Dose Levels Research Articles

Venetoclax in combination with a pediatric-inspired regimen for the treatment of newly diagnosed adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

BCL-2 protein overexpression, common in B-cell acute lymphoblastic leukemia (B-ALL), including the Philadelphia (Ph)-like subtype, mediates leukemic cell survival. We treated 24 patients with 14 days of BCL-2 inhibitor, venetoclax, 400 mg daily (dose level 1) during induction and consolidation cycles combined with the CALGB 10403 regimen in newly diagnosed adults with Ph-negative B-ALL. Median age was 31 (range: 18-53) years, 92% were Hispanic, and 12 (50%) patients had Ph-like ALL. No dose limiting toxicity occurred in the phase 1 part. Median times to neutrophil and platelet count recovery were 20 and 21 days from start of induction, respectively. The most common grade ≥3 treatment-related adverse events were leukopenia (96%), neutropenia (83%), anemia (83%), thrombocytopenia (79%), lymphopenia (71%), hyperbilirubinemia (38%), and elevated ALT (33%). One patient with non-Ph-like ALL died from asparaginase-associated pancreatitis, and 23 (96%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) following induction with or without extended induction phase. Of 22 patients who started consolidation, 20 (91%) achieved negative minimal residual disease status (MRD-) (.

Site-Specific Modification of Native IgGs with Flexible Drug-Load.

Homogeneous, site-specifically conjugated antibodies have shown to result in antibody-drug conjugates (ADCs) with improved efficacy and tolerability compared to stochastically conjugated ADCs. However, precisely controlling the drug load as well as attaching multiple payload moieties to the antibody remains challenging. Here, we demonstrate the simple and direct modification of native IgG-antibodies at the residue glutamine 295 (Q295) without the need for any protein engineering with flexible drug-to-antibody ratios of one or multiple payloads. The conjugation is enabled through short, positively charged lysine containing peptides and native, commercially available microbial transglutaminase. In proof-of-concept studies, HER2-targeting ADCs based on trastuzumab were generated with drug-to-antibody ratios (DARs) of 2 and 4 of the same or different payloads using orthogonal conjugation chemistries. Quantitative biodistribution studies performed with 111In-radiolabeled conjugates showed high tumour uptake and low accumulation of radioactivity in non-targeted tissues. A single dose study of trastuzumab conjugated to the highly potent payload α-Amanitin demonstrated complete and long-lasting tumour remission and was well-tolerated at all dose levels tested.

Gut dysbiosis mediates the association between antibiotic exposure and chronic disease

Antibiotics are safe, effective drugs and continue to save millions of lives and prevent long-term illness worldwide. A large body of epidemiological, interventional and experimental evidence shows that exposure to antibiotics has long-term negative effects on human health. We reviewed the literature data on the links between antibiotic exposure, gut dysbiosis, and chronic disease (notably with regard to the “developmental origins of health and disease” (“DOHaD”) approach). Molecular biology studies show that the systemic administration of antibiotic to infants has a rapid onset but also often a long-lasting impact on the microbial composition of the gut. Along with other environmental factors (e.g., an unhealthy “Western” diet and sedentary behavior), antibiotics induce gut dysbiosis, which can be defined as the disruption of a previously stable, functionally complete microbiota. Gut dysbiosis many harmful long-term effects on health. Associations between early-life exposure to antibiotics have been reported for chronic diseases, including inflammatory bowel disease, celiac disease, some cancers, metabolic diseases (obesity and type 2 diabetes), allergic diseases, autoimmune disorders, atherosclerosis, arthritis, and neurodevelopmental, neurodegenerative and other neurological diseases. In mechanistic terms, gut dysbiosis influences chronic disease through direct effects on mucosal immune and inflammatory pathways, plus a wide array of direct or indirect effects of short-chain fatty acids, the enteric nervous system, peristaltic motility, the production of hormones and neurotransmitters, and the loss of intestinal barrier integrity (notably with leakage of the pro-inflammatory endotoxin lipopolysaccharide into the circulation). To mitigate dysbiosis, the administration of probiotics in patients with chronic disease is often (but not always) associated with positive effects on clinical markers (e.g., disease scores) and biomarkers of inflammation and immune activation. Meta-analyses are complicated by differences in probiotic composition, dose level, and treatment duration, and large, randomized, controlled clinical trials are lacking in many disease areas. In view of the critical importance of deciding whether or not to prescribe antibiotics (especially to children), we suggest that the DOHaD concept can be logically extended to “gastrointestinal origins of health and disease” (“GOHaD”) or even “microbiotic origins of health and disease” (“MOHaD”).

