Early Stages Of Therapy Research Articles

Current perspectives in obesity management: unraveling the impact of different therapy approach in real life obesity care

BackgroundThe challenge of addressing obesity persists in healthcare, necessitating nuanced approaches and personalized strategies. This study aims to evaluate the effects of diverse therapeutic interventions on anthropometric and biochemical parameters in individuals with overweight and obesity within a real-world clinical context.MethodsA retrospective analysis was conducted on 192 patients (141 females, 51 males) aged 18 to 75, with a BMI ranging from 25 to 30 (14.1%) and BMI ≥ 30 (85.9%), observed over a 12-month period at our Endocrinology Unit. Treatment cohorts comprised individuals following different regimens: Mediterranean Diet (MD), with an approximate daily intake of 1500 kcal for women and 1800 kcal for men (71% patients); Ketogenic Diet (KD), utilizing the VLCKD protocol characterized by a highly hypocaloric dietary regimen < 800 kcal/day (14% patients); metformin, administered using the oral formulation (5% patients); pharmacological intervention with GLP1-RA administered via subcutaneous injection with incremental dosage (10% patients). Supply constraints limited the efficacy of Liraglutide, whereas Semaglutide was excluded from comparisons due to its unavailability for obesity without diabetes. Blood tests were conducted to assess lipid profile, glycemic profile, and anthropometric parameters, including BMI, waist circumference, and waist-to-height ratio.ResultsSignificant BMI changes were observed from baseline to 6 months across MD, KD, and Liraglutide groups (p < 0.05). KD exhibited notable reductions in waist circumference and waist-to-height ratio within the initial quarter (p < 0.05), with a significant triglyceride decrease after 6 months (p < 0.05), indicating its efficacy over MD. Liraglutide demonstrated a substantial reduction in HbA1c levels in the first quarter (p < 0.05). During the first three months, the ANOVA test on fasting blood glucose showed a statistically significant impact of the time variable (p < 0.05) rather than the specific treatments themselves (Liraglutide and KD), suggesting that adherence during the early stages of therapy may be more critical than treatment choice.ConclusionsPositive outcomes from targeted interventions, whether pharmacological or dietary should encourage the exploration of innovative, long-term strategies that include personalized treatment alternation. The absence of standardized protocols underscores the importance of careful and tailored planning in managing obesity as a chronic condition.

Relationship between the outcomes of intensive phase therapy in patients with newly diagnosed infiltrative pulmonary tuberculosis and activity of purine metabolism enzymes as well as CD3+CD8+ lymphocyte level

Monitoring activity of inflammatory process and lymphocyte subsets can help assess the effectiveness of intensive phase therapy (IPT) already in the early stages of treatment. The goal is to evaluate changes in the concentration and activity of enzymes associated with purine metabolism and peripheral blood lymphocyte subset composition, and to determine their relationship with IPT effectiveness in patients with newly diagnosed infiltrative pulmonary tuberculosis (IPTb). Materials and methods. In 141 IPTb patients, the IPT data were presented as follows: “significant improvement” (SI) — disappearance of intoxication symptoms, abacillation, closure of decay cavities; “less pronounced improvement” (LMI) — eliminated symptoms of intoxication, abacillation, pronounced resorption of focal and infiltrative changes, reduction of decay cavities. We assessed the activity of adenosine deaminase in blood serum (eADA-1, 2), mononuclear cells and neutrophils, the concentration of blood serum ecto-5'-nucleotidase (eHT5E), CD26 (DPPV) in blood serum (s, soluble form) and mononuclear cells (m, membrane form), subpopulation composition. Results. Patients exhibit increased concentrations of eNT5E, mCD26 (DPPIV) and eADA-2 activity, and decreased intracellular ADA-1 activity. In the “LMI” group, after IPT, an increased sCD26 (DPPV) level was noted. The groups differed in lymphocyte counts and percentage of CD3+CD8+ cells. eADA-2 activity was higher in the LMI group and increased after IPT, in contrast to comparison group. mCD26 (DPPIV) concentrations are higher in PD patients before therapy and after IPT. Conclusion. Thus, the outcome of IPT in IPTb patients is associated with altered T-lymphocyte populations and severity of the inflammatory process. Studying the activity of membrane and soluble eADA-2, CD26 (DPPIV) and percentage of CD3+CD8+ T-lymphocytes in the early stages of therapy can provide the necessary information for correcting personalized pathogenetic therapy of patients with newly diagnosed IPTb.

