Enhancing Dose Selection in Phase I Cancer Trials: Extending the Bayesian Logistic Regression Model with Non-DLT Adverse Events Integration

This paper presents the Burdened Bayesian Logistic Regression Model (BBLRM), an enhancement to the Bayesian Logistic Regression Model (BLRM) for dose-finding in phase I oncology trials. Traditionally, the BLRM determines the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). However, clinicians often perceive model-based designs like BLRM as complex and less conservative than rule-based designs, such as the widely used 3+3 method. To address these concerns, the BBLRM incorporates non-DLT adverse events (nDLTAEs) into the model. These events, although not severe enough to qualify as DLTs, provide additional information suggesting that higher doses might result in DLTs. In the BBLRM, an additional parameter $\delta$ is introduced to account for nDLTAEs. This parameter adjusts the toxicity probability estimates, making the model more conservative in dose escalation. The $\delta$ parameter is derived from the proportion of patients experiencing nDLTAEs within each cohort and is tuned to balance the model's conservatism. This approach aims to reduce the likelihood of assigning toxic doses as MTD while involving clinicians more directly in the decision-making process. The paper includes a simulation study comparing BBLRM with the traditional BLRM across various scenarios. The simulations demonstrate that BBLRM significantly reduces the selection of toxic doses as MTD without compromising, and sometimes even increasing, the accuracy of MTD identification. These results suggest that integrating nDLTAEs into the dose-finding process can enhance the safety and acceptance of model-based designs in phase I oncology trials.Comment: 15 pages, 2 tables, 3 figures; submitted to "Statistics in Medicine" journa

Assessment of Effectiveness and Safety of Aspiration-Assisted Nephrostomic Access Sheaths in PCNL and Intrarenal Pressures Evaluation: A Systematic Review of the Literature

Background: Different suction-assisted nephrostomic sheaths have been developed for percutaneous nephrolithotomy (PCNL). Objectives: (1) To examine PCNL techniques performed with different aspiration-assisted sheaths (Clear Petra (R) sheath, Superperc, SuperminiPCNL, and a miniPCNL patented sheath), with specific regard to effectiveness and safety outcomes in adult and paediatric patients; (2) to extrapolate intrarenal pressure (IRP) data during these procedures. Methods: A systematic literature search was performed in accordance with PRISMA guidelines. Relevant articles up to 8 February 2024 were included. Results: Twenty-five studies were selected, thirteen retrospective and twelve prospective. The use of four different aspirating sheaths for miniPCNL was reported: Clear Petra (R) sheath, Superperc, SuperminiPCNL, and a miniPCNL patented sheath. Stone free rates (SFRs) across techniques ranged from 71.3% to 100%, and complication rates from 1.5% to 38.9%. Infectious complication rates varied from 0 to 27.8% and bleeding complication rates from 0 to 8.9%. Most complications were low grade ones. The trend among studies comparing aspiration- and non-aspiration-assisted miniPCNL was towards equivalent or better SFRs and lower overall infectious and bleeding complication rates in suction techniques. Operation time was consistently lower in suction procedures, with a mean shortening of the procedural time of 19 min. Seven studies reported IRP values during suction miniPCNL. Two studies reported satisfactory SFRs and adequate safety profiles in paediatric patient cohorts. Conclusions: MiniPCNL with aspirating sheaths appears to be safe and effective in both adult and paediatric patients. A trend towards a reduction of overall infectious and bleeding complications with respect to non-suction procedures is evident, with comparable or better SFRs and consistently shorter operative times. The IRP profile seems to be safe with the aid of aspirating sheaths. However, high quality evidence on this topic is still lacking

Oxidative Stress and Semen Quality Among Night- and Day-Shift Workers: A Cross-Sectional Study

