First-line Treatment Research Articles

Novel immunotherapeutic approaches in gastric cancer

Abstract Gastric cancer is a malignant tumor that ranks third in cancer-related deaths worldwide. Early-stage gastric cancer can often be effectively managed through surgical resection. However, the majority of cases are diagnosed in advanced stages, where outcomes with conventional radiotherapy and chemotherapy remain unsatisfactory. Immunotherapy offers a novel approach to treating molecularly heterogeneous gastric cancer by modifying the immunosuppressive tumor microenvironment. Immune checkpoint inhibitors and adoptive cell therapy are regarded as the promising modalities in cancer immunotherapy. FDA-approved PD1 inhibitors, such as Pembrolizumab, in combination with chemotherapy, have significantly extended overall survival in gastric cancer patients and is recommended as a first-line treatment. Despite challenges in solid tumor applications, adoptive cell therapy has demonstrated efficacy against various targets in gastric cancer treatment. Among these approaches, CAR-T cell therapy research is the most widely explored and CAR-T therapy targeting claudin18.2 has shown acceptable safety and robust anti-tumor capabilities. However, these advancements primarily remain in preclinical stages, and further investigation should be made to promote their clinical application. This review summarizes the latest research on immune checkpoint inhibitors and adoptive cell therapy and their limitations, as well as the role of nanoparticles in enhancing immunotherapy.

Evaluation of the efficacy and safety of first- and second-line immunotherapy in patients with metastatic colorectal cancer: a systematic review and network meta-analysis based on randomized controlled trials

BackgroundA multitude of randomized controlled trials (RCTs) conducted in both the initial and subsequent treatment settings for patients diagnosed with metastatic colorectal cancer (mCRC) have provided clinical evidence supporting the efficacy of immunotherapy with the use of immune checkpoint inhibitors (ICIs). In light of these findings, the U.S. Food and Drug Administration (FDA) has authorized the use of several ICIs in specific subpopulations of mCRC patients. Nevertheless, there remains a dearth of direct comparative RCTs evaluating various treatment options. Consequently, the most effective ICI therapeutic strategy for microsatellite-stable (MSS) subgroup and microsatellite instability (MSI) subgroup in the first- and second-line therapies remains undefined. To address this gap, the present study employs a Bayesian network meta-analysis to ascertain the most effective first- and second-line ICI therapeutic strategies.MethodsA comprehensive literature search was conducted across multiple databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, with the retrieval date ranging from the databases’ inception to August 20, 2024. A total of 875 studies were identified, and seven were ultimately included in the analysis after a screening process. A systematic review and network meta-analysis were conducted on the basis of the search results.ResultsThis comprehensive analysis, comprising seven RCTs, evaluated first-line and second-line immunotherapy regimens in 1,358 patients diagnosed with mCRC. The treatments under investigation consisted of five initial treatments, including three focusing on MSS patients and two on MSI patients, as well as two secondary immunotherapy regimens, both focusing on MSS patients. A total of 1051 individuals underwent first-line treatment, while 307 received second-line treatment. The application of ICIs proved to offer varying degrees clinical benefits when compared to standard-of-care therapy alone, both in two subgroups of the first and the second treatment phases. Of particular note is the performance of Nivolumab combination with ipilimumab, which demonstrated superior efficacy in improving progression-free survival (PFS) (HR=0.21; 95% CI, 0.13-0.34),. Moreover, the treatment demonstrated an optimal safety profile, with a relatively low risk of adverse events (OR = 0.33; 95% CI, 0.19–0.56), compared to other first-line treatment modalities for MSI subgroup. Regarding MSS subgroup, the improvement of PFS by Nivolumab plus standard-of-care (SOC) was relatively significant (HR = 0.74; 95% CI, 0.53-1.02). In the realm of second-line therapies for MSS subgroup, the administration of Atezolizumab plus SOC has proven to be an effective approach for prolonging PFS, exhibiting an HR of 0.66 (95% CI, 0.44–0.99). These findings underscore the clinical benefits and safety profiles of ICIs in the treatment of mCRC across various treatment lines.ConclusionsThe clinical application of ICIs in both first- and second-line treatment strategies for patients with mCRC yields substantial therapeutic benefits. A detailed assessment in this study indicates that first-line treatment with Nivolumab combination with ipilimumab may represent an efficacious and well-tolerated therapeutic approach for MSI subgroup. In terms of MSS subgroup in first-line therapy, Nivolumab plus SOC may be a relative superior choice. In the context of second-line therapy for MSS subgroup, it is evident that a combination of Atezolizumab and SOC represents a preferable option for enhancing PFS. Furthermore, it is noteworthy that other ICIs treatment regimens also exhibit great value in various aspects, with the potential to inform the development of future clinical treatment guidelines and provide a stronger rationale for the selection of ICIs in both first- and second-line therapeutic strategies for mCRC.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42024543400.

