Extreme acute radiation-induced toxicity in a patient with polymorphous low-grade adenocarcinoma of the nasopharynx and rare variants in DNA repair genes.

BACKGROUND: Polymorphous low-grade adenocarcinoma (PLGA) is an extremely rare finding in the nasopharynx. There are no guidelines for the treatment of PLGA in this localization. Radiotherapy may be administered to treat this malignancy; however, in radiosensitive individuals, it is associated with a risk of severe radiotherapy-induced toxicity. METHODS: We present a case of a 73-year-old woman with locally advanced polymorphous low-grade adenocarcinoma of the nasopharynx who developed a severe adverse acute reaction to radiotherapy leading to treatment discontinuation. Despite intensive treatment, the patient died 40 days after RT initiation. Whole genome sequencing was performed using DNA from peripheral blood mononuclear cells in the search for variants that could explain such extreme toxicity. RESULTS: We identified a combination of pathogenic variants that may have contributed to the patient's reaction to radiation therapy, including predisposing variants in XRCC1, XRCC3, and LIG4. We also identified candidate variants, not previously described in this context, which could be associated with radiation toxicity based on plausible mechanisms. We discuss previous reports of this rare tumor from the literature and known contributors to radiation-induced toxicity. CONCLUSIONS: Genetic causes should be considered in cases of extreme radiosensitivity, especially when is not explained by clinical factors.

The Efficacy and Safety of Metastasis-directed Therapy in Patients with Prostate Cancer: A Systematic Review and Meta-analysis of Prospective Studies.

CONTEXT: Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are continuously emerging from well-designed prospective studies. OBJECTIVE: To summarise and report the evidence on oncological and safety outcomes of MDT in the management of mPCa patients. EVIDENCE ACQUISITION: We searched the PubMed, Scopus, and Web of Science databases for prospective studies assessing progression-free survival (PFS), local control (LC), androgen deprivation therapy (ADT)-free survival (ADT-FS), overall survival (OS), and/or adverse events (AEs) in mPCa patients treated with MDT. A meta-analysis was performed for 1- and 2-yr PFS, LC, ADT-FS, OS, and rate of AEs. Meta-regression and sensitivity analysis were performed to account for heterogeneity and identify moderators. EVIDENCE SYNTHESIS: We identified 22 prospective studies (n = 1137), including two randomised controlled trials (n = 116). Two studies were excluded from the meta-analysis (n = 120). The estimated 2-yr PFS was 46% (95% confidence interval [CI]: 36-56%) or 42% (95% CI: 33-52%) after excluding studies using biochemical or ADT-related endpoints. The estimated 2-yr LC, ADT-FS, and OS were 97% (95% CI: 94-98%), 55% (95% CI: 44-65%), and 97% (95% CI: 95-98%), respectively. Rates of treatment-related grade 2 and ≥3 AEs were 2.4% (95% CI: 0.2-7%) and 0.3% (95% CI: 0-1%), respectively. CONCLUSIONS: MDT is a promising treatment strategy associated with favourable PFS, excellent LC, and a low toxicity profile that allows oligorecurrent hormone-sensitive patients to avoid or defer ADT-related toxicity. Integration of MDT with other therapies offers a promising research direction, in particular, in conjunction with systemic treatments and as a component of definitive care for oligometastatic PCa. However, in the absence of randomised trials, using MDT for treatment intensification remains an experimental approach, and the impact on OS is uncertain. PATIENT SUMMARY: Direct treatment of metastases is a promising option for selected prostate cancer patients. It can delay hormone therapy and is being investigated as a way of intensifying treatment at the expense of manageable toxicity.

Rectum and Bladder Toxicity in Postoperative Prostate Bed Irradiation: Dose-Volume Parameters Analysis.

