Maintenance Phase Of Treatment Research Articles

Compartmental Exudative Dynamics in Neovascular Age-Related Macular Degeneration: Volumetric Outcomes and Impact of Volatility in a Phase III Clinical Trial

PurposeTo examine retinal feature dynamics in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (anti-VEGF) therapy and the relationship of these features with visual acuity. DesignPost hoc analysis of the phase 3, randomized, HAWK nAMD clinical trial. ParticipantsParticipants randomized to the brolucizumab 6 mg or aflibercept 2 mg arms of the trial. MethodsSpectral domain optical coherence tomography (OCT) scans collected at 4-week intervals were analyzed using an automated machine learning-enhanced segmentation and feature-extraction platform with manual verification. Quantitative volumetric measures of retinal and exudative features were exported at multiple timepoints over 48 weeks. Volatility of exudative features was calculated as the standard deviation of each feature value during the maintenance phase (week 12–48) of treatment. These features were examined for their associations with anatomic and functional outcomes. Main Outcome MeasuresLongitudinal intraretinal fluid (IRF) and subretinal fluid (SRF) volume, subretinal hyperreflective material (SHRM) volume, ellipsoid zone (EZ) integrity (EZ-retinal pigment epithelium [RPE] volume/thickness), and correlation with best corrected visual acuity (BCVA). ResultsIRF, SRF, and SHRM demonstrated significant volumetric reduction from baseline with anti-VEGF therapy (P<0.001 at each timepoint). EZ integrity measures demonstrated significant improvement from baseline (P<0.001 at each timepoint). Both EZ integrity and SHRM measures significantly correlated with BCVA at all timepoints (EZ-RPE volume: 0.38≤ r ≤0.47; EZ-RPE central subfield thickness: 0.22≤ r ≤0.41; SHRM volume: -0.33≤ r ≤-0.44). Following treatment initiation, correlations of IRF and SRF volume with BCVA were weak or nonsignificant. Eyes with lower volatility of IRF, SRF, and SHRM volumes during the maintenance phase showed greater improvements in EZ integrity (all P<0.01) and greater gains in BCVA (all P<0.01) at week 48 compared to eyes with higher volatility in those exudative parameters. ConclusionsQuantitative measures of SHRM volume and EZ integrity correlated more strongly with BCVA than retinal fluid volumes during treatment. High volatility of exudative parameters, including SRF, during the maintenance phase of treatment was associated with loss of EZ integrity and BCVA.

REAL-WORLD EFFECTIVENESS OF USTEKINUMAB IN PATIENTS WITH ULCERATIVE COLITIS IN THE UNITED STATES OF AMERICA

Abstract BACKGROUND Primary treatment goals for ulcerative colitis (UC) are to induce and maintain long-term disease remission and reduce the prevalence of symptoms such as bowel urgency and abdominal pain. Ustekinumab (UST) is a biologic approved for treating adult patients with moderate-severe UC, but real-world effectiveness data remain limited. OBJECTIVE We aimed to assess real-world effectiveness of UST in patients with UC. METHODS Data were drawn from the Adelphi Real World UC Disease Specific Programme™, a cross-sectional survey with retrospective data collection of gastroenterologists and their patients in the United States of America (USA) from December 2022–September 2023. Two samples were utilised; a sample where physicians provided data for their next six consecutive patients with UC, and an oversample where physicians provided data for their next four consulting patients with UC receiving UST. Patients receiving UST for &amp;gt;1 day at time of consultation (assumed to have received ≥1 UST dose) from either sample were included in the analysis. Data collected included clinical status, disease duration and location, symptoms and treatment profiles. Remission defined by Mayo score was reported separately for advanced therapy (AT)-naïve (UST received as first AT) and AT-experienced (UST received as second or later line of AT) patients. Descriptive statistics for each variable were reported for patients with known data. McNemar’s test was used for symptom prevalence and disease severity comparisons. RESULTS Data for 160 patients were included in this study from 50 physicians. Patients had been diagnosed with UC for median (interquartile range; IQR) of 2.2 (0.5, 4.5) years; mean (standard deviation) age was 39.7 (13.0) years and 50.0% of patients were male. UST was received as first AT for 68.1% of patients, second AT for 18.1% and third AT for 11.3%. Median (IQR) time on UST was 8.7 (4.1, 18.6) months, with 83.9% of patients receiving UST for ≥3 months. For patients in maintenance phase of treatment, 65.8% were on UST USA label dose, 17.9% were receiving an increased and 16.3% decreased dose. According to Mayo scores, 53.6% of AT-naïve and 58.3% of AT-experienced patients were in remission at consultation (Table 1). Improvement in disease severity was evidenced by a reduced proportion of patients with moderate/severe disease at consultation (34.4%) compared to prior to initiation of UST (90.9%; p&amp;lt;0.01). Similarly, there was a significantly lower prevalence of all symptoms between UST initiation and consultation, including abdominal pain (72.1% vs 30.2%), bowel urgency (55.1% vs 22.0%) and bloody diarrhea (54.4% vs 17.6%) (all p&amp;lt;0.01; Figure 1). CONCLUSION Our study showed real-world effectiveness of UST in patients with UC in the USA; most patients receiving UST achieved remission and demonstrated reduced prevalence of symptoms following UST initiation. Table 1 Physician-reported characteristics of patients receiving ustekinumab at the time of consultation. Figure 1 Physician-reported prevalence of (A) symptoms and (B) moderate/severe disease severity prior to initiation of ustekinumab and at time of consultation.

