Full Course Of Treatment Research Articles

P768: GUADECITABINE (SGI-110) VS. TREATMENT CHOICE (TC) IN RELAPSED/REFRACTORY(R/R) MYELODYSPLASTIC SYNDROME (MDS), RESULTS OF A GLOBAL, RANDOMIZED, PHASE 3 STUDY.

Background: Guadecitabine (G) is a next-generation hypomethylating agent (HMA), administered as a small-volume subcutaneous (SC) injection, designed with the potential to overcome pharmacokinetic resistance to first-generation HMAs (decitabine and azacitidine). Preliminary guadecitabine phase 2 data in r/r MDS showed an overall survival of almost 12 months (Garcia-Manero,G, et al; Lancet Haematol http://dx.doi.org/10.1016/S2352-3026 [19]30029-8) leading to the ASTRAL-3 study. Aims: Compare overall survival of guadecitabine to that of TC consisting of low-dose cytarabine (LDAC), intensive chemotherapy (IC), or best supportive care (BSC). Secondary objectives included multiple standard assessments of response and safety. Methods: Subjects with r/r MDS or Chronic Myelomonocytic Leukemia (CMML) who had progressed or failed to respond after 6 full cycles of standard HMA therapy were randomized 2:1 between guadecitabine (60 mg/m2) SC Days 1-5 every 28 days vs. a pre-selected TC (BSC, IC, or LDAC). Stratification was by disease, disease burden (>10% bone marrow blasts or not, geography, and pre-selected TC option). Primary endpoint was overall survival (OS) and the study was designed with ~90% power to detect a hazard ratio of 0.68 (approximately 2.8 month difference in median survival). Results: 417 MDS/CMML subjects were randomized to G or TC (G:277, TC: 140). Demographics and disease status were reasonably balanced across the groups (see Table 1 below) as was percentage of commonly associated genetic mutations (TET2, DNMT3A, SF3Baa, RUNX1, and TP53). Median guadecitabine exposure was 4 cycles and 3 cycles for TC. Neither overall survival (G: median 9.1 months, TC: median 8.3 months, p=0.61, HR:0.94 with 95% CI: [0.74-1.19]) nor leukemia-free survival (LFS) (G: median 5.7 months, TC: median 5.9 months; p=0.38) demonstrated a significant difference between the two groups and subgroup analyses did not suggest a difference between guadecitabine and any of the different TC options or different genetic mutations. Transfusion dependence for 8 weeks was similar with 32.1% and 22.4% of the G group and 37.9% and 20.0% of the TC group being platelet transfusion or red blood cell transfusion independent, respectively. Safety was consistent with known profiles of the respective agents with the G group having a slightly higher overall incidence of adverse events (AE) (99.3% vs 92.6% for TC) and grade 3 or higher AE (92.2% vs 70.5% for TC). The AEs with the highest incidence in subjects who received guadecitabine were febrile neutropenia (38.5 vs 18.9% for TC), pneumonia (34.4% vs 18.9% for TC), neutropenia (34.1% vs 15.6% for TC), and thrombocytopenia (32.2% vs 21.3% for TC). Image:Summary/Conclusion: This large, global, randomized phase 3 study did not demonstrate superiority of guadecitabine over Standard TC in MDS/CMML patients who were refractory or relapsed following full course of prior HMA treatment.

Early response to cognitive behavioral therapy for body dysmorphic disorder as a predictor of outcomes

Individuals with body dysmorphic disorder (BDD) suffer from distressing or impairing preoccupations with perceived imperfections in their appearance. This often-chronic condition is associated with significant functional impairment and elevated rates of psychiatric comorbidity and morbidity, including depression, substance use disorders, and suicidality. Cognitive behavioral therapy (CBT) for BDD has been shown to be efficacious. However, this intervention is long (up to 24 weeks) relative to many manualized approaches for other related conditions, there is a significant shortage of clinicians trained in CBT for BDD, and some patients drop out of treatment and/or do not respond. Thus, there is great interest in understanding and predicting who is most likely to respond, to better allocate clinical resources. This secondary data analysis of participants enrolled in prior uncontrolled and controlled studies of CBT for BDD explored whether early response to CBT, operationalized as percentage change in symptom severity within the first four weeks and the first 12 weeks of this 24-week treatment, predicts clinical outcomes for patients with BDD (n = 90). The findings indicated that minimal early symptom change was not indicative of eventual non-response. This suggests that patients and clinicians should not be discouraged by limited early improvement but should instead continue with a full course of treatment before reevaluating progress and alternative interventions. Overall, the results support the view that treatment success is more likely if a longer CBT protocol is followed. More work is needed to understand mechanisms of change and thus match optimal interventions to patient characteristics.

