had one grade 5 event. Late toxicity after CRT was grade 1 in 13 patients (22%), grade 2 in two (3%), grade 3 in two (3%), grade 4 in four (7%), and grade 5 in one (2%). Median overall survival (OS) of all patients was 30 months and median progression-free survival (PFS) was 16 months. No significant differences were seen for OS (32 months vs. 25 months; p = 0.632) and PFS (16 months vs. 12 months; p = 0.696) between older patients treated with curative intent and younger ones. Trimodal therapy significantly prolonged both OS and PFS (p = 0.005; p = 0.018), regardless of age. CONCLUSION: CRT in elderly patients (≥ 65 years) with esophageal cancer is feasible and effective. Numbers for acute and late toxicities can be compared to cohorts of younger patients (< 65 years) with EC who received the same therapies. Age at treatment initiation alone should not be the determining factor. Instead, functional status, risk of treatment-related morbidities, life expectancy and patient´s preferences should factor into the choice of therapy.

Head-to-Head Comparison of [68 Ga]Ga-FAPI-46-PET/CT and [18F]F-FDG-PET/CT for Radiotherapy Planning in Head and Neck Cancer.

INTRODUCTION: In head and neck cancers (HNCs), fibroblast activation protein (FAP) is expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Preliminary evidence suggests that detection and staging is feasible with positron emission tomography (PET/CT) imaging using [68 Ga]-radiolabeled inhibitors of FAP ([68 Ga]Ga-FAPI-46) in HNCs. This study aims to compare [68 Ga]Ga-FAPI-46 PET/CT and [18F]-fluorodeoxy-D-glucose ([18F]F-FDG) PET/CT with a focus on improved target volume definition and radiotherapy planning in patients with HNC referred for chemoradiation. METHODS: A total of 15 patients with HNCs received both [68 Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT with a thermoplastic mask, in addition to initial tumor staging by conventional imaging with contrast-enhanced CT and/or MRI. Mean intervals between FAPI/FDG and FAPI/conventional imaging were 4 ± 20 and 17 ± 18 days, respectively. Location and number of suspicious lesions revealed by the different procedures were recorded. Subsequently, expert-generated gross tumor volumes (GTVs) based on conventional imaging were compared to those based on [18F]F-FDG and [68 Ga]Ga-FAPI-46 PET/CT to measure the impact on subsequent radiation planning. RESULTS: All patients had focal FAPI uptake above background in tumor lesions. Compared to FDG, tumor uptake (median SUVmax 10.2 vs. 7.3, p = 0.008) and tumor-to-background ratios were significantly higher with FAPI than with FDG (SUVmean liver: 9.3 vs. 3.2, p < 0.001; SUVmean bloodpool: 6.9 vs. 4.0, p < 0.001). A total of 49 lesions were recorded. Of these, 40 (82%) were FDG+ and 41 (84%) were FAP+. There were 5 (10%) FAP+/FDG- lesions and 4 (8%) FAP-/FDG+ lesions. Volumetrically, a significant difference was found between the GTVs (median 57.9 ml in the FAPI-GTV, 42.5 ml in the FDG-GTV, compared to 39.2 ml in the conventional-GTV). Disease stage identified by FAPI PET/CT was mostly concordant with FDG PET/CT. Compared to conventional imaging, five patients (33%) were upstaged following imaging with FAPI and FDG PET/CT. CONCLUSION: We demonstrate that [68 Ga]Ga-FAPI-46 -PET/CT is useful for detecting tumor lesions in patients with HNCs. There is now a need for prospective randomized studies to confirm the role of [68 Ga]Ga-FAPI-46 PET/CT in relation to [18F]F-FDG PET/CT in HNCs and to evaluate its impact on clinical outcome.

Dual-Tracer PET/CT Protocol with [18F]-FDG and [68Ga]Ga-FAPI-46 for Cancer Imaging: A Proof of Concept.

