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.

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.

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.

Tacrolimus: Influence of the Posttransplant Concentration/Dose Ratio on Kidney Graft Function in a Two-Year Follow-Up.

INTRODUCTION: Tacrolimus (TAC) metabolism rate has the potential to impact graft function after kidney transplantation (KTx). We aimed to analyze the relationship between the early post-KTx TAC C/D ratio (blood trough concentration normalized by total daily dose) and kidney graft function in a 2-year follow-up. METHODS: We retrospectively analyzed data from 101 post-KTx patients at 3, 6, 12, and 24 months after KTx to identify the C/D ratio cutoff value optimal for dividing patients into fast and slow TAC metabolizers. We investigated the relationship between their TAC metabolism rate and graft function. RESULTS: Patients were divided based on the TAC C/D ratio at 6 months after KTx of 1.47 ng/mL * 1 mg. Fast metabolizers (C/D ratio <1.47 ng/mL * 1 mg) presented with significantly worse graft function throughout the whole study period (p < 0.05 at each timepoint) and were significantly less likely to develop good graft function (estimated glomerular filtration rate ≥45 mL/min/1.73 m2) than slow metabolizers. Our model based on donor and recipient age, recipient sex and slow/fast metabolism status allowed for identification of patients with compromised graft function in 2-year follow-up with 66.7% sensitivity and 94.6% specificity. CONCLUSION: Estimating TAC C/D ratio at 6 months post-KTx might help identify patients at risk of developing deteriorated graft function in a 2-year follow-up.

Extracellular miRNAs as Biomarkers of Head and Neck Cancer Progression and Metastasis.

Head and neck squamous cell carcinomas (HNSCCs) contribute to over 300,000 deaths every year worldwide. Although the survival rates have improved in some groups of patients, mostly due to new treatment options and the increasing percentage of human papillomavirus (HPV)-related cancers, local recurrences and second primary tumors remain a great challenge for the clinicians. Presently, there is no biomarker for patient surveillance that could help identify patients with HNSCC that are more likely to experience a relapse or early progression, potentially requiring closer follow-up or salvage treatment. MicoRNAs (miRNAs) are non-coding RNA molecules that posttranscriptionally modulate gene expression. They are highly stable and their level can be measured in biofluids including serum, plasma, and saliva, enabling quick results and allowing for repeated analysis during and after the completion of therapy. This has cemented the role of miRNAs as biomarkers with a huge potential in oncology. Since altered miRNA expression was described in HNSCC and many miRNAs play a role in radio- and chemotherapy resistance, cancer progression, and metastasis, they can be utilized as biomarkers of these phenomena. This review outlines recent discoveries in the field of extracellular miRNA-based biomarkers of HNSCC progression and metastasis, with a special focus on HPV-related cancers and radioresistance.

Temporal dynamics of serum let-7g expression mirror the decline of residual beta-cell function in longitudinal observation of children with type 1 diabetes.

BACKGROUND/OBJECTIVE: In type 1 diabetes mellitus (T1DM), the introduction of insulin is typically followed by a brief remission period, with subsequent gradual decline in beta-cell function. Several studies described altered profile of circulating miRNAs (microRNAs) in T1DM patients and proposed them as biomarkers of associated pathologic processes. HYPOTHESIS: Serum miRNA expression profile reflects residual beta-cell function and autoimmunity in T1DM. SUBJECTS: The profiling group included patients with: GCK-MODY (N = 13), T1DM (N = 9), and 10 healthy controls. The longitudinal group included 34 patients with samples collected at diagnosis of T1DM and first, third, and fourth to eighth year since diagnosis. METHODS: We reanalyzed data from the profiling group for miRNAs differentially expressed between patients with T1DM, other types of diabetes and controls. Afterward, we shortlisted miRNAs on the basis of this reanalysis and literature review and quantified their expression with quantitative polymerase chain reaction. Additionally, we measured the levels of anti-islet antibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, IA2 antibodies, and ZnT8A) and C-peptide concentrations across the four timepoints in the longitudinal group. RESULTS: miR-24 and let-7g serum expression differed significantly between GCK-MODY, controls, and HbA1c-matched T1DM patients; P < 0.05, false discovery rate < 0.05. Autoantibodies levels showed decreasing linear trend in repeated timepoints (all P < 0.0001). C-peptide concentration peaked during the first year after diagnosis, corresponding to remission phase, and declined in consecutive measurements. This dynamic was evidenced for let-7g expression levels (P = 0.0058). CONCLUSIONS: The pattern of let-7g expression change during the course of diabetes mirrors that of C-peptide levels, hinting at this microRNA's association with the residual mass of the beta cells in patients with T1DM.

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 Prognostic Value of the Systemic Immune-Inflammation Index (SII) and Red Cell Distribution Width (RDW) in Patients with Cervical Cancer Treated Using Radiotherapy.

