Combination Regimens Research Articles

Selection and prioritization of candidate combination regimens for the treatment of tuberculosis

Accelerated tuberculosis drug discovery has increased the number of plausible multidrug regimens. Testing every drug combination in vivo is impractical, and varied experimental conditions make it challenging to compare results between experiments. Using published treatment efficacy data from a mouse tuberculosis model treated with candidate combination regimens, we trained and externally validated integrative mathematical models to predict relapse in mice and to rank both previously experimentally studied and unstudied regimens by their sterilization potential. We generated 18 datasets of 18 candidate regimens (comprising 11 drugs of six classes, including fluoroquinolone, nitroimidazole, diarylquinolines, and oxazolidinones), with 2965 relapse and 1544 colony-forming unit (CFU) observations for analysis. Statistical and machine learning techniques were applied to predict the probability of relapse in mice. The locked down mathematical model had an area under the receiver operating characteristic curve (AUROC) of 0.910 and showed that bacterial kill measured by longitudinal CFU cannot account for relapse alone and that sterilization is drug dependent. The diarylquinolines had the highest predicted sterilizing activity in the mouse model, and the addition of pyrazinamide to drug regimens provided the shortest estimated tuberculosis treatment duration to cure in mice. The mathematical model predicted the effect of treatment combinations, and these predictions were validated by conducting 11 experiments on previously unstudied regimens, achieving an AUROC of 0.829. We surmise that the next generation of tuberculosis drugs are highly effective at treatment shortening and suggest that there are several promising three- and four-drug regimens that should be advanced to clinical trials.

Systemic therapy for hepatocellular carcinoma, from the early to the advanced stage: a Japanese perspective.

Systemic therapy has now become mainstream for the treatment of hepatocellular carcinoma (HCC) and is also changing from molecular-targeted therapy, such as with sorafenib and lenvatinib, to immunotherapy, such as with the atezolizumab plus bevacizumab and durvalumab plus tremelimumab combination regimens. Molecular-targeted therapy is selected as the first-line treatment when immunotherapy is not indicated or as second- or later-line treatment when immunotherapy is ineffective. It is necessary to select the appropriate treatment taking into consideration the expected treatment efficacy and adverse events, as well as the hepatic reserve. Currently, newer agents and combination regimens as first-line/second-line treatment for advanced-stage HCC, combined therapy with transarterial chemoembolization for intermediate-stage HCC, and perioperative adjuvant therapy for curative treatment for early-stage HCC are being developed. Therefore, systemic therapy is now indicated for any stage of the disease. While local therapies were previously used as the main treatment strategy for HCC, systemic therapy in combination with local therapies is being actively attempted at present. Systemic therapy is currently the main focus of development of novel treatments for HCC.

Tumor microenvironment: obstacles and opportunities for T-cell based tumor immunotherapies.

The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells and extracellular components, significantly impedes the effector function of cytotoxic T cells (CTLs) and thus represents a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous anti-tumor immunity and improve the efficacy of T-cell based immunotherapies in cancer patients by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous anti-tumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in clinic.

Individualized antimicrobial therapy using antibiotic combination testing and therapeutic drug monitoring to treat carbapenem-resistant Acintobacter baumannii infection.

Treatment of multidrug resistant infections is challenging due to limited therapeutic options. To maximise treatment success of such infections, our infectious disease-trained pharmacists employ a two-pronged approach, using both in vitro antibiotic combination testing and therapeutic drug monitoring, to individualise antibiotic combination regimens for our patients, akin to precision medicine. This approach ensures that the most optimal antibiotic combination and dosing regimens are prescribed for our patients with multidrug resistant infection, to ensure adequate antibiotic exposure and maximal clinical efficacy. We describe the implementation of such 2-pronged approach in two of our patients infected with extensively drug-resistant Acinetobacter baumannii infections. Doses higher than manufacturer-approved regimens were administered. Both cases achieved treatment success with no adverse effects.

Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma.

