Relative Dose Research Articles

Informing the risk assessment related to lactation and drug exposure: A physiologically based pharmacokinetic lactation model for pregabalin.

Breastfeeding is important in childhood development, and medications are often necessary for lactating individuals, yet information on the potential risk of infant drug exposure through human milk is limited. Establishing a lactation modeling framework can advance our understanding of this topic and potentiate clinical decision making. We expanded the modeling framework previously developed for sotalol using pregabalin as a second prototypical probe compound with similar absorption, distribution, metabolism, and elimination (ADME) properties. Adult oral models were developed in PK-Sim® and used to build a lactation model in MoBi® to simulate drug transfer into human milk. The adult model was applied to breastfeeding pediatrics (ages 1 to 23 months) and subsequently integrated with the lactation model to simulate infant drug exposure according to age, size, and breastfeeding frequency. Physiologically based pharmacokinetic (PBPK) model simulations captured the data used for verification both in adults and pediatrics. Lactation simulations captured observed milk and plasma data corresponding to doses of 150 mg administered twice daily to lactating individuals, and estimated a relative infant dose (RID) of approximately 7% of the maternal dose. The infant drug exposure simulations showed peak plasma concentrations of 0.44 μg/mL occurring within the first 2 weeks of life, followed by gradual decline with age after week four. The modeling framework performs well for this second prototypical drug and warrants expansion to other drugs for further validation. PBPK modeling and simulation approaches together with clinical lactation data could ultimately help inform infant drug exposure risk assessments to guide clinical decision making.

Biological effectiveness of uniform and nonuniform dose distributions in radiotherapy for tumors with intermediate oxygen levels.

We propose a criterion of biological effectiveness of nonuniform hypoxia-targeted dose distributions in heterogeneous hypoxic tumors based on equivalent uniform aerobic dose (EUAD). We demonstrate the utility of this criterion by applying it to the model problems in radiotherapy for tumors with different levels of oxygen enhancement ratio (OER) and different degrees of dose nonuniformity.&#xD;Approach. The EUAD is defined as the uniform dose that, under well-oxygenated conditions, produces equal integrated survival of clonogenic cells in radiotherapy for heterogeneous hypoxic tumors with a non-uniform dose distribution. We define the dose nonuniformity effectiveness (DNE) in heterogeneous tumors as the ratio of the EUAD(DN) for a non-uniform distribution DN and the reference EUAD(DU) for the uniform dose distribution DU with equal integral tumor dose. The DNE concept is illustrated in a radiotherapy model problem for non-small cell lung cancer treated with hypoxia targeted dose escalation. A two-level cell population tumor model was used to consider the hypoxic and oxygenated tumor cells.&#xD;Results. Theoretical analysis of the DNE shows that the entire region of the OER can be separated in two regions by a threshold OERth: 1) OER>OERth where DNE>1 indicating higher effectiveness of nonuniform dose distributions and 2) OER<OERth where DNE<1 indicating higher effectiveness of uniform dose distributions. Our simulations show that the value of the threshold OERth in radiotherapy with conventional fractionation is significant in the range of about 1.2-1.6 depending on selected radiotherapy parameters. In general, the OERth increases with reoxygenation rate, relative hypoxic volume and dose escalation factor. The threshold value of OERth is smaller of about 1.1 for hypofractionated radiotherapy.&#xD;Significance. The analysis of dose distributions using the DNE shows that the uniform dose distributions may improve biological cell killing effect in heterogeneous tumors with intermediate oxygen levels compared to targeted nonuniform dose distribution. &#xD.

Investigating the Transfer of Lisinopril into Human Milk: A Quantitative Analysis.

