Dermoscopy of Chronic Radiation-Induced Dermatitis in Patients with Head and Neck Cancers Treated with Radiotherapy.

Radiotherapy (RT) is an integral part of many cancer treatment protocols. Chronic radiation-induced dermatitis (CRD) is a cutaneous toxicity that occurs in one-third of all patients treated with this method. CRD is usually observed several months after completion of treatment. Typical symptoms of CRD are telangiectasia, skin discoloration, atrophy, thickening, and cutaneous fibrosis. There are currently no data in the literature on the evaluation of the dermoscopic features of CRD. The aim of this prospective study was the identification of clinical and dermoscopic features in a group of 32 patients with head and neck cancer (HNC) in whom CRD developed after RT. CRD was assessed at 3, 6, and 12 months after RT in 16, 10, and 10 patients, respectively. CRD was assessed at one time point and two time points in 28 and 4 patients, respectively. The control included skin areas of the same patient not exposed to RT. The dataset consisted of 36 clinical and 216 dermoscopic photos. Clinical evaluation was performed according to the RTOG/EORTC radiation-induced dermatitis scale. The highest score was grade 2 observed in 21 patients. Clinical observations revealed the presence of slight and patchy atrophy, pigmentation change, moderate telangiectasias, and some and total hair loss. Dotted vessels, clustered vessel distribution, white patchy scale, perifollicular white color, white structureless areas, brown dots and globules, and white lines were the most frequently noted features in dermoscopy. Three independent risk factors for chronic toxicity, such as age, gender, and surgery before RT, were identified. The dermoscopic features that had been shown in our study reflect the biological reaction of the skin towards radiation and may be used for the parametrization of CRD regarding its intensity and any other clinical consequences in the future.

Pretreatment Circulating HPV16 DNA Viral Load Predicts Risk of Distant Metastasis in Patients with HPV16-Positive Oropharyngeal Cancer.

BACKGROUND: There are definite reasons to implement molecular diagnostics based on the measurement of human papillomavirus (HPV) DNA in liquid biopsy into clinical practice. It is a quick, repeatable, and health-safe test for cancer biomarkers in the blood. In this study, we investigated whether the circulating tumor-related HPV16 (ctHPV16) viral load (VL) in patients with oropharyngeal squamous cell carcinoma (OPSCC) was important for determining the risk of locoregional recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). METHODS: This study included 91 patients with ctHPV16-positive OPSCC who had been treated with radical radiotherapy and chemotherapy. The VL was measured using quantitative PCR (qPCR) and a probe specific for HPV16. Based on 10 years of follow-up, the 2-, 3-, 5-, and 9-year LRFS, MFS, and OS were estimated. RESULTS: The 5-year actuarial LRFS, MFS, and OS rates of patients with ctHPV16-positive/OPSCC were 88%, 90%, and 81%, respectively. The VL was significantly higher in patients who subsequently developed distant metastases (DM) than in those who did not (VL 4.09 vs. 3.25; p = 0.009). In a Cox proportional hazards regression model for MFS, a higher ctHPV16 VL appeared to be a significant independent prognostic factor for the occurrence of DM (HR 2.22, p = 0.015). The ROC curve revealed a cutoff value of 3.556 for VL (p = 0.00001). CONCLUSIONS: A high VL before treatment indicates patients with a significant risk of DM, and should be used in OPSCC treatment stratification.

Mild Cognitive Impairment Detection with Machine Learning and Topological Data Analysis Applied to EEG Time-series in Facial Emotion Oddball Paradigm.

We report a novel approach to dementia neurobiomarker development from EEG time series using topological data analysis (TDA) methodology and machine learning (ML) tools in the 'AI for social good' application domain, with possible following application to home-based point of care diagnostics and cognitive intervention monitoring. We propose a new approach to a digital dementia neurobiomarker for early-onset mild cognitive impairment (MCI) prognosis. We report the best median accuracies in a range of upper 85% linear discriminant analysis (LDA), as well above 90% for linear SVM and deep fully connected neural network classifier models in leave-one-out-subject cross-validation, which presents very encouraging results in a binary healthy cognitive aging versus MCI stages using TDA features applied to brainwave time series patterns captured from a four-channel EEG wearable.Clinical relevance- The reported study offers an objective dementia early onset neurobiomarker prospect to replace traditional subjective paper and pencil tests with an application of EEG-wearable-based and topological data analysis machine learning tools in a possibly successive home-based point-of-care environment.