Unlocking the potential of tafamidis in treating transthyretin cardiac amyloidosis: A systematic review

Cardiac amyloidosis has gained increasing attention in recent years due to substantial advancements in diagnostic techniques and treatment options. Among the most notable developments in this field is the approval of tafamidis by the U.S. Food and Drug Administration in May 2019 for treating transthyretin amyloid cardiomyopathy (ATTR-CM). This marked a pivotal step forward in managing this complex condition. This systematic review aimed to comprehensively analyze the efficacy of tafamidis in treating ATTR-CM and determine its broader applications, with a focus on its impact on patient outcomes, optimal dosing strategies, and side effect profiles. We strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, ensuring that the methodology was transparent and rigorous. This review involved an extensive search of multiple databases, including PubMed and Google Scholar, for relevant articles published between January 1, 2014 and January 9, 2024. After a comprehensive screening and quality assessment process, 16 high-quality articles were identified and included in the final analysis. These articles provided abundant data on the clinical outcomes associated with tafamidis use in ATTR-CM. The findings of our review highlight the transformative role of tafamidis in the treatment of ATTR-CM. The drug not only improves the quality of life of patients by significantly alleviating symptoms but also markedly reduces hospitalization rates and all-cause mortality. Tafamidis showed an impressive safety profile across different dosage levels, representing a key therapeutic option. As the use of tafamidis continues to expand in clinical practice, its potential to improve short- and long-term outcomes in patients with ATTR-CM becomes increasingly evident.

Review of research works done on Rajata Bhasma [Incinerated Silver] at Institute of Teaching and Research in Ayurveda, Jamnagar

Rajata a well-known metal known for its Medhya, Rasayana and Balya Karma. Rajata is cost effective compared to Swarna and possess similar properties to that of Swarna. Rajata Bhasma (RB) is a calcined silver compound widely used by practitioners of Ayurveda for various ailments like depletion of body elements, neurological disorders, muscular dystrophy, infertility, diabetes, various infectious conditions. Aim of the present study was to compile such available research works done on Rajata in the Department of Rasa Shastra and Bhaishajya Kalpana (RS and BK), ITRA, Jamnagar and provide brief information about pharmaceutical, analytical, and pharmacological studies. Total five studies on Rajata Bhasma, which revalidated the impact of classical guidelines, safety issues, and therapeutic utilities, were screened from Department of RS and BK, Institute for Teaching and Research in Ayurveda, Jamnagar. All studies revealed that Rajata Bhasma is safe clinically, experimentally at Therapeutic Equivalent Dose (TED) levels as no toxic hazards were reported during the treatment period. The clinical efficacy of Rajata Bhasma has been evaluated in Female infertility, Depression (Avasada) and memory enhancing activity. conditions. Satisfactory responses with a decrease in the intensity of signs and symptoms were reported in all the studies. Though certain limitations were observed in these researches, the results can be considered as a lead for further well stratified studies covering larger population. No adverse effects were reported in any of these studies.

