Split Dose Research Articles

Split doses versus whole dose bowel preparation using polyethylene glycol for colonoscopy: A multicentric prospective Lebanese randomized trial between 2021 and 2023.

Bowel preparation is considered as major obstacle before colonoscopy, and it is often reported as the most feared part of the procedure. The aim of this study is to determine the difference in efficacy between a split dose of PEG and the previous day regimen in cleaning the colon, using Boston bowel preparation scale. In addition, also to evaluate patient satisfaction regarding the modality of preparation. The study included 200 hospitalized patients undergoing colonoscopy at Beirut hospitals between 2021 and 2023. Oneof the two regimens will be prescribed randomly to the patients before colonoscopy: 98 (49%) in Group A (patients treated with PEG preparation as a split dose for 2 days), and 102 (51%) in Group B (patients taking PEG preparation as a whole dose). Data was analyzed using SPSS version 25. Patients were distributed between 105 (52.5%) males and 95 (47.5%) females. The top two indications for colonoscopy were bleeding (34%), change in bowel habits (constipation/diarrhea) (32%). Patients experienced adverse events noting cramps (48.5%), stomach ache (32%), headache (31%), vomiting (53%), nausea (53%), sleep disturbance (27%), bloating (26.5%), and malaise (26%). A statistically significant difference (p = 0.040) was detected in sleep disturbance: 20.4% of patients in group A and 33.3% of patients in group B. The average satisfaction score was 3.02 ± 1.03 over 4 (Group A) and 3.04 ± 0.99 over 4 (Group B) (p = 0.896). The average BBPS was 8.07 ± 1.14 (Group A) and 8.28 ± 1.0 (Group B) (p = 0.162). The two administrations were almost similar in term of satisfaction and BBPS. As multiple factors like age, sexe, comorbidities may contribute in altering how much a given drug is safe and efficace, more research is needed to choose the best 3regimen for each patient.

Investigation of the Impact of Temporal Dose Delivery Patterns of Ion Irradiation with the Local Effect Model.

We present an extension of the Local Effect Model (LEM) to include time-dose relationships for predicting effects of protracted and split-dose ion irradiation at arbitrary LET. With this kinetic extension, the spatial and temporal induction and processing of DNA double strand breaks (DSB) in cellular nuclei can be simulated for a wide range of ion radiation qualities, doses and dose rates. The key concept of the extension is based on the joint spatial and temporal coexistence of initial DSB, leading to the formation of clustered DNA damage on the µm scale (as defined e.g., by the size scale of Mbp chromatin loops), which is considered to have an increased cellular lethality as compared to isolated, single DSB. By simulating the time dependent induction and repair of DSB and scoring of isolated and clustered DSB upon irradiation, the impact of dose rate and split dose on the cell survival probability can be computed. In a first part of this work, we systematically analyze the predicted impact of protraction in dependence of factors like dose, LET, ion species and radiosensitivity as characterized by the photon LQ-parameters. We establish links to common concepts that describe dose rate effects for low LET radiation. We also compare the model predictions to experimental data and find agreement with the general trends observed in the experiments. The relevant concepts of our approach are compared to other models suitable for predicting time effects. We investigate an apparent analogy between spatial and temporal concentration of radiation delivery, both leading to increased effectiveness, and discuss similarities and differences between the general dependencies of these clustering effects on their impacting factors. Finally, we conclude that the findings give additional support for the general concept of the LEM, i.e. the characterization of high LET radiation effects based on the distinction of just two classes of DSB (isolated DSB and clustered DSB).

Performance of tomato grown under different water replacement depths and silicon application forms

Water management has a direct impact on plant development, and under deficit conditions, it often results in reduced yields. Silicon (Si), however, has the potential to alleviate stress and enhance plant performance under unfavorable conditions. This study aimed to analyze the performance of tomato plants cultivated under different water replacement depths and forms of silicon application. The experiment was laid out in a completely randomized design with a 2 × 4 factorial arrangement represented by two water replacement depths (60% and 100% of crop evapotranspiration - ETc) and four forms of silicon application (without application, soil application - full dose, soil application - split dose, and foliar applications). Four replications were used. The plants were cultivated in a protected environment using drip irrigation for water replacement, and silicon oxide served as the source of the element. The analyzed parameters included daily evapotranspiration, leaf spectral reflectance, mass accumulation (root, stem, and leaf), yield indices (fruit weight, plant yield, and defective fruits), water productivity, and post-harvest fruit weight loss. The imposition of water deficit (60% of ETc) in tomato leads to reduced crop development and yield, with the effects partially mitigated by the application of silicon. Conversely, under conditions of adequate water replacement (100% of ETc), silicon application contributes to increased development and yield of tomato. The application of silicon in the soil, whether in a full or split dose, demonstrates a more favorable response in vegetative indices and yield for tomato.

Mode and Dose of Boron Nutrition on Growth, Productivity, Nutrient Uptake and Quality of a Rice-groundnut Cropping System

