Patient Dose Reduction Research Articles

When a Number Is Just a Number: Duffy-Null Blood Group Phenotype, Absolute Neutrophil Count, and Incidence of Neutropenic Fever and Chemotherapy Dose Reductions in Patients Treated for Plasma Cell Dyscrasias

Introduction: A single nucleotide polymorphism in the promoter region of the Duffy antigen/chemokine receptor (DARC) gene results in the red blood cell (RBC) Duffy-null phenotype, which is present in up to 80% of individuals of Sub-Saharan ancestry. Duffy-null phenotype is associated with lower peripheral absolute neutrophil counts (ANC) with preserved myeloid maturation and neutrophil function. The impact of Duffy-null phenotype on patients with hematologic malignancies is largely unknown; however, lower ANC (both at baseline and during treatment) may lead to the receipt of less intense treatment (with lower upfront dosing as well as more treatment interruptions/dose reductions). Lower ANC also pose challenges in enrollment in clinical trials due to ANC cutoffs for eligibility criteria. Herein, we evaluated the impact of Duffy phenotype status on the incidence of neutropenic fever and chemotherapy dose reductions in a cohort of patients treated for multiple myeloma (MM) or light chain (AL) amyloidosis at the largest safety net hospital in New England, USA. Methods: In this retrospective study, we identified patients treated for MM or AL amyloidosis at Boston University Medical Center (BMC) who underwent phenotyping for the RBC Duffy antigen. Patients were categorized as Duffy-null phenotype, i.e., Fy (a-b-) or non-Duffy-null phenotype including Duffy heterozygous, i.e., Fy (a-b+ or a+b-) or Duffy positive, i.e., Fy (a+b+). We collected data from medical charts including patient demographics; clinical characteristics (including malignancy and treatment regimens); incidence of neutropenia (defined as ANC <1,800/µL); incidence of neutropenic fever (excluding peri-stem cell transplantation [SCT] neutropenia); and chemotherapy dose adjustments. This research was approved by the BMC Institutional Review Board. Results: Between 06/2020 and 06/2023, 136 patients had a Duffy phenotype evaluation; mean age at the time of first chemotherapy was 65 (± 11.3) years and 62/136 (46%) were female. The most common self-identified race/ethnicity was non-Hispanic Black (74/136, 54%), followed by non-Hispanic White (34/136, 25%), Hispanic (18/136, 13%), and other (10/36, 7%), and other (10/136, 6%). Plasma cell dyscrasias included MM (94/136, 69%), AL amyloidosis (34/136, 25%) (Table 1). Duffy-null Fy (a-b-) phenotype was seen in 52/136 (38%) patients, while 84/136 (62%) were non-Duffy-null, including 73/136 (54%) with Duffy heterozygosity Fy (a-b+ or a+b-) and 11/136 (8%) with Duffy positivity Fy (a+ b+). Number of lines of treatment did not differ by Duffy status (Table 1): 35/136 (26%) received 2 lines of treatment; 56/136 (41%) received ≥ 3 lines; and 28/136 (21%) received high-dose chemotherapy and autologous SCT. Among those with known baseline ANC, we observed a higher frequency of neutropenia before receipt of any chemotherapy in patients with Duffy-null status (17/50, 34%) compared to those with non-Duffy-null status (8/79, 10%), p= 0.0009. Similarly, the incidence of treatment-related neutropenia (excluding the peri-SCT period) was higher in Duffy-null patients (44/52, 85%) compared to non-Duffy-null (39/82, 48%) patients, p<0.0001. Overall, the incidence of febrile neutropenia in our cohort was low; all 7 patients who experienced a febrile neutropenic event were non-Duffy-null (7/84, 8%). None of the patients in the Duffy-null cohort (0/52, 0%) had febrile neutropenia, despite higher incidences of both baseline and treatment-related neutropenia. Treatment interruptions/delays or dose reductions due to any cause were observed in 95/136 (70%) of all patients and did not differ by Duffy phenotype status (Table 1). The proportion of patients initiated on upfront reduced-dose pomalidomide or lenalidomide was 62/106 (59%) and also did not differ by Duffy phenotype status. Conclusion: In this retrospective study, we found that compared to patients with non-Duffy-null phenotype, patients with Duffy-null phenotype treated for plasma cell dyscrasias did not have a higher incidence of neutropenic fever, treatment interruptions or dose reductions, despite having higher frequencies of both baseline and treatment-related neutropenia. Prospective validation of our results could help to inform the creation and implementation of guidelines for the management of patients with lower ANC related to Duffy-null phenotype who undergo treatment for plasma cell dyscrasias.