Real-World Treatment Patterns Among Patients with Myelodysplastic Syndromes Initiating Oral Decitabine and Cedazuridine or Intravenous/Subcutaneous Hypomethylating Agents

Introduction: Hypomethylating agents (HMAs) are recommended standard of care for patients with higher-risk myelodysplastic syndromes (HR-MDS). HMA therapies include intravenous (IV) or subcutaneous (SC) decitabine and azacitidine; however, parenteral administration of HMAs has been associated with increased patient burden. The oral HMA decitabine and cedazuridine (DEC-C) was FDA-approved in July 2020 for the treatment of MDS, and offers an alternative to IV/SC HMAs, with similar pharmacokinetic exposure and response rates compared to IV decitabine. This study examined treatment patterns among patients with MDS receiving oral DEC-C compared with IV/SC HMAs in real-world clinical practice. Methods: This was a retrospective analysis using the US Cerner Enviza claims database; medical and prescription claims data for patients were linked to mortality data from Datavant. Adults aged ≥18 years, who were diagnosed with MDS (ICD-10-CM code D46.x; all risk levels), and who had initiated a HMA (≥1 claim; August 1, 2020─August 31, 2022) were included; index date was defined as the first pharmacy or medical claim for DEC-C or IV/SC HMAs, respectively. Patients had variable follow-up after index and were followed until end of enrollment, death, or end of study. Propensity score matching (PSM; 1:1) was performed to balance for confounding factors (age, sex, acute myeloid leukemia [AML] diagnosis, Charlson Comorbidity Index [CCI] score, and red blood cell [RBC] transfusion); adjusted bivariate analysis was used to compare outcomes between treatment groups. Longitudinal persistence was assessed according to the number of cycles of therapy received during follow-up, where a cycle was defined as either 3-10 days of administration of index IV/SC HMA or 1 claim for oral DEC-C, within a 28-day cycle. Results: Of 1569 patients included, 160 (10.2%) received DEC-C and 1409 (89.8%) received IV/SC HMAs. In the DEC-C cohort, median age was 72.5 years and 66.9% were male; in the IV/SC cohort, median age was 69.0 years and 58.2% were male. Two-thirds of patients newly initiated HMAs during the study period (69.4% for DEC-C and 72.2% for IV/SC HMAs); 30.6% of the DEC-C cohort had switched from prior IV/SC HMA treatment. Both groups had high levels of comorbidity; 55.6% of patients in the DEC-C cohort and 58.4% in the IV/SC HMA cohort had CCI scores of ≥3, and 14.4% and 23.8%, respectively, had an AML diagnosis. During the 6-month pre-index period, half (55.3%) of patients in both groups received RBC transfusions, and one quarter (25.9%) received platelet transfusions. After matching, there were 158 patients in each treatment cohort and all covariates included in the PSM were balanced (standardized mean difference &amp;lt;0.2). Median age was 72.0 years and 74.0 years for the DEC-C and IV/SC HMAs matched cohorts, respectively, and 66.5% and 69.6%, respectively, were male. Mean CCI scores were 3.45 for DEC-C and 3.15 for IV/SC HMA groups and 14.6% and 15.8%, respectively, had an AML diagnosis pre index. Longitudinal persistence was comparable between the matched DEC-C and IV/SC cohorts during the first 6 months post-index, with similar proportions receiving the maximum number of treatment cycles (based on a 28-day cycle) at each month following index (73.8% vs 71.1%, 46.5% vs 48.7%, 28.6% vs 24.8%, for 2, 4, 6 months, respectively; Figure). However, a trend towards improved persistence with DEC-C versus IV/SC HMAs was observed in patients receiving treatment beyond 6 months (25.0% vs 17.0%, 18.5% vs 9.0%, 11.4% vs 7.6%, for 8, 10, 12 months, respectively). Mean time to discontinuation of treatment was also numerically higher for DEC-C compared with the IV/SC HMA group (87.7 vs 82.0 days); however, differences were not statistically significant. Conclusions: This study, which is to our knowledge the largest real-world report of oral DEC-C use to date, reveals similar but high levels of disease burden and comorbidities among patients with MDS receiving oral DEC-C and parenteral HMA therapy. Trends in treatment patterns suggest comparable persistence with oral DEC-C and IV/SC HMAs at early stages of therapy and improved persistence with oral DEC-C beyond 6 months. These data support the consideration of oral DEC-C as an alternative to chronic parenteral HMA therapy, with the potential for oral DEC-C to reduce the treatment burden associated with administration of IV/SC HMAs.

