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Cancers May 2024The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the... (Review)
Review
The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL.
PubMed: 38893177
DOI: 10.3390/cancers16112059 -
Cancers May 2024Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or...
PURPOSE
Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or full course of a platinum doublet) proved superior to chemotherapy alone in multiple clinical trials, but these strategies were not directly compared. The aim of this study is to report the real-world data results with different immunotherapy combinations in a series of patients treated in consecutive cohorts at the Ion Chiricuță Oncology Institute.
METHODS
A total of 122 patients were successively enrolled in three cohorts: (1A) nivolumab + ipilimumab (18 patients), (1B) nivolumab + ipilimumab + short-course chemotherapy (33 patients), and (2) pembrolizumab plus full-course chemotherapy (71 patients). Endpoints included overall survival (OS), progression-free survival (PFS), objective response (ORR), and univariate and multivariate exploratory analysis of prognostic factors.
RESULTS
Median follow-up in the consecutive cohorts 1A, 1B, and 2 was 83 versus 59 versus 14.2 months. Median OS and PFS for all patients were 22.2 and 11.5 months, respectively, and 2-year actuarial OS and PFS were 49% and 35%, respectively. For the nivolumab + ipilimumab (cohorts 1A and 1B) versus pembrolizumab combinations (cohort 2), median OS was 14 vs. 24.8 months ( = 0.18) and 2-year actuarial survival 42% vs. 53%; median PFS was 8.6 vs. 12.7 months ( = 0.41) and 2-year actuarial PFS 34% vs. 35%; response rates were 33.3% vs. 47.9% ( = 0.22). Older age, impaired PS (2 versus 0-1), corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate analysis of survival (limited to 2 years follow-up). The 5-year long-term survival was 30.5% and 18.8% for cohorts 1A and 1B, respectively (not enough follow-up for cohort 2).
CONCLUSIONS
Efficacy results using different immunotherapy combination strategies were promising and not significantly different between protocols at 2 years. Real-world efficacy and long-term results in our series were in line with those reported in the corresponding registration trials.
PubMed: 38893141
DOI: 10.3390/cancers16112022 -
International Journal of Molecular... Jun 2024The current standard oncotherapy for glioblastoma is limited by several adverse side effects, leading to a short-term patient survival rate paralleled by a worsening...
The current standard oncotherapy for glioblastoma is limited by several adverse side effects, leading to a short-term patient survival rate paralleled by a worsening quality of life (QoL). Recently, Complementary and Integrative Medicine's (CIM) innovative approaches have shown positive impacts in terms of better response to treatment, side effect reduction, and QoL improvement. In particular, promising potential in cancer therapy has been found in compounds coming from phyto- and mycotherapy. The objective of this study was to demonstrate the beneficial effects of a new phyto-mycotherapy supplement, named , in the human glioblastoma cell line U251, in combination with chemotherapeutic agents, i.e., Cisplatin and a new platinum-based prodrug. Choosing a supplement dosage that mimicked oral supplementation in humans (about 1 g/day), through in vitro assays, microscopy, and cytometric analysis, it has emerged that the cells, after 48hr continuous exposure to in combination with the chemical compounds, showed a higher mortality and a lower proliferation rate than the samples subjected to the different treatments administered individually. In conclusion, our data support the use of in integrative oncology protocols as a promising adjuvant able to amplify conventional and new drug effects and also reducing resistance mechanisms often observed in brain tumors.
Topics: Humans; Glioblastoma; Cell Line, Tumor; Brain Neoplasms; Cell Proliferation; Cisplatin; Dietary Supplements; Antineoplastic Agents; Cell Survival; Apoptosis
PubMed: 38892392
DOI: 10.3390/ijms25116204 -
International Journal of Molecular... May 2024FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory...
FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.
Topics: Humans; Colorectal Neoplasms; Cell Line, Tumor; Fluorouracil; Oncolytic Virotherapy; MicroRNAs; Oncolytic Viruses; Antineoplastic Combined Chemotherapy Protocols; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Enterovirus B, Human; Combined Modality Therapy; Irinotecan
PubMed: 38891807
DOI: 10.3390/ijms25115618 -
Trials Jun 2024In Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring...
Enhancing HIV pre-exposure prophylaxis outcomes among Kenyan adolescent girls and young women with a novel pharmacy-based PrEP delivery platform: protocol for a cluster-randomized controlled trial.
BACKGROUND
In Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring HIV prevention services, including pre-exposure prophylaxis (PrEP), to trusted contraceptive delivery settings offers opportunities to efficiently reach this important population. In Kenya, almost half (40%) of women accessing contraception services do so outside traditional healthcare facilities, such as retail pharmacies. Thus, integrating PrEP services into retail pharmacies may increase options for reaching adolescent girls and young women (AGYW) who could benefit from PrEP. Efforts are underway to define care pathways for pharmacy-delivered PrEP services in Kenya, including unsupported and supported models with nurse navigators.