Although prostate cancer treatment is increasingly effective, its toxicities pose a major concern. The aim of our study was to assess the rate of adverse events (AEs) and the prognostic value of dose-volume histogram (DVH) parameters for the occurrence of treatment toxicity in patients treated with post-prostatectomy prostate bed radiotherapy (RT). The AEs were scored according to the CTCAE v.5.0. The rectum and bladder were contoured according to the RTOG Guidelines. The DVH parameters were assessed using data exported from the ECLIPSE treatment-planning system. Genitourinary (GU) and gastrointestinal (GI) toxicity were analysed using consecutive dose thresholds for the percentage of an organ at risk (OAR) receiving a given dose and the QUANTEC dose constraints. A total of 213 patients were included in the final analysis. Acute grade 2 or higher (≥G2) GU AEs occurred in 18.7% and late in 21.3% of patients. Acute ≥G2 GI toxicity occurred in 11.7% and late ≥G2 in 11.2% of the patients. Five patients experienced grade 4 AEs. The most common adverse effects were diarrhoea, proctitis, cystitis, and dysuria. The most significant predictors of acute ≥G2 GI toxicity were rectum V47 and V46 (p < 0.001 and p < 0.001) and rectum wall V46 (p = 0.001), whereas the most significant predictors of late ≥G2 GI AEs were rectum wall V47 and V48 (p = 0.019 and p = 0.021). None of the bladder or bladder wall parameters was significantly associated with the risk of acute toxicity. The minimum doses to bladder wall (p = 0.004) and bladder (p = 0.005) were the most significant predictors of late ≥G2 GU toxicity. Postoperative radiotherapy is associated with a clinically relevant risk of AEs, which is associated with DVH parameters, and remains even in patients who fulfil commonly accepted dose constraints. Considering the lack of survival benefit of postoperative adjuvant RT, our results support delaying treatment through an early salvage approach to avoid or defer toxicity.

Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. Complete surgical resection of GBM is almost impossible due to the infiltrative nature of the cancer. While no evidence for recent selection events have been found after diagnosis, the selective forces that govern gliomagenesis are strong, shaping the tumor's cell composition during the initial progression to malignancy with late consequences for invasiveness and therapy response. We present a mathematical model that simulates the growth and invasion of a glioma, given its ploidy level and the nature of its brain tissue micro-environment (TME), and use it to make inferences about GBM initiation and response to standard-of-care treatment. We approximate the spatial distribution of resource access in the TME through integration of in-silico modelling, multi-omics data and image analysis of primary and recurrent GBM. In the pre-malignant setting, our in-silico results suggest that low ploidy cancer cells are more resistant to starvation-induced cell death. In the malignant setting, between first and second surgery, simulated tumors with different ploidy compositions progressed at different rates. Whether higher ploidy predicted fast recurrence, however, depended on the TME. Historical data supports this dependence on TME resources, as shown by a significant correlation between the median glucose uptake rates in human tissues and the median ploidy of cancer types that arise in the respective tissues (Spearman r = -0.70; P = 0.026). Taken together our findings suggest that availability of metabolic substrates in the TME drives different cell fate decisions for cancer cells with different ploidy and shapes GBM disease initiation and relapse characteristics.

Radiation-induced circulating microRNAs linked to echocardiography parameters after radiotherapy.

Introduction: Patients treated with radiotherapy to the chest region are at risk of cardiac sequelae, however, identification of those with greatest risk of complications remains difficult. Here, we sought to determine whether short-term changes in circulating miRNA expression are related to measures of cardiac dysfunction in follow-up. Materials and methods: Two parallel patient cohorts were enrolled and followed up for 3 years after completion of RT to treat left-sided breast cancer. In the primary group (N=28) we used a a panel of 752 miRNAs to identify miRNAs associated with radiation and cardiac indices at follow up. In the second, independent cohort (N=56) we validated those candidate miRNAs with a targeted qPCR panel. In both cohorts. serum samples were collected before RT, 24h after the last dose and 1 month after RT; cardiac echocardiography was performed 2.5-3 year after RT. Results: Seven miRNAs in the primary group showed marked changes in serum miRNAs immediately after RT compared to baseline and associations with cardiopulmonary dose-volume histogram metrics. Among those miRNAs: miR-15b-5p, miR-22-3p, miR-424-5p and miR-451a were confirmed to show significant decrease of expression 24 hours post-RT in the validation cohort. Moreover, miR-29c, miR-451 and miR-424 were correlated with the end-diastolic diameter of the left ventricle, which was also confirmed in multivariable analysis adjusting for RT-associated factors. Conclusion: We identified a subset of circulating miRNAs predictive for cardiac function impairment in patients treated for left-sided breast cancer, although longer clinical observation could determine if these can be used to predict major clinical endpoints.