The management of marginal zone lymphoma (MZL), an indolent B-cell non-Hodgkin lymphoma, requires a personalized and adaptive approach due to its clinical and prognostic heterogeneity. We believe treatment should emphasize a balanced strategy considering the subtype, disease burden, symptoms, and actionable genetic or environmental factors, such as infections or autoimmune diseases. For asymptomatic patients with low tumor burden or disseminated disease, a watch-and-wait approach remains appropriate, given MZL's indolent nature and the risks of overtreatment. Conversely, for symptomatic or high-burden cases, early intervention with chemoimmunotherapy is recommended for effective disease control. Surgery remains essential for both diagnosis and the treatment of localized disease. Incorporating molecular profiling and prognostic models, such as MZL-IPI and POD24, is crucial for decision-making and risk stratification. Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients. With ongoing advancements in understanding dysregulated signaling pathways and the tumor microenvironment, we anticipate novel targeted therapies and combination regimens will further improve outcomes. We advocate for molecular testing at diagnosis to identify actionable biomarkers, particularly for patients with refractory or relapsed disease. Finally, MZL management requires vigilant follow-up with adjustments based on evolving disease features. Treatment decisions should integrate patient preferences, clinical context, and the latest evidence to maximize survival while preserving quality of life.

Efficacy and safety of glecirasib (JAB-21822) monotherapy and in combination with cetuximab in patients with KRAS G12C-mutated advanced colorectal cancer.

191 Background: Glecirasib (JAB-21822), a highly selective, covalent and oral KRAS G12C inhibitor, has demonstrated a favorable safety profile and promising efficacy result as a monotherapy in NSCLC. We previously reported preliminary data of glecirasib monotherapy (NCT05009329) and in combination with cetuximab (NCT05194995) in KRAS G12C-mutated advanced Colorectal Cancer (CRC); here, we present the updated efficacy results. Methods: Patients (pts) with advanced CRC harboring KRAS G12C mutation were enrolled and treated with either single agent glecirasib (800mg QD) or glecirasib (800mg QD) combined with cetuximab. The primary endpoint was overall response rate (ORR). The secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: As of June 30, 2024, 44 pts received glecirasib (median follow up was 21.9 months). The median age was 55.5 years with female (38.6%) /male (61.4%), ECOG PS 0 (25.0%) /1 (75.0.%), and 79.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 22.7% (10/44) and 86.4% (38/44), respectively. Median DoR was 4.4months (95%CI: 4.2, 9.7) , median PFS was 5.6 months (95%CI: 4.1, 7.0), and median OS was 16.0 months (95%CI: 8.8, 26.3). Any grade treatment-related adverse events (TRAEs) occurred in 41 (93.2%) pts, the most common ones (>20%) being anemia, blood bilirubin increased, hypertriglyceridemia and white blood cell count decreased. Grade 3-4 TRAEs occurred in 9 (20.5%) pts. No grade 5 TRAEs occurred. No patient discontinued treatment due to TRAEs. Among the47 pts treated with combination regimen (median follow up was 18.7 months), the median age was 54.8 years with female (53.2%)/ male (46.8%), ECOG PS 0 (44.7%) /1 (55.3%), and 74.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 50% (23/46) and 87.0% (40/46), respectively. Median DoR was 5.1 months (95%CI: 4.1, 6.9), median PFS was 6.9 months (95%CI: 5.4-6.9), and median OS was 19.3 months (95%CI: 13.1, NE). Any grade TRAEs occurred in 46 (97.9%) pts, the most common ones (>20%) being rash, skin fissures, blood bilirubin increased, ALT increased, AST increased, anemia and proteinuria. Grade 3-4 TRAEs occurred in 9 (19.1%) pts. No grade 5 TRAEs occurred. 2(4.3%) pts discontinued treatment due to TRAEs. Conclusions: Glecirasib in combination with cetuximab demonstrated better efficacy compared with glecirasib monotherapy in advanced KRAS G12C mutated advanced CRC, while maintaining a favorable safety profile. Clinical trial information: NCT05009329 , NCT05194995 .

Efficacy and safety of surufatinib plus toripalimab in treatment-naive, PD-L1-positive, advanced or metastatic non-small-cell lung cancer and previously treated small-cell lung cancer: an open-label, single-arm, multicenter, multi-cohort phase II trial.