Efficacy and Tolerability of Luspatercept in Patients with Lower Risk Myelodysplastic Syndrome and Anemia: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Erythropoietin Stimulating Agents (ESAs) are the standard-of-care treatment for most patients with lower risk myelodysplastic syndrome (MDS) and anaemia. However, there has been unmet need for those who failed ESAs other than regular blood transfusion. Luspatercept is a recombinant fusion protein which binds TGF beta ligands resulting in reduction of erythroid maturation through reduction of SMAD2 and SMAD3 signaling. In recent years, studies have shown that luspatercept has significantly improved efficacy in patients with lower risk MDS who failed ESAs with some notable adverse events. The purpose of our meta-analysis is to determine efficacy by observing the rate of transfusion independence for 12 weeks or longer and haematological improvement in erythroid (HIE), and tolerability by rate of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI) or dose reduction and treatment related mortality in patients with lower risk MDS treated with luspatercept. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing luspatercept in patients with lower risk MDS that mention efficacy i.e. transfusion independence 12 weeks or longer and HIE and tolerability i.e. rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, treatment related mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results: 2 phase III RCTs (MEDALIST and COMMANDS) including total 583 patients were eligible in our meta-analysis. MEDALIST trial compared luspatercept vs placebo and COMMANDS trial compared luspatercept vs erythropoietin stimulating agent. The randomization ratios were 2:1 in MEDALIST and 1:1 in COMMANDS trials. Transfusion independence for 12 weeks or longer was noted in 141 (47%) in study arm vs 77 (33.5%) in control arm at RR of 1.67 (95% CI: 1.35 -2.06; P <0.00001). 190 (63.3%) patients in study arm achieved HIE response compared to 88 (38.3%) in control arm at RR of 1.85 (95% CI: 1.53 -2.24; P<0.00001). TD due to TEAE was reported in 21 (6.3%) of luspatercept group vs 10 (4%) in control group with RR of 1.38 (95% CI: 0.67 -2.84; P = 0.39). The incidence for TI or dose reduction due to TEAE was similar between the two groups at 18% with RR of 1.23 (95% CI: 0.88 -1.72; P = 0.22). Treatment emergent SAEs were observed in 116 (35%) in the luspatercept group vs 83 (32.9%) in control group (RR, 1.09; 95% CI: 0.87-1.38; P=0.45). Treatment related mortality was noted in 13 (3.9%) of patients in the study group compared to 16 (6.3%) in the control group with RR of 0.65 (95% CI: 0.31 -1.33; P = 0.24). Conclusions: According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

Tolerability in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Therapeutic challenge remains in older patients with acute myeloid leukemia (AML) with significant comorbidities who are not fit for induction chemotherapy and haemopoietic stem cell transplantation. Leukemic cells depend on BCL-2 protein (anti-apoptotic protein) for their survival. Venetoclax is a selective small-molecule BCL-2 inhibitor which binds to BCL-2 resulting in apoptosis of leukemic cells. In recent years, venetoclax has been approved in combination with azacitidine or low dose cytarabine in transplant-ineligible patients with newly diagnosed AML (ND AML). However, there are notable toxicities. The purpose of our meta-analysis is to determine tolerability, rates of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI), dose reduction and 30-day mortality in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention tolerability, rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, 30-day mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies.TD due to treatment emergent adverse events (TEAE) was noted in 104 (24.5%) of venetoclax group vs 45 (21.2%) in control group with RR of 1.15 (95% CI: 0.85 -1.57; P = 0.37).TI due to TEAE was higher in the venetoclax group (68.9%) compared to control group (55.6%) with RR of 1.24 (95% CI: 1.08 -1.42; P = 0.002). 21 (4.9%) of patients in venetoclax group and 10 (4.7%) in the control group required dose reduction of treatment due to TEAE, RR 1.03 (95% CI: 0.50 -2.16; P = 0.93).Treatment emergent SAEs were reported in 77.4% in the venetoclax group vs 60% in control group (RR, 1.30; 95% CI: 1.15-1.46; P <0.0001). 30-day mortality was reported in 39 (9.1%) of patients in the venetoclax group and 20 (9.4%) in the control group with RR of 0.96 (95% CI: 0.58 -1.60; P = 0.89). Conclusions Our meta-analysis showed that there was no significant difference in the rate of treatment discontinuation and dose reduction due to adverse events in transplant-ineligible patients with ND AML treated with venetoclax combination regimens, compared to control arm although rates of treatment emergent SAEs and treatment interruption were considerably higher in the venetoclax-treated arm. However, the 30-day mortality rate was similar between the two groups. Longer follow up and timely supportive care are required to improve treatment emergent SAEs and treatment interruption.

