Cisplatin overcomes radiotherapy resistance in OCT4-expressing head and neck squamous cell carcinoma

Objectives: Cisplatin is combined with radiotherapy for advanced head and neck squamous cell carcinoma (HNSCC). While providing a beneficial effect on survival, it also causes side effects and thus is an important target when considering treatment de-escalation. Currently, there are no biomarkers to predict its patientselective therapeutic utility. In this study, we examined the role of the stem cell factor OCT4 as a potential biomarker to help clinicians stratify HNSCC patients between radiotherapy and chemoradiotherapy. Materials and methods: OCT4 immunohistochemical staining of a population-validated tissue microarray (PV-TMA) (n = 166) representative of a standard HNSCC patients was carried out, and 5-year survival was analyzed. The results were validated using ex vivo drug sensitivity analysis of HNSCC tumor samples, and further crossvalidated in independent oropharyngeal (n = 118), nasopharyngeal (n = 170), and vulvar carcinoma (n = 95) clinical datasets. In vitro, genetically modified, patient-derived HNSCC cells were used. Results: OCT4 expression in HNSCC tumors was associated with radioresistance. However, combination therapy with cisplatin was found to overcome this radioresistance in OCT4-expressing HNSCC tumors. The results were validated by using several independent patient cohorts. Furthermore, CRISPRa-based OCT4 overexpression in the HNSCC cell line resulted in apoptosis resistance, and cisplatin was found to downregulate OCT4 protein expression in vitro. Ex vivo drug sensitivity analysis of HNSCC tumors confirmed the association between OCT4 expression and cisplatin sensitivity. Conclusion: This study introduces OCT4 immunohistochemistry as a simple and cost-effective diagnostic approach for clinical practice to identify HNSCC patients benefitting from radiosensitization by cisplatin using either full or reduced dosing.Peer reviewe

Emergency neck MRI: feasibility and diagnostic accuracy in cases of neck infection

Background: Computed tomography (CT) has traditionally been the first-line imaging method in neck emergencies such as deep neck infections. Due to superior soft-tissue contrast, magnetic resonance imaging (MRI) may be an alternative to CT, also in emergency situations. Purpose: To characterize the use of routine MRI in neck emergencies, with an emphasis on clinical feasibility and diagnostic accuracy in cases of neck infection. Material and Methods: We conducted a retrospective cohort study of all primary neck MRI scans performed using a 3-T MRI device during a five-year follow-up period in a tertiary emergency radiology department. Imaging data were compared with final clinical diagnosis and surgical findings as reference standards. Results: The search identified 461 primary neck MRI scans, of which 334 (72%) were performed on the basis of clinical suspicion of infection. Radiological evidence of infection was observed in 95% of these scans, and at least one abscess was detected in 229 cases (72% of confirmed infection). MRI had an overall technical success rate of 95% and had high positive predictive value for both infection (0.98) and detection of abscess (0.95). Conclusion: We found that emergency neck MRI can be successfully performed on most patients, and that MRI detects neck infection with a high accuracy. These results suggest that MRI may be an alternative to CT as the first or only imaging modality in neck emergencies.</div

Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

Clever-1/Stabilin-1 is a scavenger receptor present on lymphatic and sinusoidal endothelium as well as on a subset of type II macrophages. It is also induced on vasculature at sites of inflammation. However, its in vivo function has remained practically unknown and this work addresses those unknown aspects. We demonstrate using in vivo models that Clever-1/Stabilin-1 mediates migration of T and B lymphocytes to the draining lymph nodes in vivo and identify the adhesive epitope of the Clever-1/Stabilin-1 molecule responsible for the interaction between lymphocytes and lymphatic endothelium. Moreover, we demonstrate that Ab blocking of Clever-1/Stabilin-1 efficiently inhibits peritonitis in mice by decreasing the entrance of granulocytes by 50%, while migration of monocytes and lymphocytes into the inflamed peritoneum is prevented almost completely. Despite efficient anti-inflammatory activity the Ab therapy does not dramatically dampen immune responses against the bacterial and foreign protein Ag tested and bacterial clearance. These results indicate that anti-Clever-1/Stabilin-1 treatment can target two different arms of the vasculature - traffic via lymphatics and inflamed blood vessels.</p

Comprehensive real-time epidemiological data from respiratory infections in Finland between 2010 and 2014 obtained from an automated and multianalyte mariPOC (R) respiratory pathogen test

Respiratory viruses cause seasonal epidemics every year. Several respiratory pathogens are circulating simultaneously and typical symptoms of different respiratory infections are alike, meaning it is challenging to identify and diagnose different respiratory pathogens based on symptoms alone. mariPOC (R) is an automated, multianalyte antigen test which allows the rapid detection of nine respiratory infection pathogens [influenza A and B viruses, respiratory syncytial virus (RSV), human metapneumovirus, adenovirus, parainfluenza 1-3 viruses and pneumococci] from a single nasopharyngeal swab or aspirate samples, and, in addition, can be linked to laboratory information systems. During the study period from November 2010 to June 2014, a total of 22, 485 multianalyte respi tests were performed in the 14 participating laboratories in Finland and, in total, 6897 positive analyte results were recorded. Of the tested samples, 25 % were positive for one respiratory pathogen, with RSV (9.8 %) and influenza A virus (7.2 %) being the most common findings, and 0.65 % of the samples were multivirus-positive. Only small geographical variations in seasonal epidemics occurred. Our results show that the mariPOC (R) multianalyte respi test allows simultaneous detection of several respiratory pathogens in real time. The results are reliable and give the clinician a picture of the current epidemiological situation, thus minimising guesswork.Peer reviewe

