Withdrawal Criteria Research Articles

Prospect of emerging treatments for HBV functional cure.

Functional cure, defined as sustained hepatitis B surface antigen (HBsAg) seroclearance with unquantifiable hepatitis B virus (HBV) DNA at 24 weeks off treatment, is a favorable treatment endpoint in chronic hepatitis B (CHB). Nonetheless, functional cure is rarely attained with the current treatment modalities of nucleos(t)ide analogues (NUCs) and pegylated interferon alpha (Peg-IFNα). Multiple novel virus-targeting agents and immunomodulators are under development for HBV with functional cure as the treatment goal. Among virus-targeting agents, antisense oligonucleotides (ASOs) and small-interfering RNA (siRNAs) are the most advanced in the developmental pipeline, and can induce potent and sustainable HBsAg suppression. The other virus-targeting agents have varying effects on HBsAg and HBV DNA, depending on the drug mechanism. In contrast, immunomodulators have modest effects on HBsAg and have limited roles in monotherapy. Multiple combination regimens incorporating RNA interference agents with immunomodulators have been studied through many ongoing clinical trials. These combination strategies demonstrate synergistic effects in inducing functional cure, and will likely be the future direction of development. Despite the promising results, research is warranted to optimize treatment protocols and to establish criteria for NUC withdrawal after novel therapies. Functional cure is now an attainable target in CHB, and the emerging novel therapeutics will revolutionize CHB management.

Heliotherapy for neonates with severe-to-hazardous hyperbilirubinemia: a randomized controlled, non-inferiority trial

Filtered-sunlight phototherapy (FSPT) that blocks ultraviolet light and reduces infrared radiation is safe and non-inferior to intensive electric phototherapy (IEPT) for treating mild-to-severe neonatal hyperbilirubinemia. In this randomized non-inferiority trial, the safety, efficacy, exchange transfusion (ET), and mortality rates of FSPT versus IEPT among Nigerian neonates with severe-to-hazardous hyperbilirubinemia were investigated. Safety was defined as the absence of hyperthermia, hypothermia, dehydration, or sunburn; efficacy by the proportion of assessable treatment days during which total serum or plasma bilirubin (TSB) increased by < 0.2 mg/dL/hr for newborns aged ≤ 72 h-old or decreased for newborns > 72 h-old. A treatment day was deemed assessable if a neonate received phototherapy for ≥ 4 h, and non-inferiority was inferred for differences within a 10% margin. We enrolled 192 newborns (admission TSB ≤ 62 mg/dL), assigned to FSPT (n = 98) or IEPT (n = 94). FSPT was effective on 94.2% of the assessable treatment days compared with 97.1% for IEPT. The mean difference in efficacy between FSPT and IEPT was -2.9%, 95% CI: -7.6, 1.9). 2.6% of newborns who received FSPT developed controlled hyperthermia, and no baby met the criteria for withdrawal for safety reasons. Overall, 50.6% (39/77) of newborns who received FSPT and 53.7% (51/95) of newborns who received IEPT had ET (p = 0.89) and 7 in each group (9.1% vs 7.4%; p = 0.86) died. In conclusion, FSPT is safe and non-inferior to IEPT for treating neonates with severe-to-hazardous hyperbilirubinemia, it is not associated with significantly higher rates of ET and mortality and should be considered where practicable when IEPT cannot be assured. Clinical Trials.gov Number: NCT02612727 (24/11/2015).

Food addiction in patients on weight loss treatment.

