Identification of the optimal treatment strategy is challenging in elderly with localized non-small cell lung cancer (NSCLC). Concurrent chemotherapy with low-dose cisplatin represents an option for elderly. Outcomes (1) in elderly (≥70 years, n = 158) vs. younger patients (n = 188) and (2), independently of age, in definitive radiochemotherapy, with low-dose cisplatin (n = 125) vs. cisplatin/vinorelbine (n = 76) were studied. Elderly included more males, had a lower Karnofsky index, more comorbidities, and lower stages. Low-dose cisplatin patients (vs. cisplatin/vinorelbine) had higher age, more comorbidities, and lower stages. We observed reduced dermatitis and dysphagia and increased anemia and thrombocytopenia in elderly vs. younger patients, without increased ≥grade 3 toxicities. Low-dose cisplatin was less toxic than cisplatin/vinorelbine. Survival outcomes were lower in elderly vs. younger and comparable between low-dose cisplatin and cisplatin/vinorelbine. In elderly, gender, Karnofsky index, stage, and multimodal treatment (including additional surgery/systemic therapy) were identified as prognostic factors. In conclusion, we found evidence for an acceptable toxicity profile and the need for improvement of outcomes in elderly with localized NSCLC. Multimodal strategies (including additional surgery/systemic treatment) showed favorable outcomes and should be reasonably considered in elderly who are deemed fit enough. Low-dose cisplatin should be discussed on an individual basis due to favorable toxicity and outcomes.

Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1high tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of CTL from the tumor were correlated with significant prognostic detriment. Hypoxic tumors overall have smaller amounts of CTL, and spatial analysis revealed a repellent effect of hypoxia on CTL. In contrast to in vitro studies, specific upregulation of ADO-related enzymes CD73 and CD39 in GLUT-1high tumor regions was never observed. In this study, we could show direct in vivo evidence for hypoxia-mediated immunosuppression in melanoma. Moreover, this study suggests a significant prognostic relevance of the tumor immune phenotype, the strength of CD8 infiltration in the tumor, and the expression of hypoxia marker GLUT-1 on melanoma cells. Last, our results suggest a temporal stability of the microenvironment-mediated immunosuppressive phenotype in melanoma.

(1) Background: The immune system has physiological antitumor activity, which is partially mediated by cytotoxic T lymphocytes (CTL). Tumor hypoxia, which is highly prevalent in cancers of the head and neck region, has been hypothesized to inhibit the infiltration of tumors by CTL. In situ data validating this concept have so far been based solely upon the visual assessment of the distribution of CTL. Here, we have established a set of spatial statistical tools to address this problem mathematically and tested their performance. (2) Patients and Methods: We have analyzed regions of interest (ROI) of 22 specimens of cancers of the head and neck region after 4-plex immunofluorescence staining and whole-slide scanning. Single cell-based segmentation was carried out in QuPath. Specimens were analyzed with the endpoints clustering and interactions between CTL, normoxic, and hypoxic tumor areas, both visually and using spatial statistical tools implemented in the R package Spatstat. (3) Results: Visual assessment suggested clustering of CTL in all instances. The visual analysis also suggested an inhibitory effect between hypoxic tumor areas and CTL in a minority of the whole-slide scans (9 of 22, 41%). Conversely, the objective mathematical analysis in Spatstat demonstrated statistically significant inhibitory interactions between hypoxia and CTL accumulation in a substantially higher number of specimens (16 of 22, 73%). It showed a similar trend in all but one of the remaining samples. (4) Conclusion: Our findings provide non-obvious but statistically rigorous evidence of inhibition of CTL infiltration into hypoxic tumor subregions of cancers of the head and neck. Importantly, these shielded sites may be the origin of tumor recurrences. We provide the methodology for the transfer of our statistical approach to similar questions. We discuss why versions of the Kcross and pcf.cross functions may be the methods of choice among the repertoire of statistical tests in Spatstat for this type of analysis.

Cancer represents the leading cause of disease-related death and treatment-associated morbidity in children with an increasing trend in recent decades worldwide. Nevertheless, the 5-year survival of childhood cancer patients has been raised impressively to more than 80% during the past decades, primarily attributed to improved diagnostic technologies and multiagent cytotoxic regimens. This strong benefit of more efficient tumor control and prolonged survival is compromised by an increased risk of adverse and fatal late sequelae. Long-term survivors of pediatric tumors are at the utmost risk for non-carcinogenic late effects such as cardiomyopathies, neurotoxicity, or pneumopathies, as well as the development of secondary primary malignancies as the most detrimental consequence of genotoxic chemo- and radiotherapy. Promising approaches to reducing the risk of adverse late effects in childhood cancer survivors include high precision irradiation techniques like proton radiotherapy or non-genotoxic targeted therapies and immune-based treatments. However, to date, these therapies are rarely used to treat pediatric cancer patients and survival rates, as well as incidences of late effects, have changed little over the past two decades in this population. Here we provide an overview of the epidemiology and etiology of childhood cancers, current developments for their treatment, and therapy-related adverse late health consequences with a special focus on second primary malignancies.

Genetic variability in transforming growth factor beta pathway (TGFB) was suggested to affect adverse events of radiotherapy. We investigated comprehensive variability in TGFB1 (gene coding for TGFβ1 ligand) and TGFBR1 (TGFβ receptor-1) in relation to radiotoxicity. Prostate cancer patients treated with primary radiotherapy (n = 240) were surveyed for acute and late toxicity. Germline polymorphisms (n = 40) selected to cover the common genetic variability in TGFB1 and TGFBR1 were analyzed in peripheral blood cells. Human lymphoblastoid cell lines (LCLs) were used to evaluate a possible impact of TGFB1 and TGFBR1 genetic polymorphisms to DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, rs10512263 in TGFBR1 showed a statistically significant association with acute radiation toxicity. Carriers of the Cytosine (C)-variant allele (n = 35) featured a risk ratio of 2.17 (95%-CI 1.41-3.31) for acute toxicity ≥ °2 compared to Thymine/Thymine (TT)-wild type individuals (n = 205). Reduced DNA repair capacity in the presence of the C-allele of rs10512263 might be a mechanistic explanation as demonstrated in LCLs following irradiation. The risk for late radiotoxicity was increased by carrying at least two risk genotypes at three polymorphic sites, including Leu10Pro in TGFB1. Via comprehensive genotyping of TGFB1 and TGFBR1, promising biomarkers for radiotoxicity in prostate cancer were identified.