Imaging studies with PET tracers acting as fibroblast activation protein inhibitors (FAPIs) show promising results that could usefully complement [18F]-FDG in cancer imaging. Methods: All patients received [18F]-FDG PET/CT and dual-tracer PET/CT after an additional injection of [68Ga]Ga-FAPI-46 after the [18F]-FDG PET/CT. Two readers visually compared detection rate and analyzed target-to-background ratios for tumor and metastatic tissue in single- and dual-tracer PET/CT. Results: Detection rate in dual-tracer PET/CT was visually as good as that in single-tracer PET/CT in 4 patients and superior in 2 patients, whereas target-to-background ratios were significantly higher in dual-tracer PET/CT. Conclusion: Dual-tracer [18F]-FDG/[68Ga]Ga-FAPI-46 PET/CT within a single session is feasible and has potential. The dual-tracer approach may have superior sensitivity to [18F]-FDG PET/CT alone without compromising individual assessment of either scan.

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups.

While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184−3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059−3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285−3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112−3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309−0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271−0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299−0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253−6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288−0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm3 (HR 1.947 (1.007−3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy (p = 0.014), PTV > 3 cm3 (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.

Some like it cold: the cellular organization and physiological limits of cold-tolerant nitrite-oxidizing Nitrotoga.

Chemolithoautotrophic production of nitrate is accomplished by the polyphyletic functional group of nitrite-oxidizing bacteria (NOB). A widely distributed and important NOB clade in nitrogen removal processes at low temperatures is Nitrotoga, which however remains understudied due to the scarcity of cultivated representatives. Here, we present physiological, ultrastructural and genomic features of Nitrotoga strains from various habitats, including the first marine species enriched from an aquaculture system. Immunocytochemical analyses localized the nitrite-oxidizing enzyme machinery in the wide irregularly shaped periplasm, apparently without contact to the cytoplasmic membrane, confirming previous genomic data suggesting a soluble nature. Interestingly, in two strains we also observed multicellular complexes with a shared periplasmic space, which seem to form through incomplete cell division and might enhance fitness or survival. Physiological tests revealed differing tolerance limits towards dissolved inorganic nitrogen concentrations and confirmed the generally psychrotolerant nature of the genus. Moreover, comparative analysis of 15 Nitrotoga genomes showed, e.g. a unique gene repertoire of the marine strain that could be advantageous in its natural habitat and confirmed the lack of genes for assimilatory nitrite reduction in a strain found to require ammonium for growth. Overall, these novel insights largely broaden our knowledge of Nitrotoga and elucidate the metabolic variability, physiological limits and thus potential ecological roles of this group of nitrite oxidizers.

The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center

Elderly patients > 70 years of age with esophageal cancer (EC) represent a challenging group as frailty and comorbidities need to be considered. The aim of this retrospective study was to evaluate the efficacy and side effects of curative chemoradiation therapy (CRT) with regard to basic geriatric screening in elderly patients in order to elucidate prognostic factors. Thirty-four elderly patients > 70 years with EC treated at our cancer center between May 2014 and October 2018 fulfilled the selection criteria for this retrospective analysis. Treatment consisted of intravenous infusion of carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. Clinicopathological data including performance status (ECOG), (age-adjusted) Charlson comorbidity index (CCI), Frailty-scale by Fried, Mini Nutritional Assessment Short Form, body mass index, C-reactive protein to albumin ratio, and treatment-related toxicity (CTCAE) were assessed. Data were analyzed as predictors of overall survival (OS) and progression-free survival (PFS). All patients (ten female, 24 male) received combined CRT (22 patients in neoadjuvant, 12 patients in definite intent). Median age was 75 years and the ECOG index between 0 and 1 (52.9% vs. 35.3%); four patients were rated as ECOG 3 (11.8%). Median follow-up was 24 months. Tumors were mainly located in the lower esophagus or esophagogastric-junction with an T3 stage (n = 25; 75.8%) and N1 stage (n = 28; 90.3%). 15 patients (44.1%) had SCC, 19 patients (55.9%) AC. 26 of the patients (76.5%) were scored as prefrail and 50% were in risk for malnutrition (n = 17). In relation to the BMI, ten patients (29.4%) were ranked as overweight, and 15 patients were presented in a healthy state of weight (44.1%). Grade 3 acute toxicity (or higher) occured in nine cases (26.5%). Most of the patients did not show any late toxicities (66.7%). Trimodal therapy provides a significant prolonged OS (p = 0.049) regardless of age, but without impact on PFS. Our analysis suggests that chemoradiation therapy is feasible for elderly patients (>70 years) with tolerable toxicity. Trimodal therapy of EC shows a positive effect on OS and PFS. Further studies are needed to elucidate benefitting subgroups within the elderly. In addition to age, treatment decisions should be based on performance status, nutritional condition and multidisciplinary validated geriatric screening tools.

