Search Results (13)

We propose a novel predictor for functional time series (FTS) based on the robust estimation of the modal regression within a functional statistics framework. The robustness of the estimator is incorporated through the $L^1$-estimation of the quantile density. Such consideration improves the precision of conditional mode estimation. A principal theoretical contribution of this work is the establishment of the asymptotic normality of the proposed estimator. This result is of considerable importance, as it provides the foundation for statistical inference, including hypothesis testing and the construction of confidence intervals. Therefore, the obtained asymptotic result enhances the practical usability of the modal regression prediction. On the empirical side, we evaluate the performance of the estimator under various smoothing structures using both simulated and real data. The real data application highlights the ability of the $L^1$-conditional mode predictor to perform robust and reliable short-term forecasts, with very high effectiveness in the analysis of economic data. Full article

Real-time control of web traffic is a critical issue for network operators and service providers. It helps ensure robust service and avoid service interruptions, which has an important financial impact. However, due to the high speed and volume of actual internet traffic, standard multivariate time series models are inadequate for ensuring efficient real-time traffic management. In this paper we introduce a new model for functional time series analysis, developed by combining a local linear smoothing approach with an $L^1$-robust estimator of the quantile’s derivative. It constitutes an alternative, robust estimator for functional modal regression that is adequate to handle the stochastic volatility of high-frequency of web traffic data. The mathematical support of the new model is established under functional dependent case. The asymptotic analysis emphasizes the functional structure of the data, the functional feature of the model, and the stochastic characteristics of the underlying time-varying process. We evaluate the effectiveness of our proposed model using comprehensive simulations and real-data application. The computational results illustrate the superiority of the nonparametric functional model over the existing conventional methods in web traffic modeling. Full article

This paper introduces a new nonparametric estimator for detecting the conditional mode in the functional input variable setting. The estimator integrates a local linear approach with an $L^1$-robust algorithm and treats the modal regression as the minimizer of the quantile derivative. As an asymptotic result, we derive the theoretical properties of the estimator by analyzing its convergence rate under the almost complete consistency framework. The result is stated under standard conditions, characterizing both the functional structure of the data and the local linear approximation properties of the model. Moreover, the expression of the convergence rate retains the usual form of the stochastic convergence rate in functional statistics. Simulations and real-data applications demonstrate the algorithm’s effectiveness, showing its advantage over existing methods in high-dimensional prediction tasks. Full article

Background/Objectives: Stereotactic radiotherapy (SABR) is a recognized standard treatment modality for localized prostate cancer, though data is limited regarding the risk of increased toxicity when including the elective nodes (ENI) for high-risk disease. Placement of a peri-rectal spacer can decrease the risk of toxicity to the rectum when administering high-dose prostate radiotherapy. Herein we present toxicity findings for patients who underwent five-fraction prostate SABR with ENI in a setting with peri-rectal spacing. Methods: Genitourinary (GU) and gastrointestinal (GI) toxicity data was analyzed for patients with ≥12 months of follow-up who were treated with curative-intent five-fraction SABR with ENI. A radiopaque hydrogel spacer was placed for all eligible patients. The primary endpoints were the three-month toxicity, which was measured using CTCAEv5, and quality of life (QoL), which was measured using EPIC 26. Secondary endpoints included intermediate-term GU and GI toxicity between 6 and 12 months. Univariable logistic regression was used to assess associations between baseline patient characteristics and the presence of a peri-rectal hydrogel spacer and GU and GI toxicity. Results: Among the 100 patients treated, 69 had grade group 4/5 disease and 40 had evidence of T3a/3b extension. The ENI dose was 25 Gy/5, and 78.9% of the patients received 40 Gy to the prostate, while the remainder were given 36.25–37.5 Gy. A total of 70% underwent placement of a radiopaque hydrogel spacer. GU toxicities of grades 1, 2, and 3 were reported in 28/22/1% of the patients, respectively, at three months; in 18/11/0% at six months; in 11/9/0% at nine months; and in 5/3/0% at twelve months. GI toxicities of grades 1 and 2 were reported in 14/0% of the patients at three months and 8/1% at six months, with all cases resolving by nine months. MCICs in the urinary incontinence, urinary obstructive, and bowel domains were reported in 5%, 18%, and 4% at three months; by twelve months, these values decreased to 2%, 2%, and 0%, respectively. The presence of a hydrogel spacer resulted in reductions in high and intermediate doses to the rectum and had a significant inverse association with short-term GI toxicity (HR: 0.09, CI: 0.27–0.35, p: 0.0004). Conclusions: In this prospective series, five-fraction SABR including ENI was well tolerated, and the presence of a hydrogel spacer was associated with a lower risk of rectal toxicity. Full article

