A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Preliminary Screening on Antibacterial Crude Secondary Metabolites Extracted from Bacterial Symbionts and Identification of Functional Bioactive Compounds by FTIR, HPLC and Gas Chromatography-Mass Spectrometry.

Secondary metabolites, bioactive compounds produced by living organisms, can unveil symbiotic relationships in nature. In this study, soilborne entomopathogenic nematodes associated with symbiotic bacteria (Xenorhabdus stockiae and Photorhabdus luminescens) were extracted from solvent supernatant containing secondary metabolites, demonstrating significant inhibitory effects against E. coli, S. aureus, B. subtilus, P. mirabilis, E. faecalis, and P. stutzeri. The characterization of these secondary metabolites by Fourier transforms infrared spectroscopy revealed amine groups of proteins, hydroxyl and carboxyl groups of polyphenols, hydroxyl groups of polysaccharides, and carboxyl groups of organic acids. Furthermore, the obtained crude extracts were analyzed by high-performance liquid chromatography for the basic identification of potential bioactive peptides. Gas chromatography-mass spectrometry analysis of ethyl acetate extracts from Xenorhabdus stockiae identified major compounds including nonanoic acid derivatives, proline, paromycin, octodecanal derivatives, trioxa-5-aza-1-silabicyclo, 4-octadecenal, methyl ester, oleic acid, and 1,2-benzenedicarboxylicacid. Additional extraction from Photorhabdus luminescens yielded functional compounds such as indole-3-acetic acid, phthalic acid, 1-tetradecanol, nemorosonol, 1-eicosanol, and unsaturated fatty acids. These findings support the potential development of novel natural antimicrobial agents for future pathogen suppression.

Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Penile prosthesis implantation is safe and effective in Peyronie's disease patients with and without erectile dysfunction.

Penile prosthesis (PP) is the mainstay of treatment in Peyronie's disease (PD) with co-existent refractory erectile dysfunction (ED). This study aimed to assess the clinical outcomes of patients who underwent PP as the first-line surgical treatment in PD without ED. A total of 636 patients underwent PP for PD from 2012 to 2022, but only 168 patients who underwent PP as first-line surgical management for PD with or without ED were included in the study. The mean (SD) age of 168 patients was 56.3 years (12.4). The mean curvature of the "PD with ED" group and the "PD without ED" group were 38.2 (5.6) degrees and 42.2 (5.9) degrees. The median (IQR) follow-up was 56.0 months (34.5- 61.4). Most (86.9%) patients underwent 3-piece inflatable PP. An important finding is that 33 patients (19.6%) without ED had undergone PP. Mechanical failure requiring revision surgery was less common in the 'without ED' group than in the ED group (6.8% vs. 10.2%, p 0.04). Most PD patients without ED (87.9%, 29/33) and with ED (88.9%, 120/135) were "satisfied" after PP implantation at six months, as defined by a score of ≥4 on a 5-point Likert scale. If surgery is offered in PD, PP may be considered a safe and effective first-line surgical treatment regardless of the ED, given the acceptable complications and high satisfaction rates. However, this new concept warrants further research.

Preparation of a heterogeneous biocatalyst through Thermomyces lanuginosus lipase immobilization on pore-expanded SBA-15.

Heterogeneous biocatalysts were prepared by adsorbing T. lanuginosus lipase (TLL) onto uncalcined (SBAUC-TLL) and calcined (SBAC-TLL) SBA-15, using ammonium fluoride as a pore expander to facilitate TLL immobilization. At an enzyme load of 1 mg/g, high immobilization yields (>90 %) and recovered activities (>80 % for SBAUC-TLL and 70 % for SBAC-TLL) were achieved. When increasing the enzyme load to 5 mg/g, the immobilization yield of SBAUC-TLL was 80 %, and the recovered activity was 50 %, while SBAC-TLL had a yield of 100 % and a recovered activity of 36 %. Crosslinking with glutaraldehyde (GA) was conducted to improve stability (SBAUC-TLL-GA and SBAC-TLL-GA). Although SBAC-TLL-GA lost 25 % of initial activity after GA modifications, it exhibited the highest thermal (t1/2 = 5.7 h at 65 °C), when compared to SBAC-TLL (t1/2 = 12 min) and the soluble enzyme (t1/2 = 36 min), and operational stability (retained 100 % activity after 5 cycles). Both biocatalysts presented high storage stability since they retained 100 % of initial activity for 30 days. These results highlight SBA-15's potential as an enzyme support and the protocol's efficacy in enhancing stability, with implications for industrial applications in the food, chemical, and pharmaceutical sectors.