P628 Vedolizumab in Indian patients with Inflammatory Bowel Disease: Interim results from a prospective, multicentre, open-label, phase 4 study

Abstract Background Although anti-tumour necrosis factor (TNF)-α agents have revolutionised the management of ulcerative colitis (UC) and Crohn’s disease (CD), they have demonstrated a therapeutic ceiling with numerous safety concerns. Vedolizumab (VDZ) has consistently demonstrated safety and efficacy in patients with UC and CD in pivotal clinical trials, but its efficacy and safety data are very limited in the developing world where infectious diseases predominate. Methods This prospective, multicentre, open-label, single-arm, phase 4 study (Clinicaltrial.gov: NCT04804540) included patients (aged 18-65 years [yrs]) with moderate-to-severe active UC and CD who were non-responsive to available conventional therapies and/or anti-TNF agents. Patients received VDZ 300 mg through intravenous infusion for induction (Week [W]0, W2, W6) and maintenance (W14, W22, W30, W38, and W46) treatment phase. This interim analysis included data collected till the last patient completed W14 visit. Safety endpoints including incidence of adverse events (AE), serious AEs (SAE), adverse drug reactions (ADR), and adverse events with special interest (AESI), and efficacy endpoints including clinical response and clinical remission were analysed. Results Of 215 patients screened, 150 were eligible (UC, 102 [68.0%], median age: 39 yrs; CD, 48 [32.0%], median age: 31 yrs). Median VDZ treatment duration was 155 days in UC and 143 days in CD groups. Overall, 71 (47.3%) patients (UC, 49 [48.0%]; CD, 22 [45.8%]) experienced ≥1 AE; of these, 40.7% patients had mild AEs (UC, 40.2%; CD, 41.7%). Forty-six (45.1%) patients with UC and 22 (45.8%) patients with CD had ≥1 treatment-emergent AE (TEAE); 5 (4.9%) patients with UC had treatment-related TEAEs. Seven (4.7%) patients (UC, 6 [5.9%]; CD, 1 [2.1%]) had ≥1 SAE (2 [1.3%] were treatment-related), 5 (3.3%) had ≥1 ADR, and 4 (2.7%) had ≥1 AESI. One patient (0.7%) each reported pulmonary tuberculosis and tuberculous pleural effusion as ADR/AESI. Anaemia and small intestinal obstruction were the frequently reported TEAE and SAE, respectively. Most of the AEs were resolved and no AE-related death was reported during study (Table 1). Overall, 90 (60.0%) patients (UC, 56 [54.9%]; CD, 34 [70.8%]) at W14, 37 (63.8%) patients (UC, 29 [61.7%]; CD, 8 [72.7%]) at W30, and 4 (57.1%) patients (UC, 4 [66.7%]) at W46 had the clinical response. Similarly, 62 (41.3%) patients (UC, 40 [39.2%]; CD, 22 [45.8%]) at W14, 23 (39.7%) patients (UC, 19 [40.4%]; CD, 4 [36.4%]) at W30, and 3 (42.9%) patients (UC, 3 [50.0%]) at W46 had the clinical remission (Figure 1). Conclusion Treatment with vedolizumab was safe and effective in Indian patients with moderate-to-severe active UC and CD as per this first multicentre prospective study on vedolizumab from India.

Is the Absence of Manual Lymphatic Drainage-Based Treatment in Lymphedema after Breast Cancer Harmful? A Randomized Crossover Study.

(1) Background: Manual lymphatic drainage (MLD), included within the complex decongestive therapy, as a therapy for the treatment of lymphedema has raised controversy about its benefits for lymphedema after breast cancer. The aim of this research is to test the effects of MLD on lymphedema after breast cancer during the treatment maintenance phase. (2) Methods: A randomized, single-blinded, controlled crossover trial was conducted to analyze the effects of a manual lymphatic drainage intervention compared to a control group without MLD intervention for the treatment of lymphedema. Arm volume measured by circumference measurement, subcutaneous tissue thickness measured by ultrasound, and the sensation of pain, heaviness, and swelling were evaluated as outcome measures. (3) Results: For the control group, an increase in volume was found in some of the circumference and subcutaneous tissue thickness measurements, in addition to a worsening of arm pain, swelling and heaviness. (4) Conclusion: The absence of treatment based on MLD in lymphedema after breast cancer worsens volume measurements, as well as arm heaviness. Therefore, it would be advisable to carry out this type of therapy as part of the maintenance treatment for lymphedema in breast cancer.