Combining the programmed death-1 inhibitor toripalimab and the angio-immuno kinase inhibitor surufatinib showed preliminary antitumor activity in patients with advanced solid tumors in a phase I study. Here, we report the efficacy and safety of this combination regimen in treatment-naive advanced or metastatic non-small-cell lung cancer (NSCLC) patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or greater (PD-L1-positive) and patients with previously treated small-cell lung cancer (SCLC). This open-label, single-arm phase II study included patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC or previously treated SCLC in China. Patients received surufatinib (250mg orally, once daily) plus toripalimab (240mg intravenously, once every 3weeks). Primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Forty-three patients were treated (NSCLC cohort, n = 23; SCLC cohort, n = 20). ORRs (95% CIs) were 57.1% (34.0-78.2) in the NSCLC cohort and 15.8% (3.4-39.6) in the SCLC cohort. Median duration of response was not reached (NR) in both cohorts. Median PFS was 9.6 (5.5-NR) and 3.0months (2.8-4.1), respectively, and median OS was 24.3 (10.8-NR) and 11.0months (5.0-15.7), respectively. Grade ≥ 3 treatment-related adverse events were reported in 24 patients (55.8%) overall. Surufatinib plus toripalimab showed encouraging antitumor activity and a tolerable safety profile in patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC and previously treated SCLC.

Effects of tumor treating fields (TTFields) with FOLFIRINOX on BRCA WT pancreatic cancer cells.

753 Background: Pancreatic cancer remains one of the most aggressive malignancies, frequently diagnosed at the locally advanced or metastatic stage. In the advanced setting, first-line chemotherapy options include gemcitabine with nab-paclitaxel or FOLFIRINOX, a combination regimen of fluorouracil, oxaliplatin, irinotecan and leucovorin. The FOLFIRINOX regimen is however associated with greater toxicity and is hence used only in patients with good performance status. BRCA-mutated tumors seem to be more sensitive to FOLFIRINOX due to the DNA-damaging, platinum-based component of this treatment regimen. Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes crucial for cancer cell viability that have shown efficacy in preclinical pancreatic cancer models; and, in various cancer types, have been shown to reduce expression of proteins from the BRCA-dependent DNA repair pathway. The current study examined the potential use of TTFields for sensitization of BRCA wild-type pancreatic cancer cells to treatment with FOLFIRINOX. Methods: Human pancreatic BRCA wild-type cancer cells BxPC3 and AsPC1 were treated with TTFields (150 kHz; 0.7 and 1 V/cm RMS, respectively), using the inovitro device. FOLFIRINOX was administered to the cells at increasing concentrations, with or without co-treatment with TTFields. After 72h of treatment, cell count, colony formation, and apoptosis were measured. For mechanistical insight, gene and protein expression were evaluated following 24, 48, or 72h of TTFields treatment. Results: TTFields application to the pancreatic cells together with FOLFIRINOX elevated the cytotoxic, clonogenic and apoptotic effects induced by FOLFIRINOX or TTFields alone. RNA sequencing data revealed that TTFields downregulated DNA damage repair, DNA replication, and cell cycle related processes. Specifically, real-time PCR and Western blot analysis demonstrated reduced expression of several central players in the BRCA DNA damage repair pathway. Conclusions: TTFields application together with FOLFIRINOX in pancreatic cancer cells lacking background BRCA mutations exhibits potential improvement relative to FOLFIRINOX alone, that may be rationalized based on downregulation of key DNA repair pathways. Future studies should explore the possibility of reducing FOLFIRINOX treatment dose, potentially alleviating FOLFIRINOX-related toxicity.

Targets Selection for Precision Therapy of Relapsed/Refractory Multiple Myeloma: the Latest Advancements.

According to the guidelines, the primary treatment for multiple myeloma is still based on drugs such as carfilzomib, lenalidomide, or daratumumab. However, patients with relapsed/refractory multiple myeloma (RRMM) may be insensitive or develop resistance to the above therapeutic medications. Thus, formulating standardized and rational treatment regimens for such patients remains an area for consideration. Multidrug combinations are available for the therapy of patients with relapsed/refractory multiple myeloma to improve their clinical outcome and prevent the occurrence of multidrug resistance. For instance, combination therapy with immunomodulators, proteasome inhibitors, and CD38 monoclonal antibodies. With the development of genomics and molecular diagnostic technologies, RRMM has entered the era of precision therapy. Targeted immunotherapeutic drugs such as monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor-T (CAR-T) cells have shown promising clinical response rates and favorable safety profiles in several clinical and experimental studies. These cutting-edge medicinal treatments may provide new hope for a cure for RRMM. However, the choice of treatment regimen still needs to adhere to the principle of individualization. Generally, we recommend treatment with drugs of a new generation or novel mechanism of action for patients with RRMM who are first relapsed, such as next-generation proteasome inhibitors, next-generation immunomodulators, and CD38-based monoclonal antibody regimens.For multiple relapsed RRMM, we recommend choosing a combination regimen or participating in relevant clinical trials. Additionally, monoclonal antibodies have become the standard of care for patients with RRMM. With the introduction of CAR-T therapy, ADCs, and bispecific antibodies, RRMM patients are expected to achieve deep remissions and long-term survival again.