INTRODUCTION: There is growing interest in the prognostic value of routinely performed pre-treatment blood test indices, such as the RDW or SII, with the latter combining the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). These indices were shown to be prognostic for survival in some malignancies. The purpose of this study was to evaluate the association between pre-treatment RDW and SII, and OS in patients treated with radiotherapy for primary localised cervical cancer. MATERIAL AND METHODS: This retrospective analysis included patients treated with definitive CRT between 2011 and 2017 for histopathologically confirmed FIGO 2018 stage IB2-IVA cervical cancer. Statistical analysis was performed using the Kaplan-Meier method, two-sided log-rank tests, and Cox proportional hazards models, with the AIC serving as a prediction error estimator. RESULTS: The study group included 249 patients with a median age of 57.2 years and a median follow-up of 75.8 months. The majority were diagnosed with squamous cell carcinoma (237; 95.2%) and had FIGO stage III (211; 84.7%). Approximately half of the patients (116; 46.4%) had regional lymph node metastases. Patients with a low RDW (≤13.4%) and low SII (≤986.01) had a significantly longer OS (p = 0.001 and p = 0.002). The RDW remained as an independent prognostic factor in the multivariable model (high vs. low; HR = 2.04; 95% CI: 1.32-3.16; p = 0.001). Including RDW in the model decreased the Akaike Information Criterion from 1028.25 to 1018.15. CONCLUSIONS: The RDW is a cheap and widely available index that is simultaneously an independent prognostic factor for survival and could be used to improve pre-treatment prognosis assessments in patients with cervical cancer undergoing CRT. Available data encourage assessing the RDW as a prognostic factor in prospective trials to aid the identification of candidates for treatment escalation.

Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia.

Chromothripsis (cth) is a form of genomic instability leading to massive de novo structural chromosome rearrangements in a one-time catastrophic event. It can cause cancer-promoting alterations, such as loss of sequences for tumor-suppressor genes, formation of oncogenic fusions, and oncogene amplifications. We investigated the genetic background and clinical significance of cth in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. For this purpose, whole-genome copy number alterations were analyzed in 173 children with newly diagnosed T-ALL using high-density microarrays. Cth was identified in 10 T-ALL samples (5.78%). In six of them, cth occurred in a constitutional background of Nijmegen breakage syndrome (n = 5) or Li-Fraumeni syndrome (n = 1). Cth generated alterations, including deletions of CDKN2A/B (n = 4) and EZH2 (n = 4), amplifications of CDK6 (n = 2), and NUP214::ABL1 and TFG::GPR128 fusions. Cth-positive leukemias exhibited deletions involving the tumor-suppressor genes RB1 (n = 3), TP53 (n = 1) and MED12 (n = 2). Cth-positive T-ALL patients had a lower probability of 5-year overall survival (OS) [0.56 vs. 0.81; hazard ratio (HR) = 4.14 (1.42-12.02) p = 0.017] as did 5-year event-free survival [0.45 vs. 0.74; HR = 3.91 (1.52-10.08); p = 0.012]. Chromothripsis is an infrequent genomic phenomenon in pediatric T-ALL but is significantly associated with cancer-predisposing syndromes and may associate with inferior prognosis.

Stereotactic arrhythmia radioablation (STAR)-A systematic review and meta-analysis of prospective trials on behalf of the STOPSTORM.eu consortium.

Stereotactic arrhythmia radioablation (STAR) is a noninvasive treatment of refractory ventricular tachycardia (VT). In this study, we aimed to systematically review prospective trials on STAR and pool harmonized outcome measures in a meta-analysis. After registration in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023439666), we searched OVID Medline, OVID Embase, Web of Science Core Collection, the Cochrane Central Register of Controlled Trials, and Google Scholar on November 9, 2023, to identify reports describing results of prospective trials evaluating STAR for VT. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies of Interventions tool. Meta-analysis was performed using generalized linear mixed models. We identified 10 prospective trials in which 82 patients were treated with STAR between 2016 and 2022. The 90-day rate of treatment-related grade ≥3 adverse events was 0.10 (95% confidence interval [CI] 0.04-0.2). The proportions of patients achieving given VT burden reductions were 0.61 (95% CI 0.45-0.74) for ≥95%, 0.80 (95% CI 0.62-0.91) for ≥75%, and 0.9 (95% CI 0.77-0.96) for ≥50% in 63 evaluable patients. The 1-year overall survival rate was 0.73 (95% CI 0.61-0.83) in 81 patients, 1-year freedom from recurrence was 0.30 (95% CI 0.16-0.49) in 61 patients, and 1-year recurrence-free survival was 0.21 in 60 patients (95% CI 0.08-0.46). Limitations include methodological heterogeneity across studies and moderate to significant risk of bias. In conclusion, STAR is a promising treatment method, characterized by moderate toxicity. We observed 1-year mortality of ≈27% in this population of critically ill patients suffering from refractory VT. Most patients experience a significant reduction in VT burden; however, 1-year recurrence rates are high. STAR should still be considered an investigational approach and recommended to patients primarily within the context of prospective trials.

53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer.

53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

Dose-volume metric-based prediction of radiotherapy-induced lymphocyte loss in patients with non-small-cell lung cancer treated with modern radiotherapy techniques.