Production of carbon-11 for PET preclinical imaging using a high-repetition rate laser-driven proton source.

Most advanced medical imaging techniques, such as positron-emission tomography (PET), require tracers that are produced in conventional particle accelerators. This paper focuses on the evaluation of a potential alternative technology based on laser-driven ion acceleration for the production of radioisotopes for PET imaging. We report for the first time the use of a high-repetition rate, ultra-intense laser system for the production of carbon-11 in multi-shot operation. Proton bunches with energies up to 10-14 MeV were systematically accelerated in long series at pulse rates between 0.1 and 1 Hz using a PW-class laser. These protons were used to activate a boron target via the 11 B(p,n) 11 C nuclear reaction. A peak activity of 234 kBq was obtained in multi-shot operation with laser pulses with an energy of 25 J. Significant carbon-11 production was also achieved for lower pulse energies. The experimental carbon-11 activities measured in this work are comparable to the levels required for preclinical PET, which would be feasible by operating at the repetition rate of current state-of-the-art technology (10 Hz). The scalability of next-generation laser-driven accelerators in terms of this parameter for sustained operation over time could increase these overall levels into the clinical PET range.

Zeolites synthesis from phyllosilicates and their performance for CO2 adsorption.

Five phyllosilicates (kaolinite, montmorillonite, saponite, sepiolite and palygorskite) have been selected as starting materials for the synthesis of zeolites. Among them, kaolinite and montmorillonite display the lowest Si/Al molar ratio leading to aluminosilicates with high crystallinity. Thus, the hydrothermal treatment under basic conditions forms 4A zeolite when kaolinite is used as starting material while 13X zeolite is obtained when montmorillonite is used as starting material. The microporosity and CO2-adsorption capacity of the prepared zeolites are directly related to its crystallinity. Thus, in order to improve it, raw phyllosilicates were subjected to a microwave-assisted treatment to remove undesired Mg or Fe-species, which have a negative effect in the assembling of the zeolites by hydrothermal basic conditions in a second step. The highest adsorption value was 3.85 mmol/g at 25 °C and 760 mm of Hg for Mont-A-B sample after the consecutive treatments.

Descriptive study on substance uses and risk of sexually transmitted infections in the practice of Chemsex in Spain.

Background: In recent years, there has been an increasing use of sex-related substances (known as "Chemsex") to facilitate, intensify, and prolong the sexual experience of men who have sex with men. This phenomenon poses a public health problem, increasing the risk of sexually transmitted infections (STIs) and mental disorders. Objective: The primary aim of this study was to delve into the correlation between substance use and sexual health, specifically examining the association between different substances used and the risk of sexually transmitted infections (STIs) in the context of Chemsex in Spain. Methods: An observational, descriptive, cross-sectional study was conducted among 563 Spanish participants between January and April 2023. Non-probabilistic purposive sampling was used by the investigators. The researchers administered a questionnaire to men who have sex with men who use substances, especially in the sexual sphere, in all the autonomous communities of Spain. Results: 14.7% reported having practiced slamsex in the last year, and 17.94% were diagnosed with a Sexually Transmitted Infection in the previous 6 months. Of these, 21% were on PREP treatment, with the main STIs being gonorrhea (p < 0.001), chlamydia (p < 0.001), genital herpes (p = 0.020), and syphilis (p < 0.001). The 63.7% used methamphetamines as the main drug in the practice of chemsex. Discussion: Chemsex in Spain is linked to a high prevalence of STIs, especially gonorrhea and chlamydia, even among those on PrEP treatment. The use of various drugs during chemsex, such as amyl nitrite, GHB, ecstasy, and others, correlates with higher rates of STIs, highlighting the need for interventions to reduce risk and harm. The drugs most associated with slamsex include ketamine, mephedrone, and methamphetamine, underscoring the importance of addressing the risk behaviors associated with this activity. Conclusion: This study shows that chemsex appears to be associated with a high prevalence among men who have sex with men. Who use multiple substances in a sexual context, and are particularly exposed to sexually transmitted infections (STIs), indicating a particular need for STI prevention and care in this group.