Determinants of the level of circulating-tumor HPV16 DNA in patients with HPV-associated oropharyngeal cancer at the time of diagnosis.

Circulating tumor HPV DNA (ctHPV16) assessed in liquid biopsy may be used as a marker of cancer in patients with HPV-associated oropharyngeal cancer (HPV + OPC). Factors influencing the initial ctHPV16 quantity are not well recognized. In this study we aimed to establish what factors are related to the level of ctHPV16 at the time of diagnosis. 51 patients (37 men and 14 women, median age of 57 years old) with HPV + OPC prior to definitive treatment were included. ctHPV16 was measured by qPCR. Tumor and nodal staging were assessed according to AJCC8. Blood derived factors included squamous cell carcinoma antigen (SCC-Ag), serum soluble fragment of cytokeratin 19 (CYFRA 21-1), C-reactive protein (CRP), albumin level (Alb), neutrophils (Neut), thrombocytes (Plt) and lymphocyte (Lym) count, Neut/Lym ratio were assessed. The volumes of the primary tumor (TV) and involved lymph nodes (NV) were calculated using MRI, CT or PET-CT scans. Data were analysed using parametric and nonparametric methods. Variables for multivariable linear regression analysis were chosen based on the results from univariable analysis (correlation, univariable regression and difference). There were 9 (18%), 10 (19%) and 32 (63%) patients who had TV and NV assessed in MRI, CT or PET respectively. Primary tumor neither as T-stage nor TV was related to ctHPV16 level. Significant differences in the ctHPV16 between patients with high vs low pain (P = 0.038), NV (P = 0.023), TV + NV (P = 0.018), CYFRA 21-1 (P = 0.002), CRP (P = 0.019), and N1 vs N3 (P = 0.044) were observed. ctHPV16 was significantly associated with CYFRA 21-1 (P = 0.017), N stage (P = 0.005), NV (P = 0.009), TV + NV (P = 0.002), CRP (P = 0.019), and pain (P = 0.038). In univariable linear regression analysis the same variables predicted ctHPV16 level. In multivariable analyses, CYFRA 21-1 and CRP (both as categorical variables) were predictors of ctHPV16 level even above NV. ctHPV16 at presentation is driven by tumor volume measured mostly by N. CYFRA 21-1 and CRP are additional factors related to ctHPV16 prior to the treatment.

Communities of Uropodina (Acari: Mesostigmata) in Nest Boxes Inhabited by Dormice (Glis glis and Muscardinus avellanarius) and Differences in Percentages of Nidicoles in Nests of Various Hosts.

Bird and mammal nests and nest boxes constitute microenvironments in which various groups of invertebrates can live, including mites from the suborder Uropodina (Acari: Mesostigmata). The main aim of the current study was to ascertain the characteristics of mite communities from the suborder Uropodina, which inhabit the nests of dormice (Gliridae) built in nest boxes. The second aim of the study was to compare the habitat preferences of Leiodinychus orbicularis (C. L. Koch) and Apionoseius infirmus (Berlese), i.e., two typically nest-dwelling species of Uropodina. The material for the study was collected from nest boxes in six forest complexes in southwestern Poland. The conducted research revealed the presence of five species of Uropodina, with a total number of 559 specimens, in the examined boxes. Leiodinychus orbicularis was found in almost half of all of the examined boxes and was a superdominant species in the communities. The analysis of the habitat preferences of the two nest species of Uropodina showed that A. infirmus preferred old natural nests, in which the communities were formed from a larger number of species, without a significant statistical prevalence of one species. On the other hand, L. orbicularis occurred sporadically in open bird nests, but was very numerous and frequent in nest boxes. The significant dominance of L. orbicularis in nest boxes can probably be explained by the specific conditions prevailing in this type of microhabitat, including the very low humidity and food resources that this mite species prefers compared to other species of Uropodina.

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients.

Radiotherapy and cisplatin-based chemotherapy belong to the main treatment modalities for head and neck squamous cell carcinoma (HNSCC) and induce cancer cell death by generating DNA damage, including the most severe double-strand breaks (DSBs). Alterations in DSB response and repair genes may affect individual DNA repair capacity and treatment sensitivity, contributing to the therapy resistance and poor prognosis often observed in HNSCC. In this study, we investigated the association of a panel of single-nucleotide polymorphisms (SNPs) in 20 DSB signaling and repair genes with therapy results and prognosis in 505 HNSCC patients treated non-surgically with DNA damage-inducing therapies. In the multivariate analysis, there were a total of 14 variants associated with overall, locoregional recurrence-free or metastasis-free survival. Moreover, we identified 10 of these SNPs as independent predictors of therapy failure and unfavorable prognosis in the whole group or in two treatment subgroups. These were MRE11 rs2155209, XRCC5 rs828907, RAD51 rs1801321, rs12593359, LIG4 rs1805388, CHEK1 rs558351, TP53 rs1042522, ATM rs1801516, XRCC6 rs2267437 and NBN rs2735383. Only CHEK1 rs558351 remained statistically significant after correcting for multiple testing. These results suggest that specific germline variants related to DSB response and repair may be potential genetic modifiers of therapy effects and disease progression in HNSCC treated with radiotherapy and cisplatin-based chemoradiation.