Dosimetric impact of adding non-coplanar arcs for scalp-avoidance whole-brain irradiation with volumetric-modulated arc radiotherapy on scalp dose reduction in pediatric patients with medulloblastomas.

We performed scalp-avoidance whole-brain irradiation with volumetric-modulated arc therapy (SAWB-VMAT) as a component of craniospinal irradiation. In SAWB-VMAT with two coplanar arcs, radiation oncologists and medical physicists sometimes experience difficulty in reducing the dose to the scalp to below the cut-off equivalent dose in 2Gy per fraction (assuming α/β=2) to 50% (EQD50%scalp ). To investigate the advantage of adding coplanar or non-coplanar arcs in reducing the dose to the scalp in SAWB-VMAT, we conducted a planning study to compare the EQD50%scalp , the dose to other organs at risk (OARs), and target coverage in VMAT with two coplanar arcs (Co2arcVMAT), VMAT with three coplanar arcs (Co3arcVMAT), and VMAT with two coplanar and two non-coplanar arcs (NcVMAT). Co2arcVMAT, Co3arcVMAT, and NcVMAT plans were created for 10 pediatric patients with medulloblastoma. The planned target volume (PTV) included the regions of the whole brain, cervical spinal cord, cerebrospinal fluid space, and intervertebral foramen. The EQD50%scalp was evaluated separately for four areas (top, back, left, and right) in each case. The prescribed dose for the PTV was 35.2Gy in 22 fractions. The median EQD50%scalp of the top area was 21.9, 22.1, and 18.3Gy for Co2arcVMAT, Co3arcVMAT, and NcVMAT, respectively. The EQD50%scalp of the top area was significantly reduced in NcVMAT compared to those in Co2arcVMAT and Co3arcVMAT (p<0.05). The median EQD50%scalp of the top area for NcVMAT was<19.9Gy, which is the cut-off dose for severe permanent alopecia. There were no significant differences in EQD50%scalp in the three other areas, the dose to other OARs, or the dose coverage of PTV among the three techniques. NcVMAT could reduce the EQD50%scalp of the top area below the cut-off dose of 19.9Gy. NcVMAT appears to be a promising treatment technique for SAWB-VMAT.

Azathioprine dose tailoring based on pharmacogenetic information: Insights of clinical implementation

Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.

Dose optimization of 2D X-ray image acquisition protocols in image-guided radiotherapy

PurposeIn contemporary radiotherapy, patient positioning accuracy relies on kV imaging. This study aims at optimizing planar kV image acquisition protocols regarding patient dose without degrading image quality. Materials and methodsAn image quality test-object was placed in-between PMMA plates, suitably arranged to model head or pelvis. Constructed phantoms were imaged using default protocols, the resultant image quality was assessed and the corresponding radiation dose was measured. The process was repeated using numerous kV/mAs combinations to identify those acquisition settings providing images at lower dose than the default protocols but without deterioration in image quality. Default and dose-optimized protocols were then tested on an anthropomorphic phantom and on 51 patients during two successive treatment sessions. Image quality was independently assessed by two readers. Organ and effective doses were estimated using a Monte Carlo simulation software. ResultsLow-contrast detectability exhibited a stronger dependence on kV/mAs settings, compared to high-contrast resolution. Dose-optimized protocols resulted in significant dose reductions (anteroposterior-head 48.0 %, lateral-head 30.0 %, anteroposterior-pelvis 28.4 %, lateral-pelvis 27.0 %) compared to the default ones, without compromising image quality. Optimized protocols decreased effective doses by 54 % and 29.6 % in head and pelvic acquisitions, respectively. Regarding image quality, anthropomorphic and patient images acquired using the dose-optimized protocols were subjectively evaluated equivalent to those obtained with the corresponding default settings, indicating that the proposed protocols may be routinely used. ConclusionsGiven the potentially large number of radiotherapy fractions and the pertinent image acquisitions, dose-optimized protocols could significantly reduce patient dose associated with planar imaging without compromising positioning accuracy.