High-dose methotrexate-based chemotherapy for induction remission of newly diagnosed primary CNS lymphoma: A systematic review and meta-analysis.

This study aimed to comprehensively assess the optimal regimen for high-dose methotrexate (HD-MTX) in treating primary central nervous system lymphoma (PCNSL). We have searched 8 databases, including PubMed, EMBASE, Cochrane Library, WOS, Epistemonikos, CNKI, WAN-FANG Database, and CBM, and were selected for the clinical trials about PCNSL. A total of 37 studies were included in our analysis, consisting of 6 randomized controlled trials and 31 single-arm clinical studies. After analyzing the data from 37 clinical studies, we found that the pooled overall response rate (ORR) for low-dose (<3 g/m2), medium-dose (3-5 g/m2), and high-dose (>5 g/m2) methotrexate (MTX) were 0.78, 0.80, and 0.80, respectively. The pooled 2-year overall survival (OS) for low-dose, medium-dose, and high-dose MTX were 52%, 60%, and 71%, respectively. The ORR, complete response (CR), and 2-year OS of patients who received <5 cycles of MTX were 79%, 41%, and 59%, respectively, whereas those for PCNSL patients who received >5 cycles of MTX were 81%, 54%, and 64%, respectively. The pooled ORR for MTX, dual therapy, triplet therapy, tetrad therapy, and multiple therapy were 71%, 70%, 81%, 85%, and 80%, respectively. The pooled 2-year OS for different numbers of medication combinations were 59%, 52%, 66%, 63%, and 60%, respectively. The addition of cytarabine to MTX-based chemotherapy resulted in higher CR, although no statistically significant difference was observed in OS. Adding rituximab to the treatment regimen improved patients' progression-free survival without affecting treatment response or OS. Based on the findings of this study, the treatment strategies of MTX are associated with the prognosis and efficacy response of PCNSL patients. The results suggested that the current recommended HD-MTX dosage of 3.5 g/m2 is sufficient for PCNSL to have a favorable treatment response and prognosis. When the number of MTX treatment cycles increases, the therapeutic effect and prognosis of PCNSL patients are improved. The patients treated with MTX-based triplet combination regimens have a better ORR and CR. Although HD-MTX is generally well tolerated, it is necessary to be cautious about the use of multiple therapy that includes cytarabine to prevent potential acute toxicity.

P-796. The Deadly Raise of NTM : An Observational Study on Clinical profile and Outcome Of NTM Disease

Abstract Background NTM is ubiquitously present in the environment. When these microorganisms shed, they produce biofilms that increase the likelihood of infection. CLINICAL AND RADIOLOGICAL FEATURES OF NTM Methods STUDY PERIOD: 1 YEAR STUDY DESIGN: Cross-sectional observational study STATISTICAL ANALYSIS: Categorical variables will be expressed as % NTM VARIOUS CLINICAL SITES Results 25 cases were selected for analysis. Out of 25 (40% ) were port site infection and 12 % pulmonary. Most common symptom was discharge (60%) . Empirical antibiotics were started in 100% . ID referral was sent in all .RF were seen in 40%. Scans was showing sinus tract formation or deep seated abscess among (80%); . AFB stain was positive in 80% cases and CB-NAAT negative in 100% cases. Culture positivity in 56% , among 15 samples sent for PCR it was positive in 10 (66.6%); among 10 cases sent for sequencing 8(80%) cases were positive. Rapid growers 92% and then slow growers were seen in 8% cases. most common species was M.chelonae (28.5%) followed by M.fortuitum and abscessus (21.4%); among 3 species of abscessus sub species were able to identify in one case and it was boleti 33.3%. slow growers MAC and kansasi were identified 7% each. NTM culture was given positive but species identification was not done in 14.2% cases. Culture was negative in 44% of cases. DST was done in 14 cases and genotypic was able to do in 5 cases and erm gene detected (40%) cases. Phenotypic DST was done in all culture positive isolates(n=14), among them cotrimoxazole (92.8%); Amikacin and linezolid was sensitive in 85.7% isolates, imipenem,levofloxacin and tigecycline in 71.4% and macrolide was sensitive in 57.1% cases only. Various combination regimens were used and most common combination used were amikacin,levofloxacin,macrolide and amikacin,linezolid,levofloxacin and amikacin,levofloxacin,cotrimoxazole in 24% cases; and 1 case had treatment with amikacin,linezolid,tigecycline . 40 % cases used combination treatment for 1 year or longer;20 % cases only used 6 months of therapy. Side effects like GIT intolerance in 80% cases; renal toxicity was seen in 40% cases. Upon follow up death in 8%; resolution in 76% , culture negativity 71.4% non-resolving/recurrence 16% Conclusion Most of the patients with NTM are misdiagnosed and are treated as tuberculosis ANTIBIOTIC SUSCEPTIBILITIES AMONG VARIOUS NTM ISOLATED NTM IMAGE 4 Disclosures All Authors: No reported disclosures