Treatment interruptions and discontinuations among patients with stage III unresectable non–small cell lung cancer treated with durvalumab at the Veterans Health Administration.

8554 Background: The PD-1/PD-L1 pathway is a mechanism of immune evasion and disruption of this pathway with immune checkpoint inhibitors (ICIs) has shown clinical benefit in multiple malignancies. Based on results from the PACIFIC trial, durvalumab is approved as consolidation therapy in patients (pts) with stage III unresectable non-small cell lung cancer (UR-NSCLC) without progression following concurrent chemoradiotherapy (cCRT). Durvalumab has been used extensively in Veterans Health Administration (VHA) facilities, providing an opportunity to evaluate durvalumab treatment interruptions (TI), treatment discontinuations (TD), and the reasons for these on a national scale. Methods: Patients with stage III UR-NSCLC receiving durvalumab consolidation immunotherapy at the VHA between January 1, 2017 and June 30, 2020 with a minimum follow up for 12 months were included using ICD-10, HCPCS, and J codes and followed from their durvalumab start date through the earliest of last VHA visit, loss to follow up, death, or end of study (excluded if durvalumab therapy was ongoing at the end of the study, because the full treatment course could not be determined). TI were defined as durvalumab infusions separated by >28 days. Reasons for TI and TD are presented descriptively. Durations are reported using medians and interquartile ranges (IQR). Results: 935 pts were included (median age = 69 years; 95% males; 96% current or former smokers; 70% with COPD; histologies [squamous (50%), non-squamous (43%), other/missing (7%)]; and 77% with carboplatin-paclitaxel as their platinum-based CRT). Durvalumab TI were experienced by 19% of pts (median [IQR] number of TI = 1 [1-1], median [IQR] TI duration = 53 days [39-90]). The main reasons for TI were toxicity (8%) and social reasons (3%) (Table). The median duration of treatment (DoT) with durvalumab (TI included) was 9.0 months (IQR 2.9-11.8). Durvalumab TD occurred in 59% of pts. Top reasons for discontinuation across all 935 pts included disease progression (24%) and toxicity (18%) (Table). Conclusions: In this real world analysis of national VHA data, durvalumab DoT was similar to PACIFIC despite having a patient population with worse prognostic factors (e.g. more males, squamous, COPD) with 8% of VHA pts experiencing TI and 18% TD due to toxicity. Patients could benefit from additional efforts to prevent, identify, and manage toxicities in the UR-NSCLC population [Table: see text]

P-36 Real-world outcomes in BRAFV600E metastatic colorectal cancer – the Glasgow experience

Approximately 8 - 10% of metastatic colorectal cancers (mCRC) have a BRAF V600E mutation. BRAF V600E mutant mCRC represents a distinct clinical subset with a poor prognosis. Previous treatment guidelines have been derived from subgroup analyses of non-designated BRAF V600E trials. Real world studies have shown that outcomes and treatment practices can vary widely. Here, we report on our regional practices and outcomes. We undertook a retrospective analysis of all mCRC patients with confirmed BRAF V600E mCRC diagnosed in NHS Greater Glasgow and Clyde Health Board (Scotland, UK) between 01/01/2015 - 31/12/2020. Clinical and pathological features were obtained from electronic records. Univariate analysis of prognostic factors was performed using Kaplan Meier analysis and log-rank test. Multivariate analysis was performed using Cox regression. A total of 139 patients were identified for study with 1 excluded for missing follow up information. Median age at metastatic diagnosis was 69 years, with a female preponderance (59% female, 41% male). 31% of tumours also had deficient mismatch repair (dMMR) or high levels of microsatellite instability (MSI-H). Primary tumour site was mostly right-sided (n=102, 74%), with less left-sided (n=20, 15%) and rectal (n=15, 11%) tumours. 1 patient had 2 synchronous primaries (1 right colon and 1 rectal). 64% presented with de novo metastatic disease. For those with initial loco-regional disease, the median time to metastatic progression was 10 months. The most common metastatic sites were liver (54%), peritoneal (33%), lymph node (31%), and lung (28%). 36% of patients did not receive any systemic treatment, 36% received 1 line, and 28% received 2 or more lines of treatment. Most (69%) received a cytotoxic chemotherapy doublet as first-line treatment, and 6% received triplet cytotoxic chemotherapy. 7% received immunotherapy. Among the treated patients, only 19% received some form of targeted therapy over their full treatment course, usually a combination containing an anti-EGFR inhibitor. The median overall survival was poor at 7.2 months. Features significantly associated with shorter survival were performance status (PS) of 2 or worse (p < 0.01), the presence of lymph node metastasis (p = 0.010) and peritoneal metastasis (p < 0.01), a higher modified Glasgow Prognostic Score (GPS) of 2 (p = 0.035) and a high neutrophil-lymphocyte ratio >5 (p = 0.032). Primary tumour site was also significantly associated with survival (p < 0.01), with worse survival for right-sided tumours (6.6 months), compared to 14.0 months for left-sided/rectal tumours. Using multivariate analysis, independent prognostic markers were PS, presence of lymph node metastasis, presence of peritoneal metastasis and right-sided primary tumour location. This is a representative cohort of BRAF V600E metastatic colorectal cancer patients, which confirms previously known clinical features. Of the common metastatic sites, peritoneal or lymph node metastases confer a poorer prognosis. There was not widespread adoption of more intensive triplet chemotherapy over the study time period. Overall survival is poor, and changed treatment strategies facilitated by recent clinical trial advances with targeted therapies may improve outcomes in this poor prognostic group.