Assessment of X-ray films and image quality in diagnostic radiology departments of teaching hospitals in Iraq

Background: Patients undergo repeated X-ray examinations after their initial X-ray radiographs are rejected due to poor image quality. Reject analysis in digital radiography (CR) helps guide the education and training of staff, influences department workflow, reduces patient dose and improves department efficiency. The role of reject analysis in providing relevant information that would help achieve a sound reduction in radiation exposure. Aims:To assess the reasons for X-ray film rejection and to analyze reasons for deletions to improve the radiological services. Methods: The data were collected from about 200 rejected films from different hospitals in Iraq from January 2021 to August 2021. The reject rate, reasons for rejection for individual radiographers, examination types and projections used a structured format on which investigators recorded relevant data for rejection. The results were then collected and entered into a database for analysis. Results: Reject rate and cause of rejection were measured across all plane X-ray examinations for the hospitals in Kirkuk General Hospital at 8.1%, Mosul General Hospital at 13.9% and Al-Jumhory Hospital at 6.4%. Study cases and (appointment) 16.1%, Mass & Kv with positioning error 3.7%. The examinations with the highest percentage of deleted images were the chest, lumber spine & knee joints, 13.2%, 3.2% and 1.7%, respectively. Conclusions: Creating awareness among the student reduces the overall reject rate. The outcome of this study can be used to set up training programs to improve radiological services and reduce unnecessary radiation exposure to patients.

Evaluation of awareness and knowledge of CT technologist regarding diagnostic reference levels in Iran

The purpose of this study was to determine the level of knowledge and awareness regarding radiation protection and Dose Reference Levels (DRLs) among 102 Computed Tomography (CT) technologists working in various Iranian hospitals. A questionnaire including 20 multiple-choice and open-format questions was divided into demographic information, general radiation protection knowledge, and DRL knowledge. Regarding radiation protection knowledge concerning CT, about 56.9% of participants exhibited awareness of the dose display on the CT machine’s console, and about 78.4% selected the correct dosimetric units expressed CT dose. Unexpectedly, 90.2% of participants failed to define the concept of dose optimization. A significant association (p &lt; 0.05) was established between technologists’ radiation protection and DRL knowledge and a degree of education, type of hospital, and job experience. In addition, the findings reveal a correlation between radiographers’ DRL knowledge and their propensity to enroll in training courses. 26.5% of participants exhibited awareness of DRLs in CT practice, while 49% and 76.5% of participants were unable to correctly identify DRLs concept and function. To reduce patient dose in accordance with the As Low As Reasonably Achievable (ALARA) radiation protection principle, CT technologists must improve their knowledge of radiation dose and local DRLs should be defined at least at the local level.

Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma

Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma

Long-term, real-world experience of pasireotide dose reduction in patients with acromegaly.

Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor I (IGF-I) levels to below the upper limit of the normal range, with some patients responding within 1-3 months of treatment (n=11) and others after ≥4 months (n=9). Following pasireotide dose reduction, IGF-I levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.

Response to the FDA Decision Regarding DPYD Testing Prior to Fluoropyrimidine Chemotherapy.

Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.

Antipsychotic Dose Reduction for Patients With Behavioural and Psychological Symptoms of Dementia in the Well-being Clinic of a Community Mental Health Team for Older People

AimsTo evaluate the usefulness of the "Well-being Clinic", a specialized service aimed at reducing the dose of antipsychotic medication prescribed for patients with behavioural and psychological symptoms of dementia (BPSD). The aim of the service was to have a sustained reduction of at least 50% of the antipsychotic dose in at least 50% of the sample size.MethodsA retrospective quantitative study was performed, looking at the 6 month period between August 2022 and January 2023. Two data parameters were obtained. One, the percentage of reduction of the antipsychotic dose for each patient. Two, the number of reviews done for each patient over the specified time period.ResultsOut of a sample size of 21 patients prescribed antipsychotics for BPSD, only 1 (5%) had a sustained reduction of at least 50% of the antipsychotic dose. 2 (10%) had a dose reduction of less than 50%, 14 (67%) had no change and 4 (19%) had a dose increase.3 patients (14%) had 3 reviews in the 6 month period, whereas 10 (48%) had 2 reviews, 5 (24%) had 1 review and 3 (14%) had no reviews.ConclusionThe Well-being Clinic intends to reduce harm to patients by reducing their antipsychotic dose. However, only 5% had a satisfactory dose reduction and 62% were reviewed at least once in 3 months.Recommended actions include increasing the frequency of reviews to once in 6 weeks (in accordance with national guidelines) and implementing regular monitoring of electrocardiograms (ECGs), vital signs and blood markers to further improve practice.