Lisinopril is commonly prescribed to manage conditions such as hypertension and heart failure. While concerns about fetal toxicity have traditionally limited the use of lisinopril in women of reproductive age, recent ACOG guidelines promote aggressive treatment of hypertension, which may require the use of pharmacologic agents not previously considered in the postpartum period. We aimed to estimate infant exposure to maternal lisinopril via breastmilk and report the tolerance of the breastfed infant. Five volunteers taking lisinopril provided samples of their human milk and their associated health information for research through the InfantRisk Center Human Milk Biorepository. The milk pharmacokinetics of lisinopril were measured using liquid chromatography-mass spectrometry. The mean milk concentration of lisinopril was 0.49 ng/mL per 10 mg daily dose. The Relative Infant Dose (RID) was 0.06% for lisinopril, more than 100 times lower than the standard 10% safety threshold. The minimal transfer of lisinopril into human milk in this study suggests the drug is unlikely to pose a clinically significant risk to healthy breastfed infants.

Global Leadership Initiative on Malnutrition Criteria and Immunonutritional Status Predict Chemoadherence and Survival in Stage II/III Gastric Cancer Treated with XELOX Chemotherapy.

Adjuvant chemotherapy is crucial for the treatment of advanced gastric cancer. However, various factors negatively impact chemoadherence, with malnutrition after gastrectomy being a critical determinant. This study aims to analyze the impact of malnutrition, assessed through the Global Leadership Initiative on Malnutrition (GLIM) and other immunonutritional indices, on chemoadherence and its subsequent effect on survival. This retrospective study included 116 patients who underwent curative gastrectomy and received oxaliplatin and capecitabine (XELOX). Preoperative nutritional status was assessed using the GLIM criteria along with other immunonutritional indices, such as the prognostic nutritional index (PNI), C-reactive protein-to-albumin ratio (CAR), neutrophil-lymphocyte ratio (NLR), controlling nutritional status (CONUT) score, and modified Glasgow Prognostic Score (mGPS). Chemotherapy adherence was measured using relative dose intensity (RDI). Statistical analyses included least absolute shrinkage and selection operator (LASSO) regression to identify the key predictors of RDI and Cox proportional hazards models and assess the impact on survival. Overall, 116 patients were included in this analysis. In the multivariate analysis using LASSO regression, higher GLIM severity was independently associated with a lower RDI (coefficient = -0.0216; p < 0.01). Other significant factors influencing RDI included older age (p < 0.01), female sex (p = 0.02), higher mGPS (p = 0.03), higher CONUT score (p = 0.04), and higher CAR (p = 0.05), all of which were associated with a lower RDI. The Cox proportional hazards analysis revealed that higher RDI was significantly associated with better survival (hazard ratio [HR] = 0.06; p < 0.005). This study highlights the critical role of immunonutritional status, particularly as measured using the GLIM criteria, in maintaining adherence to chemotherapy and improving survival outcomes in patients with gastric cancer. Routine preoperative nutritional assessments using GLIM can help identify high-risk patients, and early nutritional interventions may improve chemotherapy adherence and outcomes. These findings support the integration of nutritional strategies, specifically targeting those identified by the GLIM, into standard care to enhance the efficacy and survival of chemotherapy.

Retrospective evaluation of adjuvant capecitabine dosing patterns in triple negative breast cancer.

The CREATE-X trial demonstrated that adjuvant capecitabine was effective in prolonging survival in high-risk triple-negative breast cancer (TNBC) patients. However, the recommended dose is generally not well tolerated by the US population. The goal of this study is to analyze dosing patterns in an ethnically diverse cohort to better characterize tolerability and inform future dosing guidelines. In our single-center retrospective study, we evaluated safety and tolerability in TNBC patients undergoing adjuvant capecitabine treatment. The primary endpoint, relative dose intensity (RDI) across eight cycles, was examined alongside subgroup analyses based on age, race, BMI, and initial dose. Secondary endpoints include capecitabine-related side effects and survival. 67 patients who completed adjuvant capecitabine at University of Chicago Medicine (UCM) between January 2017 and November 2022 were eligible. The mean RDI across eight cycles of treatment was 60.2% (95% CI: 0.554-0.650). When compared to the CREATE-X trial, the RDI in our population was significantly lower (0.602 vs. 0.787, p < 0.001). There was no statistically significant difference in average RDI across eight cycles for patients stratified by age, BMI, race, or initial starting dose. The most frequently reported adverse events were hand-foot syndrome (73%), diarrhea (27%), and fatigue (22%), consistent with prior studies. Our data demonstrates that a significant portion of patients have a lower tolerated dose of capecitabine in comparison to the recommended adjuvant dose. Acknowledging the limitations of our single-center analysis, RDI was not significantly affected by age, race, BMI, or initial starting dose.