BackgroundFood addiction (FA) is defined as hedonic eating behavior involving the consumption of highly palatable foods (i.e., ultra processed foods in quantities beyond homeostatic energy requirements). FA is present in a subset of patients with overweight or obesity and could contribute to the response to weight loss treatments.AimDetermine FA in individuals that fulfil the criteria of FA as measured by the YFAS 2.0, and its association with anthropometric and body composition variables in a clinical sample of patients undergoing weight loss treatment. Also, to determine the most prevalent FA criteria.MethodsAn observational, analytical, and cross-sectional study was conducted. Sampling was non-probabilistic, convenience based. A total of 158 participants were recruited from two clinical centers (private and public) focused on managing non-communicable chronic diseases. The Chilean version of YFAS 2.0 was administrated through the online REDCap platform. Anthropometric measurements were measured, and body mass index (BMI) was calculated.ResultsThe mean age was 47.8 (SD 14.9) and BMI 28.7 (SD 5.3) kg/m2. There were 12.7% patients who screened positive on the YFAS 2.0 Chilean version (3.2% for mild, 2.5% for moderate and 7.0% for severe), the mean symptom count was 2.2 (SD 2.6), with withdrawal being the most prevalent criterion (33.5%). FA patients had significantly higher body weight compared to non-FA subjects (p = 0.045). We observed a slight and significant correlation between FA symptom count and body weight (p = 0.020), waist circumference (p = 0.005), and BMI (p = 0.023).ConclusionThis is the first study in Chile that showed that FA was present in patients undergoing weight loss treatment and was associated with anthropometric measurements. In addition, it showed that withdrawal was the most prevalent criterion. Future studies should investigate whether the presence of FA and the withdrawal criterion could contribute to suboptimal clinical response to weight loss treatment.

Decision-making concordance in thoracic drain management: is necessary previous experience?

IntroductionProper management of thoracic drainages is essential in the recovery of patients after lung resection. This study evaluates the concordance in decision-making for drain removal depending on the type of drainage system used and the previous experience of the personnel. Material and methodsProspective, comparative, and stratified randomization study on interobserver variability between senior specialist doctors and inexperienced healthcare personnel in the removal of thoracic drains in patients undergoing lung resection connected to conventional systems (CS) or digital systems (DS) with continuous recording. The withdrawal criteria were established before the study, and decisions were recorded during three postoperative days. Results75 patients were included, 38 CS and 37 DS, with no statistically significant differences in sex distribution, age, intervention performed, presence of pleuropulmonary adhesions, drain time, or post-extraction complications between the groups. The overall concordance in drain removal decisions was moderate (kappa = 0.452), with notable variations in concordance depending on the drainage system used: CS (kappa = 0.188) with an overall agreement rate of 61.7% compared to DS (kappa = 0.716) with an overall agreement rate of 86.4%. Digital systems showed substantial concordance regardless of the operator's experience, with kappa values indicating high concordance on all postoperative days. ConclusionsThe use of digital systems for managing thoracic drains significantly improves concordance in clinical decision-making regardless of the experience level. These findings suggest that adopting digital systems not only optimizes patient safety but also reduces the dependence on highly specialized healthcare professionals.

Clinical Outcomes of Elective Early Discontinuation of Immunotherapy Based on Objective Response in Microsatellite Instability-High Metastatic Colorectal Cancer

BackgroundPatients with microsatellite-high (MSI-H) metastatic colorectal cancers (CRC) may experience long-lasting benefit from immune checkpoint inhibitors (ICI) upon stopping therapy. However, optimal timing and patient selection criteria for early treatment withdrawal remain undefined. In this single-center retrospective study, we characterized the clinical response and associated survival outcomes of patients who received elective early versus late treatment discontinuation. MethodsWe retrospectively analyzed patients with MSI-H metastatic CRC treated with ICI therapy from May 2015 to April 2024. Early ICI discontinuation was defined as treatment withdrawal before 2 years, and late ICI discontinuation as after 2 years. Response was assessed using Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Efficacy outcomes between early and late ICI discontinuation groups were compared using a log-rank test. ResultsOf 36 patients with MSI-H metastatic CRC, 12 underwent elective early ICI discontinuation and 9 experienced late ICI discontinuation. After a median follow-up of 32 months post-treatment, 91.7% (11/12) in the early discontinuation group remain off therapy without progression. PFS and OS outcomes between the early and late discontinuation groups were similarly favorable (P = .88 and P = .85, respectively), despite a 12-month difference in median duration of ICI therapy (13.3 and 25.6 months, respectively). The most common reason for elective early treatment discontinuation was clinical remission (n = 10), defined as a complete response, or a partial response with negative PET and/or ctDNA testing. ConclusionsEarly ICI discontinuation guided by response criteria resulted in low rates of recurrence. Survival outcomes between early and late ICI discontinuation groups were comparable, suggesting that treatment duration can be individualized based on clinical response without compromising favorable long-term prognosis.