Abstract PR003: Integration of clonal composition and tumor heterogeneity reveals novel evolutionary states and intervention targets in ovarian cancer

Abstract High-grade serous ovarian cancer (HGSC) is the most common form of epithelial ovarian cancer, typically diagnosed at advanced stage with five-year survival of only 38%. Herein, we used 149 treatment-naïve and 65 after-treatment samples subjected to whole-genome sequencing from 55 HGSC patients to reconstruct evolutionary histories, characterize clonal compositions and intra- and inter-tumor heterogeneity, in order to identify mechanisms that drive treatment failure. Using clonal information from the phylogenetic trees we quantified intra- and intertumor heterogeneity and identified three types of clonal compositions corresponding to three evolutionary states (“adaptive”, “maintaining” and “evolving”) of treatment-naïve HGSC tumors. The branch depths from phylogenetic trees were used to quantify “clonal age” for each state. The “adaptive” state showed the highest clonal age, followed by the “maintaining” state, and the “evolving” being the youngest, least evolved tumor state. The three states have significantly different survival association, “evolving” the longest and “maintaining” the shortest (p = 0.029). Pathway analysis of genes harboring branch mutations revealed that the three states are characterized by unique signaling cascades, with MAPK, PI3K/AKT, and NOTCH signaling significantly enriched at “evolving”, “maintaining”, and “adaptive” states, respectively. Furthermore, we suggest two evolutionary trajectories originating from “evolving” state towards “maintaining” via PI3K/AKT activation and extensive cytokine signaling or towards “adaptive” state via RAS/RAF/MAP cascade. Overall, altered PI3K/AKT signaling was found in half of the patients, followed by alterations in NOTCH signaling enriched in 20% of patients. To explore the effect of treatment on evolutionary states we investigated clonal compositions and enriched pathways in the after-treatment samples. Interestingly, 62% of the neoadjuvant chemotherapy treated (three cycles of platinum &amp; paclitaxel) samples remained in the same evolutionary state as compared to the treatment-naïve samples from the same patients, indicating that the neoadjuvant therapy does not significantly alter tumor composition. Analysis of relapse samples revealed that signal transduction via PI3K/AKT and NOTCH was enriched after the full course of treatment (including platinum-taxane chemotherapy, surgery, possible maintenance therapy with PARP inhibitors or angiogenesis inhibitors), which testifies for their central role in treatment failure. Taken together, our results show that integrating clonal composition and heterogeneity at diagnosis allows allocation of HGSC tumors into three states with different prognosis. Aberrations in PI3K/AKT or NOTCH signaling, distinctive for higher evolved “maintaining” and “adaptive” states, are key pathways to the development of chemoresistant clones. As the herein identified pathways can be targeted by several clinically approved drugs, our results provide a means to identify effective, combinatorial personalized treatments for HGSC patients at the relapse setting. Citation Format: Alexandra Lahtinen, Kari Lavikka, Yilin Li, Sanaz Jamalzadeh, Anni Virtanen, Rainer Lehtonen, Olli Carpén, Sakari Hietanen, Kaisa Huhtinen, Antti Häkkinen, Johanna Hynninen, Jaana Oikkonen, Sampsa Hautaniemi. Integration of clonal composition and tumor heterogeneity reveals novel evolutionary states and intervention targets in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR003.

Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment.

Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. We determined if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Радиоволновая электротерапия с радиочастотой 448 кгц в лечении пациентов с органической эректильной дисфункцией: проспективное рандомизированное простое слепое Sham-контролируемое исследование в параллельных группах

To evaluate the efficiency of radio wave electrotherapy (448 kHz) for the treatment of patients with organic erectile dysfunction (ED).A prospective, randomized, blind, sham- controlled clinical trial was carried out. Inclusion criteria were as following: 1) patients with 5 to 20 points on the IIEF-5 score; 2) patients with proven organic erectile dysfunction lasting at least 6 months; 3) patients with penile arterial insufficiency and/or venous insufficiency, confirmed by doppler study of penile vessels with pharmacological stimulation (peak systolic velocity (PSV) <25 cm/s, end-diastolic blood flow velocity (DPV) >5 cm/s, resistance index (IR) < 0.8). The participants were randomized into two groups (experimental and control) in a 1:1 ratio. The full treatment course lasted 9 weeks. Patients underwent an assessment of erectile function based on questionnaires (IIEF-5, SEP, Schramek), as well as Doppler ultrasound of the cavernous arteries before inclusion in the study as well as a after treatment.The study included 61 men (experimental group [n=31], control group [n=30]. There was a significant difference in the IIEF-5 scores after treatment between the experimental group and the control group (19.5+/-3.2 vs. 15.1+/-5.4, p=0.017, respectively). Significant differences were also noted in mean total score of the SEP questionnaire: an increase to 3.6+/-1.0 in the treatment group compared to 2.4+/-1.1 in the control group (p=0.004). The results of the Schramek questionnaire also demonstrated a significant increase in the mean score in the experimental group compared to the control group: 4.2+/-0.6 vs. 3.2+/-1.0 (p=0.011). The response time to the drug and the detumescence time also significantly differed between the two groups: 11.9+/-4.0 min vs. 15.5+/-4.1 min, p=0.001 and 126.6+/-60.7 min vs. 66.2+/-40.9, p<0.001, respectively. Neither complications nor any adverse events were recorded during treatment or after its completion.Radio wave electrotherapy with a radiofrequency of 448 kHz can improve the IIEF-5, SEP and Schramek scores, as well as the indicators of ultrasound Doppler ultrasonography in patients with organic ED. To assess the feasibility of this method in patients with organic ED of different stages, further studies are needed.

Real-world effectiveness and safety of fingolimod in patients with multiple\xa0sclerosis in the Czech Republic: results from core and extension parts of the GOLEMS study up to 48\xa0months

BackgroundFingolimod, an oral sphingosine 1-phosphate receptor immunomodulator, is approved in Europe for people with multiple sclerosis (pwMS) with highly active disease despite a full and adequate course of treatment with ≥ 1 disease-modifying therapy or patients with rapidly evolving severe relapsing–remitting MS. GOLEMS, a national, multicenter, non-interventional, single-arm, real-world study showed a favorable benefit–risk profile of 12-month treatment with fingolimod in pwMS in the Czech Republic. Here, we evaluated the long-term effectiveness and safety of fingolimod and its impact on disability progression and work capability for up to 48 months in pwMS.MethodsThe endpoints assessed were the incidence and severity of MS relapses in fingolimod-treated patients and the proportion of relapse-free patients up to 48 months of fingolimod treatment, change from baseline in the Expanded Disability Status Scale (EDSS) score, and change from baseline in work capability assessment. Efficacy outcomes were analyzed in the completed and efficacy sets, and safety was evaluated in all the enrolled patients.ResultsOf 240 enrolled patients, 237 were included into efficacy set. Patients with a minimum of a 12-month observation period in the core study who continued fingolimod treatment, were eligible to participate in the extension phase. Of 211 patients enrolled in extension study, 155 were evaluated in the completed set. Based on analysis of 48-month period of fingolimod treatment, 95/237 patients (40.1%) in the efficacy set, 54/155 (34.8%) in the completed set were free of relapses. The majority of relapses reported were moderate in intensity. Mean EDSS score remained stable throughout 48-month study period (Baseline, 3.4; Month 48, 3.6). No trend was observed in changes in work capability assessment or number of missed days of work. Of 240 enrolled patients, 147 (61.3%) had ≥ 1 treatment-emergent adverse event (AE) and 20 (8.3%) reported serious AEs. In total, 45 patients (18.8%) permanently discontinued treatment because of AEs related to study drug; two patients reported pregnancy after treatment initiation and subsequently discontinued the treatment; no deaths were reported.ConclusionGOLEMS study demonstrated the sustained effectiveness and manageable safety profile of fingolimod under real-world conditions over 48 months in patients with MS.Trial registrationNot applicable.