Seeking a Sufficient Data Volume for Railway Infrastructure Component Detection with Computer Vision Models.

Railway infrastructure monitoring is crucial for transportation reliability and travelers' safety. However, it requires plenty of human resources that generate high costs and is limited to the efficiency of the human eye. Integrating machine learning into the railway monitoring process can overcome these problems. Since advanced algorithms perform equally to humans in many tasks, they can provide a faster, cost-effective, and reproducible evaluation of the infrastructure. The main issue with this approach is that training machine learning models involves acquiring a large amount of labeled data, which is unavailable for rail infrastructure. We trained YOLOv5 and MobileNet architectures to meet this challenge in low-data-volume scenarios. We established that 120 observations are enough to train an accurate model for the object-detection task for railway infrastructure. Moreover, we proposed a novel method for extracting background images from railway images. To test our method, we compared the performance of YOLOv5 and MobileNet on small datasets with and without background extraction. The results of the experiments show that background extraction reduces the sufficient data volume to 90 observations.

Dermoscopy of acute radiation-induced dermatitis in patients with head and neck cancers treated with radiotherapy.

Head and neck cancer (HNC) was the seventh most common cancer in the world in 2018. Treatment of a patient may include surgery, radiotherapy (RT), chemotherapy, targeted therapy, immunotherapy, or a combination of these methods. Ionizing radiation used during RT covers relatively large volumes of healthy tissue surrounding the tumor. The acute form of radiation-induced dermatitis (ARD) are skin lesions that appear usually within 90 days of the start of RT. This is a prospective study which compares 2244 dermoscopy images and 374 clinical photographs of irradiated skin and healthy skin of 26 patients at on average 15 time points. Dermoscopy pictures were evaluated independently by 2 blinded physicians. Vessels in reticular distribution, white, yellow or brown scale in a patchy distribution, perifollicular pigmentation and follicular plugs arranged in rosettes were most often observed. For these dermoscopic features, agreement with macroscopic features was observed. Two independent predictors of severe acute toxicity were identified: gender and concurrent chemotherapy. Knowledge of dermoscopic features could help in the early assessment of acute toxicity and the immediate implementation of appropriate therapeutic strategies. This may increase the tolerance of RT in these groups of patients.

Influence of nutritional counseling on treatment results in patients with head and neck cancers.

OBJECTIVES: Nutritional intervention, including nutritional counseling (NC), plays a significant role in the comprehensive management of patients with head and neck cancer (HNC). The aim of this study was to investigate the effects of NC combined with oral nutritional supplements during radical treatment on weight loss and survival outcomes in patients with HNC. METHODS: The study included 310 patients who received radical treatment for HNC. Among these patients, 119 underwent NC along with oral nutritional supplements (NCONS); 191 were supported with oral nutritional supplements only (ONS). The study aimed to investigate the effects of sex, disease stage, treatment modality, and tumor site on weight loss. Additionally, the Kaplan-Meier method assessed the influence of NC on overall survival and disease-free survival. RESULTS: The present study suggested that the NC independently prevented weight loss, regardless of sex and disease stage (female: -1.6%, P = 0.001; male: -2.3 %, P = 0.003; T stage (0-2): -1.7%, P = 0.008; T stage (3-4): -2.7%, P = 0.003; N stage (0-1): 2.5%, P = 0,027; N stage (3-4): 2.9%, P < 0.001). The protective effect was most significant in patients with oral cancer and oropharyngeal cancer and in patients treated with chemotherapy (oral: -1.7%, P = 0.03; oropharynx: -3.3%, P < 0.001; radiochemotherapy: -3%, P = 0.028; induction chemotherapy preceded radiochemotherapy: -6%, P < 0.001). Furthermore, the 3-year overall survival rates were 93.4% and 85.4% in the NC along with oral nutritional supplements (NCONS) and oral nutritional supplement (ONS) groups, respectively (P = 0.031). CONCLUSIONS: Patients with HNC who received NC during radical treatment experienced reduced weight loss. This effect was particularly pronounced in patients with oral cavity or oropharyngeal cancer and those undergoing chemotherapy. Additionally, NC was associated with improved overall survival in this patient cohort. Nevertheless, further studies are required to validate and support these findings.