METHODS
The AGYW Pharmacy PrEP study is an unblinded 2-arm cluster-randomized controlled trial in Kisumu, Kenya. The objective is to determine the effect that unsupported versus supported pharmacy-delivered PrEP services has on PrEP initiation, persistence, and adherence among AGYW seeking contraception. Twenty retail pharmacies offering pharmacy provider-led PrEP delivery will be randomized 1:1 to either receive or not receive a nurse navigator to support PrEP delivery. Eligible AGYW (n = 1900 total, n = 950/arm) will be ≥ 15 years old, purchasing a method of contraception at the pharmacy. Trained pharmacy provider will offer eligible AGYW either daily oral PrEP or the monthly DPV vaginal ring. The primary trial outcomes are PrEP initiation (use of PrEP at 1 month), persistence (use of PrEP at 10 months), and adherence (quantified by levels of TFV or DPV in hair samples). Additionally, several secondary (STI incidence, PrEP method selection, predictors of PrEP adherence) and exploratory outcomes (HIV incidence, quality of care, contraceptive method mix) will be explored.
DISCUSSION
We hypothesize pharmacy-delivered PrEP services supported with nurse navigator, versus delivered by pharmacy providers alone, will improve PrEP outcomes among AGYW seeking contraception. Our results will help policy makers better understand how to potentially implement this novel differentiated service model for PrEP and prime pharmacies for the delivery of new PrEP agents in the pipeline (e.g., long-acting injectables and multi-purpose technologies). The study was initiated on May 13, 2023, and is expected to be completed by February 2025.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT05467306), with registration on July 20, 2022.
Topics: Humans; Female; Adolescent; HIV Infections; Pre-Exposure Prophylaxis; Kenya; Young Adult; Anti-HIV Agents; Randomized Controlled Trials as Topic; Medication Adherence; Treatment Outcome; Time Factors; Multicenter Studies as Topic; Community Pharmacy Services
PubMed: 38890744
DOI: 10.1186/s13063-024-08206-6 -
Journal of Orthopaedic Surgery and... Jun 2024Periprosthetic joint infection after total joint arthroplasty has a large incidence, and it may often require two or more stages of revision, placing an additional... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Periprosthetic joint infection after total joint arthroplasty has a large incidence, and it may often require two or more stages of revision, placing an additional burden on clinicians and patients. The purpose of this network meta-analysis is to evaluate the effect of four different preventive strategies during total joint arthroplasty on the prevention of periprosthetic joint infection.
METHODS
The study protocol was registered at PROSPERO (CRD: 42,023,448,868), and the literature search databases included Web of Science, PubMed, OVID Cochrane Central Register of Controlled Trials, OVID EMBASE, and OVID MEDLINE (R) ALL that met the requirements. The network meta-analysis included randomized controlled trials, retrospective cohort studies and prospective cohort studies with the outcome of periprosthetic joint infection. The gemtc R package was applied to perform the network meta-analysis to evaluate the relative results of different preventive strategies.
RESULTS
This network meta-analysis study included a total of 38 articles with 4 preventive strategies and negative controls. No improvement was observed in antibiotic-loaded bone cement compared with negative controls. Chlorhexidine showed the highest probability of delivering the best preventive effect, and povidone iodine had the second highest probability. Although vancomycin ranked after chlorhexidine and povidone iodine, it still showed a significant difference compared with negative controls. In addition, the incidence after applying chlorhexidine was significantly lower than that after applying negative controls and vancomycin. In the heterogeneity test between direct and indirect evidence, there was no apparent heterogeneity between them.
CONCLUSION
The study indicated that chlorhexidine, povidone iodine and vancomycin showed significant efficacy in preventing periprosthetic joint infection after total joint arthroplasty, while antibiotic-loaded bone cement did not. Therefore, more high-quality randomized controlled trials are needed to verify the results above.
Topics: Humans; Prosthesis-Related Infections; Network Meta-Analysis; Anti-Bacterial Agents; Arthroplasty, Replacement; Vancomycin; Bone Cements; Chlorhexidine; Povidone-Iodine; Randomized Controlled Trials as Topic
PubMed: 38890743
DOI: 10.1186/s13018-024-04738-4 -
World Journal of Surgical Oncology Jun 2024Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer...
BACKGROUND
Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC.
METHODS
Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained.
RESULTS
A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group.
CONCLUSION
Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Female; Male; Lung Neoplasms; Middle Aged; Neoadjuvant Therapy; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Aged; B7-H1 Antigen; Immune Checkpoint Inhibitors; Follow-Up Studies; Survival Rate; Adult; Prognosis; Oncogenes; Protein Kinase Inhibitors; Mutation; Programmed Cell Death 1 Receptor
PubMed: 38890622
DOI: 10.1186/s12957-024-03434-1 -
BMJ Open Jun 2024Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release...
INTRODUCTION
Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week in pregnant women undergoing expectant management (7.6 days, geometric mean ratio 1.39, 95% CI 0.99 to 1.95; p=0.057). These findings should be confirmed with a larger sample size, and we need to know if such a prolongation improves neonatal outcome. Here, we describe the protocol for such a follow-up trial.