Fluctuation corrections to Lifshitz tails in disordered systems.

Quenched disorder in semiconductors induces localized electronic states at the band edge, which manifest as an exponential tail in the density of states. For large impurity densities, this tail takes a universal Lifshitz form that is characterized by short-ranged potential fluctuations. We provide both analytical expressions and numerical values for the Lifshitz tail of a parabolic conduction band including its exact fluctuation prefactor. Our analysis is based on a replica field integral approach, where the leading exponential scaling of the tail is determined by an instanton profile and fluctuations around the instanton determine the subleading preexponential factor. This factor contains the determinant of a fluctuation operator, and we avoid a full computation of its spectrum by using a Gel'fand-Yaglom formalism, which provides a concise general derivation of fluctuation corrections in disorder problems. We provide a revised result for the disorder band tail in two dimensions.

Cost-effectiveness analysis of the diagnosis of temporal arteritis.

Temporal arteritis (TA) is the most common form of systemic vasculitis. Its diagnosis is based on criteria proposed by the American College of Rheumatology (1990), and its treatment is high-dose corticosteroids. Our objective is to assess the cost of diagnosing TA, and secondarily, cost-effective analysis of different diagnostic strategies (clinical, biopsy, doppler ultrasound) and therapeutic strategies (corticosteroid suspension). MATERIAL AND METHOD: Observational, retrospective study has been carried out on patients with AT (2012-2021). Demographic data, comorbidities, signs and symptoms suggestive of AT were collected. AT was diagnosed with a score ≥ 3 according to American College of Rheumatoloy criteria (ACR-SCORE). The costs of diagnosis and treatment modification were analysed. RESULTS: Seventy-five patients have been included, median age 77 (46-87) years. Headache, temporal pain and jaw claudication were significant for the diagnosis of TA. Patients with a halo on Doppler ultrasound and a positive biopsy have significantly elevated ESR and CRP compared to patients who do not. The cost of the AT diagnosis was 414.7 euros/patient. If we use ACR-SCORE ≥ 3-echodoppler it is 167.2 є/patient (savings 59.6%) and ACR-SCORE ≥ 3-biopsy 339.75 є/patient (savings 18%). If the corticosteroid was removed and a biopsy was performed, 21.6 є/patient (94.7% savings), if the corticosteroid was removed and Doppler ultrasound was performed, 10.6 є/patient (97.4% savings). CONCLUSIONS: Headache, temporary pain and jaw claudication are predictors of AT. Elevated ESR and CRP are predictors of positive biopsy and presence of halo on ultrasound. The uses of ACR-SCORE ≥ 3 with Doppler ultrasound or biopsy, and with corticosteroid suspension, are cost-effective.

Evaluation of the toxicological effects of Neltuma alpataco (Prosopis alpataco) pod alkaloid extract.