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it.

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it.

ODP496 Methimazole Induced Agranulocytosis Despite Minimal Intermittent Therapy

Abstract Introduction Anti-thyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of Graves Disease. Agranulocytosis is a rare but lethal adverse effect of anti-thyroid medications. Here we discuss a case that highlights the importance of monitoring not only in the early stages of therapy, but also low dosing of therapy, intermittent therapy and even missing doses/discontinuation of therapy. Case History A 65 year-old male with past medical history of end-stage renal disease on peritoneal dialysis who presented to the hospital with syncope, ventricular tachycardia, tremulousness, weight loss of 22 pounds over 2 weeks was subsequently diagnosed with pericardial effusion with tamponade as well as hyperthyroidism. Suppressed TSH of &amp;lt; 0. 005 µIU/mL, Free T4 = 4.5 ng/dL, FT3 8.4 pg/ml, Negative TSI and TPO antibodies. He was started on methimazole 30 mg daily which he received 2 doses prior to discharge as well as beta-blocker therapy. He was re-admitted 1 week later for hypotension, nausea, vomiting and reportedly not taking any medications due to the vomiting right after last discharge supported by his hyperthyroidism being unchanged with a TSH of &amp;lt;0. 005 µIU/mL, free T4 4.21, Free T3 5.8 pg/ml. He was restarted on methimazole 3 days into admission. He received 4 days total of 30 mg daily and was discharged on methimazole 20 mg bid. He was re-admitted 8 days later, during which time again he had nausea and vomiting resulting in not taking methimazole for 1 week prior to admission, maximally 1 day of therapy. At this 3rd admission he was found to have evidence of agranulocytosis with a WBC count of 0.97×10^9 and absolute granulocyte count of 0. 06×10^9. Methimazole was held, he was started on propranolol 60 q6 and cholestyramine 4g bid. Hematology Oncology consultation indicated there would be little benefit from granulocyte colony stimulating factor therapy in medication induced agranulocytosis. He was monitored inpatient for recovery of he neutrophil count. He began to improve after 3 days of monitoring and was discharged. Repeat blood counts 3 months later showed full normalization. Further work-up revealed the etiology of his hyperthyroidism as likely a sub-acute/viral thyroiditis with thyroid I-123 uptake scan at 0.8% at 4, 6, and 24 hours. His hyperthyroidism also resolved over a total of 3 months and his beta-blocker and cholestyramine were discontinued. Discussion This case demonstrates that agranulocytosis is not a dose dependent side effect and can occur with as little as 7 days of therapy that are not even sequentially given. It also may support what very few case reports have demonstrated that even discontinuation of therapy may incite agranulocytosis as a side effect. It helps prescribers inform frequency of surveillance and selection of therapy in hyperthyroidism management. Presentation: No date and time listed

Efficacy of an esophageal mucosal protectant in the treatment of patients with gastroesophageal reflux disease: a systematic review

Gastroesophageal reflux disease (GERD) is one of the most widespread gastrointestinal pathologies and the most common reason for seeking medical care at the level of a primary link of public health services in many countries around the world. The classic clinical presentations of GERD are heartburn, belching, and regurgitation (spitting up), but the overall spectrum of GERD symptoms is broader and more heterogeneous in scope, including extraesophageal symptoms. Clinical and/or endoscopic refractoriness of some patients to the standard proton pump inhibitors (PPIs) therapy remains a global challenge in the management of patients with GERD at the current stage of clinical medicine development. A medicinal product of a fundamentally new class was developed to optimize the treatment of patients with GERD – an esophageal mucosal protectant, which consists of a fixed combination of hyaluronic acid and chondroitin sulfate dissolved in a bioadhesive carrier (polymerase 407). This review is primarily aimed at systematizing data on the efficacy of the esophageal mucosal protectant in the treatment of patients with GERD. The systematic review that summarized the results of 10 studies involving 1090 patients with GERD showed that adding this esophageal mucosal protectant to the PPI therapy increased the efficacy of GERD therapy, as well as improved the frequency of symptomatic, endoscopic and morphological response to the treatment. Such combination therapy contributes to the optimization of the treatment of patients with various disease phenotypes, regress of both esophageal and extraesophageal symptoms, and potentiation of repair of the esophageal mucosa. To increase the efficacy of treatment and improve the prognosis of the disease, this approach should be implemented at the early stages of therapy in real clinical practice.

