Urology consultants versus large language models : potentials and hazards for medical advice in urology

Background Current interest surrounding large language models (LLMs) will lead to an increase in their use for medical advice. Although LLMs offer huge potential, they also pose potential misinformation hazards. Objective This study evaluates three LLMs answering urology-themed clinical case-based questions by comparing the quality of answers to those provided by urology consultants. Methods Forty-five case-based questions were answered by consultants and LLMs (ChatGPT 3.5, ChatGPT 4, Bard). Answers were blindly rated using a six-step Likert scale by four consultants in the categories: ‘medical adequacy’, ‘conciseness’, ‘coherence’ and ‘comprehensibility’. Possible misinformation hazards were identified; a modified Turing test was included, and the character count was matched. Results Higher ratings in every category were recorded for the consultants. LLMs' overall performance in language-focused categories (coherence and comprehensibility) was relatively high. Medical adequacy was significantly poorer compared with the consultants. Possible misinformation hazards were identified in 2.8% to 18.9% of answers generated by LLMs compared with <1% of consultant's answers. Poorer conciseness rates and a higher character count were provided by LLMs. Among individual LLMs, ChatGPT 4 performed best in medical accuracy (p < 0.0001) and coherence (p = 0.001), whereas Bard received the lowest scores. Generated responses were accurately associated with their source with 98% accuracy in LLMs and 99% with consultants. Conclusions The quality of consultant answers was superior to LLMs in all categories. High semantic scores for LLM answers were found; however, the lack of medical accuracy led to potential misinformation hazards from LLM ‘consultations’. Further investigations are necessary for new generations.Peer reviewe

MicroRNAs in Renal Cell Carcinoma: Diagnostic Implications of Serum miR-1233 Levels

BACKGROUND: MicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC). METHODOLOGY/PRINCIPAL FINDINGS: We first explored microrna expression profiles in tissue and serum using taqman low density arrays in each six malignant and benign samples: Although 109 microRNAs were circulating at higher levels in cancer patients' serum, we identified only 36 microRNAs with up-regulation in RCC tissue and serum of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients: miR-7-1*, miR-93, miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum of healthy controls (n = 30) and RCC (n = 33) patients were determined using quantitative real-time PCR (TaqMan MicroRNA Assays). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of 84 RCC patients and 93 healthy controls using quantitative real-time PCR (sensitivity 77.4%, specificity 37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters. CONCLUSIONS/SIGNIFICANCE: MicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a tumor-specific origin. We identify circulating miR-1233 as a potential biomarker for RCC patients. Larger-scaled studies are warranted to fully explore the role of circulating microRNAs in RCC

C‐reactive protein flare‐response predicts long‐term efficacy to first‐line anti‐PD‐1‐based combination therapy in metastatic renal cell carcinoma

Objectives Immune checkpoint blockade (IO) has revolutionised the treatment of metastatic renal cell carcinoma (mRCC). Early C-reactive protein (CRP) kinetics, especially the recently introduced CRP flare-response phenomenon, has shown promising results to predict IO efficacy in mRCC, but has only been studied in second line or later. Here, we aimed to validate the predictive value of early CRP kinetics for 1st-line treatment of mRCC with αPD-1 plus either αCTLA-4 (IO+IO) or tyrosine kinase inhibitor (IO+TKI). Methods In this multicentre retrospective study, we investigated the predictive potential of early CRP kinetics during 1st-line IO therapy. Ninety-five patients with mRCC from six tertiary referral centres with either IO+IO (N = 59) or IO+TKI (N = 36) were included. Patients were classified as CRP flare-responders, CRP responders or non-CRP responders as previously described, and their oncological outcome was compared. Results Our data validate the predictive potential of early CRP kinetics in 1st-line immunotherapy in mRCC. CRP responders, especially CRP flare-responders, had significantly prolonged progression-free survival (PFS) compared with non-CRP responders (median PFS: CRP flare-responder: 19.2 months vs. responders: 16.2 vs. non-CRP responders: 5.6, P < 0.001). In both the IO+IO and IO+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS. CRP flare-response was also associated with long-term response ≥ 12 months. Conclusions Early CRP kinetics appears to be a low-cost and easy-to-implement on-treatment biomarker to predict response to 1st-line IO combination therapy. It has potential to optimise therapy monitoring and might represent a new standard of care biomarker for immunotherapy in mRCC

Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development

Insights into Urologic Cancer

Collectively, urological malignancies account for a considerable proportion of cancer cases worldwide [...

Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma

There is growing interest in cytokine-induced killer (CIK) cells on the integrated therapy of patients with RCC, especially those in the late stage or refractory to conventional chemotherapy and radiotherapy. In this review, a total of 15 clinical studies including 681 patients enrolled in CIK cell immunotherapy were outlined. Three-hundred-and-eighty-two patients with RCC were treated with CIK cells alone or in combination with DC vaccination, targeted agents sunitinib or sorafenib, and the PD-1 inhibitor pembrolizumab. Significantly improved 3-year overall survival rate was reported in four trials, whereas remarkably longer median progression-free survival was observed in three studies. Adverse reactions were mild and usually controllable fever and fatigue. Besides, preclinical research progresses were reviewed to increase our understanding about the underlying mechanisms of CIK cell cytotoxicity and identify potential targets to enhance their anti-tumor activity. These studies suggest that CIK cell-based immunotherapy has potential clinical benefits with a good safety profile and could become a promising approach in the combined therapies of RCC patients. However, further large-scale studies are required to evaluate the clinical efficacy of CIK cells and more efforts should be performed to identify the optimal CIK cell-based therapeutic regimen for RCC patients