Use of empegfilgrastim for primary prevention of febrile neutropenia in patients receiving myelosuppressive therapy. Experience of the Arkhangelsk Clinical Oncological Dispensary

Background. Granulocyte colony-stimulating factors (G-CSFs) are used in oncology practice for prevention of febrile neutropenia caused by cytotoxic chemotherapy. Despite the proven safety of G-CSFs use in randomized clinical trials and in real clinical practice, clinicians have questions about the tolerability of this group of drugs.Aim. To demonstrate the safety profile of a long-acting G-CSF produced in Russia which was used to prevent febrile neutropenia and maintain dose intensity of drug therapy in patients with various solid tumors undergoing chemotherapy at the Arkhangelsk Clinical Oncological Dispensary.Materials and methods. The retrospective analysis included patients with a confirmed diagnosis of malignant neoplasm who received various chemotherapy regimens that required the inclusion of G-CSF. For primary prevention of febrile neutropenia, patients were prescribed empegfilgrastim (Extimia®) at a dose of 7.5 mg subcutaneously once per course of chemotherapy.Results. Data of 151 patients were analyzed for the period from July 2021 to April 2023. The average age was 57 years (28–75). The group of elderly patients (over 65 years) consisted of 38 (25 %) patients. The majority of patients were diagnosed with breast cancer (56 (37 %) patients) and gastric cancer (37 (25 %) patients). The number of empegfilgrastim injections over the entire observation period was 773. Adverse reactions associated with the use of empegfilgrastim were registered in 13 (8.6 %) patients, the most common of which was grade 1–2 leukocytosis according to the CTCAE v.5 classification. One patient developed a serious adverse reaction: grade 4 neutropenia according to the CTCAE v.5 classification. A subgroup of patients with metastatic pancreatic cancer treated with FOLFIRINOX was analyzed separately to assess the relative dose intensity of the chemotherapy courses. Nine patients with metastatic pancreatic cancer received FOLFIRINOX therapy with a median of 8 (5–12) courses. A total of 69 chemotherapy cycles were administered to 9 patients with a median of 7.5 (2–13) cycles. The relative dose intensity of the chemotherapy courses was 83.71 ± 19.33.Conclusion. Empegfilgrastim has shown a favorable safety and tolerability profile in patients with various solid tumors in real-world clinical practice including the highly toxic FOLFIRINOX regimen.

Improvement of treatment plan quality with modified fixed field volumetric modulated arc therapy in cervical cancer.

This study aims to introduce modified fixed field volumetric modulated arc therapy (MF-VMAT) which manually opened the field size by fixing the jaws and comparing it to the typical planning technique, auto field volumetric modulated arc therapy (AF-VMAT) in cervical cancer treatment planning. Previously treated twenty-eight cervical cancer plans were retrospectively randomly selected and replanned in this study using two different planning techniques: AF-VMAT and MF-VMAT, resulting in a total of fifty-six treatment plans. In this study, we compared both planning techniques in three parts: (1) Organ at Risk (OARs) and whole-body dose, (2) Treatment plan efficiency, and (3) Treatment plan accuracy. For OARs dose, bowel bag (p-value=0.001), rectum (p-value=0.002), and left femoral head (p-value=0.001) and whole-body (p-value=0.000) received a statistically significant dose reduction when using the MF-VMAT plan. Regarding plan efficiency, MF-VMAT exhibited a statistically significant increase in both number of monitor units (MUs) and control points (p-values=0.000), while beam-on time, maximum leaf travel, average maximum leaf travel, and maximum leaf travel per gantry rotation were statistically significant decreased (p-values=0.000). In terms of plan accuracy, the average gamma passing rate was higher in the MF-VMAT plan for both absolute dose (AD) (p-value=0.001, 0.004) and relative dose (RD) (p-value=0.000, 0.000) for 3%/3 and 3%/2mm gamma criteria, respectively. The MF-VMAT planning technique significantly reduces OAR doses and decreases the spread of low doses to normal tissues in cervical cancer patients. Additionally, this planning approach demonstrates efficient plans with lower beam-on time and reduced maximum leaf travel. Furthermore, it indicates higher plan accuracy through an increase in the average gamma passing rate compared to the AF-VMAT plan. Consequently, MF-VMAT offers an effective treatment planning technique for cervical cancer patients.