Clinical Profile and Histopathological Pattern of Major Salivary Gland Tumors in a Nigerian Tertiary Hospital

Abstract Background: Varieties of tumors can arise from major salivary glands primarily or secondarily. Over 30 histological subtypes have been documented by the World Health Organization, serving as a guide in diagnosis and management. Objectives: To evaluate the clinical and histological pattern of presentation of major salivary gland tumors. Materials and Methods: This is a clinical retrospective study, done at the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria, assessing records of patients with major salivary gland tumors seen between January 2018 and December 2022. Data obtained were analyzed using Statistical Package for Social Sciences version 26. The results were presented in tables and charts and comparisons were made using the Chi-squared test. Results: Out of the 57 patients with major salivary gland tumors studied, 30 (52.6%) were benign tumors, and 27 (47.4%) were malignant tumors. About 63.2% of patients were predominantly females, whereas 36.8% were males with a male-to-female ratio of 1:1.7. The most common presenting symptom was swelling. The average duration of symptoms before presentation was 24 and 12 months for benign and malignant tumors, respectively. The parotid gland (61.4% total) was the most common site of tumor presentation for both benign and malignant tumors followed by the submandibular and sublingual the least. The most common histological variant was pleomorphic adenoma (40.4%) for benign and mucoepidermoid carcinoma (28.1%) for malignant. Surgery was the first line of treatment given. Conclusion: The observed pattern of clinical and histological presentation of major salivary gland tumors will guide clinicians on the approach for the management.

Amlodipine-Induced gingival hyperplasia in a nepalese patient experiencing high dosages: a case report

Introduction and Importance: Amlodipine is a third-generation calcium channel blocker used in the treatment of Hypertension. One of the side effects associated with amlodipine is gingival hyperplasia mostly occurring at a higher dose (10 mg). There are very few cases of gingival hyperplasia associated with amlodipine at a lower dose (5 mg) or short-term administration. Case presentation: A 51-year-old male patient with diagnosed hypertension sought medical attention for gingival swelling and bleeding from the gums while brushing. He had been under amlodipine 5 mg for 12 months, which was increased to 10 mg for the last 2 months. The history and physical examination were consistent with amlodipine-induced gingival hyperplasia. The first line of treatment consisted of discontinuation of amlodipine and substitution with another class of anti-hypertensive. Clinical discussion and conclusion: The presented case highlights the challenge of balancing economic considerations with potential side effects in the use of amlodipine for hypertension in low-income countries like Nepal. Given its availability at no cost or minimal expense, amlodipine is often initiated as a first-line therapy. However, the decision to increase the dosage to 10 mg/day, influenced by economic constraints and the drug’s affordability, raises the risk of gingival hyperplasia. This case emphasizes the importance of physicians being mindful of potential adverse effects when prescribing higher doses of amlodipine and underscores the need for continued vigilance in managing hypertension in resource-limited settings.

Excellent RAI therapeutic response on a patient presenting skull metastasis of follicular thyroid cancer after 15 years.