Serum miRNA-based signature indicates radiation exposure and dose in humans: A multicenter diagnostic biomarker study.

PURPOSE: Mouse and non-human primate models showed that serum miRNAs may be used to predict the biological impact of radiation doses. We hypothesized that these results can be translated to humans treated with total body irradiation (TBI), and that miRNAs may be used as clinically feasible biodosimeters. METHODS: To test this hypothesis, serial serum samples were obtained from 25 patients (pediatric and adults) who underwent allogeneic stem-cell transplantation and profiled for miRNA expression using next-generation sequencing. miRNAs with diagnostic potential were quantified with qPCR and used to build logistic regression models with lasso penalty to reduce overfitting, identifying samples drawn from patients who underwent total body irradiation to a potentially lethal dose. RESULTS: Differential expression results were consistent with previous studies in mice and non-human primates. miRNAs with detectable expression in this and two prior animal sets allowed for distinction of the irradiated from non-irradiated samples in mice, macaques and humans, validating the miRNAs as radiation-responsive through evolutionarily conserved transcriptional regulation mechanisms. Finally, we created a model based on the expression of miR-150-5p, miR-30b-5p and miR-320c normalized to two references and adjusted for patient age with an AUC of 0.9 (95%CI:0.83-0.97) for identifying samples drawn after irradiation; a separate model differentiating between high and low radiation dose achieved AUC of 0.85 (95%CI: 0.74-0.96). CONCLUSIONS: We conclude that serum miRNAs reflect radiation exposure and dose for humans undergoing TBI and may be used as functional biodosimeters for precise identification of people exposed to clinically significant radiation doses.

Identification of BRCA1/2 mutation female carriers using circulating microRNA profiles.

Identifying germline BRCA1/2 mutation carriers is vital for reducing their risk of breast and ovarian cancer. To derive a serum miRNA-based diagnostic test we used samples from 653 healthy women from six international cohorts, including 350 (53.6%) with BRCA1/2 mutations and 303 (46.4%) BRCA1/2 wild-type. All individuals were cancer-free before and at least 12 months after sampling. RNA-sequencing followed by differential expression analysis identified 19 miRNAs significantly associated with BRCA mutations, 10 of which were ultimately used for classification: hsa-miR-20b-5p, hsa-miR-19b-3p, hsa-let-7b-5p, hsa-miR-320b, hsa-miR-139-3p, hsa-miR-30d-5p, hsa-miR-17-5p, hsa-miR-182-5p, hsa-miR-421, hsa-miR-375-3p. The final logistic regression model achieved area under the receiver operating characteristic curve 0.89 (95% CI: 0.87-0.93), 93.88% sensitivity and 80.72% specificity in an independent validation cohort. Mutated gene, menopausal status or having preemptive oophorectomy did not affect classification performance. Circulating microRNAs may be used to identify BRCA1/2 mutations in patients of high risk of cancer, offering an opportunity to reduce screening costs.

Brachytherapy boost improves survival and decreases risk of developing distant metastases compared to external beam radiotherapy alone in intermediate and high risk group prostate cancer patients.