To assess the effect of boron (B) nutrition on growth, productivity, uptake and crop quality of rice-groundnut cropping system under medium land Inceptisols Odisha, a field experiment was conducted during Kharif and Rabi 2016-17 and 2017-18. The experiment was laid out in randomized block design (RBD) with eight treatments being replicated thrice. The results revealed that rice crop showed higher growth rate (9.4 mm day-1) than groundnut crop of 9.1 mm day-1. Soil application of B in split doses maintained higher growth rate than foliar spray irrespective of crops. B fertilization to rice crop reduced chaffiness from 35% in no B fertilization to 15% in B applied in split doses. It also showed 15.6% higher number of nodules than no B application in groundnut crop. Economic yield produced in different mode of B application in rice-groundnut cropping system, the 2nd crop was influenced by 22.5% against 16.0% for the 1st crop. B improved the economic yield by 19.5%over no B application. Application of B@1kg.ha-1 to each crops increased the economic yield by 8.7% compared to its half rate application (0.5 kg.ha-1). Based on rice-equivalent yields (REY) of rice-groundnut cropping system practices followed the order: Split application (288)>Full dose basal (250)>Full dose B to groundnut (199)>Half dose B basal to each crop (188)>Full dose B to rice (186) = Foliar spray of B (186)>STD (100). The recovery of added N increased by (42.2%) when B was applied to 1st crop with full dose (53.5%), again it increased further by 60.8% when applied in split. B nutrition to rice-groundnut system influenced P and K uptake by 36.4% and 48.4% respectively over no application. In rice-groundnut cropping system split application of B@0.5 kg.ha-1 to both crops at active growth stages improved the yield, uptake, crop quality and economic benefit was found superior over no or sub optimal dose of B application in a deficient medium land Inceptisols of Jajpur district.

Effects of Farrowing Induction on Some Farrowing Characteristics in the Pig − A Review

Abstract Several farrowing induction programs have been used to increase the proportion of sow farrowing during the work period and the rate of farrowing supervision, as well as to promote the success of cross-fostering and the practice of all-in all-out in swine production. The present overview aimed to evaluate the effects of farrowing induction on farrowing duration, birth interval, birth weight, dystocia/birth assistance, and stillbirth in pigs. The results showed that via different routes of administration, either natural or synthetic prostaglandins alone or in combination mostly with uterotonic drugs, including oxytocin and carbetocin, have been used for the induction of farrowing. Sometimes other drugs, such as dexamethasone, estradiol, xylazine, ergometrine, and AGN190851, were added. Vulvar and perinatal routes reduced the intramuscular dose of prostaglandins by 50% to 75%, while equal effects remained. A split dose of prostaglandin 6 h apart should be used because it may enhance complete luteolysis. Additionally, if uterotonic drugs are used following prostaglandin injection, they should be injected after the birth of the first piglets at the earliest timepoint to ensure full opening of the cervix. These two practices decrease the farrowing duration, the birth interval, and dystocia. Induction should not be conducted more than 2 days earlier than the expected farrowing date in order to keep the stillbirth rate and birth weight unaltered. This review also revealed that certain factors, such as the rate of farrowing supervision, natural differences in piglets’ birth weights, litter size, gestation length, and treatment with altrenogest before induction, may be confounding factors that possibly alter the effect of induction programs on certain farrowing characteristics.

Lipidome analyses reveal radiation induced remodeling of glycerophospholipid unsaturation in lung tumor.

Radiotherapy is a pivotal treatment for lung cancer, significantly impacting tumor control and patient quality of life. Despite its benefits, the molecular mechanisms underlying radiotherapy-induced biological alterations in lung cancer cells remain inadequately understood. In this study, we employed a mass spectrometry-based lipidomics approach to investigate lipid profile changes in a lung cancer mouse model post-radiation. Lewis lung carcinoma (LLC) cells were injected into C57BL/6J mice, followed by radiation treatment with varying split doses. Our results showed an increase in sterol lipids and a decrease in glycerolipids, specifically triacylglycerides, indicating disrupted lipid storage. Additionally, we observed significant changes in glycerophospholipid unsaturation, suggesting a remodeling of membrane properties that may influence cell survival. Linear regression analysis demonstrated a significant negative correlation between glycerophospholipid unsaturation index and tumor weight, indicating a potential role in radiation-induced tumor cell death. These findings provide new insights into the lipid metabolic pathways affected by radiotherapy and could inform the development of improved therapeutic strategies for lung cancer treatment.

Evaluation of parameters influencing the quality of colon preparation with a split-dose regimen of sulfate salts.

Bowel cleansing is an important factor for the quality of colonoscopy. We aimed to evaluate the efficacy of split-dose oral sulfate salts on bowel preparation and to determine parameters influencing the quality of bowel cleaning. Consecutive adults who completed their preparation for colonoscopy with a regimen of sulfate salts were enrolled. Of the 446 patients, 11 were excluded from the analysis. Among the 435 patients, 257 (59.1%) were female, mean age was 62.0±11.6 years and median body mass index (BMI) 26.1 kg/m2 (interquartile range [IQR] 23.8-29.4). Indications for colonoscopy were screening 155 (35.6%), surveillance 102 (23.5%), or other 178 (40.9%). The median time between the end of second dose of the preparation regimen and colonoscopy initiation was 5:15 h (IQR 4:30-6:00, min: 2:20, max: 12:20). Minor adverse events were reported in 62 (14.3%) patients. BBPS=9 was observed in 279 (64.14%) patients. Segmental BBPS=3 was achieved in 387 (88.97%), 346 (79.54%) and 289 (66.44%) patients (P<0.001) in the descending, transverse and ascending colon, respectively. Multivariate analysis revealed that BMI (odds ratio [OR] 1.05, 95% confidence interval [CI] 1-1.1) and time between the end of the second laxative dose and colonoscopy initiation (OR 1.25, 95%CI 1.08-1.45) were associated with poorer bowel preparation. A split dose of oral sulfate salts is an efficacious and well tolerated regimen. Obesity and a longer time interval between the end of the second dose and colonoscopy initiation negatively influence bowel cleanliness.

Effect of different organic inputs on agronomic and economic performance of sesame under rainfed conditions of North Maharashtra

A field experiment was conducted at Oilseeds Research Station, MPKV, Jalgaon to assess the performance of most suitable organic source for sesame production and its economics during the kharif season of 2021. Application of FYM on N equivalent basis + foliar application of 3% Panchgavya at flowering and capsule formation stage + Foliar application of Pseudomonas and Azotobactor 2 lit /ha both + soil application of Pseudomonas and Azotobactor (2.5 lit /ha + 200 kg FYM) recorded numerically higher seed yield ( 568 kg/ ha) over rest of the treatments, whereas higher net returns ( 26078/ha) and B: C ratio of 2.13 was obtained under application of RDF ( 50 % N as basal and remaining 50 % in 2 split doses) over rest of the organic sources.