Real-World Clinical Outcomes With Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC. A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis. A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1). In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Associations between age at diagnosis and chemotherapy dose reductions in women treated for stage I-IIIA breast cancer.

99 Background: Several studies have shown that older women diagnosed with breast cancer and eligible for chemotherapy treatment are more likely to be dose-reduced than younger women; however, most prior studies were limited by small sample sizes and examined relative dose intensity of a single drug. We assessed the association between age at diagnosis with first cycle dose proportion (FCDP) and average relative dose intensity (ARDI) across multiple regimens in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study. Methods: This retrospective cohort study included 10,386 women ages 18+ years treated with adjuvant chemotherapy for stage I-IIIA breast cancer at Kaiser Permanente Northern California (KPNC) and Washington (KPWA) between 2004-2019. We examined associations between age at diagnosis with first cycle dose proportion (FCDP, defined as &lt;90% of the guideline-recommended dose, reflecting clinician intent at treatment outset) and average relative dose intensity (ARDI, defined as dose proportion &lt;90% across the course of chemotherapy). We used multivariable-adjusted generalized linear models of the Poisson family with a log link-function and robust standard errors to calculate prevalence ratios (PR) and corresponding 95% confidence intervals (CI). We adjusted for patient and tumor characteristics, with and without adjusting for pre-existing comorbidities. Results: The proportion of women with a FCDP &lt;90% ranged from 3% among women ages 18-39 years to 19% among women ages 75+ years. Women ages 75+ years were statistically significantly more likely to have a FCDP &lt;90% and ARDI &lt;90% vs women ages 40-49 years regardless of adjustment for comorbidities (Table). Conclusions: Older age at diagnosis is strongly associated with chemotherapy dose reductions relative to guideline recommendations, both at the outset of chemotherapy initiation and across the course of treatment. Understanding implications of dose reductions on chemotoxicities and survival will be particularly important for improving the quality of care and long-term outcomes for older women. Age at Diagnosis (years) FCDP &lt;90% Multivariable Adjusted*PR (95% CI) FCDP &lt;90% Additionally Adjusted* for ComorbiditiesPR (95% CI) ARDI &lt;90% Multivariable Adjusted*PR (95% CI) ARDI &lt;90% Additionally Adjusted* for ComorbiditiesPR (95% CI) 18-39 0.81 (0.53-1.23) 0.84 (0.55-1.29) 0.84 (0.68-1.03) 0.85 (0.69-1.04) 40-49 REF REF REF REF 50-64 1.32 (1.08-1.61) 1.29 (1.06-1.59) 1.16 (1.04-1.29) 1.14 (1.02-1.26) 65-74 1.72 (1.36-2.17) 1.65 (1.29-2.10) 1.34 (1.18-1.52) 1.26 (1.11-1.43) 75+ 4.90 (3.61-6.65) 4.39 (3.16-6.09) 1.94 (1.61-2.35) 1.75 (1.44-2.13) p-trend &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 *Adjusted for BMI, stage at diagnosis, year of diagnosis, study site, race/ethnicity, income, body mass index, human epidermal growth factor receptor status, grade, nodal number, estrogen and progesterone receptor status.

Intensity-modulated proton radiotherapy spares musculoskeletal structures in regional nodal irradiation for breast cancer: a dosimetric comparison.