Variety of effects of silicon dioxide colloid in the treatment of antibiotic-associated diarrhea in children

Antibiotic-associated diarrhea (AAD) is a key aspect of pediatrics concerning antibiotic therapy Purpose. The article aims at investigating the effects of colloidal silicon dioxide in the treatment of antibiotic-associated diarrhea in children. Materials and methods. Using parametric and nonparametric methods of analysis, 83 patients were examined (treatment group — 41 children who used colloidal silicon dioxide and the control group — 42 children) of both sexes (mean age (13.7 ± 2.6) years) with pathology of the lower respiratory tract (acute bronchitis or community-acquired pneumonia), who developed AAD against the background of ABT. Results. When using colloidal silicon dioxide in 75.6% of children, diarrhea decreased by the 2nd day and stopped by the 4th day (median — 0 points). Against the background of taking the drug throughout the treatment, there was a marked 3-fold decrease in all AAD values. The assessment of the efficacy and safety of the drug according to the data of medical researchers was 3.4 points. Analysis of subjective data on the tolerability of the drug showed «excellent» and «good». Against the background of the full course of treatment with colloidal silicon dioxide, a 2 times more pronounced decrease in the characteristics of AAD was noted. Conclusion. The presented data are intended to focus the attention of pediatricians on the rational use of ABT, timely diagnosis of an unwanted drug reaction in the form of AAD and its correction. The studied drug showed high efficacy and safety, which makes it possible to recommend it as a symptomatic treatment of diarrhea that developed against the background of ABT treatment in the complex therapy of diseases of the lower respiratory tract in children.

Virtual Screening for the Discovery of Microbiome β-Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity.

Despite the potency of most first-line anti-cancer drugs, nonadherence to these drug regimens remains high and is attributable to the prevalence of "off-target" drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5'-diphospho-glucuronosyltransferases through homeostatic host metabolism to form drug-glucuronide conjugates. These sugar-conjugated metabolites are generally inactive and can be safely excreted via the biliary system into the gastrointestinal tract. However, β-glucuronidase (βGUS) enzymes expressed by commensal gut bacteria can remove the glucuronic acid moiety, producing the reactivated drug and triggering dose-limiting side effects. Small-molecule βGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of novel chemical series of βGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for βGUS and applied them to large-scale vHTS against nearly 400,000 compounds within the chemical libraries of the National Center for Advancing Translational Sciences at the National Institutes of Health. From the vHTS results, we cherry-picked 291 compounds via a multifactor prioritization procedure, providing 69 diverse compounds that exhibited positive inhibitory activity in a follow-up βGUS biochemical assay in vitro. Our findings correspond to a hit rate of 24% and could inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with first-line, standard-of-care anti-cancer drugs.

Dropout from evidence-based trauma treatment in a community mental health clinic serving victims of interpersonal violence.

Trauma-focused psychotherapies are increasingly offered in community-based mental health centers, but little is known about treatment dropout in these settings. The current study explored dropout at different stages of treatment in a treatment-seeking sample of 1,186 adults who experienced interpersonal violence and were offered trauma-focused and non-trauma-focused therapies. A total of 31.6% of participants dropped out before treatment initiation, 28.0% dropped out after treatment initiation and completed a mean of 4.02 (SD = 2.41) sessions, and 40.4% completed a full course of PTSD treatment. Being unemployed, p < .001, and scoring lower on measures of environment factors, p = .045, were significant predictors of pretreatment dropout. Being female, p < .001; Latinx, p = .032; and scoring higher on a measure of social relationships, p = .024, were independent predictors of postinitiation dropout. Individuals who completed nine sessions of treatment displayed significantly lower levels of posttraumatic stress disorder, depression, and anxiety symptoms. The present study provides preliminary evidence that survivors of interpersonal violence who seek therapy tend to drop out early during treatment, and most who complete treatment attain symptom reduction.