Outcomes in Routine Clinical Practice with Methotrexate-Temozolomide-Rituximab Induction and Modified Etoposide-Cytarabine Consolidation in Newly Diagnosed Primary CNS Lymphoma

Background: Recent studies have reported improved outcomes for patients with Primary CNS lymphoma (PCNSL) with addition of agents in induction (for e.g. cytarabine, thiotepa and rituximab in IELSG studies), intense consolidation (Autologous stem cell transplant (ASCT) as in IELSG 43) and intense non-myeloablative chemotherapy with etoposide/cytarabine (EA) as in CALGB 50202). Delivery of such an intense therapy is often difficult in clinical practice due to advanced age, comorbidities, poor performance status and resource constraints. We started using induction with methotrexate, temozolomide and rituximab (MTR) as per CALGB 50202 study however the intense non-myeloablative EA consolidation was not feasible. We used a strategy of reduced dose EA consolidation for 2 cycles with etoposide at 100 mg/m 2 over 2 hours and cytarabine 2 gm/m 2 twice daily for 2 or 3 days based on clinical judgement of the treating physician. Here we report outcomes with this approach in newly diagnosed PCNSL patients treated at our centre. Method: We did a retrospective analysis of patients with newly diagnosed PCNSL treated with MTR induction followed by modified EA consolidation. Kaplan-Meier was used to estimate progression free (PFS) and overall survival (OS). Variables influencing the outcomes with P less than 0.05 were considered significant. Results: Between January 2015 to December 2022, 72 patients were treated with above protocol with a median age of 46.5 years (range, 17 to 68 years) and 50 (69.4%) were males. Median ECOG performance score at presentation was 1 with 16 (22%) patients having ECOG performance score of 3 or more. IELSG scores were high and intermediate risk in 26 (36.1%) and 27 (37.5%) respectively while only 7 (9.7%) were in the low risk (data was not available for remaining 12 (17%) patients). MSKCC scores were available for all patients with 43 (59%) patients in class 1, 14 (19%) patients in class 2 and 15 (20%) patients in class 3. MTR induction with a dose of 8 gm/m2 could be delivered for all 4 cycles in 64 (88%) patients. Dose reduction was required in 14 (19.4%) patients; reasons were renal dysfunction in 8 (11%), infections in 3 (4%), liver dysfunction in 2 (3%). Nine patients (12.5%) had disease progression during induction. Total of 54 patients received consolidation with systemic therapy. Dose reduced EA consolidation was delivered in 46 (63%) patients while 8 patients received single agent high dose cytarabine consolidation and only 3 patients underwent ASCT. Seven patients received WBRT consolidation. EA consolidation was given for 2 days in 30 (65%) patients while 16 (35%) patients received 3 days of EA consolidation. Twenty six patients received maintenance lenalidomide. With a median follow up of 39.2 months (range, 2.1 to 91), median PFS is 46.9 months and median overall OS has not reached. Three years PFS &amp; OS for all patients is 59.5% and 78% respectively ( Fig 1A &amp;B). Median PFS and OS of patients receiving EA consolidation has not been reached with a 3-year PFS and OS of 77% and 79% respectively. MSKCC score was predictive of OS with 3 year OS in class 1, 2 and 3 of 89.5%, 68% and 58% respectively. Consolidation with split dose EA was associated with better OS and PFS as compared to single agent cytarabine alone. None of the 3 patients receiving ASCT have relapsed. Patients receiving full dose methotrexate had better OS compared to patients requiring dose reduction. Two versus 3 day EA consolidation had no impact on OS. MTR induction was well tolerated with grade 3 or more toxicity as follows: renal dysfunction in 8 (11%) patients, transaminitis in 4 and febrile neutropenia in 4 patients with no treatment related deaths. EA consolidation resulted in 18 episodes of febrile neutropenia with two deaths. Grade 3 or more hematologic toxicities were common with grade 3 or more anaemia, neutropenia and thrombocytopenia in 15 (32%), 40 (86%), 33 (71%) patients respectively. There were two deaths in the consolidation phase, one due to intracranial bleeding and another due to febrile neutropenia. Conclusion: MTR induction with modified EA consolidation is feasible and results in optimal outcomes in real world setting. Higher cumulative methotrexate dose and use of EA consolidation were associated with better OS. These outcomes compare favourably to CALGB 50202 study and represent a feasible option in resource limited setting.

The Sensitization of Murine Hematopoietic Progenitors and Stem Cells to DNA Damaging Agents By Quizartinib Is Associated with the Transcriptional Downregulation of DNA Damage Repair Genes