Regional nodal irradiation (RNI) for breast cancer delivers radiation in proximity to the shoulder and torso, and radiation exposure may contribute to long-term upper extremity and postural morbidity. To date, no studies have assessed the differential dosimetric impact of proton versus photon radiation on shoulder and torso anatomy. This study examined clinically relevant musculoskeletal (MSK) structures and assessed the dose delivered with each modality. Ten MSK structures were contoured on IMPT (intensity-modulated proton therapy) and VMAT (volumetric modulated arc therapy) plans for 30 patients receiving RNI. Relevant dose metrics were compared for each of the structures. Intensity-modulated proton therapy dose was calculated using the relative biological effective value of 1.1. Hypo-fractionated plans were scaled to the equivalent dose in 2 Gy fractions (EQD2) using an alpha/beta ratio of four. Wilcoxon signed rank sum tests compared doses. Select three-dimensional and optimised VMAT plans were also informally compared. Each of the 10 structures received a statistically significantly lower dose with the use of IMPT compared with VMAT. Differences were greatest for posterior structures, including the trapezius, latissimus dorsi and glenohumeral joint. Mean absolute differences were as great as 23 Gy (supraspinatus D5cc) and up to 30-fold dose reductions were observed (deltoid D50cc). An average 3.7-fold relative dose reduction existed across all structures. Measures of low/intermediate dose (V15Gy and D50cc) showed the largest differences. Intensity-modulated proton therapy results in statistically lower radiation exposure to relevant shoulder and torso anatomy compared to photon radiation for patients requiring RNI. Prospective study is needed to correlate functional outcomes with radiation dose.

Early follow-up of outpatients with oral anticancer therapy in the ONCORAL multidisciplinary community-hospital program.

Healthcare professionals are faced with the new challenges of preventing and managing drug-related problems (DRPs) with oral anticancer therapy (OAT): side-effects, drug-drug interactions (DDIs), non-adherence, or medication errors. This study aims to assess the impact of ONCORAL, a real-life multidisciplinary care plan for cancer patients based on community and hospital follow-up, for the first OAT cycle. A prospective cohort study was conducted between October 1, 2021 and October 1, 2022 including all outpatients starting OAT treatment. During the first OAT cycle, the program consists of 6 weekly scheduled face-to-face or phone consultations to prevent and manage DRPs. Nurse and pharmacist interventions (NPIs) are realized to optimize treatments (primary outcomes). Secondary outcomes included the relative dose intensity (RDI) of the first cycle. A total of 562 NPIs were performed by the ONCORAL team: that is, 87.1% of the 209 patients included, for a mean of 3.1 ± 2.2 NPIs/patient. NPIs-concerned DRPs detected by the nurse and pharmacist (346, 61.6%), symptoms and/or adverse effects reported as PROs by the patient or family (138, 24.6%), or pathway issues (78, 13.9%). Seventy-three DDIs were detected and managed during medication review, in a quarter of patients (n = 54/209), leading to the discontinuation of a daily concomitant medication in 30 cases. The mean RDI at the end of the first cycle, calculated for 209 patients, was 83.1 ± 23.9% (17.56-144.23). In these ambulatory cancer patients, the interest in tailored monitoring of DRPs as a whole, including the prevention and management of drug interactions in addition to symptoms and adverse effects, is highlighted.

Microdosimetry for BNCT: First measurements at different site sizes

Microdosimetric techniques are a valuable tool for beam quality monitoring in BNCT, due to their capability to distinguish different contributions to the total dose and provide physics-based quantities related to biological effectiveness of this composite radiation field. To this aim, measurements are generally performed with gas detectors simulating a tissue-equivalent site size between 0.5 and 2 μm. This work presents instead measurements for site sizes up to 10 μm, performed in the thermal neutron field produced by the accelerator-based MUNES source available at INFN-LNL. An avalanche-confinement TEPC with boron doping in the cathode walls was used. Photon and neutron dose fractions were discriminated in the measured dose-weighted distributions based on their different lineal energy range. In the neutron component two separate peaks could be distinguished for site sizes of 5 μm and greater, the origin of which was tentatively related to contributions due to protons and alpha particles. These results allow to assess the impact of increasing site diameter on the measured relative dose contributions and provide valuable reference data for biological modelling and for comparison with solid-state microdosimeters.