BACKGROUND AND PURPOSE: Despite several prospective trials showing a clinical benefit of combining external beam radiotherapy (EBRT) with brachytherapy boost (BTB) for the treatment of intermediate- and high-risk prostate cancer (PCa) patients, none of these trials was designed to test for a survival difference. In this study, we aimed to collect a large multi-institutional database to determine whether BT boost was associated with a statistically significant improvement in survival and a reduction of distant metastases based on real-world data. MATERIAL AND METHODS: We collected the data of patients treated for intermediate- or high-risk PCa with definitive EBRT or BTB, with or without androgen deprivation therapy (ADT), between January 2003 and December 2014 at two tertiary institutions. The statistical endpoints included overall survival (OS), freedom from distant metastases (FFDM), and metastases-free survival (MFS). The impact of treatment modality was assessed using Cox regression models and log-rank testing after one-to-one propensity score matching. RESULTS: A total of 1641 patients treated with EBRT (n = 1148) or high-dose-rate BTB (n = 493) were analyzed. The median survival and clinical follow-up were 117.8 (IQR 78-143.3) and 60.7 months, respectively. The radiotherapy modality (BTB) remained an independent prognostic factor for OS (HR 0.75; 95% CI 0.63-0.88; p < 0.001), FFDM (HR 0.54; 95% CI 0.4-0.73; p < 0.001), and MFS (HR 0.72; 95% CI 0.61-0.85; p < 0.001). After propensity score matching, the remaining 986 patients were well-balanced in terms of age, maximum PSA, ISUP grade group, and TNM T stage. OS (p < 0.001), FFDM (p = 0.001) and MFS (p < 0.001) were significantly higher in the BTB group. CONCLUSIONS: There is a strong positive association between BTB and OS, FFDM, and MFS in PCa patients treated with definitive RT for intermediate- or high-risk PCa.

Long-Term Outcomes of Stereotactic Body Radiotherapy (SBRT) for Intraprostatic Relapse after Definitive Radiotherapy for Prostate Cancer: Patterns of Failure and Association between Volume of Irradiation and Late Toxicity.

The aim of this retrospective study was to assess the adverse effects and outcomes of salvage re-irradiation with stereotactic body radiotherapy (sSBRT) for local recurrence of prostate cancer (PCa) after definitive radiotherapy (RT). The study was focused on the adverse effects and prognostic factors for treatment toxicity, followed by an analysis of patterns of failure and survival. Patients treated with sSBRT between 2012 and 2020 at a tertiary institution were included. The exclusion criteria were a primary or salvage radical prostatectomy or a palliative sSBRT dose. Patients with oligorecurrence were eligible if all metastatic lesions were treated locally with curative intent. The Kaplan-Meier method was used to estimate time to grade ≥ 3 toxicity, local control (LC), freedom from distant metastases (FFDM), progression-free survival (PFS), biochemical control (BC) and overall survival (OS). The differences between groups (focal vs. whole-gland sSBRT) were compared using the log-rank test. The Cox proportional hazards model was used to assess prognostic factors for the listed endpoints. A total of 56 patients with a median age of 70.9 years and a median follow-up of 38.6 months were included in the analysis. The majority of them received local sSBRT only (45; 80.4%), while the rest were simultaneously treated for oligometastases (11; 19.6%). Overall, 18 (32.1%) patients experienced any grade ≥ 3 toxicity, including 1 (6.7%) patient who received focal sSBRT, and 17 (41.5%) patients treated with whole-gland sSBRT. The Planning Target Volume (per cc; HR 1.01; 95% CI 1-1.02; p = 0.025) and use of ADT (yes vs. no; HR 0.35; 95%CI 0.13-0.93; p = 0.035) were independent prognostic factors for the risk of grade ≥ 3 toxicity. The estimated rate of grade ≥ 3 adverse events was significantly higher (43.8% vs. 7.1% at 2 years; p = 0.006), and there was no improvement in the LC (92.9% vs. 85.3% at 2 years; p = 0.759) in patients treated with whole-gland sSBRT compared to focal sSBRT. The 2- and 5-year LC were 87.6% and 47.9%, respectively; the 2- and 5-year FFDM were 72.7% and 42.8%, respectively; and the 2- and 5-year PFS were 67.9% and 28.7%, respectively. The primary pattern of failure was distant metastasis. The sSBRT for local recurrence of PCa after definitive RT was associated with a high risk of severe grade ≥ 3 toxicity, which significantly increased with the volume and extent of re-irradiation.

Metanalyses on metformin's role in pancreatic cancer suffer from severe bias and low data quality - An umbrella review.