Experience with cladribine tablets for highly active multiple sclerosis in real clinical practice

Objective: to evaluate the efficacy and safety of cladribine tablets as a treatment for immune reconstitution of highly active multiple sclerosis (HAMS) in general clinical practice.Patients and methods. 34 patients with HAMS who were followed up at the Moscow Multiple Sclerosis Center in 2018–2021 received two full treatment courses. HAMS diagnosis was established in the presence of two or more exacerbations per year without treatment or one exacerbation in patients receiving pathogenetic treatment in the presence of concomitant manifestations of the activity of the pathological process on MRI. Before initiation of cladribine therapy, the median exacerbation rate was 2.3 per year, i.e., 34 patients per year had a total of 78 exacerbations.Results and discussion. Only two clinical exacerbations were registered (one each in the first and second year) during two years of treatment among all 34 patients, the average frequency of exacerbations was 0.05 per year; in three cases, a subclinical exacerbation was noted - new Gd+ lesions on T2-weighted images on MRI, the total number of events was 0.15 per year. No significant adverse events were reported.Conclusion. Cladribine tablets are a highly effective and safe treatment option for HAMS.

Effectiveness and safety of artesunate\u2013amodiaquine versus artemether\u2013lumefantrine for home-based treatment of uncomplicated Plasmodium falciparum malaria among children 6\u2013120\xa0months in Yaound\xe9, Cameroon: a randomized trial

BackgroundMany studies have reported high efficacy and safety of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) when administered under direct observation in Cameroon. There is paucity of data to support their continuous use in home-based treatment of uncomplicated Plasmodium falciparum malaria in Cameroon. Hence, this study aimed to assess the effectiveness and safety of AS-AQ versus AL for home-based treatment of uncomplicated P. falciparum malaria among children 6–120 months in Yaoundé, Cameroon.MethodsA two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) was carried out from May 2019 to April 2020 at two secondary hospitals in Yaoundé. Participants were randomized to receive either AS-AQ or AL. After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff. The conventional on-treatment and post-treatment laboratory and clinical evaluations were not done until day 3 of the full antimalarial treatment course. The evaluation of effectiveness was mainly based on per protocol polymerase chain reaction adjusted adequate clinical and parasitological response (PP PCR adjusted ACPR) on day 28 post-treatment. Safety was based on assessment of adverse events (AEs) and severe adverse events (SAEs) from day 1 to day 28.ResultsA total of 242 children were randomized to receive AS-AQ (n = 114) and AL (n = 128). The PP PCR adjusted day 28 cure rates were [AS-AQ = 96.9% (95% CI, 91.2–99.4) versus AL = 95.5% (95% CI, 89.9–98.5), P = 0.797]. Expected mild to moderate adverse events were reported in both arms [AS-AQ = 83 (84.7%) versus AL = 99 (86.1%), P = 0.774]. The most common adverse events included: transient changes of hematologic indices and fever.ConclusionsThis study demonstrated that AS-AQ and AL are effective and safe for home management of malaria in Yaoundé. The evidence from this study supports the parallel use of the two drugs in routine practice. However, the findings from this study do not describe the likely duration of antimalarial effectiveness in holoendemic areas where multiple courses of treatment might be required.Trial registration: This study is a randomized controlled trial and it was retrospectively registered on 23/09/2020 at ClinicalTrials.gov with registration number NCT04565184.

Randomized phase II trial of neoadjuvant abiraterone plus or minus cabazitaxel in high-risk prostate cancer: ACDC-RP.

224 Background: High-risk prostate cancer has a significant risk of recurrence when treated with unimodal therapy. The utility of neoadjuvant therapy prior to radical prostatectomy (RP) has yet to be defined. The ACDC-RP study investigated the use of abiraterone acetate (AA) + prednisone (P) + leuprolide (LHRH) with or without cabazitaxel prior to RP in high-risk patients. Methods: This phase II trial randomized patients to Arm A (AA/P + LHRH + cabazitaxel 20 mg/m2 with peg-filgrastim 6 cycles) or Arm B (AA/P + LHRH) for 6 months prior to RP. The primary objective was to compare the rate of pathological complete response (CR) or minimal residual disease (MRD) between treatment arms. MRD was defined as ≤5% of prostate volume involved by tumor. We present RP pathological outcomes, safety signals, and early biochemical response data. Results: Out of 78 randomized participants, 70 completed the full course of study treatment and underwent RP. Across both treatment arms, 31 (44%) men achieved either CR or MRD; 5 men had CR (2 in Arm A) and an additional 26 men exhibited MRD (15 in Arm A), p = 1 between Arm A and B. Kaplan-Meier analysis demonstrated no difference in biochemical-free survival (BFS) rate between the two treatment groups. Patients who achieved a CR/MRD experienced significantly longer BFS. Conclusions: Study findings indicate significant tumor response with 44% of patients exhibiting CR/MRD, with no significant difference observed between the two treatment arms. Patients who exhibit CR/MRD experienced better BFS rates. Genomic efforts are underway to determine predictors of response. Clinical trial information: NCT02543255. [Table: see text]