Minimal Transfer of Atorvastatin and Its Metabolites in Human Milk: A Case Series.

Background: Statins are historically contraindicated during breastfeeding due to theoretical concerns of disruptions in infant development from drug exposure and nutritional changes in milk. Breastfeeding mothers requiring statins often discontinue statins or postpone treatment until breastfeeding cessation, contributing to delays in treatment up to 14 years. This study aims to determine the transfer of atorvastatin and its active metabolites into human milk and evaluate the infant's risk of drug exposure. Materials and Methods: Milk samples and health information were released from the InfantRisk Human Milk Biorepository for three women taking 20 mg, 40 mg, and 80 mg of atorvastatin daily at steady state conditions. The concentration of atorvastatin (AT) and its active metabolites, ortho-hydroxy AT (2OH AT) and para-hydroxy AT (4OH AT), was quantified in timed milk samples using liquid chromatography-mass spectrometry. Results: The highest absolute infant dose of AT was 0.00027 mg/kg/day, and the highest weight-adjusted relative infant dose of the combined analytes was 0.09%, far below established thresholds for infant safety. Milk cholesterol levels were within previously established norms in the range of 10 mg/dL. The mothers reported no adverse outcomes in the two exposed infants. Conclusions: The transfer of atorvastatin and its metabolites was exceedingly low. While the impact on milk composition in states of hyperlipidemia (whether treated or untreated) is not well understood, it is unlikely that the drug in the milk would be present in clinically significant levels to adversely affect a breastfed infant.

Major considerations on the relationship of triple negative breast cancer with microRNAs and nutrological triggers: a systematic review

Introduction: Triple-negative breast cancer (TNBC) accounts for 15% of all cases. Its incidence is usually higher in young women (under 40 years of age). The classification as triple-negative occurs because, in this case, there are no estrogen, progesterone, and HER2 receptors, which are responsible for controlling tumor growth. Higher levels of physical activity and better diet quality are associated with lower mortality from breast cancer in observational studies. Furthermore, physical activity and optimal nutrition can improve the relative dose intensity of chemotherapy, as they can activate miRNAs that regulate several biological processes. Objective: This was to conduct a systematic review to establish the main considerations of the relationship between triple-negative breast cancer and microRNAs as biomarkers and regulators of gene expression in cancer cells, as well as to show some nutritional triggers of microRNA activation desirable for breast cancer control. Methods: The PRISMA Platform systematic review rules were followed. The search was conducted from April to June 2024 in the Web of Science, Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE and AMSTAR-2 instrument and the risk of bias was analyzed appropriately. According to the Cochrane instrument. Results and Conclusion: 112 articles were found, and 40 were evaluated in full and included in this article, 22 of which were included in the systematic review. Considering the Cochrane tool for risk of bias, the global assessment resulted in 15 studies with a high risk of bias and 25 studies that did not reach GRADE and AMSTAR-2. Most studies showed homogeneity in their results, with X2=81.5%&gt;50%. It was concluded that an increasing number of studies have shown that non-coding RNA (ncRNA), including microRNA (miRNA) and long non-coding RNA (lncRNA), play a significant role in tumorigenesis. Although a diet and exercise intervention did not affect relative dose intensity, the intervention was associated with a higher pCR in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative and triple-negative breast cancer undergoing neoadjuvant chemotherapy. High expression levels of miR-27a/b, miR-210, and miR-454 were associated with shorter overall survival, whereas high expression levels of miR-454 and miR-374a/b were associated with disease-free survival. The miRNAs associated with triple-negative breast cancer may provide new avenues for early diagnosis and treatment of breast cancer. Furthermore, specific miRNAs may serve as potential prognostic biomarkers in triple-negative breast cancer.

Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

AbstractThe multicenter, prospective phase 2 Australasian Leukaemia & Lymphoma Group NHL29 trial was conducted to assess the addition of ibrutinib to R-mini-CHOP (dose attenuated R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients aged ≥75 years with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib–R-mini-CHOP followed by two 21-day cycles of R-ibrutinib. Coprimary end points were deliverability and 2-year overall survival (OS). The median average relative total dose and average relative dose intensity for the entire regimen were both 97% (interquartile range, 82-100 and 88-100, respectively). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% confidence interval [CI], 55.6-77.4) with a 2-year progression-free survival (PFS) of 60.0% (95% CI, 47.7-70.3). Median OS and PFS were 72 months (95% CI, 35 to not reached) and 40 months (95% CI, 20.4 to not reached), respectively. The overall response rate was 76% (61/79) of patients, with a complete response rate of 71% (56/79). Deaths occurred in 34 of 79 patients (43%), including 17 from progressive disease and 5 treatment related. Overall, 67% patients experienced at least 1 serious adverse event. Most common adverse events were infections and diarrhea (the majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score, and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.

Real world data of cabozantinib in patients with hepatocellular carcinoma: Focusing on dose setting and modification.

To investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification. We retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients. Sixteen patients received ≥40 mg (high-dose group), and 18 patients received 20 mg (low-dose group). Dose escalations were performed in 27.8% of the patients in the low-dose group. Although median duration of the first dose reduction or interruption in the low-dose group was twice that in the high-dose group (28 vs. 14 days, p < 0.001), there were no significant differences in the relative dose intensity (RDI) during 6 weeks, progression free survival (PFS), and overall survival (p = 0.162, p = 0.950, p = 0.817, respectively) between the two groups. Patients who received RDI during 6 weeks ≥33.4% showed a trend toward longer median PFS (p = 0.054). Each serum aldolase value during the 6 weeks was significantly correlated with the Ctrough at any point (r = 0.500, p < 0.001). In multivariate analyses, aldolase ≥8.7 U/L within 2 weeks was significantly associated with the very early dose reduction or interruption (odds ratio 20.0, p = 0.002). An initial dose of 20 mg cabozantinib could be a safe option in Japanese patients. The serum aldolase value could be useful for making appropriate dose modifications of cabozantinib.

1869P Risk factors for reduced relative dose intensity (RDI) in patients with solid tumors receiving chemotherapy (CT) and primary prolonged G-CSF prophylaxis by empegfilgrastim: Analysis of DEFENDOR study

1869P Risk factors for reduced relative dose intensity (RDI) in patients with solid tumors receiving chemotherapy (CT) and primary prolonged G-CSF prophylaxis by empegfilgrastim: Analysis of DEFENDOR study

Subcutaneous Semaglutide during Breastfeeding: Infant Safety Regarding Drug Transfer into Human Milk.

Postpartum mothers and their healthcare providers often face the challenge of limited data regarding the safety of drug therapies during lactation. Pregnancy can lead to sustained weight gain, and obesity can negatively impact both physical and psychological well-being. The introduction of GLP-1 agonists to augment weight loss has become a topic of interest for many postpartum mothers. Our study aims to investigate the transmission of semaglutide into human milk in the first steps to ensure the safety and health of both lactating mothers and their breastfed infants. Semaglutide quantification was performed using high-resolution liquid chromatography-mass spectrometry. InfantRisk Center Human Milk biorepository released milk samples from eight women collected at 0, 12 and 24 h post-semaglutide administration. Semaglutide was extracted using protein precipitation in methanol, followed by chromatographic separation. Linear calibration curves for the method ranged between 2.5-30 ng/mL, with a limit of detection of 1.7 ng/mL and a limit of quantification of 5.7 ng/mL (LLOQ). Semaglutide was not detected in any of the collected human milk samples. A worst-case scenario of the relative infant dose (RID) was calculated using the LLOQ as the drug concentration in milk when considering semaglutide's bioavailability and long-acting dose profile. The maximum RID projected was 1.26%, far below the standard 10% safety threshold. While questions about long-term infant outcomes, the safety of maternal nutrient intake, and the nutrient content of breast milk remain, our findings suggest that semaglutide concentrations in human milk are unlikely to pose clinical concerns for breastfed infants. These results support healthcare providers in making informed decisions regarding postpartum therapeutic interventions.