Analisis Faktor-Faktor yang Mempengaruhi Kinerja Keuangan Sektor Perbankan di Bursa Efek Indonesia

The purpose of this study is to determine the partial to simultaneous influence of Capital, Asset, Management, Earnings, Liquidity variables as well as sensitivity to market risk on Return on Assets (ROA). This research was conducted on Banking Sector companies listed on the Indonesia Stock Exchange. The research approach uses quantitative research. The total population in this study is 46 banking companies that have entered and listed stocks during the observation period of 2018-2022, which is 5 years. The company met the sample withdrawal criteria, namely the entire population of 40 companies, so the sample in this study was 40 x 5 = 200 financial statements. The analysis tool in this study is Eviews version 13. The data analysis technique uses panel data regression analysis. The results of his research show that partially CAR has a significant positive effect on ROA. NPLs have no positive and insignificant effect on ROA. LDR has a significant positive effect on ROA. BOPO has a significant positive effect on ROA. PDN had a significant positive effect on ROA and NPM had no positive and insignificant effect on ROA. Meanwhile, simultaneously the variables CAR, NPL, LDR, BOPO, PDN and NPM simultaneously had a significant positive influence on ROA. The contribution of all variables was 53.30%.

Rotation from methadone to buprenorphine using a micro-dosing regime in patients with opioid use disorder and serious mental illness: A case series.

Inducting buprenorphine from methadone has traditionally involved initial opioid withdrawal, with risk of mental state deterioration in patients with serious mental illness (SMI). Micro-dosing of buprenorphine, with small incremental doses, is a novel off-label approach to transitioning from methadone and does not require a period of methadone abstinence. Given the limited literature about buprenorphine microdosing, we aimed to evaluate the feasibility and safety of inducting buprenorphine in a series of patients on methadone with SMI. For this retrospective case series, we reviewed the records of 16 patients with SMI at a Melbourne addiction treatment centre, from January 2021 to July 2022, who transitioned via micro-dosing, from high-dose methadone (>30 mg) to buprenorphine and depot-buprenorphine. Psychiatric diagnoses, mental state, other substance withdrawal, transfer success, transition time, opioid withdrawal symptoms and overall patient experience were collected via objective and subjective reporting. Methadone to buprenorphine transfer was completed by 88% of patients. Mental health measures remained stable with the exception of mildly increased anxiety. Median transfer time was 6.5 days for inpatients, 9 days for mixed setting and 10 days for outpatients. Most patients (93%) rated their experience 'manageable' reporting mild withdrawal symptoms. One patient met study criteria for precipitated withdrawal. This retrospective case series provides evidence that the use of a micro-dosing buprenorphine induction for methadone to buprenorphine transitions, including to depot-buprenorphine, has negligible risk, is tolerated by patients with SMI and is unlikely to precipitate an exacerbation of their mental illness.

A phase 3 trial of fixed dose combinations of fianlimab (anti–LAG-3) + cemiplimab (anti–PD-1) versus relatlimab + nivolumab in patients with unresectable or metastatic melanoma.

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of &gt;6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs &gt; upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .

Network analysis of DSM-5 criteria for gambling disorder: considering sex differences in a large clinical sample.

The fifth version of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) and its revised version (DSM-5-TR) propose severity levels for gambling disorder (GD) based on the number of criteria met. However, this taxonomy has some limitations. We aimed to assess the centrality of each criterion and its relationship by conducting a network analysis while considering sex differences. We performed a network analysis with the DSM-5 criteria for GD with data from 4,203 treatment-seeking patients (3,836 men and 367 women) diagnosed with GD who sought for treatment in a general tertiary hospital which has a unit specialized in behavioral addictions. The withdrawal criterion ("Restless or irritable when attempting to cut down or stop gambling") showed the highest centrality values in both sexes. In men, the second most central criterion was the tolerance criterion ("Needs to gamble with increasing amounts of money in order to achieve the desired excitement"); while among women, the second was the chasing losses criterion ("After losing money gambling, often returns another day to get even"). The most central criteria identified are associated with compulsivity-driven behaviors of the addictive process. Taking into account the high relevance and transitive capacity of withdrawal in both men and women, as well as tolerance in men, and chasing losses in women, the recognition and understanding of these symptoms are fundamental for the accurate diagnosis and severity assessment of GD.