Background: The FLT3 inhibitor quizartinib induces quiescence of murine hematopoietic progenitors, and this affords their protection from S phase specific chemotherapies. In this study we investigated whether quizartinib can also protect hematopoietic progenitors from the cytotoxic effects of DNA damaging chemotherapies and radiation. Methods: C57BL/6 mice were primed with 30 mg/kg of quizartinib or vehicle (5% cyclodextrin) by oral gavage, and treated with DNA damaging chemotherapies, either cyclophosphamide, carboplatin, cisplatin, temozolomide or mitoxantrone 6 hours later, or 5.5Gy total body irradiation (TBI) after 9 hours. This TBI dose represents half the 11 Gy split dose used for bone marrow conditioning of C57BL/6 mice prior to HSC transplantation. Bone marrow cells were analyzed by flow cytometry after 3 to 6 days to identify progenitor and stem cell populations. Results: In contrast to quizartinib's protection against the cytotoxic effects of 5-FU and gemcitabine, all 5 DNA-damaging chemotherapies caused an increased loss of total bone marrow cellularity when mice were primed with quizartinib compared to vehicle primed controls. Flow cytometry analysis revealed that the numbers of myeloid and multipotent progenitors, and short-term and long-term hematopoietic stem cells (HSCs), were markedly lower in the quizartinib-treated mice. DNA damage and the resultant cell death caused by ionizing radiation is cell cycle specific, particularly for cells traversing from G 1 to S phases of the cell cycle. The ability of quizartinib to induce quiescence in myeloid and multipotent progenitors suggested that quizartinib may protect these cells from radiation. To test this, mice were dosed with vehicle or 30 mg/kg of quizartinib and 9 hours later exposed mice to 5.5 Gy of TBI. Analysis of bone marrow cells at day 6 revealed that total bone marrow cellularity and the numbers of progenitor and stem cells were markedly reduced in quizartinib-dosed mice compared to vehicle controls. For subsequent experiments mice were treated with 3 Gy TBI because the combination of quizartinib and 5.5 Gy caused severe myeloablation. As part of a series of experiments examining the kinetics of quizartinib's sensitization of bone marrow cells we tested whether the sensitization was maintained when mice were dosed with quizartinib 24 hours prior to 3 Gy TBI. Analysis of bone marrow cells 6 days later revealed that quizartinib dosed mice showed a significantly greater loss of total bone marrow cells, progenitor cells and stem cells compared to vehicle dosed mice (Figure 1). To identify possible mechanisms by which quizartinib sensitizes hematopoietic progenitors to DNA damaging agents we investigated quantitative gene expression profiling of the HPC7 hematopoietic progenitor cell line. These cells provide a suitable in vitro model since quizartinib induces their quiescence and provides protection against 5-FU. HPC7 cells were treated with 100 µM quizartinib, or vehicle, for 18 hr before RNA was harvested and sent for Next-generation sequencing. We found that quiescence induction in HPC7 cells by quizartinib correlated with the transcriptional downregulation of a wide range of genes involved in DNA damage repair pathways (including Brca1/2, Rad51, Palb2, Chek1 and Nbn), thus providing a possible mechanism for the enhanced cytotoxic effects of DNA damaging agents. Conclusions: Quizartinib sensitizes hematopoietic progenitors and stem cells to DNA-damaging agents, an effect that correlates with the transcriptional downregulation of many DNA damage repair genes. The enhanced depletion of hematopoietic progenitors and stem cells by DNA damaging agents in the presence of quizartinib has important clinical implications. Administering concurrent DNA damaging chemotherapy or radiotherapy with quizartinib treatment should be avoided. However, this interaction could facilitate a reduction in radiation/chemotherapy doses administered for bone marrow conditioning prior to HSC transplantation. By reducing these doses, but not compromising the conditioning process, non-hematopoietic side effects could be minimized and may allow currently excluded patients to be considered for HSC transplantation. Disclosure: This study was partly funded by Daiichi Sankyo.

The role of video capsule endoscopy in the diagnosis of gastrointestinal diseases: experience of the Department of Diagnostic and Operative Endoscopy

Introduction. Video capsule endoscopy (VSE) is a gold standard diagnostic method for small bowel diseases and is widely used in clinical practice. The presented analysis of the VCE results demonstrates the possibilities of this diagnostic tool and is the largest one of the analysis that were recently published in Russia. Aim. To demonstrate the possibilities of video capsule endoscopy in the diagnosis of small bowel diseases. Materials and methods. A total of 300 video capsule endoscopies were performed in patients with suspected and already established small bowel diseases between 2014 and 2022. All patients who underwent a video capsule endoscopy in the settings of the National Medical Research Center of Coloproctology named after A.N. Ryzhikh were over 18 years old. The study cohort included 158 men and 142 women. The average age of patients at the time of the video capsule endoscopy was 42 ± 15.4 years. The patients were recommended a standard preparation regimen: 3 days before the study, a protein diet was prescribed, and the day before, a two-stage administration of a PEGbased drug (“split dose”). To reduce gas production and decrease the amount of foamy intestinal contents, which worsens the quality of the endoscopic image, oral administration of an antifoam agent simethicone was prescribed: 80 mg on the eve of the endoscopy and 80 mg on the day of the endoscopy. Results. The video capsule endoscopy demonstrated high information value in the diagnosis of inflammatory bowel diseases: its sensitivity was 86%, and specificity – 90%. Similar results were obtained during video capsule endoscopy used to diagnose the source of possible bleeding: sensitivity and specificity were 87 and 68%, respectively. Conclusion. Video capsule endoscopy is an effective, safe and well-tolerated tool for diagnosing small bowel diseases. The video capsule endoscopy findings contribute to establishing a correct diagnosis and selecting treatment strategies.

Long-Term Efficacy and Safety of Obecabtagene Autoleucel (obe-cel) in Adult Patients (pts) with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia ([R/R B-ALL]; Pooled Analysis from ALLCAR19 and FELIX Phase Ib Studies) or Other B-cell Malignancies (ALLCAR19 Extension Study)