Impact of deep learning-determined smoking status on mortality of cancer patients: never too late to quit

BackgroundPersistent smoking after cancer diagnosis is associated with increased overall mortality (OM) and cancer mortality (CM). According to the 2020 Surgeon General's report, smoking cessation may reduce CM but supporting evidence is not wide. Use of deep learning-based modeling that enables universal natural language processing of medical narratives to acquire population-based real-life smoking data may help overcome the challenge. We assessed the effect of smoking status and within-1-year smoking cessation on CM by an in-house adapted freely available language processing algorithm.Materials and methodsThis cross-sectional real-world study included 29 823 patients diagnosed with cancer in 2009-2018 in Southwest Finland. The medical narrative, International Classification of Diseases-10th edition codes, histology, cancer treatment records, and death certificates were combined. Over 162 000 sentences describing tobacco smoking behavior were analyzed with ULMFiT and BERT algorithms.ResultsThe language model classified the smoking status of 23 031 patients. Recent quitters had reduced CM [hazard ratio (HR) 0.80 (0.74-0.87)] and OM [HR 0.78 (0.72-0.84)] compared to persistent smokers. Compared to never smokers, persistent smokers had increased CM in head and neck, gastro-esophageal, pancreatic, lung, prostate, and breast cancer and Hodgkin's lymphoma, irrespective of age, comorbidities, performance status, or presence of metastatic disease. Increased CM was also observed in smokers with colorectal cancer, men with melanoma or bladder cancer, and lymphoid and myeloid leukemia, but no longer independently of the abovementioned covariates. Specificity and sensitivity were 96%/96%, 98%/68%, and 88%/99% for never, former, and current smokers, respectively, being essentially the same with both models.ConclusionsDeep learning can be used to classify large amounts of smoking data from the medical narrative with good accuracy. The results highlight the detrimental effects of persistent smoking in oncologic patients and emphasize that smoking cessation should always be an essential element of patient counseling.</p

Plasticity of Blood- and Lymphatic Endothelial Cells and Marker Identification

Peer reviewe

Developmental and pathological lymphangiogenesis: from models to human disease.

The lymphatic vascular system, the body's second vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological processes. It participates in the maintenance of normal tissue fluid balance, the immune functions of cellular and antigen trafficking and absorption of fatty acids and lipid-soluble vitamins in the gut. Recent scientific discoveries have highlighted the role of lymphatic system in a number of pathologic conditions, including lymphedema, inflammatory diseases, and tumor metastasis. Development of genetically modified animal models, identification of lymphatic endothelial specific markers and regulators coupled with technological advances such as high-resolution imaging and genome-wide approaches have been instrumental in understanding the major steps controlling growth and remodeling of lymphatic vessels. This review highlights the recent insights and developments in the field of lymphatic vascular biology

IGF-I and ventilation after short-term progestin in postmenopausal women with chronic respiratory insufficiency

AbstractProgestins stimulate respiration. We have previously shown prolonged ventilatory improvement in chronic respiratory failure with short-term medroxyprogesterone acetate (MPA). The mechanism of the sustained respiratory effect is unknown. Insulin-like growth factor-I (IGF-I) and insulin have anabolic effects which could also improve ventilation in the long-term. To better understand the interactions between hormones and control of breathing, we evaluated the degree and duration of changes in IGF-I, insulin and cortisol after short-term MPA therapy in chronic respiratory insufficiency.Fourteen postmenopausal women with permanent or episodic hypercapnic or hypoxaemic respiratory failure were recruited for a placebo-controlled single-blind trial. After 14 days of placebo treatment and 7 days of washout, a daily dose of 60 mg MPA was administered for 14 days. Serum IGF-I, insulin and cortisol were measured five times at 3-week intervals: at baseline, after 14 days on placebo, after 14 days on MPA, and during the washout, on days 21 and 42.Serum IGF-I levels were 15·2 (SD 4·6), 20·8 (SD 6·8) and 17·2 (SD 6·4) at baseline, on MPA and after a 3-week washout. Serum insulin levels did not change [12·5 mU l−1(SD 4·1), 12·2mU l−1(SD 4·8) and 14·5mU l−1(SD 3·6), respectively]. Serum cortisol did not change. On MPA, IGF-I increased on average by 5·6 nmol l−1[95% confidence interval (95% CI) 1·4 to 9·9] or 42·0 % (95% CI 6·3 to 77·8) from baseline. The IGF-I response coincided with the previously reported ventilatory improvement.MPA 60 mg daily for 2 weeks increases serum IGF-I in postmenopausal women with chronic respiratory insufficiency. During follow-up after MPA, there was a trend towards increased IGF-I and insulin levels. The role of these two hormones to induce prolonged ventilatory stimulation could not be excluded and further studies in larger populations are warranted