AIMS: Discrepancies in the preclinical evidence, retrospective studies, and randomized trials evaluating metformin's role in pancreatic cancer are difficult to disentangle. We aimed to critically and systematically examine the quality and sources of heterogeneity between meta-analyses investigating the association between metformin intake and the prognosis of patients with pancreatic cancer. MATERIALS AND METHODS: We performed a literature search on PubMed, MEDLINE, Embase, and Scopus on October 31, 2021 to identify meta-analyses investigating the impact of metformin treatment on the prognosis of patients with pancreatic cancer. Meta-analyses quality was assessed using according to the AMSTAR 2 criteria. We assessed bias in individual studies included in the meta-analyses, with particular attention to immortal time bias and quality of reporting. RESULTS: Eleven meta-analyses describing 24 individual studies were included. All meta-analyses were rated low (n = 5) or critically low (n = 6) quality. Only 4 followed PRISMA reporting guidelines and only in 5 presented data were sufficient to replicate the analyses. Most meta-analyses combined results from clinical trials and retrospective studies (n = 6); patients with different cancer stages (resectable vs advanced) and from studies with different control group definitions. Immortal time bias was present and not accounted for in most (65.2%) of the individual retrospective studies; almost all (n = 9) meta-analyses failed to identify and correct for this source of bias. CONCLUSIONS: Meta-analyses describing the association of metformin use in patients with pancreatic cancer are plagued by various types of bias inherent in retrospective studies. The quality of evidence linking metformin to decreased pancreatic cancer mortality is generally low.

Loss of the volume-regulated anion channel components LRRC8A and LRRC8D limits platinum drug efficacy.

In recent years platinum (Pt) drugs have been found to be especially efficient to treat patients with cancers that lack a proper DNA damage response, e.g. due to dysfunctional BRCA1. Despite this knowledge, we are still missing helpful markers to predict Pt response in the clinic. We have previously shown that volume-regulated anion channels, containing the subunits LRRC8A and LRRC8D, promote the uptake of cisplatin and carboplatin in BRCA1-proficient cell lines. Here, we show that the loss of LRRC8A or LRRC8D significantly reduces the uptake of cis- and carboplatin in BRCA1;p53-deficient mouse mammary tumor cells. This results in reduced DNA damage and in vivo drug resistance. In contrast to Lrrc8a, the deletion of the Lrrc8d gene does not affect the viability and fertility of mice. Interestingly, Lrrc8d-/- mice tolerate a two-fold cisplatin maximum-tolerable dose. This allowed us to establish a mouse model for intensified Pt-based chemotherapy, and we found that an increased cisplatin dose eradicates BRCA1;p53-deficient tumors, whereas eradication is not possible in WT mice. Moreover, we show that decreased expression of LRRC8A/D in head and neck squamous cell carcinoma patients, who are treated with a Pt-based chemoradiotherapy, leads to decreased overall survival of the patients. In particular, high cumulative cisplatin dose treatments lost their efficacy in patients with a low LRRC8A/D expression in their cancers. Our data therefore suggest that LRRC8A and LRRC8D should be included in a prospective trial to predict the success of intensified cis- or car-boplatin-based chemotherapy.

Pre-Treatment Hemoglobin Concentration and Absolute Monocyte Count as Independent Prognostic Factors for Survival in Localized or Locally Advanced Prostate Cancer Patients Undergoing Radiotherapy.

The prognostic value of inflammatory indices, such as the absolute monocyte count (AMC), has been a subject of interest in recent prostate cancer (PCa) studies, while hemoglobin concentration (HGB) has been recognized as a survival factor in castration-resistant metastatic prostate cancer, but its value remains unclear in localized diseases. The aim of this study was to test the prognostic value of these two simple and inexpensive biomarkers for survival and was based on a cohort of 1016 patients treated with primary radiotherapy and androgen deprivation therapy for localized or locally advanced intermediate- or high-risk PCa. Complete survival data were available for all cases and were based on the National Cancer Registry, with a median observation time of 120 months (Interquartile Range (IQR) 80.9-144.7). Missing blood test data were supplemented using the Nearest Neighbor Imputation, and the Cox Proportional Hazards Regression model was used for analysis. The median age was 68.8 years (IQR 63.3-73.5). The five-year overall survival was 82.8%, and 508 patients were alive at the time of analysis. The median time between blood tests and the first day of radiotherapy was 6 days (IQR 0-19). HGB (p = 0.009) and AMC (p = 0.003) were independent prognostic factors for survival, along with age, Gleason Grade Group, clinical T stage and maximum prostate-specific antigen concentration. This study demonstrates that HGB and AMC can be useful biomarkers for overall survival in patients treated with radiotherapy for localized intermediate- or high-risk PCa.