Background: Obe-cel is an autologous CD19 chimeric antigen receptor (CAR) T cell product designed to reduce toxicity and improve persistence through a fast off-rate CD19 binding domain. The clinical activity of obe-cel has been explored in adults with R/R B-ALL in a Phase I study (ALLCAR19, NCT02935257; Roddie C et al. J Clin Oncol 2021) and a Phase Ib/II study (FELIX, NCT04404660; Roddie C et al. J Clin Oncol 2023;41[16 Suppl]:7000). Additionally, obe-cel has been tested in pts with R/R B-cell chronic lymphocytic leukemia (B-CLL) and R/R B-cell non-Hodgkin lymphoma (B-NHL) (ALLCAR19 extension; Roddie C et al. Blood 2022;140[1 Suppl]:7452-3). Pts from the ALLCAR19 and FELIX Phase Ib studies are in long-term follow up (≥22 mos), and the ALLCAR19 extension has been recruiting for 3 years. We report an analysis of long-term efficacy and safety data from the ALLCAR19 and FELIX Phase Ib studies, as well as data from the ALLCAR19 extension. Methods: ALLCAR19 is a multicenter, non-randomized, open-label Phase I study in pts aged ≥16 years with B-cell malignancies. ALLCAR19 initially recruited pts with R/R B-ALL but was then amended (extension study) to also include pts with R/R B-CLL and R/R B-NHL. FELIX is a global, single-arm Phase Ib/II study enrolling pts aged ≥18 years with R/R B-ALL.Study designs have been presented previously. Obe-cel was administered as a split dose in pts with B-ALL (target dose 410 × 10 6 CAR T cells) and pts with CLL (target dose 230 × 10 6 CAR T cells), and as a single infusion in pts with B-NHL (target dose 200 × 10 6 CAR T cells); the pt populations in the two studies were similar. Pts with B-ALL from the ALLCAR19 and FELIX Phase Ib studies are being followed long term for disease progression and survival. For this analysis, data in pts with B-ALL from the ALLCAR19 and FELIX Phase Ib studies were pooled. Data in pts with CLL or B-NHL are presented from the ALLCAR19 extension study. Results: Outcomes in pts with R/R B-ALL: Data in pts with B-ALL were pooled (20 pts from ALLCAR19 [data cut-off Jun 26, 2023] and 16 from FELIX Phase Ib [data cut-off Mar 16, 2023]). The median age of the pooled cohort was 41.5 (range 18 to 74) years and pts had received a median of 3 (range 2 to 6) prior lines of treatment. Twenty-nine of the 36 pts (81%) achieved complete remission (CR)/CR with incomplete hematologic recovery post obe-cel infusions, per investigator assessment. The event-free survival rate was 64% at 6 mos and 49% at 12 mos. With a median follow up of 43 (range 19 to 62) mos, 13/36 pts (36%) remain in remission (8 from ALLCAR19; 5 from FELIX Phase Ib). Among these 13 ongoing responders, 2 (15%) had consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ten of the 11 ongoing responders (91%) who did not receive allo-HSCT still had detectable CAR T cells at the last follow up. All ongoing remissions were measurable residual disease negative at last available assessment. The estimated 2-, 3- and 4-year overall survival rates were 44%, 39% and 39%, respectively. Outcomes in pts with R/R B-CLL/B-NHL: The extension phase of the ALLCAR19 study enrolled 35 pts with B-CLL or B-NHL, of which 26 (B-CLL n=5; B-NHL n=21) received obe-cel (data cut-off Jun 26, 2023). The median age of this combined cohort was 61 (range 39 to 79) years and pts had received a median of 3 (range 2 to 8) prior lines of treatment. At a median follow up of 24 mos, the overall response rate for this cohort was 92% (n=24), and 58% of responders (n=14) were alive without disease progression at last follow up. Late toxicity: Of the 11 long-term R/R B-ALL responders who had not received consolidation allo-HSCT, 10 have ongoing B-cell aplasia. Of the 14 ongoing responders in the R/R B-CLL/B-NHL cohort, 12 have ongoing B-cell aplasia (&amp;lt;20 B cells/µl). Of note, ongoing B-cell aplasia did not correlate with an increased risk of late serious infection. No other long-term toxicity ascribed to obe-cel was reported. Conclusions: The combined analysis of data from the ALLCAR19 and FELIX Phase Ib studies shows long-term efficacy and safety of obe-cel in pts with R/R B-ALL, with approximately one-third of pts still in remission without consolidative allo-HSCT after a median follow up of &amp;gt;3 years. Durable responses of &amp;gt;2 years were also seen in pts with R/R B-CLL and R/R B-NHL.B-cell aplasia was commonly found in long-term follow up of obe-cel recipients, but without a corresponding rise in serious late infections. Obe-cel can effect durable long-term remissions in B-cell malignancies.

Belantamab Mafodotin in Combination with Lenalidomide Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Efficacy Analysis of DREAMM-6 Trial Arm-a