Machine learning approach for early onset dementia neurobiomarker using EEG network topology features.

Introduction: Modern neurotechnology research employing state-of-the-art machine learning algorithms within the so-called "AI for social good" domain contributes to improving the well-being of individuals with a disability. Using digital health technologies, home-based self-diagnostics, or cognitive decline managing approaches with neuro-biomarker feedback may be helpful for older adults to remain independent and improve their wellbeing. We report research results on early-onset dementia neuro-biomarkers to scrutinize cognitive-behavioral intervention management and digital non-pharmacological therapies. Methods: We present an empirical task in the EEG-based passive brain-computer interface application framework to assess working memory decline for forecasting a mild cognitive impairment. The EEG responses are analyzed in a framework of a network neuroscience technique applied to EEG time series for evaluation and to confirm the initial hypothesis of possible ML application modeling mild cognitive impairment prediction. Results: We report findings from a pilot study group in Poland for a cognitive decline prediction. We utilize two emotional working memory tasks by analyzing EEG responses to facial emotions reproduced in short videos. A reminiscent interior image oddball task is also employed to validate the proposed methodology further. Discussion: The proposed three experimental tasks in the current pilot study showcase the critical utilization of artificial intelligence for early-onset dementia prognosis in older adults.

Sacubitril/valsartan for cardioprotection in breast cancer (MAINSTREAM): design and rationale of the randomized trial.

AIMS: In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment-related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin-angiotensin-aldosterone inhibitors, might reduce the risk of treatment-related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early-stage breast cancer, which is the aim of the trial. METHODS AND RESULTS: MAINSTREAM is a randomized, placebo-controlled, double-blind, multicentre, clinical trial. After the run-in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti-human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103 mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24 months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24 months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy-related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. CONCLUSIONS: The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031).

Songbird nests on the ground as islands of diversity of ptyctimous mites (Acari: Oribatida) in the primeval Bialowieza Forest (Poland).

Due to specific microclimatic conditions and accumulation of organic matter, bird nests are microhabitats that are often inhabited by various invertebrates, including mites (Acari). We tested whether nests of the ground-nesting passerine Phylloscopus sibilatrix (Bechstein) (Passeriformes: Phylloscopidae) [wood warbler] were associated with an increased local diversity of ptyctimous mites (Acari: Oribatida) on the forest floor in the Bialowieza National Park, East Poland. In 2019-2020, we analysed 150 warbler nests shortly after they had been vacated by the birds, and additionally we sampled mites in leaf litter at 1 and 6 m distances from 21 of the collected nests. We found on average more mite species in nests sampled in 2020 than in nests sampled in 2019. Although the species composition largely overlapped between bird nests and the litter, bird nests contained a greater average number of mite species than litter samples, including species found only - Microtritia minima (Berlese) and Phthiracarus crenophilus Willmann - or mostly - Euphthiracarus cribrarius (Berlese) and Phthiracarus globosus (C.L. Koch) - in bird nests. The results suggest that the presence of bird nests may increase the local diversity of the invertebrate species assemblage.

Results of Primary Treatment and Salvage Treatment in the Management of Patients with Non-Squamous Cell Malignant Tumors of the Sinonasal Region: Single Institution Experience.