METHODS
The PI 3 trial is a phase III, intention-to-treat, double-blind, placebo-controlled randomised clinical trial to assess if metformin XR can prolong gestation and improve neonatal outcomes in women undergoing expectant management for preterm pre-eclampsia. We will recruit women who are between 26+0 and 31+6 weeks pregnant. Women will be randomised to receive either 3 g metformin XR or an identical placebo in divided daily doses. The primary outcome is prolongation of pregnancy. Secondary outcomes are neonatal birth weight and length of neonatal care admission (an indicator of neonatal health at birth). All other outcomes will be exploratory. We will record tolerability and adverse events. We plan a sample size of 500 participants to be powered for the primary and secondary outcomes.
ETHICS AND DISSEMINATION
PI 3 has ethical approval (Health Research Ethics Committee 2, Stellenbosch University, Protocol number M21/03/007, Project ID 21639, Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), and is registered with the Pan African Clinical Trial Registry (PACTR202104532026017) and the South African Medicine Control Council (20211211). Data will be presented at international conferences and published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER
PACTR202104532026017).
Topics: Humans; Pregnancy; Female; Metformin; Pre-Eclampsia; Double-Blind Method; South Africa; Hypoglycemic Agents; Infant, Newborn; Randomized Controlled Trials as Topic; Adult; Pregnancy Outcome
PubMed: 38890136
DOI: 10.1136/bmjopen-2023-082880 -
BMJ Open Jun 2024There is an unmet need to develop high-quality evidence addressing tuberculosis (TB)-related mental health comorbidity, particularly in the context of...
INTRODUCTION AND OBJECTIVES
There is an unmet need to develop high-quality evidence addressing tuberculosis (TB)-related mental health comorbidity, particularly in the context of lower-middle-income countries. This study aims to examine the effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) versus enhanced treatment as usual (ETAU) in improving depressive symptoms in people with TB and comorbid depression, enhancing adherence with anti-TB treatment (ATT) and its implementation in the real-world setting of Pakistan.
METHODS
We will conduct a pragmatic parallel arm randomised control trial with an internal pilot. A brief psychological intervention based on CBT has been developed using a combination of qualitative and ethnographic studies. The inbuilt pilot trial will have a sample size of 80, while we plan to recruit 560 (280 per arm) participants in the definitive trial. Participants who started on ATT within 1 month of diagnosis for pulmonary and extrapulmonary TB or multidrug resistant TB (MDR-TB) and meeting the criteria for depression on Patient Health Questionnaire-9 (PHQ-9) will be randomised with 1:1 allocation to receive six sessions of CBT (delivered by TB healthcare workers) or ETAU. Data on the feasibility outcomes of the pilot will be considered to proceed with the definitive trial. Participants will be assessed (by a blinded assessor) for the following main trial primary outcomes: (1) severity of depression using PHQ-9 scale (interviewer-administered questionnaire) at baseline, weeks 8, 24 and 32 postrandomisation and (2) ATT at baseline and week 24 at the end of ATT therapy.
ETHICS AND DISSEMINATION
Ethical approval has been obtained from Keele University Research Ethics Committee (ref: 2023-0599-792), Khyber Medical University Ethical Review Board (ref: DIR/KMU-EB/CT/000990) and National Bioethics Committee Pakistan (ref: No.4-87/NBC-998/23/587). The results of this study will be reported in peer-reviewed journals and academic conferences and disseminated to stakeholders and policymakers.
TRIAL REGISTRATION NUMBER
ISRCTN10761003.
Topics: Humans; Cognitive Behavioral Therapy; Pilot Projects; Pakistan; Depression; Pragmatic Clinical Trials as Topic; Tuberculosis; Multicenter Studies as Topic; Cost-Benefit Analysis; Antitubercular Agents; Adult
PubMed: 38889941
DOI: 10.1136/bmjopen-2023-083483 -
Biomedicine & Pharmacotherapy =... Jun 2024Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and histone deacetylase 8 (HDAC8) have been shown to be associated with the development of several...
Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and histone deacetylase 8 (HDAC8) have been shown to be associated with the development of several cancers. Here, we identified a dual-target DYRK2/HDAC8 inhibitor (DYC-1) through a combined virtual screening protocol. DYC-1 exhibited nanomolar inhibitory activity against both DYRK2 (IC = 5.27 ± 0.13 nM) and HDAC8 (IC = 8.06 ± 0.47 nM). Molecular dynamics simulations showed that DYC-1 had positive binding stability with DYRK2 and HDAC8. Importantly, the cytotoxicity assay indicated that DYC-1 exhibited superior antiproliferative activity against human liver cancer, especially SK-HEP-1 cells, and had no significant inhibition on normal liver cells. Moreover, DYC-1 showed a strong inhibitory effect on the growth of SK-HEP-1 xenograft tumors with no significant side effects. These data suggest that DYC-1 is a high-efficacy and low-toxic antitumor agent for the treatment of hepatocellular carcinoma.
PubMed: 38889633
DOI: 10.1016/j.biopha.2024.116839