TAS2R38 Bitter Taste Receptor Expression in Chronic Rhinosinusitis with Nasal Polyps: New Data on Polypoid Tissue.

Studies have shown differences in TAS2R38 receptor expression in patients with chronic rhinosinusitis (CRS) compared to healthy controls. Known agonists of TAS2R38 stimulate epithelial cells, leading to robust intracellular nitric oxide (NO) production, which damages bacterial membranes, enzymes, and DNA, but also increases ciliary beat frequency. In this study we examined, using qRT-PCR, the expression of TAS2R38 receptor in nasal polyps (NP) of patients with CRS (N = 107) and in inferior turbinate mucosa (ITM) of patients with CRS and controls (N = 39), and confronted it with clinical features and the severity of the disease. The expression was shown in 43 (50.00%) samples of ITM in the study group (N = 107), in 28 (71.79%) in the control group (N = 39) (p = 0.037), and in 43 (46.24%) of NP. There were no differences in levels of the expression in all analyzed tissues. Patients who rated their symptoms at 0-3 showed higher TAS2R38 expression in ITM in comparison to the patients with 8-10 points on the VAS scale (p = 0.020). A noticeable, however not significant, correlation between the TAS2R38 expression in ITM and the Lund-Mackay CT score was shown (p = 0.068; R = -0.28). Patients with coexisting asthma had significantly higher receptor expression in the NP (p = 0.012). Our study is the first to confirm the presence of the TAS2R38 receptor in NP. Expression of the TAS2R38 receptor is reduced in the sinonasal mucosa in patients with more advanced CRS with NP.

A Retrospective Study Assessing the Outcomes of Immediate Prepectoral and Subpectoral Implant and Mesh-Based Breast Reconstruction.

(1) Introduction: In response to patient concerns about breast cancer recurrence, increased use of breast magnetic resonance imaging and genetic testing, and advancements in breast reconstruction techniques, mastectomy rates have been observed to rise over the last decade. The aim of the study is to compare the outcomes of prepectoral and subpectoral implants and long-term, dual-stage resorbable mesh-based breast reconstructions in mutation carriers (prophylactic surgery) and breast cancer patients. (2) Patients and methods: This retrospective, two-center study included 170 consecutive patients after 232 procedures: Prepectoral surgery was performed in 156 cases and subpectoral was performed in 76. (3) Results: Preoperative chemotherapy was associated with more frequent minor late complications (p < 0.001), but not major ones (p = 0.101), while postoperative chemotherapy was related to more frequent serious (p = 0.005) postoperative complications. Postoperative radiotherapy was associated with a higher rate of minor complications (31.03%) than no-radiotherapy (12.21%; p < 0.001). Multivariate logistic regression found complications to be significantly associated with an expander (OR = 4.43), skin-reducing mastectomy (OR = 9.97), therapeutic mastectomy vs. risk-reducing mastectomy (OR = 4.08), and postoperative chemotherapy (OR = 12.89). Patients in whom prepectoral surgeries were performed demonstrated significantly shorter median hospitalization time (p < 0.001) and lower minor complication rates (5.77% vs. 26.32% p < 0.001), but similar major late complication rates (p = 0.915). (4) Conclusions: Implant-based breast reconstruction with the use of long-term, dual-stage resorbable, synthetic mesh is a safe and effective method of breast restoration, associated with low morbidity and good cosmesis. Nevertheless, prospective, multicenter, and long-term outcome data studies are needed to further evaluate the benefits of such treatments.

Prostate-specific antigen kinetics and metastasis-free survival in patients treated with external beam radiotherapy combined with high-dose-rate brachytherapy boost and androgen deprivation therapy for localized prostate cancer.