Introduction: Belantamab mafodotin (belamaf) is a first-in-class, antibody-drug conjugate that targets B-cell maturation antigen. In the recent ALGONQUIN study, clinical activity associated with belamaf in combination with the immunomodulatory drug pomalidomide were increased in triple-class exposed/refractory multiple myeloma (MM) patients, highlighting the potential for belamaf-based combinations in this population (Trudel, et al. Blood. 2022;140 (Suppl 1):7306-07). Preclinical data indicate that belamaf combined with other immunomodulatory agents, such as lenalidomide (Len) may also provide additional benefit. Arm A of the Phase I/II DREAMM-6 (NCT03544281) study aimed to assess the safety and clinical activity of belamaf doses/schedules in combination with the standard of care (SOC) of Len plus dexamethasone (Dex) in patients with relapsed/refractory MM (RRMM). Methods: Patients were eligible to participate if they had received ≥1 prior line of therapy (LOT). In Part 1 (dose escalation), up to two dose levels of belamaf (1.9 mg/kg [dose level -1 Q4W]; 2.5 mg/kg Q4W [dose level 1]) and alternative dosing schedules were administered in combination with the fixed SOC dose. In Part 2 (dose expansion), patients received belamaf at the following doses/schedules: 1.9 mg/kg Q8W, 1.9 mg/kg Q4W, 2.5 mg/kg Q4W, or 2.5 mg/kg Q4W split dose (50% on Days 1 and 8 of a given cycle). For this study, Len 25 mg was administered orally (10 mg if estimated glomerular filtration rate &amp;lt;60 mL/min/1.73m 2) on days 1-21 and Dex 40 mg was administered (20 mg for patients &amp;gt;75 years old, patients with BMI &amp;lt;18.5, or patients with prior tolerability issues to Dex) on Days 1, 8, 15, and 22 of every 28-day cycle. The primary outcome of Part 1 was the number/percent of subjects with adverse events (AE) or dose-limiting toxicity (as reported previously). The primary outcome of Part 2 wassafety profile (AEs and serious AEs) and efficacy (overall response rate [ORR]). Pharmacokinetics (PK) and anti-drug antibodies were secondary outcomes. Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were exploratory endpoints. Results: Overall, 45 patients were enrolled across Parts 1 and 2. At the final analysis cutoff date (Feb 28, 2023), the median (range) age was 68 (36-80) years; patients had received a median (range) of 3 (1-10) prior LOTs, and 26/45 (57.8%) patients were Len-exposed (Table). The median (range) follow-up was 23.7 (0.5- 51.3) months. Incidence of AEs resulting in permanent discontinuation and dose reduction/delays of any study treatment were similar across groups; however, interpretation is limited due to the small sample size. The most common drug-related Grade 3+ AEs were keratopathy, visual acuity decline, and neutropenia. Safety and efficacy data are presented in the Table below. The ORR ranged from 58% to 75% across groups. The greatest depth of response (≥very good partial response [VGPR] 56%, ≥complete response 44%) was observed in the 2.5 mg/kg Q4W cohort. Interpretation of DOR, PFS, and OS was limited due to the small sample size in each cohort (Table). PK characteristics of belamaf were consistent with those previously reported for belamaf monotherapy considering baseline patient characteristics. Higher Cycle 1 peak and average concentrations (C ave) were observed with higher doses, with large overlap among cohorts; lower peak concentrations were seen with the split dosing regimen. Len PK were consistent with historical data. PK data indicated no drug-drug interaction between belamaf and Len. A positive trend was observed between belamaf Cycle 1 C ave and the probability of achieving PR or better. Conclusion: Belamaf in combination with SOC (Len/Dex) demonstrated deep and durable responses with a manageable safety profile in patients with RRMM. As anticipated, there was no drug-drug interaction between belamaf and Len. These findings support the use of belamaf in combination with SOC for patients with RRMM.

Obecabtagene Autoleucel (obe-cel, AUTO1) for Relapsed/Refractory Adult B-cell Acute Lymphoblastic Leukemia (R/R B-ALL): Pooled Analysis of the Ongoing FELIX Phase Ib/II Study

Background: Obe-cel is an autologous chimeric antigen receptor (CAR) T cell product with a novel CD19 binding domain CAT conferring a fast antigen off-rate designed to mitigate safety concerns and improve persistence over approved CD19 CAR T therapies. Early results from the pivotal FELIX study Phase IIA cohort (N=94) were recently presented (Roddie C et al. J Clin Oncol 2023;41[16 Suppl]:7000). We report findings from a pooled analysis of all patients (pts) treated to date with obe-cel in the FELIX Phase Ib/II study (NCT04404660), with a focus on pts with low leukemia burden prior to obe-cel infusion. Methods: The FELIX study enrolled adults with R/R B-ALL at screening with either morphological disease ≥5% bone marrow (BM) blasts (Cohort A), or in ≥2 nd complete remission (CR)/CR with incomplete hematologic recovery (CRi) with measurable residual disease (MRD) (Cohort B), or with isolated extramedullary disease (EMD) (Cohort C). The Phase Ib part of the study enrolled Cohorts A and B; the Phase II part enrolled Cohorts A, B, and C. CAR T products were generated from leukapheresis material using an automated process. Pts received bridging therapy as needed and lymphodepletion with fludarabine (4 × 30mg/m 2) and cyclophosphamide (2 × 500mg/m 2). A target dose of 410 × 10 6 CAR T cells was infused as a split dose on Days 1 and 10 based on pre-lymphodepletion BM blast burden. The primary endpoint was overall remission rate (best response of CR/CRi by independent review). Secondary endpoints included duration of remission (DoR), MRD negative remission rate, safety, and CAR T expansion/persistence. This pooled analysis included data from pts treated with obe-cel across all cohorts in the Phase Ib/II parts of the study. Low leukemia burden was defined as morphological remission per investigator assessment (&amp;lt;5% BM blasts without EMD) as measured at screening or at the start of lymphodepletion. Results: Between September 2020 and December 2022, 152 pts were enrolled and underwent leukapheresis. As of 16 March 2023, obe-cel was successfully administered to 126/152 (83%) pts (Phase Ib: Cohort A n=13, B n=3; Phase II: Cohort A n=94, B n=9, C n=7). Baseline characteristics at screening (n=126): median age 46.5 (range 20-81) yrs; Philadelphia positive B-ALL 27%; median 2 (range 1-6) prior lines of therapy; prior blinatumomab/inotuzumab 42%/32%; median BM blast burden 37% (range 0-100) including 23% pts with EMD; prior allogeneic stem cell transplant 44%. At a median follow up of 11.0 (range 0.9-30.6) months, the CR/CRi rate was 77% (95/124 response evaluable pts) with CR rate 57% (71/124). Among MRD evaluable responders, 96% achieved MRD negative status by central flow cytometry analysis. Median DoR was not reached at the current follow up. Low rates of Grade (Gr) ≥3 cytokine release syndrome (CRS; 2.4%) and/or Gr ≥3 immune effector cell associated neurotoxicity syndrome (ICANS; 7.1%) were observed. CAR T expansion was similar across the Phase Ib/II cohorts and CAR T persistence was ongoing in the majority of responders at the current follow up. Preliminary data indicate favorable efficacy and safety in pts with low leukemia burden prior to obe-cel infusion. Among 12 pts with MRD at screening (Cohort B), two pts were not evaluable and 9/10 evaluable pts achieved CR/CRi, with 100% achieving MRD negative status by central flow cytometry analysis post obe-cel. Median DoR was not reached at the current follow up. In this subset, no Gr ≥3 CRS was observed; one pt had Gr ≥3 ICANS. In a subset of 28 pts (across all cohorts) in morphological remission at the time of lymphodepletion, 24/27 (89%) response evaluable pts achieved CR/CRi and 100% of MRD evaluable responders achieved MRD negative CR/CRi by central flow cytometry analysis post obe-cel. Median DoR was not reached at the current follow up. In this subset, no pts experienced Gr ≥3 CRS/ICANS. Conclusions:This pooled analysis of data from all pts treated to date in the FELIX study demonstrates high rates of CR/CRi after obe-cel treatment, durable responses (median DoR not reached), and a favorable safety profile. Preliminary data suggest better outcomes in pts with low leukemia burden at screening/lymphodepletion, with higher rates of deep MRD negative complete remission, median DoR not reached at the current follow up, no Gr ≥3 CRS and one Gr ≥3 ICANS. These data support further exploration of CAR T therapy earlier in the treatment algorithm for adults with ALL.