Quantitative CT evaluation after two cycles of induction chemotherapy to predict prognosis of patients with locally advanced oesophageal squamous cell carcinoma before undergoing definitive chemoradiotherapy/radiotherapy

ObjectiveTo investigate the performance of quantitative CT analysis in predicting the prognosis of patients with locally advanced oesophageal squamous cell carcinoma (ESCC) after two cycles of induction chemotherapy before definitive chemoradiotherapy/radiotherapy.MethodsA total of 110 patients with locally advanced ESCC were retrospectively analysed. Baseline chest CT and CT after two cycles of induction chemotherapy were analysed. A multivariate Cox proportional-hazard regression model was used to identify independent prognostic markers for survival analysis. Then, a CT scoring system was established. Time-dependent receiver operating characteristic (ROC) curve analysis and the Kaplan-Meier method were employed for analysing the prognostic value of the CT scoring system.ResultsBody mass index, treatment strategy, change ratios of thickness (ΔTHmax), CT value of the primary tumour (ΔCTVaxial) and the short diameter (ΔSD-LN), and the presence of an enlarged small lymph node (ESLN) after two cycles of chemotherapy were noted as independent factors for predicting overall survival (OS). The specificity of the presence of ESLN for death after 12 months was up to 100%. Areas under the curve value of the CT scoring system for predicting OS and progression-free survival (PFS) were higher than that of the RECIST (p < 0.05). Responders had significantly longer OS and PFS than non-responders.ConclusionQuantitative CT analysis after two cycles of induction chemotherapy could predict the outcome of locally advanced ESCC patients treated with definitive chemoradiotherapy/radiotherapy. The CT scoring system could contribute to the development of an appropriate strategy for patients with locally advanced ESCC.Key Points• Quantitative CT evaluation after two cycles of induction chemotherapy can predict the long-term outcome of locally advanced oesophageal cancer treated with definitive chemoradiotherapy/radiotherapy.• A CT scoring system provides valuable imaging support for indicating the prognosis at the early stage of therapy.• Quantitative CT evaluation can assist clinicians in personalising treatment plans.

Abstract #1183007: A Case of Methimazole Induced Agranulocytosis Despite Minimal Interrupted Therapy

Anti-thyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of Graves Disease. Agranulocytosis is a rare but lethal adverse effect of anti-thyroid medications which are a common staple in the management of hyperthyroidism. We present a case that highlights the importance of monitoring not only in the early stages of therapy, but also in the setting of low dosing, intermittent administration, and even discontinuation of therapy.

Early biomarkers of nephrotoxicity associated with the use of anti-VEGF drugs.

Anti-angiogenic anticancer drugs that block vascular endothelial growth factor (VEGF) can cause kidney damage. An early assessment of the risk of nephrotoxicity would allow the development of optimal treatment approaches and allow for relatively safer therapeutic regimens. The aim of this study was to assess the utility of neutrophilic gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), hypoxia inducible factor-1α (HIF-1α) and nephrin levels in urine as early biomarkers for the nephrotoxicity of anti-VEGF drugs. The study included 50 patients who received anti-VEGF drugs (aflibercept, bevacizumab or ramucirumab) for 8 weeks. The levels of KIM-1, NGAL, HIF-1α and nephrin in urine samples were determined by ELISA before treatment and after 1, 2, 4 and 8 weeks of treatment. To assess risk factors for nephrotoxicity, a logistic regression analysis was performed with the inclusion of the primary clinical and laboratory parameters. The primary outcome measure was a decrease in glomerular filtration rate (GFR) to <60 ml/min/1.73 m2 at 8 weeks, and nephrotoxicity resulting in discontinuation within 9 months. The primary outcome goal was achieved in 21 (42%) patients treated with anti-VEGF drugs. Increased NGAL, KIM-1, HIF-1α and nephrin levels in urine at 1 week of treatment predicted the development of nephrotoxicity. High sensitivity and specificity of these urinary biomarkers were established by ROC analysis: KIM-1 [area under the curve (AUC) 0.69], NGAL (AUC 0.7), HIF-1α (AUC 0.7) and nephrin (AUC 0.7). The unfavorable predictors of nephrotoxicity were an initial decrease in estimated GFR, a history of arterial hypertension, and an increase in urinary concentration KIM-1 OR of 1.1 [CI 95% 1.02-1.183], and HIF-1α OR of 5.6 [CI 95% 3.601-8.949] (P<0,05) at 1 and 2 weeks of treatment. Urinary NGAL, KIM-1, HIF-1α and nephrin are early biomarkers of nephrotoxicity following treatment with anti-VEGF anticancer drugs. The independent risk factors for nephrotoxicity are the initial decrease in GFR, arterial hypertension, and an increase in the concentration of KIM-1 and HIF-1α in the urine in the early stages of therapy.