PURPOSE: Serum prostate-specific antigen (PSA) kinetics has been linked to prognosis in prostate cancer (PCa) patients. Our goal was to analyze the association between PSA kinetics and metastasis-free survival (MFS) in patients with localized PCa treated with high-dose-rate (HDR) brachytherapy (BT) boost combined with external beam radiotherapy (EBRT). MATERIAL AND METHODS: We retrospectively analyzed multiple PSA kinetics related to PSA nadir (nPSA), PSA bouncing, and biochemical recurrence (BCR) in 186 PCa patients treated with neoadjuvant androgen deprivation therapy (ADT), followed by EBRT combined with HDR-BT boost. Uni- and multivariate Cox regression models were calculated to assess the value of PSA-related parameters for the prediction of MFS. RESULTS: 5- and 10-year MFS were 95% and 84%, respectively. Median nPSA was 0.011 (IQR, 0.007-0.057) ng/ml and predicted MFS in multivariable analysis. Implementation of nPSA improved c-index of baseline model from 0.8 to 0.68. nPSA of 0.2 ng/ml offered the most optimal discriminatory ability for identifying patients with better prognoses. Time to nPSA (median, 11 months; IQR, 8-18 months) and PSA bounce, which occurred in 12.4% of patients, were not significantly associated with MFS. CONCLUSIONS: Lower values of nPSA are significantly associated with decreased risk of developing metastases in patients treated with EBRT combined with HDR-BT boost and ADT, and improve the accuracy of a clinical model for MFS.

Anti-Xa Activity of Enoxaparin for Prevention of Venous Thromboembolism in Severe Nephrotic Syndrome-A Single Center Prospective Study.

Severe nephrotic syndrome (NS) is associated with high risk of venous thromboembolic events (VTE), as well as presumably altered heparin pharmacokinetics and pharmacodynamics. Although prophylactic anticoagulation is recommended, the optimal dose is not established. The aim of the study was to test two co-primary hypotheses: of reduced enoxaparin effectiveness and of the need for dose-adjustment in NS. Forty two nephrotic patients with serum albumin ≤2.5 g/dL were alternately assigned to a standard fixed-dose of enoxaparin (NS-FD: 40 mg/day) or ideal body weight (IBW)-based adjusted-dose (NS-AD: 1 mg/kg/day). Twenty one matched non-proteinuric individuals (C-FD) also received fixed-dose. Co-primary outcomes were: the achievement of low- and high-VTE risk threshold of antifactor-Xa activity (anti-FXa) defined as 0.2 IU/mL and 0.3 IU/mL, respectively. Low-VTE-risk threshold was achieved less often in NS-FD than C-FD group (91 vs. 62%, p = 0.024), while the high-VTE-risk threshold more often in NS-AD than in NS-FD group (90 vs. 38%, p < 0.001). Two VTE were observed in NS during 12 months of follow-up (incidence: 5.88%/year). In both cases anti-FXa were 0.3 IU/mL implying the use of anti-FXa >0.3 IU/mL as a target for dose-adjustment logistic regression models. We determined the optimal dose/IBW cut-off value at 0.8 mg/kg and further developed bivariate model (termed the DoAT model) including dose/IBW and antithrombin activity that improved the diagnostic accuracy (AUC 0.85 ± 0.06 vs. AUC 0.75 ± 0.08). Enoxaparin efficacy is reduced in severe NS and the dose should be adjusted to ideal body weight to achieve target anti-FXa activity.

Prediction of Radiation-Induced Hypothyroidism Using Radiomic Data Analysis Does Not Show Superiority over Standard Normal Tissue Complication Models.