Background/Objectives: Neuropsychological impairment (NI) is common in newly diagnosed patients with multiple sclerosis (pwMS). This study has two main objectives; the systematic review aims to describe the relationship between NI and molecular biomarkers in newly diagnosed pwMS, and the meta-analysis aims to explore the relationship between NI, age, disability status, and disease duration in this patient group. Methods: We conducted a systematic review, with 20 studies meeting the inclusion criteria. Out of these, 12 studies were included in the meta-analysis. We analyzed three key cognitive measures—the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), and the Selective Reminding Test–long-term storage (SRT-LTS)—in relation to demographic and MS-related characteristics. Results: Neurofilament light chain (NfL) levels were consistently associated with NI, especially a slower information processing speed (IPS). Other biomarkers, including chitinase 3-like 1 (CHI3L1), brain-derived neurotrophic factor (BDNF), apolipoprotein E4 allele (APOE4), and vitamin D, also showed promising correlations with NI. A meta-regression analysis of 2380 pwMS indicated a negative association between SDMT score and disability status (p = 0.01). No significant associations were found for the PASAT with age, disability status, or disease duration (p > 0.05). Conclusions: These findings highlight the role of NfL as a biomarker related to NI in newly diagnosed pwMS and the association between IPS and disability status. Further research is needed with more homogeneous samples in terms of the disease duration, along with standardized cognitive assessments and a broader range of biomarkers, to improve our understanding and management of cognitive difficulties in the early stages of MS. Full article

A new predictor in functional time series (FTS ) is considered. It is based on the asymmetric weighting function of quantile regression. More precisely, we assume that FTS is generated from a single-index model that permits the observation of endogenous–exogenous variables by combining the nonparametric model with a linear one. In parallel, the $L^1$-modal predictor is estimated using the M-estimation of the derivative of the conditional quantile of the generated FTS. In the mathematical part, we prove the complete convergence of the constructed estimator, and we determine its convergence rate. An empirical analysis is performed to prove the applicability of the estimator and to evaluate the impact of different structures involved in the smoothing approach. This analysis is carried out using simulated and real data. Finally, the regressive nature of the constructed predictor allows it to provide a robust instantaneous predictor for environmental data. Full article

Immunotherapy has emerged as a promising treatment approach in oncology, as it is specifically designed to boost the strength and accuracy of the immune system, allowing it to target tumor cells but spare non-tumor tissue. This treatment not only demonstrates potential for improved clinical outcomes but may also be associated with fewer adverse effects compared to traditional therapies. Despite its early success, the application of immunotherapy has largely been limited to adult cancer patients, with slow adoption noted in the treatment of pediatric cancer patients. Our objective is to demonstrate a single institution’s experience with immunotherapy in pediatric cancer patients and to discuss the use of these treatment modalities in this unique patient population. We performed a retrospective chart review and identified patients who received immune checkpoint inhibitors (ICIs) and/or underwent immunohistochemistry (IHC) testing for programmed death ligand 1 (PD-L1), quantification of tumor mutational burden (TMB), and classification of microsatellite instability (MSI) status. In total, we identified seven pediatric cancer patients who received therapy with ICIs. Four of these patients demonstrated positive PD-L1 expression, high TMB, and/or MSI-high status. These patients were treated with nivolumab alone or in combination with ipilimumab or brentuximab. The diagnoses included: multifocal epithelioid and spindle cell hemangioma (n = 1); metastatic melanoma (n = 2); histiocytic sarcoma (n = 1); rectal adenocarcinoma in the setting of constitutional mismatch repair deficiency syndrome (CMMRD) (n = 1); and Hodgkin lymphoma (n = 2). The patients received between four and nineteen cycles of immunotherapy. Immunotherapy-related adverse events included: mild allergic reaction; prodromal symptoms; anemia; neutropenia; transaminitis; endocrinopathies; and self-limiting neuritis. Of the seven patients, three are still being treated with immunotherapy (the patients with rectal adenocarcinoma, metastatic melanoma, and multifocal epithelioid and spindle cell hemangioma) with positive treatment responses observed on imaging, one is being treated with other modalities (the patient with Hodgkin lymphoma), two have achieved remission (the patients with metastatic melanoma and Hodgkin lymphoma), and one has relapsed (the patient with histiocytic sarcoma). The three patients who completed their immunotherapy regimens have been followed for 1 month, 4 months, and 10 months, respectively. This report of a single-institution experience with immunotherapy in pediatric cancer patients highlights the positive impact immunotherapy can have, especially when utilized to treat relapsed/refractory malignancies, as tumor regression or stabilization of disease burden was achieved in six of the patients described (CR = 2; PR = 4). Further research is needed to accurately identify pediatric oncology patients who could benefit from immunotherapy. Full article