Chlorophyll films for radiation dosimetry: a feasibility study

Abstract Novel Chlorophyll-PVA composite films have been prepared and tested for the dosimetry of therapeutic radiation. The radiation response has been quantified using UV–vis spectroscopy. FTIR and XRD spectroscopies have been used to characterize the physical properties and irradiation response of the films. The films have shown response towards the therapeutic x-rays beams of 6 MV nominal energy in the tested dose range of 0.25 Gy to 32 Gy in discrete dose levels occurring in the geometric progression series of 2. The dosimeter has been found to exhibit sensitivity at a low dose of 0.25 Gy. The dose response curve of the dosimeter exhibits an exponential relationship of the absorbance and absorbed dose. A region of saturated absorbance has been observed beyond 4 Gy. The peak intensities of the FTIR spectra have been found to decrease with increasing doses as compared to the unirradiated samples, because of the changes in the bond polarities and molecular geometries. The XRD spectra indicates a change in the molecular orientation resulting in a decrease in peak intensity with increasing dose. This study indicates the feasibility of chl-PVA films in the dosimetry of therapeutic radiation. This film dosimeter can be processed locally with minimum resources and standardized against a known standard before clinical use. The chlorophyll molecules need careful handling owing to their sensitivity to light and temperature.

A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies

IntroductionRecombinant human interleukin-15 (rhIL-15) is an immunotherapeutic which enhances NK-cells to augment the antibody directed cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CCR4 directed monoclonal antibodies that exerts cytotoxicity through ADCC and depletes regulatory T-cells within the tumor microenvironment. MethodsWe conducted a phase 1 clinical trial of rhIL-15 combined with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF) and Sezary syndrome (SS) received fixed dose mogamulizumab combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). ResultsSix patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection and fever (67%, in all). Two patients (33%) had grade 4 acute kidney injury and 25% of cycles had grade ≥3 anemia. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles due to grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. DiscussionOur small study suggests that rhIL-15 combined with mogamulizumab leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remain rational. NCT04185220

A Phase 1 Study of ABI-009 (Nab-sirolimus) in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors-A Children's Oncology Group Pediatric Early Phase Clinical Trial Network Study ADVL1514.

Nab-sirolimus (ABI-009, nab-rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin-bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose-limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab-sirolimus in combination with temozolomide and irinotecan. Using a rolling 6 design, Nab-sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab-sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) and irinotecan (90 mg/m2/dose) orally, daily on D1-5. Cycle duration was 21 days. Three dose levels (DL) of Nab-sirolimus were investigated (DL1: 35 mg/m2/dose, DL-1: 20 mg/m2/dose, and DL-2: 15 mg/m2/dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2. Thirty-three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median (range) age 12 (2-20) years and six additional patients were enrolled (four evaluable for toxicity) on a pharmacokinetic cohort. C1 or C2 DLTs were primarily thrombocytopenia including 2/5 patients at DL1, 2/6 patients at DL-1, and 1/6 patients at DL-2. One patient (DL1) with Ewing Sarcoma had a partial response and remained on study for 35 cycles. Rapamycin clearance was dose dependent. Irinotecan clearance and its active metabolite SN-38 exposure were not affected by coadministration with Nab-sirolimus. The MTD for Nab-sirolimus was 15 mg/m2/dose IV on D1 and D8 in combination with temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose daily for 5 days during 21D cycles. ClinicalTrials.gov identifier NCT02975882.

A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.

Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial

Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. AstraZeneca.

Survey on the distribution of medical imaging frequencies and dose levels for CT examinations in a comprehensive hospital in Shanghai.