Background and Purpose: Radiation-induced lymphopenia (RIL) is a common side effect of radiotherapy (RT) that may negatively impact survival. We aimed to identify RIL predictors in patients with non-small-cell lung cancer (NSCLC) treated intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Materials and Methods: We retrospectively analysed data of 306 patients who underwent radical RT for NSCLC. Absolute lymphocyte count (ALC) loss was evaluated for each patient by fitting an exponential decay curve to data from first 45 days since treatment start, and percentage ALC loss relative to baseline was calculated based on area under the decay curve and baseline ALC. We compared IMRT and VMAT treatment plans and used linear regression to predict ALC loss. Results: ALC decreased during RT in the whole patient group, while neutrophil counts remained stable and decreased only in those treated with concurrent chemoradiotherapy (CRT). Percentage ALC loss ranged between 11 and 78 % and was more strongly than lymphocyte nadir correlated with dose-volume metrics for relevant normal structures. We found evidence for the association of high radiation dose to the lungs, heart and body with percentage ALC loss, with lung volume exposed to 20-30 Gy being most important predictors in patients treated with IMRT. A multivariable model based on CRT use, baseline ALC and first principal component (PC1) of the dose-volume predictors showed good predictive performance (bias-corrected R2 of 0.40). Conclusion: Percentage lymphocyte loss is a robust measure of RIL that is predicted by baseline ALC, CRT use and dose-volume parameters to the lungs, heart and body.

Clinical outcomes of pelvic bone marrow sparing radiotherapy for cervical cancer: A systematic review and meta-analysis of randomised controlled trials.

Background: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer. We investigated how additional bone marrow sparing (BMS) affects the clinical outcomes. Methods: We queried MEDLINE, Embase, Web of Science Core Collection, Google Scholar, Sinomed, CNKI, and Wanfang databases for articles published in English or Chinese between 2010/01/01 and 2023/10/31. Full-text manuscripts of prospective, randomised trials on BMS in cervical cancer patients treated with definitive or postoperative CRT were included. Risk of bias (RoB) was assessed using Cochrane Collaboration's RoB tool. Random-effects models were used for the meta-analysis. Results: A total of 17 trials encompassing 1297 patients were included. The majority were single-centre trials (n = 1268) performed in China (n = 1128). Most trials used CT-based anatomical BMS (n = 1076). There was a comparable representation of trials in the definitive (n = 655) and postoperative (n = 582) settings, and the remaining trials included both.Twelve studies reported data on G ≥ 3 (n = 782) and G ≥ 2 (n = 754) haematologic adverse events. Both G ≥ 3 (OR 0.39; 95 % CI 0.28-0.55; p < 0.001) and G ≥ 2 (OR 0.29; 95 % CI 0.18-0.46; p < 0.001) toxicity were significantly lowered, favouring BMS. Seven studies (n = 635) reported data on chemotherapy interruptions, defined as receiving less than five cycles of cisplatin, which were significantly less frequent in patients treated with BMS (OR 0.44; 95 % CI 0.24-0.81; p = 0.016). There was no evidence of increased gastrointestinal or genitourinary toxicity.There were no signs of significant heterogeneity. Four studies were assessed as high RoB; sensitivity analyses excluding these provided comparable results for main outcomes. The main limitations include heterogeneity in BMS methodology between studies, low representation of populations most affected by cervical cancer, and insufficient data to assess survival outcomes. Conclusions: The addition of BMS to definitive CRT in cervical cancer patients decreases hematologic toxicity and the frequency of interruptions in concurrent chemotherapy. However, data are insufficient to verify the impact on survival and disease control.

Retrospective comparative analysis of two medical evacuation systems for Ukrainian patients affected by war.

INTRODUCTION: Coordinated medical evacuations represent an important strategy for emergency response when healthcare systems are impaired by armed conflict, particularly for patients diagnosed with life-threatening conditions such as cancer. In this study, we compare the experiences of two parallel medical evacuation systems developed to meet the medical needs of Ukrainians affected by war. METHODS: This retrospective study compared outcomes of two medical evacuation systems, developed by the European Union Emergency Response Coordination Centre (ERCC) and Supporting Action for Emergency Response in Ukraine (SAFER Ukraine) collaborative, in the first 10 months after the war's intensification in Ukraine (February 24 to December 21, 2022). Each groups' respective registries served as data sources. Patient demographics and allocation data were summarized descriptively. Median time for patient referral were analyzed statistically. RESULTS: The ERCC pathway evacuated 1385 patients (median age: 36 [0 - 85] years) to 16 European countries; 78.7 % (n = 1091) suffered from trauma-related injuries and 13.4 % (n = 185) from cancer. SAFER Ukraine evacuated 550 patients (median age: 9 [0 - 22] years) to 14 European and North American countries; 97.1 % (n = 534) were children diagnosed with cancer or blood disorders. The median evacuation time for the SAFER Ukraine cohort was shorter than the ERCC cohort (p < 0.001), though comparable (six versus seven days). CONCLUSION: The ERCC and SAFER Ukraine collaborative successfully developed medical evacuation pathways to meet the needs of Ukrainian patients impacted by war. System comparison provides opportunity to identify strategies for parallel system harmonization and a pragmatic example of how to anticipate support of these patients in future armed conflicts.

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.

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.

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.

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.

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.

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.