Полікомпонентні колоїдно-гіперосмолярні розчини як ефективний компонент інфузійної терапії у хворих на гострий панкреатит

Стаття присвячена одному з найбільш тяжких та прогностично несприятливих гострих захворювань органів черевної порожнини — гострому панкреатиту. Наведені дані дослідження клінічної ефективності та ролі перфузійних розчинів у комплексному хірургічному лікуванні хворих із гострим панкреатитом на ранньому етапі лікування. Отримані результати дозволили зробити висновок, що включення перфузійних розчинів гідроксіетилкрохмалю у схему корекції гіповолемічних порушень сприяє стабілізації стану пацієнтів, чинить мікроциркулярний ефект та забезпечує раннє відновлення перистальтики.

The effect of active diuretic therapy on the sodium balance in patients with acute decompensation of chronic heart failure

Background. Active dehydration of patients with acute decompensation of chronic heart failure (АDCHF) was often accompanied by the development of hyponatremia. This increased the time of hospitalization and worsened the prognosis. The complication was associated with the side effects of furosemide.&#x0D; Aim. To compare the effect of dehydration and the state of sodium balance after using different methods of parenteral administration of furosemide at an early stage of treatment of АDCHF.&#x0D; Materials and methods. Patients with АDCHF (n=125) were divided into two groups. Group 1 received furosemide as bolus injections, group 2 as an extended intravenous infusion. The process of dehydration was controlled by the amount of urine and body weight loss per day. The effect was considered satisfactory if the body weight decreased by 1.02.0 kg per day. The plasma sodium level was studied on 1, 5, 10 days.&#x0D; Results. In group 2, the satisfactory effect of dehydration was observed 1.7 times more often than in group 1 (p0.05). In group 2 patients on the 5th day of therapy, the number of cases of hyponatremia was 2.3 times less (p0.05). Hyponatremia developed little in patients with a satisfactory effect of dehydration. On the 10th day, the number of cases of hyponatremia in the groups did not significantly differ.&#x0D; Conclusion. Prolonged intravenous infusion of furosemide allowed more control of the dehydration process and the plasma sodium level at an early stage of therapy in patients with АDCHF.

ЭФФЕКТИВНОСТЬ И БЕЗОПАСНОСТЬ СОЧЕТАННОГО ПРИМЕНЕНИЯ ПЕПТИДНОГО КОМПЛЕКСА И ДИАЦЕРЕИНА ПРИ ОСТЕОАРТРИТЕ КОЛЕННОГО СУСТАВА

As part of a prospective study, it was evaluated the efficacy and safety of the combined use of drugs from the group of symptomatic slow acting agents (SYSADOA): Diacerein and glycosaminoglycan peptide complex (GPC) in patients with knee osteoarthritis. The dynamics of pain according to Visual Analoguе Scale (VAS), need for non-steroidal anti-inflammatory drugs, the WOMAC index, EQ-5D score, and OMERACT-OARSI criterion, the presence of adverse events were analyzed, and the effect of Diacerein on the components of the metabolic syndrome was assessed. It was shown that the concomitant use of GPC and Diacerein demonstrated high efficiency and equivalent safety in comparison with the isolated use of GPC: a decrease in the pain intensity in the early stages of therapy, a decrease in the need for NSAIDs, a tendency to improve lipid and purine metabolism.

Analyzing the Therapeutic Efficacy of Bis-Choline-Tetrathiomolybdate in the Atp7b-/- Copper Overload Mouse Model.