P-81. A Decade of Culture-Negative Native Vertebral Osteomyelitis: Insights from the Mayo Clinic

Abstract Background Culture-negative native vertebral osteomyelitis (CN-NVO) is increasingly common, rising from 0.3 to 1.8 cases per 100,000 between 1995 and 2008. The lack of microbial identification complicates optimal treatment and creates prognostic uncertainties. We describe our decade-long clinical experience with CN-NVO, focusing on patient characteristics, treatment, and outcomes. Patient Characteristics Methods We retrospectively analyzed adult patients with radiographic evidence of NVO between January 1, 2011, and July 31, 2021. CN-NVO required clinical indicators such as back pain and fever, elevated inflammatory markers, and negative cultures from at least one spine biopsy. Patients with infected instrumentation were excluded. Diagnostic Evaluation Values represent median, lower quartile, and upper quartile for continuous variables unless otherwise specified, 2 whereas frequencies and percentages are presented for categorical variables. ^ All results returned negative *Biopsies number two and three did not result in additional findings or change clinical management. Results Seventy-two patients were included. Their characteristics are presented in Table 1. Most (77.8%) had received antibiotics within the 4 weeks preceding the biopsy. Disc space enhancement on MRI was the primary finding, with the lumbar spine being the most frequently involved (Table 2). Blood cultures were positive in 39.4% of the patients within 3 months of symptom onset. Streptococcus spp. (n=9, median time between positive culture and diagnosis: 6.5 days [IQR 2.25, 26.75]) and Staphylococcus aureus (n=7, 40 days [IQR 37.5, 51.5]) were most common. Definitive antibiotics were administered in 98.6% of the cases, primarily IV β-lactam + vancomycin. Oral antibiotics (PO) were used in 46.5% of the patients, primarily as step-down therapy (91%) (Table 3). Surgery was required in 8.5% of the patients for abscess drainage or relief of spinal cord compression. Treatment failure occurred in 9.4% of patients, and 37.5% died during the median follow-up of 568.5 days, with two deaths related to the infection. Treatment and Outcomes ^ defined as requiring another course of antibiotics and/or surgery for suspected ongoing infection ¶ Clinical findings include back pain or fevers; laboratory findings indicate abnormal or uptrend in inflammatory marker values # Defined as MRI findings concerning ongoing or worsening infection as per the interpretation of the Radiologist, Infectious Disease physician, and/or Orthopedic Surgeon Conclusion Patients with CN-NVO often require prolonged antibiotic therapy, typically combination regimens, with favorable treatment outcomes. Our treatment failure rate is similar to other studies, although comparability may be limited by heterogeneity in definitions. Mortality rates in the range of 6 and 36% have been reported, with the higher end driven mostly by comorbidities. Enhanced diagnostics and standardized treatment protocols are needed to further improve patient outcomes. Disclosures All Authors: No reported disclosures

Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy.

Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells. The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers. Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL-IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high-risk stages has improved. Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment-free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen. Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed-duration therapies have gained territory in the management of CLL, as they are cost-effective, avoid the emergence of resistance, and offer treatment free time to the patient. The cure rate of these novel combination regimens is unknown. Moreover, the optimal sequencing of targeted therapies remains to be determined. A medical challenge is to treat patients who are double-refractory to both BTK and BCL2 inhibitors. These patients need to be treated within experimental protocols using novel drugs.