With the continuous advancement and clinical application of CT technology, the increasing collective dose burden from CT scans and associated potential health risks have become significant concerns in radiation protection. Current research increasingly focuses on the cumulative effective dose (CED) resulting from multiple CT scans, often revealing patients with high CEDs, even exceeding 100 mSv. However, reports on CEDs from multiple CT scans in China are scarce. Therefore, we investigated the distribution of CT scan frequencies and CEDs at a comprehensive hospital in Shanghai, examining data from October 1, 2022, to April 30, 2024, sourced from the hospital's radiology information system. The effective dose (E) was estimated using conversion factors k and DLP values from Radiation Dose Structured Reports (RDSR). We assessed the number of CT examinations conducted per patient and evaluated the CED over 1.6 years. During this period, 112,339 CT examinations were performed. Significant differences in CT examination frequencies were observed across different age groups and examination regions (P < 0.01). A total of 78.43% of patients underwent only one CT examination in 1.6 years, while 0.03% had more than 10 examinations, with a maximum of 15. Of the patients, 67.78% (76,142 individuals) received a CED less than 10 mSv, 0.05% (53 patients) received a CED over 50 mSv, and one patient exceeded 100 mSv. In conclusion, this study underscored the necessity of monitoring patients with high CT examination frequencies and CEDs, highlighting the importance of justification and optimization in medical radiation protection.

In vivo pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models.

Nystatin, a polyene, is one of the oldest antifungal drugs with wide in vitro potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using in vivo invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including Aspergillus fumigatus, Candida albicans, Candida auris, and Candida glabrata. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for A. fumigatus studies. For all Candida studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate Aspergillus in the lung and colony forming units (CFU) counts for Candida in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (Cmax)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for C. glabrata. Increasing exposures were needed for same outcome for C. auris at 18.7, C. albicans at 29.3, and A. fumigatus at 102.4. Cmax/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. Cmax/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.

Trihalomethane Formation Potential at the Barekese Water Treatment Plant and the Related Cancer Risk to Consumers in the Kumasi Metropolis of Ghana

The prevalence of disinfection by-products in drinking water supplies is a global concern due to their carcinogenicity. However, the monitoring of DBPs such as trihalomethanes (THMs) and haloacetic acids (HAAs) in drinking water supplies is non-existent in many developing Asian, South American, and African countries. The formation of THMs during disinfection arises from a reaction between the disinfectant and natural organic matter in the water, particularly, dissolved organic carbon (DOC). This reaction is hastened by increases in temperature, high levels of disinfectant doses or residual, elevated water pH, long disinfection contact times, and high DOC concentrations. However, the inclusion of a granular activated carbon adsorption process in the water treatment process is the most effective method for the removal of the main precursor (DOC) for the formation of THMs in treated water. The Barekese WTP, which disinfects with chlorine, has no adsorption process for DOC removal, and supplies over 80% of pipe-borne water to the city of Kumasi in Ghana, was assessed for the THM formation potential (THMFP). A THM predictive model was used to determine the potential THM concentration in the final water. The THMFP at the Barekese WTP ranged between 22.42 and 38.94 µg/L, which was below the 100 µg/L threshold set by the WHO. The lifetime average daily doses were 3.9494 × 10−4 µg/Kg/d and 3.9294 × 10−4 µg/Kg/d for male and female consumers, respectively. The lifetime integrative cancer risks associated with consumption of the water were 1.817 × 10−5 and 1.808 × 10−5 for males and females, respectively. The cancer risk posed was acceptably low. However, direct measurement of DBPs is required to corroborate these findings and verify the cancer risk posed to the consumers of treated water from the Barekese WTP to inform policies, regulations, public health interventions, and investment.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Phase 1 Study of ROR1 Specific CAR T Cells in Advanced Hematopoietic and Epithelial Malignancies.

The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells. Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion. Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1. ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.