Severe pulmonary hypertension-interstitial lung disease presenting as right ventricular failure: stabilisation with intravenous prostacyclin and maintenance with inhaled prostacyclin.

Pulmonary hypertension (PH) leads to increased morbidity and mortality in interstitial lung disease (ILD). While the INCREASE trial highlighted the use of inhaled prostacyclin in PH-ILD patients, such therapy may be inadequate when right ventricular failure (RVF) is also present. In this study, we report the use of intravenous prostacyclin in three PH-ILD patients to stabilise right ventricular (RV) function, with a subsequent transition to maintenance therapy with inhaled prostacyclin. We evaluated three consecutive PH-ILD patients with RVF. RV afterload and pulmonary vascular resistance (PVR) were treated with intravenous prostacyclin during the induction phase of the therapy. Patients transitioned from intravenous prostacyclin to the maintenance phase of the treatment with inhaled prostacyclin once three transition criteria were met: cardiac index (CI) >2 L·min-1·m-2, PVR <7 Wood units (WU) and tricuspid annular plane systolic excursion (TAPSE) change >1 mm or TAPSE >1.6 cm. Pre-treatment parameters for the three patients were a mean PVR of 14.3 WU, a mean Fick CI of 1.8 L·min-1·m-2 and a mean TAPSE of 1.4 cm. The average intravenous prostacyclin dose at the time of transition to maintenance therapy was 20.7 ng·kg-1·m-2 of treprostinil. At 3-months follow-up, the mean PVR was 6.3 WU, Fick CI 2.2 L·min-1·m-2 and TAPSE 1.7 cm. This case series of three PH-ILD patients with RVF introduces the concept of an initial intravenous prostacyclin induction phase, followed by a transition to maintenance therapy with inhaled prostacyclin. Further development of this treatment algorithm with a refinement of the transition criteria, potential testing in a clinical trial and a longer-term follow-up period is warranted to improve the outcomes of advanced PH-ILD patients with concomitant RVF.

Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial

Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of>3mL/min/1.73m2. This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of≥30mL/min/1.73m2. Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Patients were randomized (1:1:1) to empagliflozin 10mg, 25mg, or placebo in addition to standard of care. Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P<0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of>5mL/min/1.73m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P<0.001). This is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established. Patients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug. The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. clinicaltrials.gov ID: NCT01131676.

A Phase II Study of Intermittent Duvelisib Dosing in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background. Targeting phosphatidylinositol 3-kinase (PI3K) has emerged as an efficacious approach for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). However, toxicities of the PI3K inhibitors are an important concern limiting their use. Duvelisib is a potent oral inhibitor of both the PI3K-δ and PI3K-γ isoforms with proven efficacy in CLL/SLL. Here we report the results of a phase 2 study evaluating efficacy and safety of duvelisib with intermittent dosing in patients with relapsed/refractory CLL/SLL Methods. This open-label, single arm, phase 2 study enrolled patients with CLL/SLL treated with at least 1 prior line of therapy with active disease as defined by the iWCLL 2008 criteria. Duvelisib was given at a dose of 25 mg PO BID for 28-day cycles for a total of 12 weeks during the induction phase, followed by 75 mg PO BID 2 days on and 5 days off for repeated 28-day cycles during the maintenance phase until death, intolerance or disease progression. The primary endpoint was progression free survival (PFS) at 12 months; secondary endpoints were safety and clinical benefit. The trial was originally planned to enroll 27 patients but was stopped early due to difficulties with enrollment following changing FDA guidance for the use of PI3K inhibitors. Results. Fifteen patients were enrolled. Median age was 74 (59-82) years, 8/15 (53%) were female; patients were primarily Caucasian (13/15; 87%); performance status was 0-1, with 27% (4/15) ECOG 0 and 73% (11/15) ECOG 1. This was a heavily pre-treated patient population with a median of 3 prior lines of therapy (1-6). Among patients where results were available, 79% (11/14) had abnormal FISH results including 36% with TP53 gene loss, 27% del(13q), and 18% del(11q). Sixty-seven percent (8/12) had unmutated IGHV. Of the 15 patients treated, 4 were not evaluable for efficacy due to coming off study early for toxicity (2), development of MDS unrelated to study drug (1) or death due to complications from COVID-19 infection (1). Among the 11 efficacy-evaluable patients, 82% achieved PR, and 18% had stable disease. The 12-month PFS was 43% (95%CI: 18%-66%) and the median PFS was 9.9 months (95% CI: 5.5-NA). Among the 9 responders, the median duration of response (DOR) was 5.3 months (95%CI: 1.9-NA) and 12-month DOR was 22% (95%CI:3%-51%). Five patients (33%) discontinued therapy due to adverse events, which occurred during the induction phase in 4/5 of the patients. Five patients (33%) discontinued due to progressive disease - all during the maintenance phase of treatment. Additionally, 2 patients discontinued due to MD decision; one patient developed MDS which was unrelated to duvelisib; one patient died during treatment due to complications from COVID-19. Treatment was generally well tolerated with the most common grade 3 or higher adverse events being leukocytosis (20%), alanine aminotransferase (ALT) increase (13%), aspartate aminotransferase (AST) increase (13%), oral mucositis (13%) and colitis (13%). The adverse events leading to treatment discontinuation occurred primarily during induction. The most common adverse events of any grade included fatigue in 5 patients (33%), leukocytosis, vomiting, ALT increase, AST increase, diarrhea, and elevation of alkaline phosphatase, which occurred in 4 patients each (27%). Conclusions. We report the results of an open-label, phase 2 study utilizing a continuous dosing induction phase followed by an intermittent dosing maintenance phase of the PI3K inhibitor duvelisib in patients with relapsed/refractory CLL/SLL. Patients who received duvelisib on an intermittent schedule achieved some clinical benefit, however, the desired 12-month PFS goal of 50% was not reached. Adverse events in general were manageable and mainly related to gastrointestinal and liver toxicity, and patient died during treatment from complications from COVID-19 pneumonia. After an initial 12 weeks of continuous duvelisib treatment, the incorporation of intermittent dosing appears to be a viable option for patients with previously treated CLL/SLL.