Comparison of short-term outcomes of D2 and D3 lymph nodes dissection for colon cancer

Background. D3 lymph node dissection remains controversial in colon cancer surgery.Aim. To compare the short-term of D2 and D3 lymph nodes dissection for colon cancer.Materials and methods. Design of the study – prospective randomize controlled study. Inclusion criteria: age over 18 years, colon adenocarcinoma cT3–4n0–2m0, patient consent to participate in the study. Exclusion criteria: distant metastases diagnosed preoperatively, cTis–T2, cT4b (pancreas, stomach, small intestine, ureter, bladder, kidney), emergent cases (limited to tumor perforation, acute bowel obstruction), history of previous chemotherapy or radiation therapy, synchronous or metachronous cancer, pregnancy or breastfeeding, refusal to participate in the study. withdrawal criteria were exploratory laparotomy/laparoscopy or other reasons for refusing resection.Results. A total of 436 patients were included in the study no differences were found in the clinical characteristics of groups D2 and D3. In the D2 lymph node dissection group the incidence of unintentional vascular injuries was in 7 (3.2 %) patients, in the D3 lymph node dissection group – in 15 (6.9 %) patients (p = 0.12). The operating time increased by 30 minutes in D3 lymph node dissection group (p p = 0.42). Hartmann’s procedure was performed in 2 (0.9 %) patients in the D2 lymph node dissection group. Complications IIIb were recorded in 5 (2.3 %) and 9 (4.1 %) patients in lymph node dissection groups D2 and D3, respectively (p = 0.42). Anastomotic leakage was not observed in the D2 lymph node dissection group; in the D3 lymph node dissection group, it was diagnosed in 3 (1.4 %) patients (p = 0.25). postoperative multiple-organ failure (Iv) or mortality (v) were not observed. grade 3 quality of the specimen was observed in 160 (73.4 %) patients in the D2 lymph node dissection group, 163 (74.8 %) in the D3 lymph node dissection group (p = 0.79). The median number of lymph node harvested was 11 more in the D3 lymph node dissection group (p &lt; 0.001). Apical lymph nodes were positive in 5 (2.3 %) patients in the D3 lymph node dissection group. There was no difference between the groups in R0 resection margin.Conclusion. D3 lymph node dissection is safe in terms of short-term outcomes in the treatment of colon cancer.

Durable Efficacy of Switching From a 3- or 4-Drug Tenofovir Alafenamide-Based Regimen to the 2-Drug Regimen Dolutegravir/Lamivudine in the TANGO Study Through Week 196.

Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO. 134 centers, 10 countries. Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196. Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term. Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.

Prevalence and management of proteinuria associated with vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitor treatment in advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer.

Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors (VEGFR-TKIs) are often used for treatment of several types of cancer; however, they are associated with an increased risk of proteinuria, sometimes leading to treatment discontinuation. We searched PubMed and Scopus to identify clinical studies examining the incidence and risk factors for proteinuria caused by VEGFR-TKIs in patients with renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The global incidence of proteinuria ranged from 6% to 34% for all grades of proteinuria, and from 1% to 10% for grade ≥3 proteinuria. The incidence of proteinuria did not differ significantly by cancer type, but in all three cancer types, there was a trend toward a higher incidence of proteinuria with lenvatinib than with other VEGFR-TKIs. In terms of risk factors, the incidence of proteinuria was significantly higher among Asians (including Japanese) compared with non-Asian populations. Other risk factors included diabetes mellitus, hypertension, and previous nephrectomy. When grade 3/4 proteinuria occurs, patients should be treated according to the criteria for dose reduction or withdrawal specified for each drug. For grade 2 proteinuria, treatment should be continued when the benefits outweigh the risks. Referral to a nephrologist should be considered for symptoms related to decreased renal function or when proteinuria has not improved after medication withdrawal. These management practices should be implemented universally, regardless of the cancer type.