A retrospective analysis of patients with very HIGH level of LDL-C and the predictors of mortality (HIGH-LDL-PM Registry)

Abstract Introduction Elevated levels of LDL cholesterol (LDL-C) significantly contribute to the development and progression of cardiovascular diseases (CVDs). In HIGH-LDL-PM Registry, we aimed to investigate the demographics and clinical characteristics of patients with very high level of LDL-C and the predictors of mortality, retrospectively. Methods We retrospectively searched the electronic database of Istanbul University-Cerrahpasa Institute of Cardiology and included patients with very high level of LDL-C (&amp;gt;190 mg/dl) in HIGH-LDL-PM registry. The study group were classified as patients with high probability of familial hypercholesterolemia (FH) and low probability of FH according to Dutch Lipid Clinic Network Score (DLCNS). Results The study group were consisted of 1127 patients and almost two thirds (61.5%) were female. The mean age was 56.5 12.2 years. Hypertension, diabetes, chronic kidney disease (CKD) were seen in 55.8%, 23.5% and 3.7%, respectively. One third of study group (31.1%) had coronary artery disease (CAD) and rest of them were primary prevention patients. the main rhythm was sinus in most of the patients (92,2) and 7.8% patients had atrial fibrillation (AF). Only minority of patients (3.9%) had stigmata for elevated cholesterol levels. While 41.8% of patients had high clinical probability for FH, 58.2% of them had low probability according to DLCNS. While 69% of patients were using lipid lowering treatments (LLTs), 42% of them had drug adherence. High dose (HD) statins (atorvastatin 40-80 and rosuvastatin 20-40 mg) were prescribed in more than half (55.2%) of patients with LLTs. Ezetimibe was the preferred agent as combination therapy in 6.9% and PCSK-9is were prescribed only in 2.5% of patients with LLTs. In 38.8% of study population, ASA was prescribed. 50% decrease in LDL-C levels or decreasing LDL-C below 70 or 100 mg/dl as a treatment goal were achieved in 37.1% and 15% of study population. MACE (MI, stroke, PCI or peripheral revascularization) was recorded in 21% of study population and the mortality rate was 10.4% at 12-years FU (6-145 months). Patients with low probability of FH had better survival than patient with high probability (91.4% vs 88.4%). The age, low dose statin use and higher level of LDL-C at FU were predictors of mortality in Cox-regression analysis. Conclusion Our retrospective analysis of patients with very high levels of LDL-C underscores the multifaceted nature of dyslipidemia management and its impact on cardiovascular outcomes. Despite advancements in pharmacotherapy, suboptimal adherence to lipid-lowering treatments remains a significant challenge, contributing to a notable burden of major adverse cardiovascular events and mortality. Identification of predictors of mortality, such as age, statin dosage, and LDL-C levels, highlights the importance of individualized risk assessment and tailored treatment approaches in this high-risk population.

Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101

Abstract Introduction ALXN2220 (formerly NI006) is an investigational human monoclonal antibody in development for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). ALXN2220 is designed to deplete cardiac amyloid transthyretin (ATTR) deposits in patients with ATTR-CM on top of standard of care. Data from the first-in-human, ascending dose study NI006-101 show that ALXN2220 is safe and well tolerated. A reduction of surrogate markers of cardiac amyloid load and cardiac biomarkers was observed in participants receiving doses of ≥ 10mg/kg of ALXN2220 over a period of 12 months of treatment. Purpose Long-term safety, tolerability and efficacy of ALXN2220 treatment beyond 12 months was studied in a prolonged Open-Label Extension (OLE) of the NI006-101 study. Methods Participants completing 12 months in dose cohorts ≤ 30 mg/kg were allowed to receive additional 6 to 12 monthly open-label ALXN2220 infusions with up-titration of all participants to 30 mg/kg. Cardiac biomarkers were measured centrally, and serial cardiac imaging was performed with echocardiography and cardiac MRI or scintigraphy. Results Out of 27 participants completing 12 months, 23 (18 ATTRwt, all male, median age 70 years at screening (range 28-83)) continued treatment in the prolonged OLE. Median number of infusions of ALXN2220 received and median time followed across the full study were 20 infusions (range 11-24) and 125 weeks (range 83-153). Overall adherence to treatment was high in the prolonged OLE, 97% of planned infusions administered, 87% of participants received all planned doses. No severe or serious adverse events were considered related to ALXN2220 or resulted in the discontinuation during OLE, and no events of cytokine release syndrome or thrombocytopenia were observed. None of the participants had anti-drug antibodies throughout the trial. Cardiac biomarkers (NT-proBNP, troponin) and cardiac imaging indicated continued treatment effects beyond 12 months and supported the up-titration of participants who previously received lower doses of ALXN2220. Conclusions Up-titration and long-term treatment at a dose level of 30 mg/kg in the OLE was safe and well tolerated, with overall good adherence to treatment. Cardiac imaging and cardiac biomarker data indicated continued treatment effects beyond 12 months and supported the up-titration of patients to 30 mg/kg.