Introduction: Infertility affects 15% of couples, with oxidative stress recognized as a key contributor to male infertility. Night-shift work, through circadian disruption, may exacerbate oxidative imbalance and impair reproductive function. This study investigates the impact of night-shift work on oxidative stress and semen quality and evaluates the potential benefits of antioxidant supplementation in this context. Materials and Methods: We retrospectively analysed 96 white-European men aged 18–45, seeking fertility assessment at a single academic centre. Participants were classified as day or night workers based on their shift schedule, and all underwent standardised clinical, hormonal, and semen evaluations. Oxidative stress was assessed using the d-ROMs test. A subgroup of 40 patients (20 per group) treated for 3 months with antioxidant supplementation (Drolessano) to evaluate changes in oxidative stress and semen parameters was also considered. Statistical comparisons were performed using non-parametric tests and logistic regression analyses. Results: Night-shift workers exhibit significantly higher oxidative stress levels compared to day workers (median D-ROMs values of 340 vs. 280 U.CARR, p = 0.01), and a greater proportion of men exceeding the oxidative stress threshold (74.4% vs. 24.4%, p = 0.01). Logistic regression confirmed night-shift work as an independent predictor of elevated oxidative stress (OR 2.1, p = 0.001), even after adjusting for age and smoking. Following three months of antioxidant supplementation with Drolessano, both groups experienced significant reductions in oxidative stress (all p < 0.01), but night workers showed a substantially greater decrease (mean change −58.5 vs. −15.4 U.CARR, p = 0.001). Improvements in semen quality, including sperm concentration, motility, and morphology, were also more pronounced in the night group after treatment. Conclusions: At baseline, night-shift workers had significantly higher oxidative stress than day workers, likely due to circadian disruption. Both groups improved after antioxidant treatment, but night workers showed a greater reduction in D-ROMs. This pilot study might suggest a potential benefit of antioxidant therapy particularly in night workers

Transient ureteral obstruction after mini-percutaneous nephrolithotomy is associated with stone volume and location: results from a single-center, real-life study

Purpose: To evaluate the rate of and predictors of ureteral obstruction after mini-percutaneous nephrolithotomy (mPCNL) for kidney stones. Methods: We analyzed data from 263 consecutive patients who underwent mPCNL at a single tertiary referral academic between 01/2016 and 11/2022. Patient's demographics, stone characteristics, and operative data were collected. A nephrostomy tube was placed as the only exit strategy in each procedure. On postoperative day 2, an antegrade pyelography was performed to assess ureteral canalization. The nephrostomy tube was removed if ureteral canalization was successful. Descriptive statistics and logistic regression models were used to identify factors associated with a lack of ureteral canalization. Results: Overall, median (IQR) age and stone volume were 56 (47-65) years and 1.7 (0.8-4.2) cm3, respectively. Of 263, 55 (20.9%) patients showed ureteral obstruction during pyelography. Patients without ureteral canalization had larger stone volume (p < 0.001), longer operative time (p < 0.01), and higher rate of stones in the renal pelvis (p < 0.01) than those with normal pyelography. Length of stay was longer (p < 0.01), and postoperative complications (p = 0.03) were more frequent in patients without ureteral canalization. Multivariable logistic regression analysis revealed that stone volume (OR 1.1, p = 0.02) and stone located in the renal pelvis (OR 2.2, p = 0.04) were independent predictors of transient ureteral obstruction, after accounting for operative time. Conclusion: One out of five patients showed transient ureteral obstruction after mPCNL. Patients with a higher stone burden and with stones in the renal pelvis are at higher risk of inadequate ureteral canalization. Internal drainage might be considered in these cases to avoid potential complications

Vacuum-assisted mini-percutaneous nephrolithotomy is associated with lower rates of infectious complications compared to vacuum-cleaner procedure in patients at high risk for infections: a single-center experience

Purpose: To evaluate the impact of vacuum-assisted mini-percutaneous nephrolithotomy (vamPCNL) vs. vacuum-cleaner mPCNL (vcmPCNL) on the rate of postoperative infectious complications in a cohort of patients with high risk factors for infections. Methods: We retrospectively analysed data from 145 patients who underwent mPCNL between 01/2016 and 12/2022. Patient's demographics, stones characteristics and operative data were collected. vamPCNL and vcmPCNL were performed based on the surgeon's preference. High-risk patients were defied as having ≥ 2 predisposing factors for infections such as a history of previous urinary tract infections, positive urine culture before surgery, stone diameter ≥ 3 cm, diabetes mellitus and hydronephrosis. Complications were graded according to modified Clavien classification. Descriptive statistics and logistic regression models were used to identify factors associated with postoperative infectious complications. Results: vamPCNL and vcmPCNL were performed in 94 (64.8%) and 51 (35.2%) cases, respectively. After surgery, infectious complications occurred in 43 (29.7%) participants. Patients who developed infectious complications had larger stone volume (p = 0.02) and higher rate of multiple stones (p = 0.01) than those who did not. Infectious complications occurred more frequently after vcmPCNL than vamPCNL (55.9% vs. 44.1%. p = 0.01) in high-risk patients. Longer operative time (p < 0.01) and length of stay (p < 0.01) were observed in cases with infectious complications. At multivariable logistic regression analysis, longer operative time (OR 1.1, p = 0.02) and vcmPCNL (OR 3.1, p = 0.03) procedures were independently associated with the risk of infectious complications post mPCNL, after accounting for stone volume. Conclusion: One out of three high-risk patients showed infectious complications after mPCNL. vamPCL and shorter operative time were independent protective factors for infections after surgery