State-of-art normal tissue complication probability (NTCP) models do not take into account more complex individual anatomical variations, which can be objectively quantitated and compared in radiomic analysis. The goal of this project was development of radiomic NTCP model for radiation-induced hypothyroidism (RIHT) using imaging biomarkers (radiomics). We gathered CT images and clinical data from 98 patients, who underwent intensity-modulated radiation therapy (IMRT) for head and neck cancers with a planned total dose of 70.0 Gy (33-35 fractions). During the 28-month (median) follow-up 27 patients (28%) developed RIHT. For each patient, we extracted 1316 radiomic features from original and transformed images using manually contoured thyroid masks. Creating models based on clinical, radiomic features or a combination thereof, we considered 3 variants of data preprocessing. Based on their performance metrics (sensitivity, specificity), we picked best models for each variant ((0.8, 0.96), (0.9, 0.93), (0.9, 0.89) variant-wise) and compared them with external NTCP models ((0.82, 0.88), (0.82, 0.88), (0.76, 0.91)). We showed that radiomic-based models did not outperform state-of-art NTCP models (p > 0.05). The potential benefit of radiomic-based approach is that it is dose-independent, and models can be used prior to treatment planning allowing faster selection of susceptible population.

Adherence to Pharmacotherapy and Lifestyle Recommendations Among Hemodialyzed Patients and Kidney Transplant Recipients.

OBJECTIVE: Success in treatment with hemodialysis (HD) and kidney transplantation (KTx) requires good adherence. The objective of this study was to evaluate adherence to pharmacotherapy and health recommendations among HD and KTx patients using subjective and objective measures. METHODS: Two hundred thirty-nine enrolled patients, with 132 KTx (39F, 93M) and 107 HD (48F, 59M) completed a questionnaire regarding over-the-counter (OTC) medications and dietary supplements (DS), adherence to pharmacotherapy, lifestyle recommendations, and self-evaluation of knowledge on them. The surveys were supplemented with objective data from patients' medical records, including interdialytic weight gain and laboratory parameters. RESULTS: About 42.1% HD and 39.4% KTx patients reported using OTC medications without medical consultation (P = .677); 43.9% HD and 31.1% KTx used DS (P = .040); more HD than KTx failed to notify a doctor about it (52.2% vs. 21.4%; P < .001). More HD patients skipped medication doses (33.6% vs. 9.7%; P < .001). About 40.2% HD and 20.5% KTx patients drank alcohol (P < .001), 22.4% HD and 10.5% KTx smoked (P = .013). About 46.7% HD and 66.4% KTx patients limited their caloric intake (P = .002), 73.8% HD and 84.9% KTx limited their salt intake (P = .030). HD patients drank 1.17 ± 0.57 L of fluids daily and KTx drank 2.51 ± 0.67 L (P < .001). In HD patients, interdialytic weight gains positively correlated with dialysis vintage (R = 0.26, P = .02) and fluid (R = 0.28, P = .011) but not salt intake (P = .307). The variability of trough levels of calcineurin inhibitors was unrelated to use of DS or OTC medications. KTx rated their knowledge on recommendations higher compared with HD (mean score 4.0 ± 1.0 vs. 3.7 ± 1.0, P = .040). CONCLUSION: KTx recipients exhibit better adherence and rate their knowledge on recommendations higher than HD patients.

Serum microRNA as indicators of Wolfram syndrome's progression in neuroimaging studies.

INTRODUCTION: Patients with the ultra-rare Wolfram syndrome (WFS) develop insulin-dependent diabetes and progressive neurodegeneration. The aim of the study was to quantify microRNAs (miRNAs) in sera from patients with WFS, correlate their expression with neurological imaging over time and compare miRNA levels with those observed in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: We quantified miRNA expression (Qiagen, Germany) in two groups of patients: with WFS at study entry (n=14) and after 2 years of follow-up and in 15 glycated hemoglobin-matched (p=0.72) patients with T1DM. RESULTS: We observed dynamic changes in the expression of multiple miRNAs in patients with WFS parallel to disease progression and in comparison to the T1DM patients group. Among miRNAs that differed between baseline and follow-up WFS samples, the level of 5 increased over time (miR-375, miR-30d-5p, miR-30e-30, miR-145-5p and miR-193a-5p) and was inversely correlated with macular average thickness, while the expression of 2 (let-7g-5p and miR-22-3p) decreased and was directly correlated with neuroimaging indicators of neurodegeneration. CONCLUSIONS: Our findings show for the first time that serum miRNAs can be used as easily accessible indicators of disease progression in patients with WFS, potentially facilitating clinical trials on mitigating neurodegeneration.