Short-term effects on sacubitril/valsartan therapy on right ventricle work and mechanics in patients with heart failure and reduced ejection fraction

Abstract Introduction In previous studies, sacubitril/valsartan (ARNI) therapy has been shown to have a positive effect on right ventricle (RV) function and on systolic pulmonary artery pressure in addition to improvement of left ventricle (LV) function in patients with heart failure and reduced ejection fraction (HFrEF). Recently, it was shown that a short-term ARNI therapy compared to valsartan-only therapy led to reduced systemic blood pressure and LV mechanical work, contributing to reduced LV myocardial perfusion and oxygen consumption. Purpose This paper aimed to study the effect of short-term ARNI therapy on RV mechanics and work and pulmonary and LV filling pressures compared to valsartan-only therapy in patients with HFrEF. Methods The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with NYHA class II–III heart failure and LV ejection fraction (LVEF) &amp;lt;= 35 %. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, and cardiac and systemic hemodynamics were quantified using echocardiography and 11C-acetate PET before and after 6 weeks of therapy (on stable dose) in 55 patients. The analyses were done with ANCOVA adjusting for pre-randomization values. Results The RV myocardial resting perfusion (mean difference of 0.056 (95% CI, 0.02 to 0.109) ml/g/min, p = 0.041) and RV myocardial oxygen consumption (0.005 (0.001 to 0.010) 1/min, p = 0.015) were significantly lower in the ARNI group compared with the valsartan-only group. The left atrial end-diastolic volume indexed to body surface area (geometric mean difference of 1.071 (95% CI, 0 to 1.148) ml/m2, p = 0.048) and the ratio of early mitral inflow velocity to medial mitral annular early diastolic velocity (mean difference of 2.467 (95% CI, 0.096 to 4.838), p = 0.042) were also significantly lower in the ARNI group compared with the control group. There was no difference between the groups in peak systolic right ventricle to right atrial pressure gradient. Still, the tricuspid annular plane systolic excursion was significantly higher in the valsartan-only group compared with the ARNI group (0.221 (0.039 to 0.404) cm, p = 0.018). There was no difference in RV free wall strain, fractional area change or systolic excursion velocity between the treatment arms (p&amp;gt; 0.262). Conclusions In addition to our earlier findings, sacubitril when added to valsartan appears to reduce also right ventricle myocardial perfusion and oxygen consumption. There was also a reduction in left atrial end-diastolic volume and in early mitral inflow to medial mitral annular early diastolic velocity in the sacubitril/valsartan group as compared to the valsartan-only group, which suggest decreased LV filling pressure.

Image Quality Comparison of Three 3D Mobile X-Ray Imaging Guidance Devices Used in Spine Surgery: A Phantom Study