Research on the Identification Criteria of Capital Withdrawal by Company Shareholders

Research on the Identification Criteria of Capital Withdrawal by Company Shareholders

New hope for esophageal stricture prevention: A prospective single-center trial on acellular dermal matrix.

Given the high incidence of esophageal cancer in China, an increasing number of patients there are undergoing endoscopic mucosal dissection (ESD). Although the 5-year survival rate after ESD can exceed 95%, esophageal stricture, the most common and serious postoperative complication, affects the long-term prognosis of patients and the quality of life. Autologous mucosal grafts have proven to be successful in preventing stricture after ESD for early esophageal cancer. To examine the viability of acellular dermal matrix (ADM) as an alternative to autologous mucosa for the prevention of stricture after ESD. This is a prospective, single-center, controlled study. Consecutive patients who underwent ESD surgery and were willing to undergo autologous mucosal transplantation were recruited between January 1 and December 31, 2017. Consecutive patients who underwent ESD surgery and were willing to undergo ADM transplantation were recruited between January 1 to December 31, 2019. A final three-year follow-up of patients who received transplants was conducted. Based on the current incidence of esophageal stricture, the sample size required for both the autologous mucosal graft group and the ADM group was calculated to be 160 cases. Due to various factors, a total of 20 patients with autologous mucosal grafts and 25 with ADM grafts were recruited. Based on the inclusion exclusion and withdrawal criteria, 9 patients ultimately received autologous mucosal grafts and completed the follow-up, while 11 patients received ADM grafts and completed the follow-up. Finally, there were 2 cases of stenosis in the autologous mucosal transplantation group with a stenosis rate of 22.22% and 2 cases of stenosis in the ADM transplantation group with a stenosis rate of 18.18%, with no significant difference noted between the groups (P = 0.94). In this prospective, single-center, controlled trial, we compared the effectiveness of autologous mucosa transplantation and ADM for the prevention of esophageal stricture. Due to certain condition limitations, we were unable to recruit sufficient subjects meeting our target requirements. However, we implemented strict inclusion, exclusion, and withdrawal criteria and successfully completed three years of follow-up, resulting in valuable clinical insights. Based on our findings, we hypothesize that ADM may be similarly effective to autologous mucosal transplantation in the prevention of esophageal stricture, offering a comparable and alternative approach. This study provides a new therapeutic idea and direction for the prevention of esophageal stricture.

Cross-Cultural Adaptation and Psychometric Evaluation of the Persian Version of Hearing Handicap Questionnaire for the Elderly

Background and Aim: Hearing handicap, as one of the common health problems among older people, affects life activities. The Hearing Handicap Questionnaire (HHQ) is one of the scales that provide criteria for social withdrawal, participation restriction, and emotional distress. The present study aims to translate the HHQ into Persian and determine its psychometric properties. Methods: After translation into Persian, the content validity of the questionnaire was determined based on the Lawashe’s method. Then, the Persian HHQ (P-HHQ) and the Persian Hearing Handicap Inventory for Elderly-Screening version (P-HHIE-S) were completed by 110 hearing-impaired seniors (49 females) over 60 years. The concurrent validity was determined by Spearman correlation test, and the discriminant validity was analyzed by Kruskal-Wallis test and independent t-test. The test-retest reliability was assessed in 47 subjects after two weeks by Spearman correlation test and paired t-test. Results: The P-HHQ had high face validity. The mean total score of P-HHQ was 1.89±1.05. It had a significant positive correlation with the score of P-HHIE-S (r=0.87) and pure tone average of the better ear (r=0.72). There was a significant difference between three groups of elderly with different degrees of hearing impairment (p&lt;0.001). Cronbach’s α values were in the range of 0.94–0.97. There was a strong correlation between test and retest scores of P-HHQ (r=0.97) which indicates a high test-retest reliability. Conclusion: The P-HHQ has acceptable validity and reliability and can be used as a suitable instrument to evaluate hearing handicap of the elderly in research studies and clinical settings. Keywords: Elderly; handicap; hearing handicap questionnaire; presbycusis; self-report