Understanding non-routine discharge: Factors that are associated with premature termination from higher levels of care in adults with anorexia nervosa

ABSTRACT This study sought to replicate and extend associations between clinical and demographic features at admission and types of premature treatment termination for adults diagnosed with anorexia nervosa (AN) in higher-level-of-care settings. Secondary data analyses examined a study population comprised of adults with AN (N = 565) who were admitted to one of two United States eating disorder treatment centers (April 2015–April 2020) for intensive outpatient, partial hospitalization, residential, or inpatient services. There were no significant differences in the type of non-routine discharge according to level of care. At admission, those with lower BMI were more likely to discharge against medical advice, and those with lower cognitive restraint and elevated binge eating were more likely to discharge against medical advice or by staff-initiated request, respectively. Discharge by parent/patient request was more likely among those who were older or who reported lower baseline desire for muscularity. Overall older age, elevated binge eating, and lower weight, desire for muscularity, and cognitive restraint may be associated with less tolerance/acceptability for AN treatment. Increased understanding of how to better support patients who admit to higher levels of care with these clinical features will contribute to better odds of completion of a full course of treatment.

The Effectiveness of Traditional Chinese Medicine Combined With Surgery to Treat Granulomatous Mastitis: A Propensity-Matched Analysis.

PurposeThe etiology and pathology of granulomatous mastitis (GLM) are still unknown. Expert consensus on the treatment of GLM has not been developed. The objective of this study is to study the effectiveness of traditional Chinese medicine (TCM) combined with surgery in treating GLM.Materials and MethodsA retrospective cohort study was implemented at Longhua Hospital of Shanghai University of Traditional Chinese Medicine in China between September 2019 and August 2021. Female patients were included according to the propensity-score matching (PSM) method and balanced according to age and BMI. Patients with GLM diagnosed by pathology and a course of disease ≥ 6 months were included in this trial. Patients were divided into the TCM alone group or TCM + surgery group.ResultsIn total, 168 female patients were assessed and 102 patients were included in the study after PSM (51 in the TCM group and 51 in the TCM + surgery group). The average age of the patients was 32 years (21-47 years). There was no significant baseline characteristics difference between two groups after PSM. The suppuration rate in the TCM + surgery group was less than that in the TCM group (64.7% vs. 83.35%, P < 0.05), and the TCM + surgery group had a higher 9-month cure rate than the TCM group (86.3% vs. 52.9%, P < 0.05). The full course of disease in the TCM + surgery group was shorter than that in the TCM group (253.9 ± 117.3 days vs. 332.5 ± 111.6 days, P < 0.05).ConclusionsTCM combined with surgery can improve the cure rate and shorten the full course of GLM treatment, indicating surgery should be integrated in the clinical management of GLM.

Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary.

People with multiple sclerosis (also shortened to MS) may have difficulties staying on treatment due to side effects. Cladribine tablets, approved for treating relapsing forms of MS, are given by mouth for four short periods over two years. The benefit of convenient dosing may be lost if side effects prevent people with MS from finishing their treatment. This is the summary of a study that examined side effects from cladribine tablets treatment in the first 12 weeks of two clinical studies called CLARITY and ORACLE-MS. Overall, 34.7% of participants who took cladribine tablets experienced drug-related side effects compared to 23.2% of participants who took placebo. Most side effects were mild and were seen in 54.8% of participants taking cladribine tablets and 59.1% taking the placebo. A low number of participants discontinued treatment due to side effects (1.6% of participants who took cladribine tablets; 1.4% of participants who took placebo). The researchers concluded that cladribine tablets are well-tolerated and people with MS are likely to complete the full treatment course. ClinicalTrials.gov NCT numbers: CLARITY study - NCT00213135 and ORACLE-MS study - NCT00725985.

Topical Treatment of Recurrent Vulvovaginal Candidiasis: An Expert Consensus.

Background: Recurrent vulvovaginal candidiasis (RVVC), defined as three or more confirmed infections over 1 year, occurs in up to 10% of women. In these women, the objective is often symptomatic control rather than mycologic cure. Current Centers for Disease Control and Prevention (CDC) guidelines recommend oral fluconazole as first-line maintenance, but state if this oral regimen is not feasible, intermittent topical treatments can be considered. No specific recommendations for type or frequency of topical applications are provided by the CDC.Methods: A panel of vulvovaginal experts convened to develop a consensus recommendation for topical maintenance dosing for RVVC.Results: Data suggest that clotrimazole, miconazole, terconazole, and intravaginal boric acid are suggested recommendations for recurrent vulvovaginitis caused by both Candida albicans and nonalbicans species. Nystatin ovules may not be as effective as azoles. Identification of species will influence treatment decisions. In addition, treatment may be modified based on prior response to a specific agent, especially in nonalbicans species. Fluconazole, ibrexafungerp, and intravaginal boric acid should be avoided during pregnancy.Conclusions: The expert consensus for women with RVVC is an initial full course of treatment followed by topical maintenance beginning at one to three times weekly, based on chosen agent. Twice a week dosing was the regimen most often utilized. In some women, episodic treatment may be used, but maintenance should remain an option for this population.

White matter markers and predictors for subject-specific rTMS response in major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) has established therapeutic efficacy for major depressive disorder (MDD). While translational research has focused primarily on understanding the mechanism of action of TMS on functional activation and connectivity, the effects on structural connectivity remain largely unknown especially when rTMS is applied using subject-specific brain targets. This study aims to use novel diffusion magnetic resonance imaging (dMRI) analysis to examine microstructural changes related to rTMS treatment response using a unique cohort of 21 patients with MDD treated using rTMS with subject-specific targets. White matter dMRI microstructural measures and clinical scores were captured before and after the full course of treatment. We defined disease-relevant fiber bundles connected to different subregions of the left prefrontal cortex and analyzed changes in diffusion properties as well as correlations between the changes of dMRI measures and the changes in Hamilton Depression Rating Scale (HAMD). No significant changes were observed in tracts connected to the TMS targets. rTMS significantly increased the extra-axonal free-water volume, fractional anisotropy and decreased the radial diffusivity in anterior-medial prefrontal fiber bundles but did not lead to raw changes in lateral prefrontal tracts. That said, the microstructural changes in the lateral prefrontal white matter were significantly correlated with treatment response. Moreover, pre-rTMS dMRI measures of the dorsal anterior cingulate cortex and lateral prefrontal cortex connections are correlated with changes in HAMD scores. Microstructural changes in the anterior-medial and lateral prefrontal white matter are potentially involved in treatment response to TMS, though further investigation is needed using larger datasets.

Investigating EEG biomarkers of clinical response to low frequency rTMS in depression

Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention for major depressive disorder (MDD). Completing a full treatment course, however, is costly and time-consuming. Biomarkers of clinical outcome such as baseline resting-state brain activity measured with electroencephalography (EEG) may spare people futile treatment and conserve limited clinical resources. Additionally, investigating changes in EEG power post-treatment could provide insights into the working mechanism of rTMS. 39 MDD patients received 6 daily sessions of accelerated low-frequency (LF) rTMS over the right dorsolateral prefrontal cortex (DLPFC) for 5 days followed by a tapering course of 25 once-daily sessions. Resting-state EEG and heart rate (HR) measures were acquired immediately before and after a single rTMS session at 3 different timepoints: baseline, one week after the final accelerated session, and upon completion of the tapering course. The primary clinical outcome measure was the Beck Depression Inventory II (BDI-II). High relative baseline theta power in prefrontal areas and high baseline HR were associated with poorer clinical outcome. HR decreased acutely at the beginning of the patients’ first rTMS session but this effect was not associated with treatment outcome. The main limitations were small sample size and a lack of sham and healthy control group. Our results suggest that high relative theta power at baseline may be a marker of poorer response to right-sided LF rTMS. If validated, this easily applicable measure could inform rTMS protocol choice for the individual, thereby potentially speeding up patient recovery and saving clinical resources.