Dose optimisation of linezolid in critically ill patients based on a population pharmacokinetic model: A two-centre prospective interventional study

ObjectivesThis study evaluated the intervention effect of clinical pharmacist-mediated optimisation of a linezolid regimen using a population pharmacokinetic (PPK) model. MethodsPatients treated with linezolid in two medical centres from January 2020 to June 2021 were retrospectively included in the control group; those treated from July 2021 to June 2022 were prospectively enrolled in the intervention group. Clinical pharmacists optimised the dosage regimen according to a published linezolid PPK model in the intervention group. An interrupted times series approach was used to analyse the data. The incidence of linezolid-induced thrombocytopenia (LIT), target attainment of pharmacokinetic/pharmacodynamic parameters and other adverse drug reactions (ADRs) were compared between the two groups. ResultsIn total, 77 and 103 patients were enrolled in the control and intervention groups, respectively. The intervention group had a lower incidence of LIT and other ADRs than the control group (10.7% vs. 23.4%, P = 0.002; 1.0% vs. 7.8%, P = 0.027). The intervention group exhibited a considerably lower trough concentration (Cmin) and area under the concentration–time curve/MIC ratio (AUC24/MIC) (P = 0.001 and P < 0.001). Cmin and AUC24/MIC rates within the target range were substantially higher in the intervention group (49.6% vs. 20.0%, adjusted P < 0.05; 48.1% vs. 25.6%, adjusted P < 0.05). ConclusionInterventions by clinical pharmacists reduced the incidence of LIT and other ADRs. Implementation of model-informed precision dosing (MIPD) for linezolid markedly increased the Cmin and AUC24/MIC rates within the target range. We recommend MIPD-guided linezolid dose reduction for patients with renal impairment.

Optimal Treatment of Hormone Receptor-positive Advanced Breast Cancer Patients With Palbociclib.

Palbociclib was the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved worldwide. Currently, CDK4/6 inhibitors are strongly recommended for endocrine therapy in the first or second line with hormone receptor-positive advanced breast cancer. It is expected the use of CDK4/6 inhibitor will further increase. Therefore, the aim was to investigate and better understand the use of palbociclib. We retrospectively analyzed the data of patients with advanced breast cancer who were treated with palbociclib in three hospitals between 2018 and 2022. Clinical data were obtained from the patients' medical electronic records. A total of 143 patients were enrolled. The median age was 66 years (range=33-89), and the majority (90.9%) were postmenopausal patients. In total, median time-to-treatment discontinuation (TTD) (95% confidence interval, CI) was 7 (6-10) months. Median TTD (95% CI) was 13 (7-20) months for the first or second line, and significantly prolonged compared to TTD for the third or later lines with palbociclib (p<0.0001). The importance of front-line use was indicated. Multivariate analyses showed that no visceral metastasis or first or second line therapy influenced the longer TTD. Between patients above or below 70 years of age, older age did not negatively affect TTD, though there were significantly more cases of dose reduction or withdrawal in patients over 70 years old. The variation of adverse events (AEs) among hospitals was very large (9.0%, 31.3%, 4.5%). We found that understanding of AE management was important. This study showed that dose reduction or withdrawal of palbociclib had no harmful effects in Japanese patients. Efficacy was also high in older patients. It is important to manage palbociclib administration more safely and appropriately. A combination of dose reduction and withdrawal is key to this therapeutic strategy.

Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm?

Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.

Application of repeat image analysis to radiation therapy imaging modalities as a quality improvement tool for image guided radiotherapy.