Trial in Progress: An Open Label Phase I/II, Multicenter Study Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a BCL-2 Inhibitor Combined with Azacitidine in Adults with Previously Untreated Acute Myeloid Leukemia Ineligible for Intensive Treatment

Preclinical and clinical data support combining Bcl-2 inhibitors (Bcl-2i) with hypomethylating agents (HMAs) in the treatment of acute myeloid leukemia (AML). S65487, a potent intravenous Bcl-2i, has shown promising synergistic activity when combined with azacitidine against in vitro AML models. Based on those data, we initiated a Phase I/II multicenter study of S65487 combined with azacitidine for newly diagnosed patients aged 18 years or older with de novo or secondary AML ineligible for intensive chemotherapy in 6 countries in Europe and Asia (NCT04742101). Secondary AML was defined as those related to previous leukemogenic therapies or transformed from a myelodysplastic syndrome. Patients with AML originating from myeloproliferative disorders were excluded. Ineligibility to intensive chemotherapy was defined as age of at least 75 years or the presence of significant co-morbidities. Previous use of HMA was allowed in the first six dose levels tested in the Phase I portion of the study, but was excluded afterwards, including during the Phase II part. Other eligibility criteria were standard for this patient population. Each cycle of therapy lasts for 28 days. Subcutaneous or intravenous azacitidine is administered at a dose of 75mg/m 2 in 7 consecutive administrations per cycle starting on day (D) 1 with a 2-day interval during weekends. Three schedules of S65487 are planned to be tested during the Phase I part to increase its concurrent administration with azacitidine and their synergism. Schedule 1 consists of weekly administrations (doses on D1, 8, 15, and 22). Two more intensified schedules consist of S65487 administration on D1, D3, D5, D8 (schedule 2) or D1 through D5, D8, and D9 (schedule 3) on the same days of azacitidine dosing. S65487 is administered over 30 minutes. When administered on the same day, S65487 is given first followed by azacitidine within 30 to 60 minutes. Treatment should be discontinued due to disease progression, or if other standard withdrawal criteria are met. The Phase I portion of the study follows a standard design guided by an adaptive Bayesian Logistic Regression Model with overdose control to estimate the maximum tolerated dose (MTD) based on the occurrence of dose-limiting toxicities during cycle 1. Patient accrual for the Phase I portion of this study is ongoing. The planned testing of schedule 1 is limited due to the expected low synergism with azacitidine. Once the recommended Phase II dose (RP2D) or MTD are established for schedules 2 and 3, the Phase II part will start and will be comprised of a maximum of two cohorts, each containing up to 27 patients. A Bayesian optimal design based on complete remission rate will guide the Phase II. Interim futility analyses are planned after enrollment of 10 and 20 evaluable patients. Randomization will not be used to allocate patients to one of the two cohorts planned during the Phase II portion of the study. The primary objective during the Phase I is to determine the safety, tolerability, and the RP2D or MTD of S65487 in combination with azacitidine. The primary objective of the Phase II is to assess the efficacy of this therapy. Pharmacokinetic analyses are included as secondary objectives in both parts of the study. Measurable residual disease will be assessed as a secondary objective in the Phase II part using a well validated, standard flow-cytometry panel. Pharmacodynamic analyses are conducted as exploratory objectives in both parts of the study. In particular, the disruption of the BCL2/BIM complex is followed in peripheral-blood mononuclear cells to guide the estimation of the RP2D.

A Phase 1 Cohort Dose Escalation and Expansion Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose, and Preliminary Antineoplastic Activity of IKS03 in Patients with Advanced B-Cell Non-Hodgkin Lymphomas (NHL)