Long-term maintenance treatment of rosacea: experts' opinion.

Rosacea is a chronic inflammatory dermatosis characterized by remissions and flares. Although the rosacea active treatment phase is well established, the long-term maintenance phase is still challenging. To discuss and make recommendations on how to treat patients during the long-term maintenance phase for the main rosacea phenotypes. A panel of six board-certified Brazilian dermatologists and one American dermatologist gathered to compose a consensus based upon an initial statement on how to treat rosacea during the long-term maintenance phase based on the methodology Nominal Group Technique. The experts discussed each factor based upon an initial statement on how to treat rosacea patients in the long-term maintenance phase. A sequence of comprehensive narrative reviews was performed; a questionnaire preparation about the definition of the maintenance phase and its management was presented; an interpersonal discussion and ranking of the ideas were conducted. Recommendations were made if the specialists had 75% agreement. The maintenance treatment phase, which starts by achieving IGA 0 or 1 grades at the active phase, should be considered at least during the 9-month period after remission. The recommendations of all treatments target this period. Daily skincare regimen and sunscreen are crucial. Active treatment phase should be recommended if signs or symptoms reappear or worsen. Maintenance phase success depends on patient's adherence to daily skin care, appropriate treatments, continued follow-up with dermatologist, and self-assessment to identify new signs and symptoms indicating disease relapse.

Addition of Chidamide to a Sandwich Protocol, Pegaspargase, Gemcitabine and Oxaliplatin Chemotherapy Combined with Radiotherapy, As First-Line Treatment in Early Stage NK/T-Cell Lymphoma: Real World Outcomes in a Retrospective Study

Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT) is a highly invasive tumor with a short doubling time and poor prognosis. Clinically, it usually involves the upper aerodigestive tract and mainly presents with early-stage. Initially, intensity modulated radiation therapy (IMRT) has been considered the preferred first-line therapy for early-stage ENKTL due to its high response rate. In recent years, more and more studies show that adding chemotherapy, especially asparaginase (ASP)-based regimens, provide survival benefit in early-stage patients. However, the optimal chemotherapy regimen has not been fully defined. Epigenetic regulatory mechanisms related to histone deacetylase (HDAC) have been found to play a role in the evolution and progression of ENKTL. Chidamide, a new HDAC inhibitor, has been confirmed to be effective and tolerable to treat lymphoma. Recently, Xue et al showed that chidamide in combination with cisplatin, etoposide or gemcitabine showed synergistic effect and reversed the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Here, we investigate the safety and efficacy of adding chidamide to a sandwich protocol, P-GEMOX (pegaspargase/gemcitabine/oxaliplatin) regimen (CP-GEMOX) combined with IMRT as first-line treatment in early-stage ENKTL-NT patients. Methods: We retrospectively reviewed data of early-stage ENKTL-NT patients in the first affiliated hospital of Soochow University from March 2020 to April 2023. A total of 21 patients diagnosed with early-stage (stage Ⅰ or Ⅱ) ENKTL-NT were enrolled and treated with 2 cycles of CP-GEMOX followed by IMRT and 1 or 2 cycles of CP-GEMOX sequentially as consolidation. After consolidation, chidamide was administrated as a maintenance therapy for 1 year. In the induction therapy phase, chidamide was administered orally at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period; During the maintenance treatment phase, the original dose of chidamide was still maintained and used without pause. The baseline clinical features for the 21 patients were summarized in Table 1. Results: Among 21 patients, 14 were males and 7 were females, and their median age was 57 (range, 41-75) years. Elevated lactate dehydrogenase, elevated β2-microglobulin, stage II disease and primary tumor invasion were present in 4.8% (1/21), 19.0% (4/21), 61.9% (13/21) and 61.9% (13/21) patients. According to the early stage-adjusted nomogram-revised risk index, the majority of patients (76.2%, 16/21) were classified into intermediate- (1-2) and high (≥3) risk groups. The baseline clinical features for the 21 patients were summarized in Table 1. During treatment, all patients were well-tolerated and the most common adverse events were hematological toxicities with neutropenia, thrombocytopenia and anemia. Among non-hematological adverse events, nausea, vomiting and reduced appetite were most common. Other side effects included coagulation dysfunction, skin reaction, diarrhea, serum amylase and alanine aminotransferas /aspartate aminotransferase /bilirubin elevation. No anaphylactic reaction to pegaspargase, hemophagocytic syndrome, pancreatitis or sepsis were observed during chemotherapy. Some patients had mucositis and xerostomia when receiving local radiotherapy. All side effects could be reversed with proper treatment, and there were no therapy related mortality. All patients completed 2 cycles of CP-GEMOX, 19 patients achieved complete remission (CR) and 2 patients achieved partial remission (PR) with a CR rate of 90.5% (19/21) and overall response rate (ORR) of 100.0% (21/21) after 2 cycles of CP-GEMOX. Among the 21 patients, 18 patients completed treatment and CR rate was improved to 100.0% (18/18), giving an ORR of 100% (18/18). After a median follow-up of 25.6(range, 2.6-39) months , all patients were alive except one patient relapsed 20 months after treatment and died of COVID-19 related pneumonia 1 month later. The 2-year progression-free survival and overall survival were all 91.5% (Figure 1). Conclusions: This study demonstrates that sandwich CP-GEMOX chemoradiotherapy is a safe and promising approach to managing patients with early-stage ENKTL-NT. Keywords: Extranodal NK/T-cell lymphoma; chidamide; pegaspargase; gemcitabine; radiation therapy.

Lost and Found: A Mixed Methods Study on Treatment Abandonment in Acute Leukemia

Introduction: Acute leukemias represent an important public health problem due to their high morbidity and mortality. Treatment failure due to abandonment or loss of follow-up (LOF) is a contributing factor to poor outcomes. Objective: to determine the causes and outcomes of LOF in a cohort of adults with a diagnosis of acute leukemia and its impact on survival in a limited-resource setting. Materials and Methods: We conducted a prospective, single-center cohort study from 2016 to 2022 in the university hospital; this institution is subsidized with funds from private and public sources. We included patients undergoing induction, consolidation, and maintenance phases of treatment for acute lymphoblastic (ALL) and acute myeloid leukemia (AML). LOF events were defined as discontinuation of follow-up beyond the last documented visit in the electronic medical records, with a timeframe of 2 to 4 weeks during the induction and 4 to 8 weeks in the consolidation or maintenance phases. Patients with LOF were contacted via telephone. Those who responded underwent a structured interview that assessed factors potentially contributing to the discontinuation of treatment. Treatment response, event-free survival (EFS), and overall survival (OS) in patients who lost follow-up were also assessed. Results: From January 1, 2016, to October 31, 2022, a total of 391 patients were treated n=99 patients were found to have lost follow-up during first-line treatment, and 73 patients, (%) answered the phone call, 75.3% had been diagnosed with ALL, and 24.7% with AML. Of the 55 patients diagnosed with ALL, 52.7% were women, the median age was 26 years (range 18-86), and 96.4% were classified as a high-risk disease according to age, white blood cell count at diagnosis, CNS involvement, or steroid response. Most patients lived in an urban area (90.9%), and 74.5% didn't have healthcare coverage. Among the patients diagnosed with AML, 50% were male, the median age of diagnosis was 33 years (range 23-67), 94.4% resided in urban areas, and 83.3% of the patients did not have healthcare coverage, thus and molecular risk could not be determined due to the high cost of comprehensive genetic analysis. All patients were classified as low socioeconomic status, with a median income of $130 US dollars per month, (range, 81 -378 USD) for the ALL cohort and $180 USD for the AML group. Based on the findings of the telephone survey, it was evident that economic constraints were the primary driver of treatment abandonment in both ALL and AML patients, accounting for 92.8% and 94.4% of cases, respectively. Specifically, 92.7% of the ALL group expressed difficulties in covering the costs of treatment, while 83.3% in the AML group faced similar challenges. For ALL patients LOF was more frequent during the maintenance phase, (61.8%) compared to consolidation in AML patients (44%). Despite telephone contact, 76.4% of those with ALL and 77.8% of those with AML, could not continue follow-up. Concerning disease status, 11.1% of patients diagnosed with ALL and 34.5% of patients with AML that resumed follow-up after the phone call were diagnosed with relapsed disease. OS at 2 years from the time LOF was identified 49.1% for ALL and 61.1% for AML. Additionally, the 2-year EFS rates were 43.6% for ALL and 44.4% for AML. Conclusions: Lack of access to financial resources and catastrophic healthcare expenditures were the main reason for abandoning treatment in patients with acute leukemia. Despite the loss of follow-up, the overall survival in both groups of patients showed favorable long-term outcomes; however, risk assessment strategies should be employed, and support programs implemented to improve outcomes in vulnerable populations.