Bis-choline-tetrathiomolybdate, introduced as WTX101 (now known as ALXN1840), is a first-in-class copper-protein-binding agent for oral therapy of Wilson’s disease. In contrast to other decoppering agents such as trientine or D-penicillamine it acts by forming a tripartite complex with copper and albumin, thereby detoxifying excess liver and blood copper through biliary excretion. Preclinical animal experimentation with this drug was typically done with the alternative ammonium salt of tetrathiomolybdate, which is expected to have identical properties in terms of copper binding. Here, we comparatively analyzed the therapeutic efficacy of ALXN1840, D-penicillamine and trientine in lowering hepatic copper content in Atp7b−/− mouse. Liver specimens were subjected to laser ablation inductively conductively plasma mass spectrometry and electron microscopic analysis. We found that ALXN1840 caused a massive increase of hepatic copper and molybdenum during early stages of therapy. Prolonged treatment with ALXN1840 reduced hepatic copper to an extent that was similar to that observed after administration of D-penicillamine and trientine. Electron microscopic analysis showed a significant increase of lysosomal electron-dense particles in the liver confirming the proposed excretory pathway of ALXN1840. Ultrastructural analysis of mice treated with dosages comparable to the bis-choline-tetrathiomolybdate dosage used in an ongoing phase III trial in Wilson’s disease patients, as well as D-penicillamine and trientine, did not show relevant mitochondrial damage. In contrast, a high dose of ALXN1840 applied for four weeks triggered dramatic structural changes in mitochondria, which were notably characterized by the formation of holes with variable sizes. Although these experimental results may not be applicable to patients with Wilson’s disease, the data suggests that ALXN1840 should be administered at low concentrations to prevent mitochondrial dysfunction and overload of hepatic excretory pathways.

Bispecific CAR-T Cells Targeting Both BCMA and CD24: A Potentially Treatment Approach for Multiple Myeloma

Introduction: Anti-myeloma BCMA-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising new treatment strategy, with high response rates observed in the early stages of therapy. However, the responses are not durable. One known mechanism of relapse has been traced to the loss of BCMA expression following long-term CAR-T therapy. Another potential reason is that while BCMA CAR-T cells eliminate the bulk of BCMA-positive MM cells, a small subset of BCMA-negative, very drug-resistant MM cells, such as tumor-initiating cells (TICs) survive and seed relapses. There is a strong correlation between the presence of MM TICs with minimal residual disease, acquired drug resistance and relapse. This suggests that TIC-targeted therapies could improve outcomes. We have previously demonstrated that MM cells expressing CD24 also exhibit features of TICs, e.g. self-renewal, increased expression of embryonic stem cell genes and drug resistance. We have generated bispecific CAR-T cells which recognize both BCMA and CD24 antigens and have tested their therapeutic efficacy in MM cells in vitro and in vivo models.Methods: We constructed a bispecific BCMA-CD24 CAR vector, with 2 complete CAR units: BCMA CAR and CD24 CAR. P2A was inserted between these two CARs. The BCMA CAR contains a safety switch in the hinge region, and a CD28 co-activation domain with CD3ζ. The CD24 CAR contained a 4-1BB co-activation domain with CD3ζ. To decrease the risk of severe immunological side effects, we integrated RQR8, an immunological safety switch with epitopes for CD34 and CD20 as a suicide molecule into the hinge region. Lentivirus particles were used to transduce primary human T cells. CAR-T cells were detected on day 7 by flow cytometry using antibodies to CD34. We performed co-culture killing assays, detected the T cell activation marker CD69 and measured the cytokines in the supernatant. We determined whether BCMA-CD24 CAR-T cells targeted the TIC population by flow cytometry and microscopy. The NOD. Cg-Prkdc scidIl2rg tm1Wjl/SzJ (NSG) xenograft mouse model was used for in vivo studies. 8-week-old NSG mice were administered 2 × 10 6 MM cells by intravenous injection. On day 7 after MM cells injection, 1 × 10 6 CAR-T cells were administered. Mice were weighed and monitored for signs of distress every two days. Bioluminescence images were acquired 10 min after D-luciferin injection. Myeloma progression was monitored every 7 days until the mice develop hind limb paralysis or the bioluminescence signal (ROI) is more than 2 × 10 10.Results: CAR-T cells were detected by flow cytometry using the RQR8-specific CD34 antibody. The BCMA-CD24 CAR was found to be expressed on roughly 13% of T-cells. To determine the selective lysis by the CAR-T cells, we performed co-culture killing assays in which MM cell lines over-expressing CD24 (ARP-1 CD24OE or OCI CD24OE cells) were incubated with CAR-T cells. When the CAR-T: MM ratio was 5:1, the lysis percentage of target cells was 99% (ARP-1 CD24OE) and 89% (OCI CD24OE). CAR-T cell activation was determined by increased CD69 expression and IL-2 production. As expected, exposure to CD24 + MM cells resulted in strong activation of CAR-T cells, and CAR-T cells did target and kill the TIC population. Bioluminescence imaging showed CAR-T mediated antitumor activity, yielding near-complete tumor clearance. Additionally, mice treated with CAR-T cells exhibited increased survival compared with mice in the control groups.Conclusion and Significance: This study developed a BCMA-CD24 CAR-T, a novel MM immunotherapy. We have demonstrated strong cytotoxic activity and selectivity for MM cells in vitro and in vivo. Future studies will be aimed at determining if BCMA-CD24 CAR-T can target TIC-mediated relapses. DisclosuresNo relevant conflicts of interest to declare.