Examining latest costs and prescribing on Liothyronine (T3) by dose levels with respect to the 2017 Competition and Market Authority (CMA) investigation into liothyronine prices and the implementation of 2023 British Thyroid Association (BTA) guidance for appropriate patients suggesting Liothyronine daily dose levels of 5-10mg at possible split dose twice day

Examining latest costs and prescribing on Liothyronine (T3) by dose levels with respect to the 2017 Competition and Market Authority (CMA) investigation into liothyronine prices and the implementation of 2023 British Thyroid Association (BTA) guidance for appropriate patients suggesting Liothyronine daily dose levels of 5-10mg at possible split dose twice day

Splitting Mealtime Insulin Doses for Mixed Fat and Protein Meals in Children and Adolescents with Type 1 Diabetes Using Multiple Daily Injection Regimen: A Randomized Cross-Over Trial

Aims. Assessment of the glycemic outcomes of increasing and splitting mealtime insulin doses for mixed fat and protein meals in pediatric patients with type 1 diabetes mellitus (T1DM) using multiple daily injection regimen and comparing the effects of regular insulin and fast-acting insulin on glycemic outcomes following those meals. Methods. This single-center, randomized, cross-over trial included 43 children and adolescents with T1DM randomly assigned to receive three interventional insulin doses for lunch meals over 3 consecutive days; Intervention A (100% insulin-to-carbohydrate ratio (ICR) dose given as premeal insulin lispro with an additional insulin sensitivity factor-calculated correction dose after 3 hr), Intervention B (130% ICR dose split into 60% premeal insulin lispro and 40% postmeal insulin lispro after 30 min), and Intervention C (130% ICR dose split into 60% premeal insulin lispro and 40% postmeal regular insulin after 30 min). The test meal consisted of two slices of pizza (weight: 150 g, carbohydrates: 40 g, fat: 15 g, protein: 20 g, and calories: 380 kcal). Postprandial blood glucose levels were monitored for 6 hr. Results. There were no significant differences in postprandial blood glucose excursions following the three interventions. However, Intervention C had a significantly lower late (3–6 hr) blood glucose area under the curve ( p = 0.01 ). Postprandial hypoglycemia developed in 12 participants (27.9%) following Interventions A and B and in 17 participants (39.5%) following Intervention C ( p = 0.32 ). Conclusions. Using regular insulin as a postmeal portion of increased and split insulin doses provided better late postprandial glycemic outcomes following mixed fat and protein meals. However, the amount of additional insulin used needs optimization to reduce the frequency of postprandial hypoglycemia. This trial is registered with NCT04783376.

Elotuzumab: Empiric analysis of dexamethasone administration schedule.

Elotuzumab in combination with dexamethasone and immunomodulating agents (IMiDs) lenalidomide or pomalidomide is 2nd to 4th line therapy for multiple myeloma. The labelled dosage of dexamethasone for use in conjunction with elotuzumab and IMiDs splits the dexamethasone dose into two administrations, one oral and one intravenous, on the days of each elotuzumab infusion. Administration of split dose dexamethasone on days of elotuzumab administration is based on the registration trials submitted for drug approval and was intended to ensure standard well-timed immunotherapy premedication using pharmacologically equivalent dexamethasone doses for both study arms. Administration of dexamethasone in the manner delineated by the elotuzumab product label adds complexity to the delivery of care. This commentary provides an empirical assessment of established medication safety and effectiveness which supports administration of dexamethasone standard intermittent dose instead of the split dose approach delineated on elotuzumab package insert. Simplification of regimen administration improves medication adherence, reduces the risk of inadvertent omission or duplication of medication therapy, and improves the workflow required for delivery of care.

What Is the Optimal Bowel Preparation for Capsule Colonoscopy and Pan-intestinal Capsule Endoscopy? A Systematic Review and Meta-Analysis