The pods of Neltuma spp. have shown potential as a source of protein and energy in livestock. However, prolonged consumption of some of these species can lead to neurological symptoms in ruminants. This study aimed to determine the alkaloid content, as well as the in vitro and in vivo effects of an alkaloid-enriched extract (AEE) from N. alpataco pods. High performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) identified juliprosine and juliprosopine as primary alkaloids, with juliprosine being most abundant. AEE from N. alpataco demonstrated dose-dependent cytotoxicity on glioma cells after 48 h, with a 50% cytotoxic concentration (CC50) of 24.69 µg/mL. However, the release of LDH was observed only at the highest tested concentration, indicating cellular damage. Further examination through phase-contrast microscopy and dual acridine orange/ethidium bromide fluorescence staining revealed morphological changes consistent with an apoptotic mechanism of cell death, ultimately leading to secondary necrosis. Finally, the LD50 after intraperitoneal injection in mice was determined to be 12.98 mg/kg. Taken together, these findings demonstrated for the first time the in vivo and in vitro toxicity of the AEE from N. alpataco pods.

Genomic Characterization and Clinical Outcomes of Patients with Peritoneal Metastases from the AACR GENIE Biopharma Collaborative Colorectal Cancer Registry.

Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment. SIGNIFICANCE: Utilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors.

Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab. SIGNIFICANCE: Analysis of methylation and fragment length in plasma using cfMeDIP-seq provides a tumor-naive approach to measure ctDNA with results comparable with a tumor-informed bespoke ctDNA. Early kinetics within the first weeks of treatment in methylation and fragment quantity can predict outcomes with pembrolizumab in patients with various advanced solid tumors. This article is featured in Selected Articles from This Issue, p. 897.

Perceived Stressful Life Events and Suicide Risk in Adolescence: The Mediating Role of Perceived Family Functioning.

AIM: Suicidal behavior is a serious public health problem and a major cause of death among adolescents. Three categories of major risk factors have been identified: psychological factors, stressful life events, and personality traits. Severe and objective stressful life events (SLEs), such as childhood mistreatment or abuse, have been clearly associated with higher rates of suicide risk. However, the relationship between suicide risk and adolescents' perceptions of the SLE impact is not as clear. This paper studies the relationship between SLE impact perception and suicide risk and the possible mediating role of perceived family functioning in this relationship. The need for longer-term or more intense psychological or psychiatric treatment in relation to SLE impact perception is also addressed. METHOD: One hundred forty-seven adolescents aged 11-17 were consecutively recruited from the Child and Adolescent Mental Health Outpatient Services Department of a general hospital in Madrid, Spain. Self-informed questionnaires were used to assess suicide risk, SLEs, and family functioning. In addition, the clinical records of the participants were consulted to collect information about their treatment histories, including the number of appointments and the duration of follow-up. RESULTS: SLE impact perception correlates significantly with suicide risk, the number of clinical appointments, the duration of treatment, and the perceived level of family functioning. The mediation model of the family functioning perception variable in the relationship between SLE impact perception and suicide risk is significant. The linear regression model of SLE impact perception and family functioning perception on suicide risk is also significant, accounting for 25.7% of the variance. CONCLUSIONS: Beyond the clear and proven effect of serious and objective SLEs, the perceived impact of SLEs reported by adolescents is related to an increased risk of suicide and more intense psychological and/or psychiatric follow-up. This relationship is mediated by the perceived level of family functioning. Adolescents' perceptions of their life experiences and perceived family support may be key determinants of suicide risk prevention.

Perceived burdensomeness, thwarted belongingness, and hopelessness as predictors of future suicidal ideation in Spanish university students.

The Interpersonal Theory of Suicide (IPTS) has received support for its role in understanding suicidal thoughts and behaviors. However, few longitudinal studies have focused on testing this theory in university students. The present study aimed to confirm the theoretical model of the IPTS in a sample of 225 Spanish university students, using path analysis in a longitudinal study. We assessed thwarted belongingness and perceived burdensomeness at T1 and hopelessness and suicidal ideation at T2, 12-14 weeks later. Moreover, we assessed suicidal ideation weekly for 14 weeks. Path analyses confirmed the Interpersonal Theory of Suicide model, with thwarted belongingness and perceived burdensomeness as direct and indirect predictors of suicidal ideation through hopelessness. Providers of guidance and clinical services in university settings should be trained to identify perceived burdensomeness, social belongingness, hopelessness, and suicidal ideation when screening for suicide prevention.