(1) Aims: The main objective of this retrospective study was to assess the long-term stability of difficult orthodontic treatments treated to an excellent result and to correlate stability to possible prognostic factors. Secondary objectives were to observe the changes in retention protocol over time and to assess Oral Health-related Quality of Life (OHRQoL) after a long-term post-treatment follow-up. (2) Methods: Cases presented for final examination by orthodontic postgraduate students were retrospectively screened for eligibility. Eligible patients were recalled for a post-treatment recall appointment (T2), consisting of a clinical examination and intraoral scan, and were asked to complete the Oral Health Impact Profile-14 (OHIP-14-DK). Gender, age at treatment commencement (T0), treatment modality and duration, and retention protocol were extracted from the records. At T2, the duration of the retention period was recorded, and retainers in place were clinically compared to the original retention protocol. The following variables were assessed on the sets of models at T0, T1 (end of treatment), and T2: arch length and width, overjet and overbite, Dental Aesthetic Index (DAI), Peer Assessment Rating score (PAR), and Little’s Irregularity Index (LII). Multiple regression models were conducted. (3) Results: Eighty-five subjects attended T2. The mean post-treatment follow-up was 9.4 years +/− 2.4. In the upper arch, at T1, 74 patients had a combination of fixed and removable retainers, while at T2, 55 had a fixed retainer only. In the lower arch, at T1, 67 patients had a fixed retainer only, with this number increasing to 76 at T2. From T0 to T1, the PAR score improved by 96.1%, with the improvement remaining at 77.5% at T2. The stability of lower inter-canine and upper inter-premolar widths was significantly correlated with the extent of changes during treatment. The presence of a lower fixed retainer at T2 and a low LII at T1 were prognostic factors for stability. The mean weighted total OHIP-14 score at T2 was very low (1.6 ± 2.4 points). (4) Conclusions: In a sample with an initial high-severity malocclusion and treated to an excellent outcome, long-term stability was very good. Good stability can be retained when a lower fixed retainer is present at T2 and when a low LII is achieved at T1. Full article

Some studies have shown that sorafenib could significantly prolong the overall survival of patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE). However, other studies revealed that patients had no access to sorafenib-related survival benefits after TACE. To identify the predictive biomarkers of therapeutic efficacy of sorafenib, we explored the potential predictive value of vascular endothelial growth factor (VEGF) and other clinical variables for survival benefits from sorafenib in patients treated with TACE previously. The results demonstrated that patients with tumor size > 7 cm or total bilirubin ≤ 17.3 μmol/L showed significant survival benefits from sorafenib after TACE treatment compared with those with tumor size ≤ 7 cm or total bilirubin > 17.3 μmol/L. Meanwhile, patients with VEGF > 131.09 pg/mL may obtain sorafenib-associated survival benefits after TACE when compared to those with VEGF ≤ 131.09 pg/mL, which needs further confirmation. The abovementioned results are helpful to confirm the specific population who are sensitive to targeted therapy. (1) Background: VEGF plays a crucial role in modulating proliferation and metastasis in HCC. We aimed to explore the relationship between VEGF and the prognosis, as well as the mortality risk of HCC patients who received TACE, and whether it and other variables could be considered as potential biomarkers for predicting the benefits from sorafenib. (2) Method: A total of 230 consecutive newly diagnosed patients with unresectable HCC treated with either TACE or TACE–sorafenib were collected retrospectively. Cox regression analyses were performed to evaluate the prognostic value of VEGF. Furthermore, restricted cubic splines were fitted to assess the nonlinear associations between VEGF and OS, and the threshold effect analysis was subsequently performed. Lastly, the potential factors for predicting the survival benefits from sorafenib after the TACE procedure were identified using the Cox proportional hazard model with an interaction term. (3) Results: VEGF was recognized as an independent prognostic factor for OS in the TACE alone cohort (HR = 3.237, p = 0.013). A nonlinear relationship was observed between VEGF and OS in HCC patients with TACE administration after adjustment for confounders (p for nonlinearity = 0.030); the mortality risk increased with increasing the baseline VEGF before the inflection point, and the HR for death was 1.008. There was no significant interaction between the VEGF levels and treatment modality (p for interaction = 0.233), and further studies are needed to identify its predictive value on the efficacy of sorafenib. Patients with tumor size > 7 cm or total bilirubin ≤ 17.3 μmol/L derived significant sorafenib-related benefits in OS when compared to those with tumor size ≤ 7 cm or total bilirubin > 17.3 μmol/L (p for interaction = 0.004 and 0.031, respectively). (4) Conclusions: Within a certain concentration range, elevated baseline VEGF meant an increased risk of death in HCC patients treated with TACE. Significant improvements in OS associated with sorafenib were observed in patients with higher tumor size and lower total bilirubin after TACE treatment. Full article