Efficacy and safety of various drug combinations in treating plaque Psoriasis: A meta-analysis

Background Psoriasis, a chronic inflammatory disease affecting the skin, joints, and nails (2-3% worldwide), significantly affects quality of life. Genetic and environmental factors also play key roles. Topical corticosteroids, calcineurin inhibitors, and oral corticosteroids help to manage plaque psoriasis symptoms, but combination therapies might offer greater effectiveness and improved safety profiles. These combinations could potentially reduce medication dosages and side effects in patients. Objective To assess the efficacy and safety of various drug combinations over conventional monotherapies in the treatment of moderate to severe plaque psoriasis, which incorporates palmoplantar psoriasis and psoriasis vulgaris, by discovering and utilizing research articles comprising the same or similar variables as PASI 75 and evaluating the information using RevMan v5.4.1. Method We reviewed the efficacy and safety of combination therapy vs. monotherapy/placebo for moderate-to-severe plaque psoriasis (palmoplantar and vulgaris) using PASI 75 via RevMan v5.4.1. Risk of bias assessment and funnel plots were employed to assess the heterogeneity of each paper. Inclusion criteria – Publications &lt; 20yrs, RCTs, plaque/palmoplantar/psoriasis vulgaris; exclusion criteria – Guttate/arthritic psoriasis, pediatric and pregnant individuals, publications &gt; 20 yrs. Results Seventeen studies were analyzed, comprising a total of 2291 patients (n=1147 with combination regimens and n=1144 with control regimen in the analysis). A significant PASI 75- response was observed in the pioglitazone combination subgroup as compared to placebo (OR=4.92,95% CI 2.19-11.05, P = 0.0001); methotrexate combination subgroup as compared to placebo (OR=2.56, 95% CI 1.67-3.94, P&lt; 0.0001) test of subgroup differences showed P= 0.14, I2= 34%. Incidence rate of abnormality in levels of liver enzymes (OR=1.89,9.5% CI 6.69-5.22, P=0.22), nausea (OR=1.28,95% CI 0.77-2.14, P=0.34), headache (OR=1.28,95% CI 0.77-2.14, P=0.58), fatigue (OR=0.89, 95% CI 0.41-1.90, P=0.45).] Conclusion This study showed that combination therapy is very effective for plaque psoriasis, with promising combinations of pioglitazone. While safety seems similar between the groups, larger studies are needed to determine the long-term effects. These findings suggest that personalized treatment plans could improve outcomes; however, confirmation through larger trials is crucial before wider use. This opens doors to research on optimal combinations for individual patients.

Evaluation of ampicillin plus ceftobiprole combination therapy in treating Enterococcus faecalis infective endocarditis and bloodstream infection

Enterococcus faecalis is responsible for numerous serious infections, and treatment options often include ampicillin combined with an aminoglycoside or dual beta-lactam therapy with ampicillin and a third-generation cephalosporin. The mechanism of dual beta-lactam therapy relies on the saturation of penicillin-binding proteins (PBPs). Ceftobiprole exhibits high affinity binding to nearly all E. faecalis PBPs, thus suggesting its potential utility in the treatment of severe E. faecalis infections. The availability of therapeutic drug monitoring (TDM) for ampicillin and ceftobiprole has prompted the use of this drug combination in our hospital. Due to the time-dependent antimicrobial properties of these antibiotics, an infusion administration longer than indicated was chosen. From January to December 2020, twenty-one patients were admitted to our hospital for severe E. faecalis infections and were treated with this approach. We retrospectively analyzed their clinical characteristics and pharmacological data. Most patients achieved an aggressive PK/PD target (T > 4–8 minimum inhibitory concentration, MIC) when this alternative drug combination regimen was used. Our analysis included the study of E. faecalis biofilm production, as well as the kinetics of bacterial killing of ceftobiprole alone or in combination with ampicillin. Time-kill experiments revealed strong bactericidal activity of ceftobiprole alone at concentrations four times higher than the MIC for some enterococcal strains. In cases where a bactericidal effect of ceftobiprole alone was not evident, synergism with ampicillin and bactericidal activity were demonstrated instead. The prolonged infusion of ceftobiprole, either alone or with ampicillin, emerges as a valuable option for the treatment of severe invasive E. faecalis infections.