Non-squamous cell carcinoma-related malignant sinonasal tract tumors (non-SCC MSTT) are rare and diverse malignancies. In this study, we report our experience in the management of this group of patients. The treatment outcome has been presented, involving both primary treatment and salvage approaches. Data from 61 patients treated radically due to non-SCC MSTT between 2000 and 2016 at the National Cancer Research Institute, Gliwice branch, were analyzed. The group consisted of the following pathological subtypes of MSTT: adenoid cystic carcinoma (ACC), undifferentiated sinonasal carcinoma (USC), sarcoma, olfactory neuroblastoma (ONB), adenocarcinoma, small cell neuroendocrine carcinoma (SNC), mucoepidermic carcinoma (MEC), and acinic cell carcinoma, which were found in nineteen (31%), seventeen (28%), seven (11.5%), seven (11.5%), five (8%), three (5%), two (3%) and one (2%) of patients, respectively. There were 28 (46%) males and 33 (54%) females at the median age of 51 years. Maxilla was the primary tumor localization followed by the nasal cavity and ethmoid sinus in thirty-one (51%), twenty (32.5%), and seven (11.5%) patients, respectively. In 46 (74%) patients, an advanced tumor stage (T3 or T4) was diagnosed. Primary nodal involvement (N) was found in three (5%) cases, and all patients underwent radical treatment. The combined treatment consisted of surgery and radiotherapy (RT) and was given to 52 (85%) patients. The probabilities of overall survival (OS), locoregional control (LRC), metastases-free survival (MFS), and disease-free survival (DFS) were assessed in pathological subtypes and grouped together, along with the ratio and effectiveness of salvage. Locoregional treatment failure was seen in 21 (34%) patients. Salvage treatment was performed in fifteen (71%) patients and was effective in nine (60%) cases. There was a significant difference in OS between patients who underwent salvage and those who did not (median: 40 months vs. 7 months, p = 0.01). In the group of patients who underwent salvage, OS was significantly longer when the procedure was effective (median: 80.5 months) than if it failed (median: 20.5 months), p < 0.0001. OS in patients after effective salvage was the same as in patients who were primary cured (median: 80.5 months vs. 88 months, p = 0.8). Distant metastases developed in ten (16%) patients. Five and ten year LRC, MFS, DFS, and OS were 69%, 83%, 60%, 70%, and 58%, 83%, 47%, 49%, respectively. The best treatment results were observed for patients with adenocarcinoma and sarcoma, while USC gave the poorest results in our set of patients. In this study, we indicate that salvage is possible in most patients with non-SCC MSTT with locoregional failure and that it may significantly prolong their overall survival.

Low-Dose Radiotherapy for Patients with Pneumonia Due to COVID-19: A Single-Institution Prospective Study.

PURPOSE: Results of the low-dose radiation therapy (LDRT) in patients with pneumonia due to COVID-19 has been presented. METHODS: Fifteen patients received a single-fraction radiation dose of 1 Gy to the bilateral lungs due to pre-ARDS pneumonia in the course of COVID-19. Follow-up was performed on days 1, 3, 5, 7, 14 after LDRT. RESULTS: Eleven patients (73%) were released up until day 28. Median hospitalization was 20 days; 28-day mortality was 13%. Median O2 saturation improved within 24 h after LDRT in 14/15, with median SpO2 values of 84.5% vs. 87.5% p = 0.016, respectively. At day 14 of hospitalization, 46% did not require oxygen supplementation. Significant decline in CRP and IL-6 was observed within 24 h post LDRT. No organ toxicities were noted. CONCLUSION: LDRT is feasible, well tolerated and may translate to early clinical recovery in patients with severe pneumonia. Further studies are needed to determine optimal candidate, time and dose of LDRT for COVID-19 patients with pneumonia.

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.

Circulating HPV16 DNA in Blood Plasma as Prognosticator and Early Indicator of Cancer Recurrence in Radio-Chemotherapy for Anal Cancer.

BACKGROUND: Implementation of anal squamous cell carcinoma (ASCC) treatment modifications requires reliable patient risk stratification. The circulating tumor-related human papillomavirus type 16 (ctHPV16) may play a role in predicting survival or assessing treatment response. METHODS: The study included 62 ASCC patients treated with chemoradiotherapy. A threshold of 2.5 was used to determine the maximum standardized uptake value (SUVmax). The ctHPV16 viral load (VL) was quantified by qPCR. RESULTS: In the multivariate Cox analysis, lower SUVmax (p = 0.047) and ctHPV16-positive (p = 0.054) proved to be independent prognostic factors for favorable overall survival (OS). In the subgroup with the higher SUVmax, ctHPV16 and nodal (N) status were independent prognostic factors with p = 0.022 for ctHPV16 and p = 0.053 for N. The best survival rate (95%) presented ctHPV16-positive/N-negative patients. High ctHPV16 VL tended to be slightly specific for patients younger than 63 years (p = 0.152). The decrease in ctHPV16 VL to undetectable level after the end of treatment correlated with the overall clinical response. CONCLUSIONS: A prognostic stratification by SUVmax, ctHPV16 and N-positive status allows consideration of more aggressive treatment in high-risk patients (those with high SUVmax, ctHPV16-negative, and N-positive) or de-intensification of therapy in low-risk patients (those with low SUVmax, ctHPV16-positive and N-negative). However, prospective clinical trials on a large group are needed.