BackgroundThe rate of adequate cleansing (ACR) and complete examinations (CR) are key quality indicators in capsule colonoscopy (CC) and pan-intestinal capsule endoscopy (PCE).AimsTo evaluate the efficacy of bowel preparation protocols regarding ACR and CR.MethodsWe conducted a systematic review and meta-analysis, search terms regarding colon capsule preparation, publication date from 2006/01, and date of search 2021/12, in six bibliographic databases. Multiple steps of the cleansing protocol were assessed: diet, adjunctive laxatives, purgative solution, use of prokinetic agents, and “booster”. The meta-analytical frequency of ACR and CR was estimated, and subgroup analyses performed. Strategies associated with higher ACR and CR were explored using meta-analytical univariable and multivariable regression models.ResultsTwenty-six observational studies and five RCTs included (n = 4072 patients). The pooled rate of ACR was 72.5% (95% C.I. 67.8–77.5%; I2 = 92.4%), and the pooled rate of CR was 83.0% (95% C.I. 78.7–87.7%; I2 = 96.5%). The highest ACR were obtained using a low-fibre diet [78.5% (95% C.I. 72.0–85.6%); I2 = 57.0%], adjunctive laxatives [74.7% (95% C.I. 69.8–80.1%); I2 = 85.3%], and split dose < 4L polyethylene glycol (PEG) as purgative [77.5% (95% C.I. 68.4–87.8%); I2 = 47.3%]. The highest CR were observed using routine prokinetics prior to capsule ingestion [84.4% (95% C.I. 79.9–89.2%); I2 = 89.8%], and sodium phosphate (NaP) as “booster” [86.2% (95% C.I. 82.3–90.2%); I2 = 86.8%]. In univariable models, adjunctive laxatives were associated with higher ACR [OR 1.81 (95% C.I. 1.13; 2.90); p = 0.014]. CR was higher with routine prokinetics [OR 1.86 (95% C.I. 1.13; 3.05); p = 0.015] and split-dose PEG purgative [OR 2.03 (95% C.I. 1.01; 4.09), p = 0.048].ConclusionsMain quality outcomes (ACR, CR) remain suboptimal for CC and PCE. Despite considerable heterogeneity, our results support low-fibre diet, use of adjunctive sennosides, split dose < 4L PEG, and routine prokinetics, while NaP remains the most consistent option as booster.

Impact of chemical weed management in sugar beet ( Beta vulgaris) on productivity, quality and economics

Weeds in sugar beet ( Beta vulgaris L.) can contribute to a significant reduction in the root yield. The species composition of these plants is an important factor influencing the competition with crops. The aim of the 2-year field experiment with mixtures of: phenmedipham + ethofumesate + metamitron + quinmerac; ethofumesate + metamitron + metamitron + + quinmerac + triflusulfuron-methyl; phenmedipham + ethofumesate + metamitron + + quinmerac + triflusulfuron-methyl + clopyralid + lenacil, and phenmedipham + ethofumesate + metamitron + quinmerac + triflusulfuron-methyl + clopyralid applied in split doses, microdoses and Conviso Smart technology was to determine the weed species community composition and effectiveness of weed control strategies. The most common species occurring in both years were: Chenopodium album L., Fallopia convolvulus L., and Geranium pusillum L. The communities had the highest values of biodiversity indices in 2020 and lower values in 2021. There were no statistically significant differences in the herbicidal effectiveness of the tested herbicidal technologies over both years of research and for individual main weed species – 95–99%. The use of all herbicide variants contributed to achieving significantly higher yields than untreated treatments, and contributed to an increase in profitability of cultivation, but this result depended on the selected strategy. The presented herbicide solutions were characterized by direct income at a similar level.

Radiobiological Insights of Staged Brachytherapy Using Eye Plaque for Large Uveal Melanoma

I-125 radioactive seeds embedded in an eye plaque is used to deliver the radiation dose of 85Gy to the apex of the tumor. However, it is challenging to treat a lesion in height (>10 mm) because of a high dose (> 500 Gy) to sclera. A staged radiotherapy (SRT) has been implemented successfully in stereotactic radiosurgery when a single dose is risky for a bigger sized lesion. The hypothesis of this work is that the SRT works for eye plaque brachytherapy of uveal melanoma to break the single fraction into two. To apply the concept of SRT, the following questions need to be answered: What are the two fraction doses? What is the time interval between the two fractions? In this work, the two split fraction doses and time interval are calculated using the "incomplete-repair' model. Equation (1) is the linear-quadratic (LQ) model. f(x) is the cell survival curve (SC). Equation (2) and (3) are radiobiological model developed dealing with the split doses by considering the incomplete repair. Ln(f(x)) = -αx - βx2 (1) Ln(fn(x, Ɵ)) = nLn(f(x))-nβx2hn(Ɵ) (2) hn(Ɵ) = (2/n)[ Ɵ/(1- Ɵ)][n-(1- Ɵn)/(1- Ɵ)] (3) Ɵ = exp(-µΔt) (4) x represents the fraction dose, Ɵx is the initial segment of the survival curve, Ɵ determines the rate at which repair proceeds. n is fraction number and µ represent repair constant which equals to ln2/T1/2. T1/2 is the half-life of I-125. For continuous dose vt delivered at dose rate v for time t, with repair constant µ, the LQ model is modified as Ln (f(vt, µ)) = -α(vt) -β(vt)2g(µt) (5) g(µt) = 2[µt-1+exp(-µt)]/(µt)2 (6) Assuming biological effective dose (BED) is the same for the single fraction and split two fractions, SC when n = 1 should be same as when n = 2. Therefore, the equation (7) is derived. Ɵ = [(α/β)x1 - 2(α/β)(x2)2 + (x1)2]/2(x2)2 - 1 (7) x1 is single fraction dose of 85Gy, x2 is the split dose to two fractions. α/β ratio of 10 Gy is used. By fitting the equation (7), the ranges of doses and time intervals were determined. The fraction doses and time interval to get the same BED as single fraction of 85 Gy are determined from 45 Gy to 50 Gy with time interval of 22 days to 76 days for staged brachytherapy eye plaque (SBEP). Our result is matched the treatment protocol for SBEP reported, e.g., 1st fraction dose of 40Gy and 50 Gy of 2nd fraction with 73 days of time interval are used. The max. dose of scleral dose is 328 Gy compared to the single fraction scleral dose of 543Gy. This work could provide guidelines in SBEP in dosage and time interval. The height of tumor matters the most in the SBEP since the taller the tumor, the higher dose to the sclera is. Reference.