Chemotherapy-Induced Alopecia in Ovarian Cancer: Incidence, Mechanisms, and Impact Across Treatment Regimens

Background/Objectives: Ovarian cancer is the fifth most common cancer among women, with an estimated 19,680 new cases projected in 2024. Adjuvant chemotherapy remains the standard treatment for epithelial ovarian cancers but is frequently associated with adverse events, such as chemotherapy-induced alopecia (CIA). CIA is a particularly distressing side effect that significantly affects the body image, self-esteem, and quality of life of patients. Unfortunately, CIA remains underexplored in patients with ovarian cancer. Methods: This scoping review analyzed PubMed- and EMBASE-indexed studies investigating the incidence, severity, and mechanisms of CIA in ovarian cancer patients. Eighteen studies were included for analysis. Results: Our analysis identified platinum-based compounds, taxanes, and topoisomerase I inhibitors as the agents most strongly correlated with severe alopecia, particularly in combination regimens such as carboplatin–paclitaxel (CP), and cyclophosphamide, adriamycin, and cisplatin (CAP). Among the monotherapies, taxanes, including paclitaxel and docetaxel, posed the highest risk of CIA. Mild-to-moderate alopecia was observed in patients treated with gemcitabine or pegylated liposomal doxorubicin. Alternative factors such as dosing schedules and prior chemotherapy exposure also significantly influence CIA severity. Conclusions: Given the profound psychosocial impact of CIA, optimizing treatment protocols to reduce the severity of alopecia without compromising therapeutic efficacy is crucial. These findings offer insights that may guide future therapeutic strategies for improving patient outcomes and quality of life.

New Combination Regimens vs. Fludarabine, Cytarabine, and Idarubicin in the Treatment of Intermediate- or Low-Risk Nucleophosmin-1-Mutated Acute Myeloid Leukemia: A Retrospective Analysis from 7 Italian Centers

Background: Nucleophosmin-1 (NPM1) mutation accounts for 30% of acute myeloid leukemia (AML) cases and defines either low- or intermediate-risk AML, depending on FLT3-ITD mutation. New combination regimens (NCRs), adding midostaurin and gemtuzumab ozogamicin (GO) to the 3 + 7 scheme, are commonly used, though there are no data that compare NCRs with intensive induction chemotherapy. Methods: To evaluate the efficacy and safety of NCRs and FLAI in NPM1+ AML, we retrospectively analyzed 125 patients treated with FLAI (n = 53) or NCRs (n = 72) at seven Italian Centers. Results: The median age was 61 years and 51/125 (41%) were FLT3-ITD+. The complete remission (CR) rate was 77%, slightly better with NCRs (83% vs. 68%; p = 0.054). NCRs yielded a superior median overall survival (OS) (not reached (NR) vs. 27.3 months; p = 0.002), though the median event-free survival (EFS) was similar (NR vs. 20.5 months; p = 0.07). In low-risk AML, CR was higher in NCRs (94% vs. 72%, p = 0.02), as were median OS (NR vs. 41.6 months; p = 0.0002) and EFS (NR vs. 17.8 months; p = 0.0085). In intermediate-risk AML (FLT3-ITD+), there were no differences in CR (60% vs. 71%; p = 0.5), OS (p = 0.27), or EFS (p = 0.86); only allogeneic transplantation improved OS (NR vs. 13.4 months; p = 0.005), regardless of induction regimen. The safety profile was similar, except for delayed platelet recovery with FLAI (22 vs. 18 days; p = 0.0024) and higher-grade II–IV gastrointestinal toxicity with NCRs (43% vs. 18.8%; p = 0.0066). Conclusions: Our data suggest the superiority of NCRs over FLAI in low-risk patients, while all outcomes were comparable in intermediate-risk patients, a setting in which only transplants positively impacted on survival.