miR-129-5p: A key factor and therapeutic target in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurological disease characterized by the selective degeneration of motor neurons. No effective therapy is available for this disease. Several lines of evidence indicate that alteration of RNA metabolism, including microRNA (miRNA) processing, is a relevant pathogenetic factor and a possible therapeutic target for ALS. Here, we showed that the abundance of components in the miRNA processing machinery is altered in a SOD1-linked cellular model, suggesting consequent dysregulation of miRNA biogenesis. Indeed, high-throughput sequencing of the small RNA fraction showed that among the altered miRNAs, miR-129-5p was increased in different models of SOD1-linked ALS and in peripheral blood cells of sporadic ALS patients. We demonstrated that miR-129-5p upregulation causes the downregulation of one of its targets: the RNA-binding protein ELAVL4/HuD. ELAVL4/HuD is predominantly expressed in neurons, where it controls several key neuronal mRNAs. Overexpression of pre-miR-129-1 inhibited neurite outgrowth and differentiation via HuD silencing in vitro, while its inhibition with an antagomir rescued the phenotype. Remarkably, we showed that administration of an antisense oligonucleotide (ASO) inhibitor of miR-129-5p to an ALS animal model, SOD1 (G93A) mice, result in a significant increase in survival and improved the neuromuscular phenotype in treated mice. These results identify miR-129-5p as a therapeutic target that is amenable to ASO modulation for the treatment of ALS patients

Perioperative and Survival Outcomes of Patients Treated With Robot-Assisted Partial Nephrectomy and Percutaneous Microwave Ablation for Small Renal Masses: A Single Center Experience

Background: Robot assisted partial nephrectomy (RAPN) and microwave ablation (MWA) are 2 of the most advanced techniques for the management of localized small renal masses. Purpose: To compare the perioperative, functional and oncological results of RAPN and MWA. Materials and methods: Data from 171 consecutive patients undergoing either RAPN or MWA for a localized small renal mass at a single academic center was retrospectively collected. Baseline features included patients' demographics and masses' characteristics. Procedures were compared in terms of perioperative outcomes and renal function variation Progression of a persistent lesion or local recurrence after a complete treatment defined local tumor progression. Descriptive statistics and survival analysis tested the association between predictors and local tumor progression. Results: Of all, 109 and 62 patients underwent RAPN and MWA. Patients in the MWA group were older (P = .002) had higher Charlson Comorbidity Index (CCI) (P < .001) and higher frequency of preoperative chronic kidney disease (P < .001). MWA led to a shorter postoperative hospitalization time (P < .001) and lower incidence of medical complications (6.5% vs. 22.9%, P = .02) than RAPN. GFR decline was similar between groups both at discharge (P = .39) and at the time of last follow up (P = 1.00). A lower rate of secondary interventions (11.7% vs. 2.8%, P = .037) and a better disease-free survival (83.2% vs. 96.5%, P = .027) were reported after RAPN. Conversely, cancer specific and overall survival were comparable (P > .05). At univariate regression analysis, MWA was associated with local tumor progression (HR 3.46, P = .040). Conclusion: MWA displayed a lower perioperative impact, while functional outcomes were similar after each intervention. RAPN resulted superior in terms of tumor eradication, but no difference was noted regarding cancer specific survival. Thus, MWA represents a valid alternative in frail patients, though less radical than RAPN

Vacuum-assisted mini-percutaneous nephrolithotomy is associated with lower rates of infectious complications compared to standard procedures in low-risk patients: a single-center experience