An image-quality CT phantom was scanned with three different 3D X-ray imaging guidance devices in the operating theatre: O-Arm, Loop-X, and Airo TruCT. Default acquisition and reconstruction parameters for lumbar spine procedures were used on each device. The tube current was set to a dose level of around 27 mGy. A task-based image quality assessment was performed by calculating the noise power spectrum (NPS) and task transfer function (TTF). A detectability index (d’) was calculated for three simulated bone lesions. The noise magnitude of the O-Arm was higher than the Airo TruCT, and the Loop-X had higher noise than the Airo TruCT. The highest average NPS frequency was for the O-Arm images, and the lowest was for the Loop-X. The TTFs at 50% values were similar for the Airo TruCT and Loop-X devices. Compared to Airo TruCT, the TTF at 50% value increased with the O-Arm by 53.12% and 41.20% for the Teflon and Delrin inserts, respectively. Compared to Airo TruCT, the d’ value was lower with Loop-X by −26.73%, −27.02%, and −23.95% for lytic lesions, sclerotic lesions, and high-density bone, respectively. Each 3D-imaging spine surgery guidance device has its own strengths and weaknesses in terms of image quality. Cone-beam CT systems apparently offer the best compromise between noise and spatial resolution for spine surgery.

The value of a multimodal approach combining radical surgery and intraoperative radiotherapy in the recurrence treatment of gynecological malignancies - analysis of a large patient cohort in a tertiary care center

BackgroundRecurrent and locally advanced gynecological malignancies have a poor prognosis. In particularly, pelvic local recurrence after previous radiotherapy and/or positive resection margins during surgical treatment for recurrent disease result in low survival rates. Consequently, locoregional control is of utmost importance in this cohort of patients. The aim of this study was to analyze treatment outcomes and determine prognostic factors for patients treated with surgery and intraoperative radiotherapy (IORT) for recurrent and locally advanced gynecological malignancies.Methods40 patients who underwent surgical treatment and IORT between 2010 and 2022 were eligible for inclusion. The median follow-up time was 22 months. The outcomes measured were locoregional control (LRC), overall survival (OS), and survival without distant metastases (DMFS). The Cox proportional hazards model was used for univariate and multivariate analysis to assess the impact of patient variables and treatment factors on the endpoints mentioned. The following variables were analyzed: age at surgical treatment and IORT and initial diagnosis (< 65 vs. ≥65 years, each), disease-free interval (DFI) between initial diagnosis and first recurrence, DFI to surgical treatment and IORT, grading, histology, IORT dose (≤ 13 vs. >13 Gy) and technique (high dose radiotherapy (HDR) vs. IORT using electrons, (IOERT)). Survival curves were generated using the Kaplan-Meier method.ResultsThe mean IORT dose was 13.8 Gy (range 10–18 Gy). Cervical carcinoma was most frequently found in 27.5% of patients followed by endometrial carcinoma and vulvar carcinoma in 25% respectively. The final histopathologic results after surgery with IORT showed no residual tumour in 24 patients (60%), microscopic residual disease in 5 patients (12.5%), resection status could not be evaluated in three patients (7.5%) and the resection status was unknown in eight patients (20%). Subsequently, 27.5% of patients also received adjuvant radiotherapy of the local recurrence bed. However, after IORT, 65% of the women suffered a recurrence. Of these, the recurrences were localized: in-field 32.5%, out-of-field 22.5% and margin-of-field 12.5%. The 3- and 5-year OS was 69% and 55% respectively. The 3- and 5-year LRC was 56% respectively. The 3- and 5-year DMFS was 66% and 49%. Whereas the comparison between groups by IORT dose level (≤ 13 vs. >13 Gy) showed a non-significant trend in favor of the higher dose only for OS (p = 0.094), but not in LRC and DMFS (p > 0.05). OS and DMFS, but not LRC, differed significantly between the HDR-IORT and IOERT groups (p = 0.06 and p = 0.03,) in favor of the HDR-IORT technique. For HDR-IORT technique a trend towards superior OS and LRC was observed in the univariate analysis: HR 3.76, CI 95%: 0.95–14.881, p = 0.059 and HR 2.165 CI 95%: 0.916–5.114, p = 0.078ConclusionsThe survival rate for pelvic recurrence in gynecological malignancies remains poor and comparable with historical data from the last two decades. Particularly HDR-IORT, appears to provide a long-term oncological benefit in carefully selected patients.