Clinical efficacy of donepezil combined with nerve growth factor in the treatment of patients with Parkinson’s disease dementia and its impact on adiponectin and soluble tumor necrosis factor-alpha receptor-1

Objective: To explore clinical efficacy of donepezil combined with nerve growth factor (NGF) in the treatment of Parkinson’s disease dementia (PDD) and its potential impact on serum levels of adiponectin (APN) and soluble tumor necrosis factor receptor-1 (sTNFR-1). Methods: Clinical data of 140 patients with PDD treated in Taizhou First People’s Hospital from March 2021 to December 2023 were retrospectively analyzed. Patients were grouped based on the treatment received. Patients who received donepezil alone (n=68) comprised the Donepezil group, and patients who were treated with a combination of donepezil and NGF (n=72) were assigned into the Donepezil &amp; NGF group. Treatment effects, symptom improvement before and after the treatment, APN and sTNFR-1 levels, and incidence of adverse reactions were compared between two groups. Results: The overall efficacy of the combination therapy was higher than that of donepezil regimen alone (P&lt;0.05). After treatment, symptom improvement in the Donepezil &amp; NGF group was significantly better than that in the Donepezil group (P&lt;0.05). Post-treatment serum levels of APN in the Donepezil &amp; NGF group were significantly higher than that of Donepezil group, while the level of sTNFR-1 was significantly lower (P&lt;0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P&gt;0.05). Conclusion: Combined regimen of donepezil and NGF is more effective than donepezil monotherapy in improving cognitive function, neurological function, and severity of the condition of patients with PDD, and is associated with the suppression of the inflammatory response without a significant increase in the incidence of adverse reactions. The study provides a basis for the clinical application of the combined regimen, but it still needs to be confirmed by more basic and clinical research. doi: https://doi.org/10.12669/pjms.41.2.11191 How to cite this: Hu M, Ye J. Clinical efficacy of donepezil combined with nerve growth factor in the treatment of patients with Parkinson’s disease dementia and its impact on adiponectin and soluble tumor necrosis factor-alpha receptor-1. Pak J Med Sci. 2025;41(2):372-377. doi: https://doi.org/10.12669/pjms.41.2.11191 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Surgical Advancements, Immunotherapy, Targeted and Conventional Therapies, Biopsy, Colposcopy, and Pap Smear Integration in the Management of Cervical Cancer.

Cervical cancer remains a significant global health concern, making it essential to investigate new treatment options continuously. This page provides an overview of the latest advancements and best practices in detection and intervention, including Pap smears, colposcopy, biopsy, immunotherapy, targeted therapies, chemotherapy, radiation therapy, and surgery. Surgical techniques such as radical hysterectomy and minimally invasive procedures have advanced to enhance patient outcomes and quality of life. Simultaneously, radiation therapy methods have been refined to maximize tumour control while reducing adverse effects. Chemotherapy remains vital, with new drugs and combination regimens demonstrating improved tolerance and efficacy. Immunotherapy, notably immune checkpoint inhibitors, has shown promise in advanced stages of cervical cancer. Additionally, targeted therapies that focus on specific biochemical pathways offer the potential for personalized treatment approaches. This review critically assesses ongoing research, evaluates existing data, and emphasizes the opportunities and challenges of each therapeutic approach. Ultimately, integrating these diverse treatment strategies is the key to enhancing patient outcomes.

Advancement Opportunities and Endeavor of Innovative Targeted Therapies for Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an intractable disease with rapid progression and high mortality, presenting a persistent obstacle impeding clinical management. Although recent advancements in immunotherapy have enhanced the response rates of platinum-based chemotherapy regimens, the emergence of acquired resistance invariably leads to recurrence and metastasis. Consequently, there is an urgent necessity to explore novel therapeutic targets and optimize existing treatment strategies. This article comprehensively reviews the currently available therapeutic modalities for SCLC. It delves into the immunologic prognostic implications by analyzing selected immune-related signatures. Moreover, it conducts an in-depth exploration of the molecular subtyping of SCLC and the associated molecular pathways to identify potential therapeutic targets. Specifically, the focus is on clinical interventions targeting delta-like ligand 3 (DLL3), elucidating its resistance mechanisms and demonstrating its notable antitumor efficacy. Furthermore, the study examines the mechanisms of chimeric antigen receptor (CAR) T and antibody-drug conjugate (ADC), covering resistance issues and strategies for optimizing resistance management, with particular emphasis being placed on analyzing the prospects and clinical value of CAR T therapy in the context of SCLC. Moreover, the effectiveness of poly ADP-ribose polymerase and ataxia telangiectasia and rad3/checkpoint kinase 1 inhibitors is discussed and underscores the advantages of combining these inhibitors with standard chemotherapy to combat chemoresistance and enhance the antitumor effects of immunotherapies. Overall, this study investigates emerging strategies for targeted therapies and optimized combination regimens to overcome resistance in SCLC and highlights future strategies for new therapeutic technologies for SCLC.