Three-Dimensional H-Scan Ultrasound Imaging of Early Breast Cancer Response to Neoadjuvant Therapy in a Murine Model.

Three-dimensional (3D) H-scan is a new ultrasound (US) technique that images the relative size of acoustic scatterers. The goal of this research was to evaluate use of 3D H-scan US imaging for monitoring early breast cancer response to neoadjuvant therapy using a preclinical murine model of breast cancer. Preclinical studies were conducted using luciferase-positive breast cancer-bearing mice (n = 40). Anesthetized animals underwent US imaging at baseline before administration with an apoptosis-inducing drug or a saline control. Image data were acquired using a US scanner equipped with a volumetric transducer following either a shorter- or longer-term protocol. The later included bioluminescent imaging to quantify tumor cell viability. At termination, tumors were excised for ex vivo analysis. In vivo results showed that 3D H-scan US imaging is considerably more sensitive to tumor changes after apoptosis-inducing drug therapy as compared with traditional B-scan US. Although there was no difference at baseline (P > 0.99), H-scan US results from treated tumors exhibited progressive decreases in image intensity (up to 62.2% by day 3) that had a significant linear correlation with cancer cell nuclear size (R2 > 0.51, P < 0.001). Results were validated by histological data and a secondary longitudinal study with survival as the primary end point. Experimental results demonstrate that noninvasive 3D H-scan US imaging can detect an early breast tumor response to apoptosis-inducing drug therapy. Local in vivo H-scan US image intensity correlated with cancer cell nuclear size, which is one of the first observable changes of a cancer cell undergoing apoptosis and confirmed using histological techniques. Early imaging results seem to provide prognostic insight on longer-term tumor response. Overall, 3D H-scan US imaging is a promising technique that visualizes the entire tumor and detects breast cancer response at an early stage of therapy.

Application of Diffusion Weighted Imaging in Prostate Cancer Bone Metastasis: Detection and Therapy Evaluation.

Bone metastasis is one of the most common complications of Prostate Cancer (PCa). The detection of distal bone metastasis at the time of initial PCa diagnosis is valuable for the determination of therapeutic methods and for the prognosis of PCa. Many current therapeutic methods target PCa bone metastasis, but no uniform evaluation standard for therapeutic efficacy has been established; in addition, traditional therapeutic evaluation standards that rely on changes in the measured tumor volume are quite controversial. In clinical practice, the volumes of some tumors often change nonsignificantly at the early stage of therapy (especially targeted therapy), while the volumes of other tumors, such as metastatic bone lesions, are difficult to measure. Diffusion-Weighted Imaging (DWI) not only reflects the diffusion characteristics of tissues but can also allow the analysis of microstructural and functional changes in tissues. Therefore, DWI is suitable for evaluations of early responses to tumor therapy. This study mainly reviews the principle of DWI and its progress in the detection and therapy evaluation of PCa bone metastasis. PubMed was searched to identify eligible articles up to December 26, 2020. The keywords of the analysis included DWI, PCa, bone metastasis, therapeutic response, targeted therapy, Bone Scintigraphy (BS), Positron Emission Tomography/Computed Tomography (PET/CT) and metastatic Castration-Resistant Prostate Cancer (mCRPC). This review based on collected articles achieved an imaging biomarker for detection and therapy evaluation of PCa bone metastasis. DWI is a promising imaging method for the detection and therapeutic evaluation of PCa bone metastases.

Encephalopathy caused by disulfiram

IntroductionDisulfiram is an alcohol detox drug that has been approved by the FDA for over 50 years. Among the various side effects that can cause there is encephalopathy. Its incidence is currently unknown, according to some authors it is estimated between 1 and 20%.ObjectivesIn this article we report the case of a 48-year-old woman diagnosed with borderline personality disorder and alcohol use disorder, presenting with encephalopathy.MethodsWe discuss about our diagnostic and therapeutic approach.ResultsFortunately, the rapid identification of this rare condition led to a favorable outcome in our patient.ConclusionsEarly detection of any acute change in mental state, especially in early stage of therapy, is important. Cessation of disulfiram is recommended in case of suspicion about disulfiram encephalopathy. This case underscores the importance of awareness of this serious complication during disulfiram treatment. If suspected early, appropriate diagnosis and treatment can prevent rapid progression.DisclosureNo significant relationships.

Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS.Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response.Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI).Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

Abstract PS3-28: Three-dimensional H-scan ultrasound imaging for acute detection of breast cancer response to neoadjuvant treatment - Initial results using a preclinical animal model

Abstract Introduction: The use of noninvasive ultrasound (US) for tumor tissue characterization is an exciting prospect for anticancer treatment response monitoring. To that end, our group has developed a new technology termed H-scan US imaging, which links differences in the raw backscattered US signals to various-sized tissue structures. The purpose of this research project was to develop a 3-dimensional (3D) H-scan US imaging system and method for tissue characterization in volume space and evaluate using a preclinical animal model of breast cancer. Methodology: Preliminary studies were conducted using female nude athymic mice (N = 20, Charles River Laboratories) implanted in the mammary fat pad with 1 million breast cancer cells (MDA-MB-231, ATCC). Once tumors reached about 1 cm in size, animals were sorted into four groups so that mean tumor size in each was comparable (N = 5 per group). Animals were then US imaged at baseline and before receiving intraperitoneal injections, namely: (1) 0.3 mg sterile saline (control), (2) 0.2 mg of agnostic TRA-8 monoclonal antibody to human death receptor 5 (DR5) + 0.1 mg sterile saline, (3) 0.1 mg paclitaxel + 0.2 mg sterile saline, and (4) 0.1 mg TRA-8 + 0.2 mg paclitaxel. Image data was acquired using a programmable US scanner (Vantage 256, Verasonics Inc) equipped with a volumetric imaging transducer (4DL7, Vermon) at baseline and again every 24 hours for 3 days. To generate the H-scan US images, a set of Gaussian-weighted Hermite filters were convolved with the radiofrequency (RF) data to measure the relative strength of the received signals. The signal envelope for each of the filtered signal then was calculated using a Hilbert transformation. Finally, the lower frequency backscattered signals were assigned to a red (R) channel and the higher frequency components to a blue (B) channel. The unfiltered original RF signal was assigned to the green (G) channel to complete the RGB colormap and 3D H-scan US image display. After US imaging on day 3, animals were humanely euthanized and tumors excised for histological processing using the TUNEL HRP-DAB assay and immunofluorescent staining for activated caspase-3, PARP1, Ki-67, and DAPI. Results: The in vivo results show that 3D H-scan US imaging is considerably more sensitive to tumor changes after neoadjuvant treatment as compared to traditional B-scan US. While there was no difference at baseline (p = 0.52), repeat H-scan US results from treated tumors exhibited progressive increases in image intensity (164.9 ± 23.4%, 180.29 ± 11.6%, and 229.2 ± 14.6% for groups 2, 3, and 4 at day 3, respectively; p &amp;lt; 0.05) due to cancer cell nuclear condensation and apoptotic activity. Moreover, 3D H-scan US exhibited less variance than planar measurements due to increased sample size and statistical averaging. Histological findings also confirmed increased apoptosis and decreased proliferation that matched H-scan US data trends. Conclusions: 3D H-scan US imaging is a promising technique that allows visualization of the heterogenous tissue microenvironment and improves the evaluation of treatment at an early stage of therapy as validated by histologic findings. Citation Format: Haowei Tai, Shreya Reddy, Jane Song, Mawia Khairalseed, Kenneeth Hoyt. Three-dimensional H-scan ultrasound imaging for acute detection of breast cancer response to neoadjuvant treatment - Initial results using a preclinical animal model [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-28.

Neoadjuvant immune checkpoint inhibitors in cancer, current state of the art.

Immunotherapy has been a revolution in cancer management in the metastatic setting. This has led to a prompt evaluation of such therapies in earlier stages. This article discusses the still limited amount of data finding the rationale to assess such therapy in this setting and reviews preclinical and clinical data available. Overall, neoadjuvant immunotherapy is a promising approach for the treatment of cancers and the rationale supporting its use is strong. Neoadjuvant immunotherapy resulted, in the majority of clinical trials, in improved pathologic complete response rates with a favorable toxicity profile and no delay in surgery. Various regimens were effective: inhibitory immune check-point blockers (IICPB) alone, combination of PD-1 and CTLA-4 inhibitors, combination of chemotherapy (CT) and IICPB, phased CT and IICPB (either IICPB before CT or IICPB after CT). Yet the question whether neoadjuvant immunotherapy will benefit to patients in terms of disease-free and, ultimately, overall survival remains unknown.