Effect of MEF2A and SLC22A3-LPAL2-LPA gene polymorphisms on warfarin sensitivity and responsiveness in Jordanian cardiovascular patients.

This study aims to investigate the influence of MEF2A and SLC22A3-LPAL2-LPA polymorphisms on cardiovascular disease susceptibility and responsiveness to warfarin medication in Jordanian patients, during the initiation and maintenance phases of treatment. Several candidate genes have been reported to be involved in warfarin metabolism and studying such genes may help in finding an accurate way to determine the needed warfarin dose to lower the risk of adverse drug effects, resulting in more safe anticoagulant therapy. The study population included 212 cardiovascular patients and 213 healthy controls. Genotyping of MEF2A and SLC22A3-LPAL2-LPA polymorphisms was conducted to examine their effects on warfarin efficiency and cardiovascular disease susceptibility using PCR-based methods. One SNP (SLC22A3-LPAL2-LPA rs10455872) has been associated with cardiovascular disease in the Jordanian population, whereas the other SNPs in the MEF2A gene and SLC22A3-LPAL2-LPA gene cluster did not have any significant differences between cardiovascular patients and healthy individuals. Moreover, SLC22A3-LPAL2-LPA rs10455872 was correlated with moderate warfarin sensitivity, the other SNPs examined in the current study have not shown any significant associations with warfarin sensitivity and responsiveness. Our data refer to a lack of correlation between the MEF2A polymorphism and the efficacy of warfarin treatment in both phases of treatment, the initiation, and maintenance phases. However, only rs10455872 SNP was associated with sensitivity to warfarin during the initiation phase. Furthermore, rs3125050 has been found to be associated with the international normalized number treatment outcomes in the maintenance phase.

Enhancing panic disorder treatment with mobile-aided case management: an exploratory study based on a 3-year cohort analysis.

Individuals with panic disorder frequently face ongoing symptoms, suboptimal treatment adherence, and increased relapse rates. Although mobile health interventions have shown promise in improving treatment outcomes for numerous mental health conditions, their effectiveness, specifically for panic disorder, has yet to be determined. This study investigates the effects of a mobile-aided case management program on symptom reduction and quality of care among individuals with panic disorder. This 3-year cohort study enrolled 138 participants diagnosed with panic disorder. One hundred and eight participants joined the mobile-aided case management group and 30 in the treatment-as-usual group. Data were collected at baseline, 3-month, 6-month, and 12-month treatment checkpoints using self-report questionnaires, in-depth interviews, direct observation, and medical record analysis. During the maintenance treatment phase, the mobile-assisted case management group decreased both panic severity (p = 0.008) and state anxiety (p = 0.016) more than the control group at 6 months. Participants who underwent case management experienced enhanced control over panic symptoms, heightened self-awareness, and elevated interpersonal support. The mobile-aided case management is beneficial in managing panic disorder, especially maintenance treatment.

Repetitive transcranial magnetic stimulation use in neuropathic pain with comorbid depression: a review of efficient treatment protocols’ parameters

Neuropathic pain affects 7 % of the general population worldwide, it is often resistant to analgesic treatments and is complicated with depressive states in 57–65 % of this patients’ cohort. Ongoing research of current therapeutic approaches, including repetitive transcranial magnetic stimulation (rTMS) use in neuropathic pain and depression, grants new data about the details of treatment protocols’ designs. The aim of our literature review was to evaluate those parameters of the treatment protocols which proved significant efficacy in the management of the neuropathic pain with comorbid depression.Focusing on the Scopus, Elsevier and PubMed databases search, we have found 639 peer‑review articles. 23 studies have been included into the data analysis, whereas others were excluded based on their heterogeneous study design. Across the data analysis we evaluated such rTMS parameters as the type of a coil, type of stimulation area, locus of gained evoked motor potential, amplitude of stimulation, duration of session, frequency/number of sessions per day/month, tie duration between sessions, number and frequency of trains, amount and frequency of pulses containing and efficacy of treatment. Those studies that performed repetitive transcranial magnetic stimulation using the figure‑of‑8 coil over the M1 brain area, for 10 or more daily sessions with duration from 7 up to 40 minutes, of 10–20 Hz frequency, intensity 80–90 % of resting motor threshold and total pulses number over 1500 per session demonstrated the greater efficacy in pain level decrease and depression scores reduction among neuropathic pain patients with comorbid depression. Conducting an additional maintenance phase of treatment prolonged the therapeutic effect of the course.Based on the data review, the parameters of the most efficient rTMS protocols’ designs in management of patients with neuropathic pain and comorbid depression have been revealed. Further research requires investigation of other promising indicators of rTMS efficacy use in neuropathic pain with comorbid depression, such as stimulation over multiple brain areas, the duration/timing of additional maintenance phase of treatment, and the figure‑of‑8 coil orientation options.