Changes in Skeletal Muscle Volume During Preoperative Chemotherapy Affect the Outcome of Pancreatic Cancer.

This study aimed to investigate the effects of changes in clinicopathological factors during preoperative chemotherapy for pancreatic cancer, including skeletal muscle volume, on recurrence and prognosis after pancreatectomy. Data from 41 patients who underwent resection for pancreatic cancer after preoperative chemotherapy from 2012 to 2021 were retrospectively reviewed. Skeletal muscle volume was substituted for the psoas muscle area (PMA) at the level of the third lumbar vertebra. We investigated the relationship of clinicopathological factors during preoperative chemotherapy with disease-free survival (DFS) and overall survival (OS). The association between clinicopathological factors and a decrease in PMA was investigated. In the multivariate analyses for DFS and OS, the factors associated with recurrence were as follows: decrease in PMA (P = 0.003) and the absence of adjuvant therapy (P = 0.03), and the factors associated with poor prognosis were as follows: decrease in PMA (P = 0.04) and the absence of adjuvant therapy (P = 0.008), and the resectability of borderline resectable and unresectable-locally advanced tumors (P = 0.033). All patients with partial response according to the Response Evaluation Criteria in Solid Tumors (version 1.1) had no decrease in PMA (P = 0.01). The proportion of patients with Evans classification ≥ II was significantly higher in the group without a decrease in PMA (P = 0.02). The proportion of patients with an average relative dose intensity of adjuvant therapy ≥0.6 was significantly higher in the group without a decrease in PMA (P = 0.02). Changes in preoperative skeletal muscle volume during preoperative chemotherapy for pancreatic cancer is a potential predictor of recurrence and prognosis after pancreatectomy.

Impact of 10% Dose Reductions and Duration of Treatment Delays in the Management of Chemotherapy-Induced Neutropenia in Dogs Treated With Common Chemotherapy Protocols: A Single-Centre Experience.

Neutropenia is a common chemotherapy-associated adverse event (AE) in dogs and a significant cause of decreased relative dose intensity. Dose reductions (DRs) and treatment delays (TDs) are frequently applied to decrease the risk of further neutropenic events (NEs) and AEs, but there is no standardised approach. The two main objectives of this retrospective study were to determine: (1) the failure rate of a 10% DR to prevent a subsequent inadequate absolute neutrophil count (ANC), defined as a nadir ANC <0.75 × 109/L or pretreatment ANC <1.5 × 109/L; and (2) if the duration of TDs due to pretreatment neutropenia affects the occurrence of subsequent NEs. A total of 1056 chemotherapy treatments were recorded for 128 dogs that developed at least one NE. In 75 of 124 (60.5%, 95% CI: 51.2%-69%) evaluable NEs, a nadir ANC of ≥0.75 × 109/L and pretreatment ANC of ≥1.5 × 109/L were achieved after a single 10% chemotherapy DR, while a 10% DR failed to prevent a subsequent inadequate ANC in the remaining 49/124 (39.5%, 95% CI: 30.1%-48.3%). The only variable associated with failure was the drug prescribed. DR failure occurred in 22/39 (56.4%, 95% CI: 40.9%-70.6%) lomustine DRs, 14/27 (51.9%, 95% CI: 33.9%-69.2%) cyclophosphamide DRs, but only 2/22 (9.1%, 95% CI: 2.5%-27.8%) doxorubicin DRs and 2/24 (8.3%, 95% CI: 2.3%-25.8%) vincristine DRs. Seventy-three evaluable TDs (mean: 5 days, SD ± 2.2 days) were prescribed. There was no association between TD duration and subsequent NEs (p = 0.11).