Clinical Benefit Research Articles

The intrauterine device: how to deploy this strategy in the molecular world?

Progestin-based therapy can safely be offered to a subset of patients with atypical endometrial hyperplasia or Grade 1 endometrioid endometrial cancer who desire fertility preservation. A recent study shows that levonorgestrel intrauterine device confers durable clinical benefit and identifies possible immune mechanisms of relapse and resistance.

Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017-2020).

The cardiometabolic index (CMI) is an emerging and effective indicator for predicting the presence of metabolic-associated fatty liver disease (MAFLD). This study aims to investigate the relationship between CMI and MAFLD using data from NHANES 2017-2020. In this cross-sectional study, a total of 3,749 subjects were included. The study conducted a thorough analysis of CMI with three multivariate logistic regression models, subgroup analyses, and restricted cubic splines (RCS) were utilized. Using multifactorial logistic regression as the primary method of analysis, we found that a higher CMI was also significantly associated with an increased risk of MAFLD (OR = 1.45, 95% CI (1.05-2.01)). This result was further visualized by the RCS curve: There was a non-linear positive correlation between CMI and MAFLD incidence (the turning point is CMI = 0.4554). These findings were strongly reinforced by subsequent subgroup and sensitivity analyses. There is a robust positive relationship between the CMI and the risk of MAFLD, providing valuable clinical benefits for early detection and screening of MAFLD. It is important to highlight the presence of a non-linear association between CMI and MAFLD, with an inflection point identified at CMI = 0.4554.

Multimodal Analgesia Approach in Acute Low Back Pain Management: A Phase III Study of a Novel Analgesic Combination of Etoricoxib/Tramadol.

Pain and disability management are crucial for a speedy recovery. Combining analgesics with different mechanisms of action provides greater pain relief with lower doses, promoting efficient multimodal analgesia. This study evaluated the efficacy and safety between two fixed-dose combinations (FDC): etoricoxib/tramadol compared to paracetamol/tramadol for the management of acute low back pain (LBP) in a 7-day treatment. We conducted a phase IIIb, prospective, randomized, and multicenter study in patients with acute LBP treated with etoricoxib 90mg/tramadol 50mg (one packet of granules diluted in 100ml of water, once a day [QD], for 7 days) or paracetamol 975mg/tramadol 112.5mg (one tablet of 325mg/37.5mg, three times a day [TID], for 7 days) to assess the efficacy (in terms of pain and disability improvement) and safety. One hundred and twenty-four patients were randomized to receive either etoricoxib/tramadol QD (n = 61) or paracetamol/tramadol TID (n = 63). From the magnitude of change in pain evaluations, differences were observed between the treatment groups at 3 [p = 0.054, CI 95% -0.648 (-0.010 to 1.306)] and 5days (p = 0.041). The proportion of patients with a 30% reduction in Visual Analogue Scale (VAS) score was statistically significant when comparing the treatment groups on the third day of follow-up [p = 0.008, CI 95% 0.241 (0.061-0.421)]. An improvement in LBP's disability to perform activities of daily routine (Oswestry and Roland-Morris questionnaires) was observed in both treatment groups. A total of 79 adverse events (AEs) (38 [48.1%] with etoricoxib/tramadol and 41 [51.9%] with paracetamol/tramadol) were reported. The most frequent AEs were nausea (17.7%) and dizziness (16.4%). The results show the clinical benefits of etoricoxib/tramadol FDC, such as the sparing effect of tramadol dose per day, early therapeutic response rate compared with paracetamol/tramadol; which translates into faster pain relief, better adherence, less tramadol drug dependency, and a reduction of related AEs incidence. ClinicalTrials.gov identifier, NCT04968158.

FZ-AD005, a Novel DLL3-Targeted Antibody–Drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models

Abstract Delta-like ligand 3 (DLL3) is overexpressed in small cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine was the first DLL3-targeted antibody–drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with rovalpituzumab tesirine. In this study, we developed a novel DLL3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody, FZ-A038, and a valine–alanine (Val–Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line–derived xenograft and patient-derived xenograft models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable, and the highest nonseverely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of patients with SCLC.

Integrated germline and somatic features reveal divergent immune pathways driving response to immune checkpoint blockade.