Repeat images contribute to excess patient dose and workflow inefficiencies and can be analyzed to identify potential areas for improvement within a program. Although routinely used in diagnostic imaging, repeat image analysis is not widely used in radiation therapy imaging, despite the role of imaging in the delivery of precise radiation treatments. Repeat image analysis was performed for on-board cone beam CT imagers and CT simulators within a radiation therapy department. Both the rate of repeat images and the reasons for the repeat images were analyzed. Data from nine conventional linear accelerators and three CT simulators were analyzed retrospectively over a 5-month period. Repeated images that were not part of the standard of care were considered repeat images. The repeat rate was expressed as the number of repeat scans as percentage of the total number of scans performed. The reasons for the repeats were collected and classified as either patient preparation, patient setup, patient motion, or machine error. These reasons were further classified into sub-categories. The overall repeat rate across the linear accelerators was 3.3%, with a maximum of 5% on any single machine. The repeat rate for the three CT simulators was 1.5%. The most common reasons for repeat images were patient preparation (incorrect bladder or rectal filling) and patient setup or positioning. Greater positioning challenges led to higher repeat rates on units that treat a large number of breast patients, palliative patients, or pediatric patients. Repeat image analysis can be applied within a radiation therapy department. Establishing baseline repeat rates and analyzing reasons for the repeat images can identify opportunities for improvements in terms of patient dose reduction and workflow efficiency for the program. Periodic repeat image analysis also permits monitoring the program for changes and for comparison against rates at other institutions.

New-Generation ASiR-V for Dose Reduction While Maintaining Image Quality in CT: A Phantom Study

Over the last few decades, the need to reduce and optimize patient medical radiation exposure has prompted the introduction of novel reconstruction algorithms in computed tomography (CT). Against this backdrop, the present study aimed to assess whether reduced radiation dose CT images reconstructed with the new-generation adaptive statistical iterative reconstruction (ASiR-V) maintain the same image quality as that of routine image reconstruction. In addition, the optimization of image quality parameters for the ASiR-V algorithm (e.g., an optimal combination of blending percentage and noise index (NI)) was investigated. An abdominal reference phantom was imaged using the routine clinical protocol (fixed noise index of 18 and 40% ASiR reconstruction). Reduced radiation dose CT scans were performed with varying NI (22, 24, and 30) and using the ASiR-V reconstruction algorithm. Quantitative and qualitative analyses of image noise, contrast, and resolution were performed against NI and reconstruction blending percentages. Our results confirm the ability of the ASiR-V algorithm to provide images of high diagnostic quality while reducing the patient dose. All the parameters were improved in ASiR-V images as compared to ASiR. Both quantitative and qualitative analyses showed that the best agreement was obtained for the images reconstructed using ASiR-V with NI24 and a high percentage of blending (70–100%). This preliminary study results show that ASiR-V allows for a significant reduction in patient dose (about 40%) while maintaining a good overall image quality when appropriate NI (i.e., 24) is used.

Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China.

Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China. We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy. The median age was 46 years (interquartile range: 33-55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%). This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.

Patient radiation dose estimation during pelvis, hip joint and lumber spine radiography in Majmaah city, Saudi Arabia hospital

The purpose of this work was to estimate entrance surface air kerma (ESAK) for adult patients examined for pelvis, hip joint and lumber spine radiography in the governmental hospital of Majmaah City, Saudi Arabia. The ESAK was estimated for 377 patients (male and female) undertaking AP pelvis, hip joint and lumber spine radiography. The ESAK was calculated based on the measurement of X-ray tube output and the knowledge of exposure factors. The X-ray output was measured using a Rad-Check ionization chamber for each X-ray tube. In total, seven X-ray tubes were enrolled to assess the patients’ ESAK. The exposure factors included the tube potential (kVp), tube loading (mAs) and X-ray source to image detector distance-SID (cm). The factors were recorded for each patient, together with demographic data (age and gender). The mean ESAKs in this study were 3.19 ± 0.78 for lumbar spine (AP), 4.02 ± 0.78 for lumbar (LAT), 1.84 ± 1.17 for hip joint and 2.93 ± 0.99 for pelvis. The corresponding average values of the kVp used for this examination ranged from 72.9 to 113.75 kVp; the mAs ranged from 11.7 to 42.1 mAs, and the SID range was between 100 and 115 cm. The calculated ESAK values of all examinations in both projections, PA and LAT, were less than the values recommended by national and international associations, IAEA and EU RP108. The role of optimizing radiography parameters for reducing the patient dose is a significant issue. Periodic checks and quality control testing are highly recommended to reduce patient doses.

Risk factors associated with relapse after methotrexate dose reduction in patients with rheumatoid arthritis receiving golimumab and methotrexate combination therapy.

To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy. Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline. A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076). Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse.