Standard Of Care For Treatment Research Articles

Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.

Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300-1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.

LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration

BackgroundPediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use.MethodsLOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator’s choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate.DiscussionThe promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG.Trial registrationClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

Additive value of superficial parasternal intercostal plane block and serratus anterior plane block in lung transplantation surgery: a retrospective exploratory study

BackgroundAdequate pain control following lung transplantation (LTx) surgery is paramount. Thoracic epidural analgesia (TEA) is the gold standard; however, the potential use of extracorporeal membrane oxygenation (ECMO) and consequent anticoagulation...

Efficacy and safety of acupuncture in treating low back and pelvic girdle pain during pregnancy: A systematic review and meta-analysis of randomized controlled trials

Background: Low back and pelvic girdle pain (LBPGP) is common during pregnancy. Acupuncture is an effective and safe therapy for pain relief. However, further evidence is required to confirm the efficacy and safety of acupuncture in treating LBPGP during pregnancy. Objectives: This study aimed to systematically review and investigate the clinical efficacy and safety of acupuncture for the treatment of pregnancy-related LBPGP. Methods: The PubMed, EMBASE, Cochrane Library, CNKI, VIP, and WanFang databases were searched from January 2000 to August 2023. Only the randomized controlled trials (RCTs) involving pregnant women between 16 and 34 weeks of gestation diagnosed with LBPGP were included in the study. A meta-analysis was conducted and pooled risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs) were compared. Results: Meta-analysis included 12 RCTs involving 1641 participants. Eleven trials compared acupuncture alone or acupuncture combined with standard care (SC), of which three trials also used nonpenetrating or placebo acupuncture as the control group. One trial compared acupuncture alone with nonpenetrating acupuncture. Compared with SC, acupuncture combined with SC group significantly decreased visual analog scale score (MD = −2.83, 95%CI = −3.41 to −2.26, P ＜ 0.00001), cesarean section rate (RR = 0.69, 95%CI = 0.49 to 0.97, P = 0.03), preterm birth rate (RR = 0.42, 95%CI = 0.27 to 0.65, P &lt; 0.0001), labor duration (MD = −1.97, 95%CI = −2.73 to −1.20, P &lt; 0.0001), and Oswestry disability index score (MD = −9.14, 95%CI = −15.68 to −2.42, P =0.008). In addition, acupuncture combined with SC significantly improved SF-PCS. No significant differences were observed in the spontaneous delivery rate, newborn weight, drowsiness, and SF-MSC between the two groups. Adverse events such as needle pain and needle bleeding were aggravated in both the SC and acupuncture treatment groups but none were associated with acupuncture during or after the treatment period. Conclusions: Meta-analysis showed that acupuncture combined with SC had better efficacy than SC alone and could be a potential therapy for LBPGP during pregnancy. The safety results imply that acupuncture caused few adverse reactions; however, more evidence is required for further confirmation.

Acetazolamide for acute kidney injury in patients undergoing high dose methotrexate therapy: a systematic review and meta-analysis.

Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictoryevidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate. The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently. Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48-1.29, P = 0.34, I2 = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI - 1.9 to 2.04, P = 0.95, I2 = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI -0.8 to 2.31, P = 0.34, I2 = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group). This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication.

Immune checkpoint blockade in hematological malignancies: current state and future potential.

Malignant cells are known to evade immune surveillance by engaging immune checkpoints which are negative regulators of the immune system. By restoring the T-lymphocyte mediated anti-tumor effect, immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors but have met rather modest success in hematological malignancies. Currently, the only FDA approved indications for ICI therapy are in classic hodgkin lymphoma and primary mediastinal B cell lymphoma. Multiple clinical trials have assessed ICI therapy alone and in combination with standard of care treatments in other lymphomas, plasma cell neoplasms and myeloid neoplasms but were noted to have limited efficacy. These trials mostly focused on PD-1/PDL-1 and CTLA-4 inhibitors. Recently, there has been an effort to target other T-lymphocyte checkpoints like LAG-3, TIM-3, TIGIT along with improving strategies of PD-1/PDL-1 and CTLA-4 inhibition. Drugs targeting the macrophage checkpoint, CD47, are also being tested. Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies.

New standards of care for treatment of diffuse large B-cell lymphoma.

Treatment of newly diagnosed diffuse large B-cell lymphoma with rituximab and CHOP (R-CHOP) has been largely unchanged for the last two decades. The Guideline by Fox etal. provides new evidence-based therapeutic strategies informed by positive results of randomised clinical trials. Commentary on: Fox etal. The management of newly diagnosed large B-cell lymphoma: A British Society for Haematology Guideline. Br J Haematol 2024; 204:1178-1192.

A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with CAPRIN-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS420 Background: CAPRIN-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-1.1 In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. CAPRIN-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients.2 A Phase II clinical trial in gastric/GEJ cancer patients with strong CAPRIN-1 is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with CAPRIN-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in stage 2. In total 146 patients will be enrolled (40 patients in one arm and 53 patients in the other two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .

Dialysis and Nutrition: Optimizing Dietary Support for Patients Undergoing Blood Purification

This study evaluated the effectiveness of individualized dietary interventions in improving the nutritional status and general health of individuals undergoing dialysis. A total of 120 patients undergoing dialysis were equally allocated to the Standard Care Group and Intervention Group. The recipients of individualized dietary counseling had their plans modified monthly in accordance with their nutritional needs, personal preferences, and clinical circumstances. Nutritional adherence, biochemical parameters, clinical outcomes, and quality of life were evaluated and compared between groups. At baseline, both groups exhibited comparable demographic characteristics. Compared to baseline values, the Intervention Group showed substantial enhancements in albumin, hemoglobin, potassium, and phosphorus levels after six months (P &lt; 0.05). The Intervention Group had a considerably higher rate of adherence to dietary recommendations than the Standard Care Group (92% vs. 75%, P &lt; 0.01). Nutritional intake analyses revealed a noteworthy enhancement in energy and protein consumption, while sodium, potassium, and phosphorus intake decreased (P &lt; 0.05). The results of the quality-of-life evaluation demonstrated notable improvements in physical, emotional, social, and overall health perception scores (P &lt; 0.05). Thus, personalized dietary interventions substantially improve the nutritional status, biochemical profile, and overall quality of life of patients undergoing dialysis.

Abstract A072: Keratin 17-signature for stratification of chemotherapy in pancreatic adenocarcinoma

Abstract Introduction: Keratin 17 (K17) is a hallmark of the most aggressive molecular subtype of pancreatic ductal adenocarcinoma (PDAC). However, it is still unknown if K17 can predict the response to the two standard-of care treatments for PDAC: 1) 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FFX) and 2) Gemcitabine/nab-paclitaxel (Gem/Nab). Thus, we hypothesized that K17 expression in patient tumors could be utilized as a biomarker to guide clinical decision-making in predicting the most effective standard-of-care treatment for patients with PDAC. Given that 85% of patients do not undergo resection, to circumvent this limitation we tested the predictive value of K17 using the tissue collected during endoscopic biopsies, which are routine in PDAC diagnosis. Methods: Our pilot study included 68 patients diagnosed with PDAC from Yale-New Haven Hospital treated with either FFX or Gem/Nab. Endoscopic biopsies were evaluated for tumor cellularity and then underwent an immunohistochemical (IHC)-based K17 test using the ABC detection method. Samples were scored by two independent pathologists using the PathSQ method. Results: Of the 68 patients included in the study, 20 (29.4%) were treated with Gem/Nab and 48 (70.6%) were treated with FFX. Based on Akaike’s Information Criterion, a K17 threshold of 45% and 60% were found to maximize stratification of patients by therapy response. At the 45% cutoff, 17 (25.0%) patients were found to have high K17 expression. At the 60% cutoff, 12 (17.6%) patients were found to have high K17 expression. Patients with low K17 expression were found to have similar overall survival (OS) despite treatment. However, patients with high K17 expression both at the 45% cutoff (p=0.031 and HR = 2.68 (CI 0.8, 8.99)) and 60% cutoff (p=0.006, HR = 6.79 (1.20, 38.32)) had decreased survival when treated with Gem/Nab compared to FFX. Conclusions: Patients with high K17 expression had lower overall survival than those with low K17 expression, validating our previous findings of K17 as a negative prognostic biomarker in PDAC. High K17 expression may be a promising predictive biomarker in PDAC, with an observed increase in OS in high K17-expressing patients treated with FFX compared to patients treated with Gem/Nab, indicating a potential biomarker to best determine response to standard-of-care treatments. Citation Format: Sumedha Chowdhury, Deanne Yugawa, Robert Tseng, Mauricio Mejia, Jill Lacy, Timil Patel, Luisa Escobar-Hoyos, Kenneth Shroyer, Guoping Cai, Marie Robert, Michael Cecchini, John Kunstman, James Farrell, Kimberly Johung. Keratin 17-signature for stratification of chemotherapy in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A072.

Subcutaneous Marzeptacog Alfa (Activated) for On-Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors.

Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in patients with hemophilia A/B and was studied in a phase III trial evaluating MarzAA compared with standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized four-point efficacy scale (poor, fair, good, and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure (poor/fair), and treatment success (good/excellent)). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (> 33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (≤ 3 hours) whereas at later timepoints (> 12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (P < 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.

Clinical Uses of Nanopore Sequencing in Recurrent Acute and Chronic Otitis Media

Background. Otitis Media (OM) is a widespread problem that has an incidence of 10.85% worldwide, 51% occurring under the age of 5. Emergence of drug resistant bacteria contribute to high incidence of recurrent acute otitis media (AOM) and chronic otitis media with effusion (COME). Despite this, the standard of care for treatment is empiric antibiotics. Molecular microbiology diagnostics may enable clinicians to provided pathogen directed antibiosis. Nanopore sequencing is a highly accurate method of identifying a broad range of pathogens when compared with multiplex PCR. We hypothesize that nanopore sequencing is an effective method for detection of pathogens in the middle ear and nasopharynx of patients with recurrent or chronic OM.&#x0D; Methods. Bacterial Culture, multiplex PCR (BioFire PNA panel), and nanopore sequencing (MinIon, Oxford Nanopore Technologies) were tested on 60 middle ear and nasopharynx samples. Chi-Square test was used to examined differences in bacterial identification among the methods.&#x0D; Results. Bacterial identification using nanopore proves to be more sensitive in identification of 16 of the 18 unique pathogens when compared with multiplex testing. Of the 5 most common OM bacterial pathogens (S. pneumoniae, M. catarrhalis, H. influenza, S. aureus, P. aeruginosa), nanopore identified 3 pathogens (S. pneumoniae, M. catarrhalis, P. aeruginosa) at higher levels, 1 at the same rate (H. influenza), and 1 did not receive any readings (S. aureus).&#x0D; Conclusion. This is the first study to utilize nanopore sequencing to assess pathogens in the middle ear fluid of children with OM. While nanopore genomic sequencing is still in the early stages of use, it has potential to comprehensively identify bacteria with more sensitivity when compared to the current clinical standards. The next step of data analyzation will include bacterial identification in nanopore that multiplex PCR and traditional bacterial cultures cannot test for.

Role of Ivermectin and Colchicine in Treatment of COVID-19: A Randomized Controlled Clinical Trial

Objective: To assess the effectiveness of ivermectin and colchicine as treatment options for COVID-19. Patients and methods: A three-arm randomized controlled clinical trial was conducted in triage clinic of family medicine department at Ain Shams University Hospitals on participants who had been diagnosed as COVID-19 patients with moderate severity. Patients aged &lt;18 years or &gt;65 years with any co-morbidities, pregnant or lactating female and with mild or severe COVID-19 confirmed cases were excluded. Randomization was done by using sealed envelopes for intervention or control. Patients are followed up to improvement of patient’s symptoms with no development of new symptoms over one month. Results: A total of 120 patients with COVID-19 were enrolled in the study, 40 patients in each arm. Their mean age was 40.16(SD 10.74) years. Out of them, 44 (36.6%) were male, 76(63.4%) were female. Mean duration of symptoms was 9.58 (SD 2.206), 9.9 (SD 2.07), and 9.53 (SD 2.37) in the ivermectin, colchicine and control groups, respectively. Most patients (67.5%, 70% and 72.5%) cured with residual symptoms with no difference in between the ivermectin, colchicine and control groups, respectively (P&gt;0.05). Conclusion: Ivermectin and colchicine have no beneficial effect over the standard care in treatment of COVID-19.

Immunological Effect of the drug “Immune”- an Ayurveda medication in COVID-19 patients- A Randomized Control Trial

Introduction: The Pandemic of SARS COV-2 continues to be a global health threat which has affected 140 million cases all over the world with 3.01million deaths with the main underlying main cause of raised inflammatory markers. India is well known for the birth of Ayurveda – the potential therapeutic agents have been developed having combination of already proven drugs for research. Objectives: To measure the effect of drug- “Immune” on the neutralizing antibody levels along with inflammatory markers among mild to moderate symptomatic COVID-19 subjects. Material and methods: Triple blinded Randomized Controlled Trial was adopted in our study among mild and moderate cases of COVID-19. Two groups- each having 25 subjects were intervened along with standard care of treatment where one was getting the drug immune consisting of Withania somnifera , glycrrhizine gabra , Cederus Deodara and Leptadenia Reticulata in Arka preparation and other were getting placebo which was blinded by labelling as drug A and Drug B. These two groups were followed up for antibody testing and inflammatory markers such as interleukin-6,D-dimer,serum ferritin and lactate dehydrogenase were also assessed. Results: There was a statistical significant rise in antibody titres(P value&lt;0.05) with drug A compared to drug B which was later revealed to be drug immune and we could also found reduction in inflammatory marker mainly lactate dehydrogenase. Conclusion: This drug “Immune” proved to be of clinical significance with raised antibody titre and reduction of some of the inflammatory markers. And this can play a pivotal therapeutic agent to reduce the morbidity and mortality associated with SARS COV-2

Plant medicine metabolite Yulinzhu treating neurological disorder causing polycystic ovary syndrome: a systematic review and a meta-analysis.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder that affects women of reproductive age, characterized by chronic anovulation, hyperandrogenism, and polycystic ovarian morphology. Emerging evidence indicates that neurological disorders play a significant role in the etiology of PCOS, highlighting the complex interplay between the central nervous system (CNS) and ovarian function. Yulinzhu, a traditional Chinese medicine (TCM) formulation, has been traditionally used to regulate menstrual cycles and improve fertility. This study aims to investigate the efficacy and mechanisms of Yulinzhu in treating PCOS induced by neurological disorders. An extensive literature search was performed across electronic databases such as PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI), covering publications up to 1 June 2024. The review included randomized controlled trials (RCTs) that compared Yulin Zhu with placebo, standard care, or other active treatments in patients with PCOS. Two reviewers independently carried out data extraction and quality assessment. Meta-analyses were conducted using both fixed and random-effects models, with heterogeneity evaluated using the I2 statistic. We screened 891 records and included 6 studi es in the meta-analysis. The meta-analysis revealed that Yulinzhu about effective rate [RR = 1.19, 95% CI (1.10, 1.29), p < 0.0001], pregnancy rate [RR = 2.80, 95% CI (1.65, 4.76), p < 0.0001] and ovulation rate [RR = 1.33, 95% CI (1.10, 1.62), p = 0.04]. Meta-analysis shows the results of follicle estrogen [WMD = 0.69, 95% CI (-0.39, 1.78), p = 0.21], luteinizing hormone [WMD = -2.27, 95% CI (-3.86, -0.67), p = 0.005], testosterone [WMD = -0.44, 95% CI (-0.64, -0.25), p < 0.0001], estradiol [WMD = 16.20, 95% CI (2.74, 29.67), p < 0.0001]. This study demonstrates that plant medicine compund Yulinzhu may effectively treats PCOS including hormonal regulation, anti-inflammatory actions, and neuroprotection. We expect further research with larger, well-designed clinical trials to substantiate our conclusions.

Effect of a short-term integrative program on clinical parameters of patients: Pilot study

Background: Combining conventional oncology with evidence-based complementary treatment approaches is an emerging field that aims to treat patients comprehensively to improve their well-being and spiritual and psychological needs. Objective: To evaluate the effectiveness of an integrative program comprising physical and psychological domains delivered for five consecutive days on several parameters of patients with different health issues. Methods: Eight patients (mean age 56.5 years) enrolled in the program as an add-on to their standard of care treatments. Their health parameters were measured at 3 points during the study: at baseline before the start of the intervention, on the fifth (last) day of the intervention, and four weeks after completion. Conclusion: An integrative intervention can provide non-pharmacologic recovery support that optimizes their well-being and reduces the symptom burden in patients

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus.

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model-based meta-analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG-based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate-level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti etal. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE.

Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab - Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017

Background: One of the key questions in trial AIEOP-BFM ALL 2017 focused on the reduction of treatment-related complications by replacing parts of the highly intensive consolidation phase by two courses of Blinatumomab (Blina) in a prospective randomized trial. Herein, we report the toxicity profile of B-cell acute lymphoblastic leukemia (B-ALL) patients (pts) with high-risk (HR) characteristics pending final outcome data. Patients and Methods: 728 pts with HR B-ALL were enrolled from July 15, 2018 to October 31, 2022 in this multicenter trial run in 8 different countries. Patients were included in the HR group in view of the presence of at least one of the following criteria: induction failure; high levels of minimal residual disease (MRD) at day 15 of induction, or at the end of induction (EOI), or at the end of consolidation (EOC); presence of KMT2A::AFF1, of IKZF1+ and positive MRD at EOI (Stanulla et al, JCO 2018), TCF3::HLF, or hypodiploidy. B-ALL pts with one or several of these characteristics represented 20.8% of all pts aged 0-18 years of age with B-ALL. After a 4-drug induction phase, and two weeks of consolidation treatment, patients were randomized to receive Bortezomib in addition to standard consolidation (not part of this report). Before treatment continued with intensive consolidation block HR-1', MRD was analyzed in order to identify patients eligible for subsequent hematopoietic stem cell transplantation (HSCT) based on MRD results. After block HR-1', all B-ALL HR pts were randomized to receive either two courses of consolidation (blocks HR-2', and HR-3'), or two 28-day courses of Blina at 15µg/m 2/d administered by continuous IV infusion (with a 2-week treatment-free interval). Two intrathecal injections of methotrexate (MTX) for CNS prophylaxis were given on days 1 and 29 of each Blina course, respectively. Out of 728 HR B-ALL pts, 619 pts were eligible for randomization [reasons for non-eligibility were: Event (death or relapse) before randomization was due (26), Down syndrome (25; scheduled for a non-randomized intervention with Blina), presence of TCF3::HLF (3; could receive any alternative therapy including Blina), discontinuation/substantial change of preceding therapy (23) or other protocol exclusion criteria (32)]. 572 pts were randomized (92.4% of those eligible). One pt assigned to the experimental arm (EA) and 4 pts assigned to the control arm (CA) received the other arms, respectively. Results: Toxicity was evaluated in randomized pts according to treatment administered during the randomized phase, respectively, until next element started: 268 pts were treated in the control and 281 in the EA (see Table). 16 of them switched in/after the first Blina cycle to the HR blocks due to toxicity or poor response to Blina (due to increasing MRD, &amp;gt;=1x10 -4). Medically relevant adverse reactions of special interest (ARSI) according to MedDRA (specified in the protocol) were evaluated in the randomized treatment phases (CA: HR-2‘/HR-3‘ block, EA: 2 Blina cycles). ARSI were recorded in 61 of 268 pts in the CA (22.8%, 71 ARSI) and in 29 of 281 pts in the EA (10.3% [p&amp;lt;0.001], 33 ARSI); 3 of the 33 ARSI in the EA were related to HR blocks and were observed in 3 of the 16 pts that switched to HR blocks. Life-threatening SAR were seen in 14 pts of the control group (5.2%) and in no patient in the EA (p&amp;lt;0.001). Conclusions: Taken together, these results show for the first time in newly diagnosed pts with HR B ALL, the favorable toxicity profile previously reported with Blinatumomab in pediatric relapsed ALL (Locatelli F et al, JAMA 2021; Brown P et al, JAMA 2021). We have demonstrated that the toxicity profile of Blinatumomab is much more favorable as compared to the intensive chemotherapy approach using HR-blocks. If upcoming analyses of outcome data will show no inferiority of the EA, blinatumomab replacement of some of the intensive chemotherapy blocks will become the new standard of care for treatment if newly diagnosed patients with HR B-ALL.

Management and Evolution after VTE Recurrence and/or Bleeding in Cancer Patients Receiving Anticoagulant Therapy for VTE: A Nationwide Cohort Study in France

CONCLUSION Until recently, the standard of care for treatment of venous thromboembolism ( VTE) in cancer patients was low molecular weight heparins (LMWH). Despite anticoagulation therapy (AC), patients remain at high risk of treatment failure (VTE recurrence and/or bleeding). To determine the characteristics, management and the course of treatment after experiencing a recurrent VTE and/or bleeding event in VTE cancer patients receiving LMWH. A nationwide retrospective cohort study of all adult patients (identified via the French national health data system: SNDS) with VTE and active cancer prescribed LMWH from 2013 to 2018. Of 31,771 patients administered LMWH, 1,256 patients (mean age 64.1 years) experienced a recurrent VTE (median time to the first recurrent VTE event: 1.2 months) and 1,129 patients (mean age 67.5 years) experienced a bleeding event leading to hospitalization (median time to the first bleeding event: 1.5 months) during the first six months, and among them 46.7% and 40.9% patients experienced the event within the first month. The proportion of patients with recurrent VTE and bleeding varied according to cancer sites (7.3%, 6.5% and 5.1% for recurrent VTE and 5.0%, 6.1% and 4.1% for bleeding, respectively in lung, colorectal and breast cancer) (Figure 1). The management of patients with recurrent VTE consisted of a switch to another AC treatment in 370 patients, in whom 262 switched to an oral AC (179 to a DOAC and 83 to a VKA), the remaining continuing LMWH. The management of patients with bleeding consisted of a switch to another AC treatment in 159 patients. Among the 159 switched patients, 94 switched to an oral AC (73 to a DOAC and 21 to a VKA), &amp;lt;10 stopped AC (Figure 2). Our results indicate that recurrent VTE and bleeding events lead to a heterogenous switch of AC therapy. Further research is needed to optimize secondary AC management in VTE cancer patients. This study was sponsored by Pfizer and Bristol Myers Squibb Keywords : venous thromboembolism; cancer; anticoagulants; bleeding; low molecular weight heparin; treatment pattern

Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report

Introduction T-cell acute lymphoblastic leukemia (T-ALL) is an orphan disease diagnosed mostly in adolescent and young adults. In adult population, 5-10% of T-ALL patients (pts) will be primary refractory and 30-40% will relapse. In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration. On behalf of the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), we launched the ALL-TARGET project combining a precision medicine platform dedicated to R/R T-ALL and T-cell lymphoblastic lymphoma (T-LL), and an observatory to evaluate therapeutic proposals based on mutational profile and intracellular signaling pathways alterations. Objectives and methods Leukemic samples from pts with R/R T-ALL/LL were shipped to the GRAALL T-ALL central laboratory in France (V. Asnafi, Hôpital Necker). Biological characterization comprised oncogenetic, phenotypic and in some cases functional analysis. Clinical data from R/R T-ALL/LL pts were collected in a real-life observatory (NCT05832125). Adults pts were eligible if an oncogenetic characterization was available at diagnosis or relapse, and if they received a salvage, either with conventional therapy or with a targeted therapeutic option (TTO). For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7R ALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3K ALT). The ALL-TARGET Observatory primary endpoint was overall response rate (ORR) including complete remission (CR), CR with incomplete hematological recovery and partial response. We report here the results of the first pts included, with a focus on those who received TTOs as salvage therapy. Results Eighty-nine were analyzed, including 80 T-ALL and 9 T-LL. Sex ratio was 3 and median age at diagnosis was 37.5y, and 51y at the time of the first TTO. Seventy-one pts were in relapse (79.7%) and 18 primary refractory (20.2%). Relapses occurred after a median first CR duration of 16.6 months (range: 2.5-92), with 62.8% in bone marrow, 30% in CNS and 30.3% in other extramedullary sites. Phenotype at diagnosis was available for 68 pts, including 36 Early T-cell Precursor (ETP or near-ETP) (52.9%), 6 immature non-ETP (8.8%), 20 cortical (29.4%) and 6 mature phenotype (8.8%). IL7R-expression was available for 53 pts, of whom 40 were IL7R+ (75.5%) and 13 IL7R- (24.5%). Out of 50 samples with available BCL2-expression, 47 were BCL2+ (94%) and 3 BCL2- (6%). IL7R ALT were evidenced in 41 pts (48.2%), PI3K ALT in 21 pts (24.7%), RAS pathway alterations (RAS ALT) in 19 pts (22.4%) and epigenetic dysregulation in 42 pts (49.4%). Ten pts harbored TP53/ATM mutations (11.7%) . These different alterations could coexist. At relapse, 33 phenotypes were reported, showing 22 ETP (66.6%), 2 immature non-ETP (6%) and 9 cortical (27.3%). IL7R-expression was available for 26 pts, among which 21 were IL7R+ (63.6%) and 5 IL7R- (19.2%). NGS was performed in 24 patients, revealing IL7R ALT in 9 pts (37.5%), PI3K ALT in 6 pts (25%), RAS ALT in 5 pts (20.8%) and epigenetic dysregulation in 15 pts (62.5%). Nine patients had TP53 mutations (37.5%). Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%). Among these, 8 were in first salvage (32%), 10 in 2 nd (40%), and 6 in 3 rd/4 th salvage (28%). Of note, 14 patients received Ven associated with chemotherapy, including 4 Nelarabine-Ven, and 3 Ven in monotherapy. By 3 months, the cumulative incidence of response under the chosen TTO was 70.7% (95%CI:51-88) (Figure). Ten of 14 patients were in response after Aza/Ven (ORR 71.4%), 4 of 8 patients after Tofa/Ven (50%) and 2 of 2 patients treated with Tem/Erw/Ven (100%). Five patients were bridged to allogeneic stem cell transplantation. Conclusion Our results demonstrate the feasibility of the ALL-TARGET project. A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.