Background and objectives: Improving early diagnosis and advances in colorectal cancer (CRC) treatment leads to longer survival of these patients. The purpose of this study was to identify the main surgical factors affecting long-term Quality of life (QoL) among colorectal cancer patients after surgery. Materials and Methods: QoL was prospectively evaluated in patients undergoing elective colorectal cancer resection operations in three CRC surgery centers of Lithuania using EORTC generic (QLQC-30) and disease-specific (QLQ-CR29) questionnaires at the time of preoperative admission and 1, 24, and 72 months after surgery. QoL was evaluated among different patient groups, diagnostic and treatment modalities, disease, and postoperative complications. Non-parametric tests and multivariate logistic regression models were used for statistical analysis. Results: Eighty-eight consecutive CRC patients from three institutions were included in the study over a three-month inclusion period, 42 (47.73%) women and 46 (52.27%) men, mean age 64.2 ± 11.5 years. Most tumors were localized in the sigmoid colon and rectum. The largest number of patients had stage III cancer. Twenty-nine patients died—a 6-year survival rate was 67%. 50 of 59 live patients (84.8%) responded to the questionnaire 6 years after their operation. Evaluating changes in quality of life 72 months after surgery with assessments before surgery, both questionnaire responses revealed good long-term CRC surgical treatment results: improved general and functional scale estimates and decreased symptom scale ratings. The multivariate analysis found that age, stoma formation, and rectal cancer were independent risk factors for having worse QoL six years after surgical intervention. Conclusions: Six years after surgery, QoL returns to preoperative levels. Age, stoma formation, adjuvant treatment, and rectal cancer reduce long-term QoL. Full article

Background and Aims: A higher frequency of dyslipidemia is reported in children with type 1 diabetes (T1D) and celiac disease (CD). Recently, continuous subcutaneous insulin infusion (CSII) has been associated with better lipid profiles in patients with T1D. The aim of this study was to investigate the association between treatment modality and lipid profile, metabolic control, and body mass index (BMI)-SDS in children with both T1D and CD. Methods: Cross-sectional study in children registered in the international SWEET database in November 2020. Inclusion criteria were children (2–18 years) with T1D and CD with available data on treatment modality (CSII and injections therapy, IT), triglyceride, total cholesterol, HDL, LDL, dyslipidemia, HbA1c, and BMI-SDS. Overweight/obesity was defined as > +1 BMI-SDS for age. Data were analyzed by linear and logistical regression models with adjustment for age, gender, and diabetes duration. Results: In total 1009 children with T1D and CD (female 54%, CSII 54%, age 13.9 years ±3.6, diabetes duration 7.2 years ±4.1, HbA1c 7.9% ±1.4) were included. Significant differences between children treated with CSII vs. IT were respectively found; HDL 60.0 mg/dL vs. 57.8 mg/dL, LDL 89.4 mg/dL vs. 94.2 mg/dL, HbA1c 7.7 vs. 8.1%, BMI-SDS 0.4 vs. 0.6, overweight and obesity 17% vs. 26% (all p < 0.05). Conclusions: CSII is associated with higher HDL and lower LDL, HbA1c, BMI-SDS, and percentage of overweight and obesity compared with IT in this study. Further prospective studies are required to determine whether CSII improves lipid profile, metabolic control and normalize body weight in children with both T1D and CD. Full article

The administration of antibodies blocking the immune checkpoint molecules programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion, cytokine secretion, and cytotoxic activity of CD4⁺ and CD8⁺ T lymphocytes, resulting in enhanced antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1 antibodies for the treatment of tumor patients. However, the majority of patients have failed to respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to the identification of potential biomarkers distinguishing between responders and non-responders, the discovery of modes of treatment resistance, and the design of improved immunotherapeutic strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1 or anti-PD-L1 therapy. Full article

The current study investigates if contrast-enhanced ultrasound (CEUS) or cytokine expression analysis (CEA) evaluating vascularization are capable of predicting the outcome of non-union therapy. Patients with tibial non-unions were surgically treated and participated in our follow-up program including perioperative collection of blood as well as CEUS analysis. Two groups were formed: Responders in group 1 (G1, N = 8) and Non-Responders in group 2 (G2, N = 5). Serum cytokine expression and local microperfusion were compared and correlated to the radiologic outcome. Evaluation of TNF-α expression revealed significantly lower values prior to first surgery in G1 (G1: 9.66 ± 0.96 pg/mL versus G2: 12.63 ± 1.2 pg/mL; p = 0.045); whereas after treatment both CEA and CEUS indicated a higher potential for angiogenesis in Responders. Logistic regression modelling revealed the highest predictive power regarding eventual osseous consolidation for the combination of both CEUS and serum CEA. The results provide first evidence regarding a link between changes in the serum expression of distinct pro-angiogenic cytokines and alterations in the local microperfusion assessed via both non-invasive and radiation-free diagnostic modalities. In addition, a combination of CEUS and CEA is a promising novel tool in early prediction of the outcome of non-union therapy. Full article