The Role of Ketamine in the Treatment of Bipolar Depression: A Scoping Review

Bipolar depression remains a clinical challenge with a quarter of patients failing to respond to initial conventional treatments. Although ketamine has been extensively studied in unipolar depression, its role in bipolar disorder remains inconclusive. The aim of our scoping review was to comprehensively synthesize the current clinical literature around ketamine use in bipolar depression. A total of 10 clinical studies (5 randomized controlled trials and 5 open label studies) were selected. The preliminary evidence, albeit weak, suggests that ketamine is a promising treatment and calls for further interest from the research community. Overall, ketamine treatment appeared to be tolerable with minimal risk for manic/hypomanic switching and showed some effectiveness across parameters of depression and suicidality. Moreover, ketamine is a potential treatment agent in patients with treatment-resistant bipolar depression with promising data extracted from extant controlled trials and real-world effectiveness studies. Future studies are needed to identify ketamine’s role in acute and maintenance treatment phases of bipolar depression. Moreover, future researchers should study the recurrence prevention and anti-suicidal effects of ketamine in the treatment of bipolar depression.

Incidence and determinants of hematotoxicity in acute lymphoblastic leukemia children who received 6-mercaptopurine based maintenance therapy in Addis Ababa, Ethiopia.

The maintenance phase of acute lymphoblastic leukemia treatment is the final and longest stage of treatment, mainly focused on antimetabolite therapy. This phase is essential to eliminate residual leukemic clones and prevent relapse. However, dose-limiting hematotoxicity is a major problem during this phase resulting in dose reduction or treatment discontinuation. In this cohort study, the clinical features and risk factors of hematological toxicity during the maintenance phase of treatment were analyzed in pediatric patients from Ethiopia. A total of 160 patients from Tikur Anbessa specialized hospital were included in the study of which 142 had sufficient data available for analysis. Patient characteristics as well as information about the care-givers, sides-effects as reported by the care-givers and clinical factors were collected. Bivariable followed by multivariable analysis was performed to investigate which factors were associated with hematological toxicity during the maintenance phase. During the first six months of maintenance phase treatment grade 4 neutropenia was detected in 52.8% of the patients. The risk of developing grade 4 neutropenia was increased by about two fold in children with the age of 6 years and less compared to those with the age of more than 6 years. Similarly, the rate of developing grade 4 neutropenia among children with less than 4,500 maintenance day 1 white blood cell counts was significantly higher than that of children with normal maintenance day 1 white blood cell counts (AHR 2.477, 95% CI = 1.461-4.200, p = 0.001). In conclusion, child's age and day 1 maintenance white blood cell/absolute neutrophil counts significantly affected the occurrence of grade 4 hematotoxicity. Close monitoring for white blood cell and absolute neutrophil counts during maintenance phase treatment is recommended for early diagnosis of hematotoxicity.

LUNG-IST-127: A pilot phase II study of maintenance cabozantinib plus pembrolizumab for patients with metastatic squamous non-small cell lung cancer (sqNSCLC) with disease control following induction therapy.