Purpose: To evaluate the impact of vacuum-assisted mini-percutaneous nephrolithotomy (vamPCNL) vs. vacuum-cleaner mPCNL (vcmPCNL) on the rate of postoperative infectious complications in a cohort of patients with low risk factors for infections. Methods: We retrospectively analysed data from 229 patients who underwent mPCNL between 01/2016 and 09/2024. Patient’s demographics, stones characteristics and operative data were collected. vamPCNL and vcmPCNL were performed based on the surgeon’s preference. Low-risk patients were defied as: preoperative negative urine culture, no history of previous UTIs and immune system disease, no preoperative indwelling stent or catheter, single-stage procedure. Complications were graded according to modified Clavien classification. Descriptive statistics and logistic regression models were used to identify factors associated with postoperative infectious complications. Results: Median (IQR) age and stone volume were 56 (47–66) years and 1.7 (0.8–3.6) cm3, respectively. vamPCNL and vcmPCNL were performed in 177 (77.2%) and 52 (22.8%) cases, respectively. Infectious complications occurred in 23 (10.0%) cases after surgery. Patients who developed infectious complications were more frequently female (59% vs. 32.3%, p = 0.02), had larger stone volume (p = 0.02) and higher rate of multiple stones (p = 0.02) than those who did not. Infectious complications occurred more frequently after vcmPCNL than vamPCNL (19.6% vs. 6.8%, p = 0.01) in this cohort of low-risk patients. Longer operative time (p < 0.01) and length of stay (p < 0.01) were observed in cases with infectious complications. At multivariable logistic regression analysis, vcmPCNL procedures (OR 4.1, p = 0.01) were independently associated with the risk of infectious complications post mPCNL, after accounting for stone volume. Similarly, female gender (OR 2.6, p = 0.03) emerged as a predictor for infectious complications in low-risk patients even after accounting for vcmPCNL procedures. Conclusion: In a cohort of patients with kidney stones and low-risk factors for infections, approximately 10% of participants developed infectious complications after mPCNL. Patients with infectious complications had higher stone burden and longer procedural time than those who did not, as expected. vamPCNL confirmed to be associates with lower risk of infections, compared to vcmPCNL, even in patients with low risk factors

Abstract 2636: Targeting Autotaxin to suppress stromal signaling in the tumor microenvironment to improve outcome to therapy in fibrotic tumor types

Abstract Recent findings indicate that in cancer, host immune suppression and resistance to therapy is orchestrated by the presence and activity of stromal cells in the tumor microenvironment. Therefore novel approaches to overcome stromal mediated resistance to therapy represent a potential strategy to improve the outcome to chemotherapy and immune checkpoint blockade, particularly in tumors that have a fibrotic microenviroment. Autotaxin is an enzyme that converts Lysophosphatidylcholine (LPC) to Lysophosphatidic Acid (LPA), a key pathway that is aberrantly activated in fibrosis. LPA has also been described to act directly on tumor cells, promoting their growth and proliferation via G protein-coupled LPA Receptors (LPARs). IOA-289 is a novel, potent, selective and orally bioavailable inhibitor of Autotaxin, a target with known clinical application in fibrotic diseases and with a strong rationale for exploration in cancer. In preclinical models, IOA-289 modulated levels of circulating LPA in a dose dependent manner. At doses achieving at least 50% reduction of circulating LPA, IOA-289 showed monotherapeutic efficacy in in vivo mouse models of cancer. Notably the effects were most prominent in orthotopic models that recapitulate the stromal components of the microenvironment. In vitro studies investigated the mechanism of action of IOA-289, and it was shown to be driven by: (i)Direct anti-tumor activity on cancer cell lines in vitro (ii)Modulation of the secretory profile of fibroblasts(iii)Increased T cell infiltration in vitro and in vivo In a healthy volunteer study following a single oral ascending dose, IOA-289 showed a dose dependent increase in plasma and a corresponding decrease in circulating LPA. We also demonstrated that ATX was elevated in plasma from pancreatic cancer patients compared to samples from healthy volunteers and are correlated with soluble CA19-9. Based on our preclinical data we postulate that inhibition of the ATX/LPA pathway with IOA-289 may be a beneficial therapeutic strategy for cancer patients with fibrotic tumor microenvironments. The predicted biologically effective dose of IOA-289 has been calculated using PK/PD modelling combining data from preclinical studies and from the phase Ia healthy volunteer study. IOA-289 is scheduled to enter a phase Ib clinical trial in pancreatic cancer. Citation Format: Zoe Johnson, Marcel Deken, Ragini Medhi, Lauren Maggs, Alan Carruthers, Anne Cheasty, Alessia Tagliavini, Andrea Nizzardo, Marco Pergher, Karolina Niewola, Amy Fraser, Lars van der Veen, Pritom Shah, Luigi ZIviani, Stefano Milleri, Michael Lahn. Targeting Autotaxin to suppress stromal signaling in the tumor microenvironment to improve outcome to therapy in fibrotic tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2636.</jats:p