Background: IKS03 is an antibody-drug conjugate (ADC) comprising an anti-CD19 antibody conjugated with novel ConjuALL technology to a highly potent proprietary DNA-crosslinking pyrrolobenzodiazepine (PBD) prodrug payload for the treatment of CD19-positive hematologic malignancies. Both the payload and the linker of IKS03 incorporate an innovative tumor-selective chemistry that takes advantage of the overexpression of beta glucuronidase in cancer cells compared to most normal tissues. Payload release and activation require cleavage of glucuronide moieties that are incorporated into the linker payload structure providing improvements in both efficacy and safety compared to traditional ADC formats. This “glucuronide trigger” is stable while in circulation with minimal to no systemic payload release from the ADC. Following binding and internalization of IKS03 into a CD19-positive cancer cell, beta glucuronidase can release the active PBD payload leading to cell death. Normal tissues without CD19 expression and/or with low levels of the beta glucuronidase enzyme have limited ADC uptake, are less able to process IKS03 and are differentially spared. In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft models at single doses of 0.1 to 1 mg/kg. IKS03 demonstrated greater activity than the clinical benchmark ADC loncastuximab tesirine. IKS03 is also highly effective in patient-derived xenograft models that contain some of the genetic alterations commonly found in relapsed/refractory NHL patients. Results from toxicology studies in cynomologus monkey suggest a manageable safety profile at single doses, well above those required for in vivo activity. Pharmacokinetics are favorable with a mean total ADC half-life of 8 days and undetectable levels of the active PBD payload in circulation confirming targeted delivery of the payload. Study Design and Methods: This Phase 1 multicenter, open label, non-randomized study of IKS03 will consist of two parts: dose-escalation (Part I) and dose-expansion (Part II) together enrolling approximately 140 adult patients with relapsed or refractory B-cell NHL after at least two prior lines of systemic therapy. Patients will receive repeat doses of study drug by IV infusion on Day 1 of each 21-day cycle, until disease progression, unacceptable toxicity, or another withdrawal criterion is met. Key exclusion criteria include: active central nervous system involvement with NHL; clinically significant cardiovascular, pulmonary or hepatic disease; or receipt of other CD19-directed therapy within 3 months. Part I dose escalation will enroll patients with confirmed CD19-positive, measurable or non-measurable advanced B-cell NHL. Eligible subtypes include DLBCL, MCL, FL, high-grade B-cell, and marginal zone lymphoma as per WHO 2016 classification. Patients with Burkitt's lymphoma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia are excluded. In Part 1, the primary objective is establishment of the recommended Phase 2 dose (RP2D) by evaluation of safety, tolerability and the maximum tolerated dose (MTD) of IKS03. Dose escalation will follow a 3+3 design. A two cycle Dose-Limiting Toxicity (DLT) assessment period will be observed, and dose-escalation decisions will be guided by a study safety committee. Dose escalation increments will be adjusted based on occurrence of protocol-specified DLTs as well as overall tolerability. Secondary objectives include characterization of immunogenicity and pharmacokinetic (PK) profile of IKS03. Exploratory objectives include preliminary antineoplastic activity per Lugano criteria (Cheson et al, JCO 2014) and evaluation of pharmacodynamic markers. Part II will further evaluate the antineoplastic activity of IKS03 at the RP2D in expansion cohorts of patients with selected NHL subtypes and with measurable disease. Sample size will be determined for each subtype using a Simon Two-Stage design. Secondary objectives include further evaluation of safety, tolerability, immunogenicity and PK profile of IKS03 as well as confirmation of the RP2D. Clinical trial information: NCT05365659.

Prevalence and correlates of DSM-5 opioid withdrawal syndrome in U.S. adults with non-medical use of prescription opioids: results from a national sample

ABSTRACTBackground: In the U.S. non-medical use of prescription opioids (NMOU) is prevalent and often accompanied by opioid withdrawal syndrome (OWS). OWS has not been studied using nationally representative data.Objectives: We examined the prevalence and clinical correlates of OWS among U.S. adults with NMOU.Methods: We used data from 36,309 U.S. adult participants in the 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions-III, 1,527 of whom reported past 12-month NMOU. Adjusted linear and logistic regression models examined associations between OWS and its clinical correlates, including psychiatric disorders, opioid use disorder (OUD; excluding the withdrawal criterion), medical conditions, and healthcare utilization among people with regular (i.e. ≥3 days/week) NMOU (n = 534).Results: Over half (50.4%) of the sample was male. Approximately 9% of people with NMOU met criteria for DSM-5 OWS, with greater prevalence of OWS (∼20%) among people with regular NMOU. Individuals with bipolar disorder, dysthymia, panic disorder, and borderline personality disorder had greater odds of OWS (aOR range = 2.71–4.63). People with OWS had lower mental health-related quality of life (β=-8.32, p < .001). Individuals with OUD also had greater odds of OWS (aOR range = 26.02–27.77), an association that increased with more severe OUD. People using substance use-related healthcare services also had greater odds of OWS (aOR range = 6.93–7.69).Conclusion: OWS was prevalent among people with OUD and some psychiatric disorders. These findings support screening for OWS in people with NMOU and suggest that providing medication- assisted treatments and behavioral interventions could help to reduce the burden of withdrawal in this patient population.