TPS9151 Background: First-line combination chemotherapy with pembrolizumab followed by maintenance pembrolizumab is the standard of care treatment for patients with metastatic sqNSCLC. This was established by the phase III KEYNOTE-407 trial, which demonstrated a median progression-free survival (PFS) of 6.4 months in the experimental arm. Despite these advances, there remains a need to continue to improve upon survival outcomes for these patients. Cabozantinib is a small-molecule inhibitor of multiple tyrosine kinsases including MET, VEGFRs, AXL, RET, and ROS, which are receptors involved in tumor cell-proliferation, angiogenesis, and immune cell regulation. Preclinical studies have demonstrated the ability of cabozantinib to modulate both adaptive and innate immune cells and to exhibit synergistic activity when used in combination with immune checkpoint inhibitors. We hypothesize that cabozantinib in combination with pembrolizumab in the maintenance phase of first-line treatment of metastatic sqNSCLC will prolong median PFS with a tolerable toxicity profile. Methods: LUNG-IST 127 is a pilot phase II, single-arm clinical trial of maintenance cabozantinib in combination with pembrolizumab for patients with metastatic sqNSCLC who achieved disease control following standard 1L induction therapy with chemotherapy and pembrolizumab. Thirty-six patients will be enrolled at 2 US sites to receive first-line induction therapy with carboplatin, nab-paclitaxel or paclitaxel, and pembrolizumab for four cycles. After induction therapy, those who have achieved disease control based on re-staging imaging will continue onto maintenance therapy with cabozantinib 40mg PO daily in combination with pembrolizumab 200mg IV every 3 weeks. The primary endpoint is PFS estimated by Kaplan-Meier methods with associated 95% confidence intervals. Based on an exploratory power analysis using an elevated one-sided alpha level of 0.40, we hypothesize that the proposed therapy will prolong median PFS from 6.4 to 9 months. Key secondary endpoints include overall survival (OS), overall response rate (ORR), and characterizing the safety and tolerability of cabozantinib in combination with pembrolizumab. Quality of life will also be measured with the EORTC QLQ-C30. Correlative endpoints include characterizing cfDNA from biofluids and assessing the change in circulating immune cells in different phases of treatment in association with PFS and OS. This trial would be the first to address whether there is clinical benefit in utilizing combination cabozantinib and pembrolizumab in the maintenance phase of treatment in metastatic sqNSCLC. Clinical trial information: NCT05613413 .

A phase 3 multicenter study to evaluate the safety and efficacy of padeliporfin vascular targeted photodynamic therapy (VTP) in treatment of low-grade (LG) upper tract urothelial cancer (UTUC).

TPS4613 Background: Padeliporfin VTP is a combination product: drug, padeliporfin is administered IV and a device, a laser light delivery system, includes a source of light (the laser) that emits near-infrared (NIR) light at 753 nm, and optic fiber that delivers the light to the target lesion(s) in the upper tract urothelium. In Phase 1 NCT03617003 study 19 patients(pts) received up to 2 endoscopic VTP treatments with 6 mos follow-up(FU). Pts with residual or recurrent UTUC (high grade(HG)or LG) who failed prior endoscopic treatment/unable/unwilling to undergo surgery were included. Primary endpoint, Maximum tolerated dose (MTD) of laser light fluence, was identified using dose escalation model with a modified continual reassessment method with increasing light fluence (100-200 mW/cm). Secondary endpoint was efficacy, defined by absence of visible tumor and negative urine cytology 30 days post-treatment. 14(74%) pts received the MTD of 200mW/cm, 2 (11%) of whom experienced DLTs (flank pain grade 2 and 3). Response rate at 30 days was 94% (50% CR, 44% partial). 8 pts received 2nd VTP, with a final observed 68% complete response (CR) rate. Most frequent adverse events: transient flank pain (79%) and hematuria (84%). No treatment-associated ureteral strictures were reported. All patients had preserved kidney at the 6-mos FU(Wesley Yip,2022). Methods: Padeliporfin VTP is being evaluated in a phase 3 study in patients with UTUC LG,100 patients are planned to be enrolled. Enrollment started in Mar 2021 and is ongoing in USA, EU&amp;Israel,3 pts are enrolled. Pts are being treated with padeliporfin VTP in two phases: Induction and Maintenance treatment Phases (ITP and MTP). ITP consists of 1-3 VTPs every 28 days. If CR is not achieved after 1st VTP, up to 2 additional VTPs are allowed. If CR is achieved in the ITP, pts are allowed into the MTP (12 mos). In the MTP VTPs can be provided every 3 mos for pts with recurrent tumor that is deemed treatable, defined as LG with the largest tumor (index) 5 -15 mm, in up to 2 locations in the kidney or one ureter location ≤20 mm. Long Term FU Phase: Pts completing the MTP, will be followed for safety for 48 mos with no VTPs. Primary objective is to demonstrate efficacy and durability of effect of padeliporfin VTP treatment. Secondary objective-evaluation of padeliporfin VTP‐related safety and tolerability. Key inclusion criteria: Up to 2 biopsy-proven LG UTUC tumors with the largest tumor (index) 5-15 mm, located in the calyces, renal pelvis or in the ureter, with no HG cells. Ureter involvement in one location ≤ 20 mm. Key exclusion criteria: Current HG or muscle invasive urothelial bladder cancer . CIS current or previous in the upper urinary tract. History of ≥ T2 urothelial cancer in the past 2 years. DSMB last reviewed the trial in Sep 2022 and suggested the trial continue as planned. Clinical trial information: NCT04620239 .

Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan® SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Therapeutic Drug Monitoring of Vedolizumab in Inflammatory Bowel Disease Patients during Maintenance Treatment—TUMMY Study

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure-response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission.

ITPA Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia.

6-Mercaptopurine (6-MP), a thiopurine agent, is a essential medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wild-type ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wild-type ITPA (P = 0.016). HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wild-type ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.