Immune Checkpoint Blockade (ICB) has revolutionized cancer treatment, however the mechanisms determining patient response remain poorly understood. Here, we used machine learning to predict ICB response from germline and somatic biomarkers and interpreted the learned model to uncover putative mechanisms driving superior outcomes. Patients with higher infiltration of T follicular helper cells had responses even in the presence of defects in the class-I Major Histocompatibility Complex (MHC-I). Further investigation uncovered different ICB responses in tumors when responses were reliant on MHC-I versus MHC-II neoantigens. Despite similar response rates, MHC-II reliant responses were associated with significantly longer durable clinical benefit (Discovery: Median OS=63.6 vs. 34.5 months P=0.0074; Validation: Median OS=37.5 vs. 33.1 months, P=0.040). Characteristics of the tumor immune microenvironment reflected MHC neoantigen reliance, and analysis of immune checkpoints revealed LAG3 as a potential target in MHC-II but not MHC-I reliant responses. This study highlights the value of interpretable machine learning models in elucidating the biological basis of therapy responses.

Analysis of cerebral venous sinus stenosis by flat panel angiographic CT (FP-CT) to guide treatment for idiopathic intracranial hypertension.

Cerebral venous sinus stenting (CVSS) is an effective treatment for idiopathic intracranial hypertension (IIH) secondary to dural venous sinus stenosis. Traditional selection of patients for CVSS has been made by microcatheter manometry, but pressure measurements are often equivocal. Here we present the results of a series of cases in which venous flat-panel CT (FP-CT) was used as an adjunct to microcatheter manometry to improve decision making and precise stent placement during CVSS. Ten consecutive patients with IIH underwent angiography with microcatheter manometry and venous FP-CT, with CVSS if indicated by the results. Cross-sectional measurements of the narrowed sinus were obtained on FP-CT before and after stenting. After the procedure, clinical outcomes were tracked. Follow-up with quantitative MRA with sinus flow measurements was also performed, when available. There was an exponential correlation between measured pressure gradient and degree of stenosis calculated using venous FP-CT. All patients with both a high degree of stenosis measured by FP-CT and a high pressure gradient across the stenosis showed a clinical benefit from stenting. True measurement of the cross-sectional area of the dural sinus, made by venous phase FP-CT, has a high degree of correlation with elevated venous pressure gradient across the point of stenosis. Even in a limited series of cases, we found an exponential decrease in flow with increasing severity of stenosis. Furthermore, patients with both an elevated venous pressure gradient and critical stenosis of the sinus on FP-CT showed symptomatic improvement after stenting.

Approaches for posaconazole therapeutic drug monitoring and their clinical benefits.

This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods. A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed. TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM. Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment.

Oral Health and Nutraceutical Agents.

Oral health is essential for both overall health and quality of life. The mouth is a window into the body's health, and nutrition can strongly impact the state of general and oral health. A healthy diet involves the synergistic effect of various nutraceutical agents, potentially capable of conferring protective actions against some inflammatory and chronic-degenerative disorders. Nutraceuticals, mostly present in plant-derived products, present multiple potential clinical, preventive, and therapeutic benefits. Accordingly, preclinical and epidemiological studies suggested a protective role for these compounds, but their real preventive and therapeutic effects in humans still await confirmation. Available evidence suggests that plant extracts are more effective than individual constituents because they contain different phytochemicals with multiple pharmacological targets and additive/synergistic effects, maximizing the benefits for oral health. Moreover, nutritional recommendations for oral health should be personalized and aligned with valid suggestions for overall health. This review is aimed to: introduce the basic concepts of nutraceuticals, including their main food sources; examine the logic that supports their relationship with oral health, and summarize and critically discuss clinical trials testing the utility of nutraceuticals in the prevention and treatment of oral diseases.

Which Interventions Are Effective in Treating Sleep Disturbances After THA or TKA? A Systematic Review.