Relevance of Candidatus Nitrotoga for nitrite oxidation in technical nitrogen removal systems.

Many biotechnological applications deal with nitrification, one of the main steps of the global nitrogen cycle. The biological oxidation of ammonia to nitrite and further to nitrate is critical to avoid environmental damage and its functioning has to be retained even under adverse conditions. Bacteria performing the second reaction, oxidation of nitrite to nitrate, are fastidious microorganisms that are highly sensitive against disturbances. One important finding with relevance for nitrogen removal systems was the discovery of the mainly cold-adapted Cand. Nitrotoga, whose activity seems to be essential for the recovery of nitrite oxidation in wastewater treatment plants at low temperatures, e.g., during cold seasons. Several new strains of this genus have been recently described and ecophysiologically characterized including genome analyses. With increasing diversity, also mesophilic Cand. Nitrotoga representatives have been detected in activated sludge. This review summarizes the natural distribution and driving forces defining niche separation in artificial nitrification systems. Further critical aspects for the competition with Nitrospira and Nitrobacter are discussed. Knowledge about the physiological capacities and limits of Cand. Nitrotoga can help to define physico-chemical parameters for example in reactor systems that need to be run at low temperatures. KEY POINTS: • Characterization of the psychrotolerant nitrite oxidizer Cand. Nitrotoga • Comparison of the physiological features of Cand. Nitrotoga with those of other NOB • Identification of beneficial environmental/operational parameters for proliferation.

Value of PET imaging for radiation therapy.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.

Value of PET imaging for radiation therapy.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.

Pentixafor PET/CT for imaging of chemokine receptor 4 expression in esophageal cancer - a first clinical approach.

BACKGROUND: Expression of CXCR4, a chemokine (C-X-C motif) receptor that plays a central role in tumor growth and metastasis of circulating tumor cells, has been described in a variety of solid tumors. A high expression of CXCR4 has a prognostic significance with regard to overall and progression-free survival and offers a starting point for targeted therapies. In this context, [68]Ga-Pentixafor-Positron Emission Tomography/Computer Tomography (PET/CT) offers promising possibility of imaging the CXCR4 expression profile. We set out to compare a [18F] fluorodeoxyglucose (FDG)-PET/CT and a [68Ga]Pentixafor-PET/CT in (re-)staging and radiation planning of patients with localized esophageal cancer. MATERIALS AND METHODS: In this retrospective analysis, ten patients, with adeno- or squamous cell carcinoma of the esophagus (n = 3 and n = 7, respectively), which were scheduled for radio (chemo) therapy, were imaged using both Pentixafor and FDG PET/CT examinations. All lesions were visually rated as Pentixafor and FDG positive or negative. For both tracers, SUVmax was measured all lesions and compared to background. Additionally, immunohistochemistry of CXCR4 was obtained in patients undergoing surgery. RESULTS: FDG-positive tumor-suspicious lesions were detected in all patients and a total of 26 lesions were counted. The lesion-based analysis brought equal status in 14 lesions which were positive for both tracers while five lesions were FDG positive and Pentixafor negative and seven lesions were FDG negative, but Pentixafor positive. Histopathologic correlation was available in seven patients. The CXCR4 expression of four non-pretreated tumour lesion samples was confirmed immunohistochemically. CONCLUSION: Our data shows that additional PET/CT imaging with Pentixafor for imaging the CXCR4 chemokine receptor is feasible but heterogeneous in both newly diagnosed and pretreated recurrent esophageal cancer. In addition, the Pentixafor PET/CT may serve as complementary tool for radiation field expansion in radiooncology.