Outcomes of chest drain management using only air leak (without fluid) criteria for removal after general thoracic surgery-a drainology study.

Chest drain management is a variable aspect of postoperative care in thoracic surgery, with different opinion for air and drain volume output. We aim to study if acceptable safety was maintained using air leak criteria alone. A 9-year retrospective analysis of protocolised chest drain management using digital drain air leak cut off less than 20 mL/min for more than 6 h for drain removal in patients undergoing general thoracic surgery. We excluded patients if a chest drain was not required nor removed during admission or if patients underwent volume reduction or pneumonectomy. Withdrawal criteria were suspected bleeding or chylothorax. Postoperative films were reviewed to document post-drain removal pneumothorax, pleural effusion, and reintervention (drain re-insertion). Between 2012 and 2021, 1,187 patients had thoracic surgery under a single surgeon. Following exclusion and withdrawal criteria, 797 patients were left for analysis. The mean age [standard deviation (SD)] was 61 [16] years and 383 (48%) were male. Median [interquartile range (IQR)] duration of drain insertion was 1 [1-2] day with a median length of hospital stay of 4 [2-6] days. Post-drain removal pneumothorax was observed in 141 (17.7%), post-drain removal pleural effusion was observed in 75 (9.4%) and re-intervention (reinsertion of chest drain) required in 17 (2.1%). Our results demonstrate acceptable levels of safety using digital assessment of air leak as the sole criteria for drain removal in selected patients after general thoracic surgery.

ПРОБЛЕМА НЕВЫНАШИВАНИЯ БЕРЕМЕННОСТИ ПРИ АДЕНОМИОЗЕ: ПУТИ РЕШЕНИЯ

The purpose of this study is to substantiate the possibility of successful therapy of miscarriage with adenomyosis based on the study of a clinical case (the patient has a history of 7 unsuccessful IVF attempts). The analysis of this clinical case revealed that despite the presence of clinical signs of endometriosis, in particular, adenomyosis, such as copious, prolonged, painful menstruation with menarche, the absence of pregnancy for 12 months, provided regular sexual activity without the use of contraception by a married couple, unsuccessful IVF attempts in the anamnesis, the diagnosis of adenomyosis was made untimely. Although one of the signs of this disease may be the absence of spontaneous spontaneous pregnancy, despite regular ovulation, patency of the fallopian tubes and a normal spermogram in the partner, as was the case in this case. It is necessary to pay attention to the possibility of this pathology as a cause of infertility in infertile women. At the same time, each unsuccessful IVF attempt can also increase the likelihood of miscarriage, according to research. The adenomyosis revealed in this case apparently caused infertility . The treatment prescribed according to the current clinical recommendations, using progestogens in a continuous mode, in particular, dienogest at a dosage of 2 mg, showed a good result. It is important to take into account that the timing of drug administration and the time of its withdrawal are strictly individual, based on clinical criteria. In this case, as a criterion for drug withdrawal, the achievement of uniformity of the endometrium during ultrasound of the pelvic organs was used, which served as confirmation of the effective suppression of foci of endometriosis in the myometrium. To achieve this result, it took 15 months of hormone therapy with dienogest. The subsequent course of pregnancy was favorable and ended with the birth of a healthy full-term baby. This could also indicate the readiness of both the myometrium and the endometrium for fetal gestation and the normal course of pregnancy. This clinical case demonstrates the effectiveness of using dienogest at a dosage of 2 mg, prescribed with an individual selection of the duration of the course of therapy, in patients with adenomyosis in order to restore reproductive function.