Poor sleep quality is a common complaint after total joint arthroplasty (TJA), and it is associated with reports of higher pain and worse functional outcomes. Several interventions have been investigated with the intent to reduce the incidence of postoperative sleep disturbance with varying effectiveness. An aggregate of the best available evidence, along with an evaluation of the quality of those studies, is needed to provide valuable perspective to physicians and to direct future research. In this systematic review, we asked: (1) What is the reported efficacy of the most commonly studied medications and nonpharmacologic approaches, and (2) what are their side effects and reported complications? This systematic review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search using a combination of controlled vocabulary and keywords was performed utilizing Medline (Ovid), Embase (Ovid), Cochrane Central, and Web of Science databases from database inception to 2023, with the last search occurring October 24, 2023, to identify studies that evaluated a sleep intervention on the effect of patient-reported sleep quality after THA or TKA. Inclusion criteria were clinical trials, comparative studies, and observational studies on adult patients who underwent primary TKA or THA for osteoarthritis and who completed validated sleep questionnaires to assess sleep quality postoperatively. We excluded studies on patients younger than 18 years, patients with sleep apnea, TKA or THA because of trauma or conditions other than osteoarthritis, revision TJA, studies in languages other than English, and studies from nonindexed journals or preprint servers. Two investigators independently screened 1535 studies for inclusion and exclusion criteria and extracted data from the included studies. Ultimately, 14 studies were included in this systematic review, including 12 randomized controlled trials and 2 prospective comparative studies. A total of 2469 participants were included, with a mean ± SD age of 65 ± 7 years and 38% men in control groups and 65 ± 7 years and 39% men in intervention groups. Sleep quality questionnaires utilized included the Pittsburgh Sleep Quality Index, Self-Rating Scale of Sleep, 100-mm VAS - Sleep, Sleep Disturbance Numeric Rating Scale, Likert scales, and one institutionally designed questionnaire. Quality analysis was performed utilizing the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Randomized Controlled Trials, where higher scores of 13 indicated a more reliable study, and the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies, where higher scores of 9 indicated a more reliable study and scores < 5 represented a high risk of bias. Two of the randomized controlled trials scored a 12 of 13, and the remaining 10 met every criteria of the JBI checklist. Both comparative studies scored 5 of 9 possible points of the Newcastle-Ottawa Scale. Melatonin and selective cyclooxygenase-2 inhibitor rofecoxib were found to provide a clinically important benefit to sleep quality within the first postoperative week after TJA. However, rofecoxib was withdrawn from the market globally in 2004 over concerns about increased risk of cardiovascular events. Another cyclooxygenase-2 inhibitor, celecoxib, remains available. No other intervention demonstrated a clinical benefit. Side effects of melatonin include dizziness, headache, paresthesia, and nausea, and it is contraindicated in patients with liver failure, autoimmune conditions, or who are receiving warfarin. Long-term adverse effects of rofecoxib include hypertension, edema, and congestive heart failure, and it is contraindicated in patients with renal insufficiency or who are receiving warfarin. Melatonin is considered safe in older patients, but more caution should be taken with rofecoxib. Owing to limited evidence in support of most of the interventions we studied, none of these interventions can be recommended for routine use after TJA. Melatonin and rofecoxib may provide a benefit to sleep quality in some patients, but physicians need to understand the adverse effects and contraindications before recommending these interventions. Additionally, rofecoxib is no longer commercially available. Future investigation is warranted to evaluate the effectiveness of interventions with minimal side effect profiles for providers to be able to make an informed decision about interventions for sleep improvement after TJA. Level III, therapeutic study.

A bone graft from the tibial resection or patella that rectified a tibial over-resection reliably healed and improved clinical outcome scores: A retrospective study of kinematically aligned TKA.

During kinematically aligned (KA) total knee arthroplasty (TKA), the surgeon may need to rectify an over-resection of the medial, lateral or posterior tibia. This study tested the hypothesis that a bone graft taken from the tibial resection or patella and impacted beneath a tibial baseplate would heal, regardless of whether the tibial component and knee were in outlier ranges according to mechanical alignment (MA) criteria. The study also tested the hypothesis that the Oxford Knee Score (OKS) and Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR) would improve beyond the substantial clinical benefit and that the source and thickness of the bone graft would not influence their improvement. This retrospective study radiographically assessed the healing of a bone graft from the tibial resection (n = 19) or patella (n = 10) in 29 KA TKAs (18 females, mean age 65 years). The tibial component and knee alignment were categorized as in-range or outliers based on reported MA criteria for bone graft healing and implant survival. The one-sample t test identified differences in the improvement of the OKS and KOOS JR from their reported substantial clinical benefit of 16 and 20 points, respectively. At an average follow-up of 37 months, all bone grafts healed even though ≥55% of tibial components and 34% of knees were varus outliers according to MA criteria for bone healing and implant survival. Amongst the 29 patients, the mean OKS and KOOS JR improvements of 25 ± 11 and 47 ± 21 points, respectively, surpassed the threshold of their respective substantial clinical benefit (p < 0.01) and were not influenced by the bone graft's source and thickness (p ≥ 0.51). During cemented KA TKA, the surgeon can use a bone graft from the tibial resection or patella to rectify a tibial over-resection. This technique led to consistent bone healing and improved outcome scores. Level IV.

GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma.

Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.

Toxicity profiles of immune checkpoint inhibitors in nervous system cancer: a comprehensive disproportionality analysis using FDA adverse event reporting system

Background: Immune-related adverse events (irAEs) always occur during treatment with immune checkpoint inhibitors (ICIs). Patients with nervous system cancer (NSC) may gain clinical benefit from ICIs, but irAEs in NSC patients are rarely examined. Therefore, our study systematically summarized reports of irAEs in NSC. Methods: We obtained information from the FDA adverse event reporting system from the first quarter (Q1) of 2013 to the fourth quarter (Q4) of 2022. We examined use of a combination of ICIs and chemotherapy (ICI_Chemo) or chemotherapy only (ICI_Chemo) for patients with NSC. Multiple disproportionality analyses were applied to assess irAEs. Multiomics data from the gene expression omnibus (GEO) database were analyzed to explore potential molecular mechanisms associated with irAEs in NSC patients. Results: Fourteen irAEs were identified in 8,357 NSC patients after removing duplicates; the top five events were seizure, confused state, encephalopathy, muscular weakness and gait disturbance. Older patients were more likely to develop irAEs than were younger patients. From the start of ICIs_Chemo to irAE occurrence, there was a significant difference in the time to onset of irAEs between age groups. irAEs may occur via mechanisms involving the inflammatory response, secretion of inflammatory mediators, and aberrant activation of pathologic pathways. Conclusions: This study helps to characterize irAEs in NSC patients treated with ICIs. We combined GEO database analysis to explore the potential molecular mechanisms of irAEs. The results of this study provide a basis for improving the toxic effects of ICIs in NSC patients.

Experience of using lenvatinib in the treatment of hepatocellular cancer at the Republican Oncology Center of the Republic of North Ossetia-Alania in 2018–2022. Balance of efficiency and accessibility in regional practice

The overall incidence of liver cancer in the Republic of North Ossetia-Alania has remained stable over the past five years. Moreover, the initial diagnostic of HCC occurs at widespread stage, which limits the possibilities of cured therapy. The Republican Oncology Clinic has accumulated experience in using the drug lenvatinib for advanced and metastatic hepatocellular cancer. In the realities of a small regional dispensary, and has to find a balance between efficiency and availability of therapeutic options to provide effective therapy for all patients. The authors conducted a single-center retrospective analysis of the effectiveness and safety of lenvatinib in real clinical practice in patients with hepatocellular cancer at the Republican Oncology Center of the Republic of North Ossetia Alania. The analysis included 18 patients with HCC who received lenvatinib monotherapy. 11(61%) patients had concomitant viral hepatitis B or C, 15 (83%) had distant metastases to the lymph nodes, lungs, adrenal glands or other organs. A feature of this patient population is the long period of time from the prescription of drug therapy for HCC to its actual start – on average 46 days, with a range from 5 to 100 days. We believe that a delay in initiating therapy may affect the results obtained. Median PFS in 1st line of lenvatinib therapy was 10.1 months (2.3 months to 13.1 months). Median PFS2 (defined as the time from 1st line treatment on lenvatinib to progression on first subsequent therapy) was 19.1 months. 6 (33%) patients received lenvatinib in the second line after progression on another drug therapy. The median second-line PFS in this case was 5.9 months (3.8 months‑7.7 months). Lenvatinib had a manageable and predictable tolerability profile. No new safety signals were identified.Conclusion: The use of lenvatinib as monotherapy in adult patients with advanced or unresectable hepatocellular carcinoma has proven to be an effective strategy that balances clinical benefit and availability of the drug.

Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs.

We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days. Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.

A Nomogram of Predicting Healthcare-Associated Infections in Burned Children.

Healthcare-associated infections (HAIs) are a common clinical concern associated with adverse prognosis and mortality in burned children. This study aimed to construct a predictive nomogram of the risk of HAIs in burned children. Children admitted to the burn unit of Wuhan Third Hospital between 2020 and 2022 were included. The univariate and multivariate logistic regression analyses were adopted to ascertain predictors of HAIs. A nomogram was developed to predict the HAI risk of each patient, with receiver operating characteristic curves and calibration curves being generated to assess its predictive ability. Furthermore, decision and impact curves were used to assess the clinical utility. Of 1122 burned children, 61 (5.5%) patients experienced HAIs. The multivariate analysis indicated that total burn surface area, length of stay, surgery, central venous catheter use and urinary catheter use were the independent risk factors of HAIs. Using these variables, we developed a predictive nomogram of the occurrence of HAIs in burned children, and the internal validation results demonstrated good discrimination and calibration of the nomogram. The area under the curve values of the nomogram was 0.926 (95% CI, 0.896-0.957). The calibration curve showed high consistency between the actual and predicted HAIs. The decision and impact curve indicated that the nomogram was of good clinical utility and more credible net clinical benefits in predicting HAIs. The present study constructed a nomogram for predicting the risk of HAIs in burned children. This nomogram may strengthen the effective screening of patients at high risk of HAIs.

A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases

This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with HER2-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. Endpoints included intracranial objective response rate (ORR; complete or partial response in brain) per blinded independent central review (BICR) by RECIST v1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those who were treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median (95% CI) intracranial DoR was 12.3 months (9.1-17.9 months), and for those with untreated/active BMs it was 17.5 months (13.6-31.6 months). The median (95% CI) CNS-PFS and OS was 12.3 months (11.1-13.8 months) and not reached (22.1 months-not estimable [NE]) in those with treated/stable BMs, and 18.5 months (13.6-23.3 months) and 30.2 months (21.3 months-NE) in those with untreated/active BMs, respectively. Drug-related TEAEs grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration

BackgroundThe anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking.MethodsABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing.ResultsA total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48–0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62–1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival.ConclusionThis retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What’s more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment.Graphical

Daratumumab, bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone alone in transplant-ineligible Asian patients with newly diagnosed multiple myeloma: final analysis of the phase 3 OCTANS Study.

The superiority and tolerability of daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) was previously described in the global phase 3 ALCYONE study. The primary analysis of the phase 3 OCTANS study further demonstrated the superiority and tolerability of D-VMP (n = 144) versus VMP (n = 71) in transplant-ineligible Asian patients with NDMM. The current analysis describes the final efficacy and safety outcomes for D-VMP versus VMP in OCTANS, with a follow-up of > 3 years. D-VMP demonstrated a benefit versus VMP with regard to the rate of very good partial response or better (80.1% vs. 47.3%), median progression-free survival (38.7 vs. 19.2 months), median time to next treatment (46.8 vs. 20.6 months), rate of complete response or better (46.6% vs. 18.9%), median duration of response (41.3 vs. 18.5 months), achievement of minimal residual disease (MRD) negativity (40.4% vs. 10.8%), and sustained MRD negativity for ≥ 12 months (24.7% vs. 1.4%) and ≥ 18 months (15.1% vs. 1.4%). Median progression-free survival was longer among patients who achieved MRD negativity and sustained MRD negativity. The progression-free survival benefit observed with D-VMP was preserved across most clinically relevant subgroups, including patients with high-risk cytogenetics. No new safety concerns were identified with extended follow-up. This final analysis of OCTANS continues to demonstrate a clinical benefit for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM, consistent with the global ALCYONE study, and supports the use of daratumumab combinations in this population. Trial registration: ClinicalTrials.gov Identifier NCT03217812 submitted July 13, 2017.

The INSIGHT study: a randomized, Phase III study of ripretinib versus sunitinib for advanced gastrointestinal stromal tumor with KIT exon 11+17/18mutations.

Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with threeor more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11+17/18mutations detected by circulating tumor DNA.Clinical Trial Registration: NCT05734105 (ClinicalTrials.gov).