Bone is the second most common site of metastasis for differentiated thyroid carcinoma (DTC). Bone metastasis (BMs) occur in about 10% of patients with DTC and is observed more often in follicular thyroid carcinoma (FTC) (7-28%) than papillary thyroid carcinoma (PTC) (1-7%). Bone metastasis is associated with unfavorable clinical outcomes mainly including skeletal-related events (SREs), such as pathologic fractures, bone pain, spinal cord compressions, and hypercalcemia, which negatively impact the quality of life of patients and reduce their life expectancy. Patients with BMs from DTC require comprehensive and multimodal treatment approaches, including radioiodine (RAI) therapy, palliative care, surgery, external beam radiotherapy, and targeted drug therapy. RAI therapy is the first-line treatment, despite being rather ineffective, especially in large BMs. The response to RAI therapy, either alone or in combination with BM focal treatment depends on iodine avidity. This study reports a rare case of metachronous skull bone metastasis from FTC in a 72-year-old female patient 15 years after initial treatment. The patient had an excellent response to RAI therapy, which resulted in the abnormal uptake disappearing. Following treatment, the patient has been disease-free for six years. This case confirms that a complete response to RAI treatment for BM depends on the degree of dedifferentiation of cancer cells, which highlights the need for long-term follow-up, especially for FTC patients.

Economic evaluation of NALIRIFOX vs. nab-paclitaxel and gemcitabine regimens for first-line treatment of metastatic pancreatic ductal adenocarcinoma from U.S. perspective

BackgroundThe cost-effectiveness of NALIRIFOX as a potential new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) has yet to be established. Our objective was to evaluate the cost-effectiveness of NALIRIFOX vs. nab-paclitaxel and gemcitabine in this indication from the perspective of U.S. public payers.MethodsA partitioned survival model was constructed from the perspective of U.S. public payers, drawing on baseline patient characteristics and vital clinical data from the NAPOLI-3 trial. Costs and utilities were sourced from publicly accessible databases and literature. A lifetime horizon was applied, with an annual discount rate of 3%. We calculated and compared cumulative costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). To evaluate the model’s robustness, sensitivity analyses, scenario analyses, and subgroup analyses were carried out. Additionally, a price simulation for the costly liposomal irinotecan was conducted to inform the pricing strategy at the given willingness to pay (WTP) threshold.ResultsIn the base-case analysis, NALIRIFOX provided an additional 0.29 QALYs with an ICER of $206,340.69 /QALY compared to nab-paclitaxel and gemcitabine, indicating it is not cost-effective at a $150,000/QALY threshold. Sensitivity analysis showed the model was most sensitive to the costs of liposomal irinotecan, capecitabine, and post-progression care. Probabilistic sensitivity analysis indicated a 17.66% probability of NALIRIFOX being cost-effective at $150,000/QALY, rising to 47.48% at $200,000/QALY. Pricing simulations suggested NALIRIFOX could become cost-effective at $150,000/QALY if the price of irinotecan liposome drops to $53.24/mg (a 14.8% reduction).ConclusionsNALIRIFOX may not be cost-effective at its current price as a first-line treatment for patients with mPDAC in the long term. The cost of liposomal irinotecan has the greatest impact. It may become cost-effective only if its cost is reduced by 14.8%, with a WTP threshold of $150,000 /QALY.

Chemotherapy combined with regorafenib and immune checkpoint inhibitors as a first-line treatment for patients with advanced biliary tract cancer: a single arm phase II trial

ObjectiveThis study aimed to investigate the efficacy, long-term prognosis and safety of combining chemotherapy with regorafenib and immune checkpoint inhibitors as first-line treatment for patients with advanced biliary tract carcinoma (BTC).MethodsIn this single arm phase II trial, twenty-nine patients with advanced BTC were included, all of whom received gemcitabine-based chemotherapy combined with regorafenib and immune checkpoint inhibitors as the first-line treatment. And the study analyzed anti-tumor efficacy, long-term prognosis, and adverse reactions.ResultsAmong the patients, 0 patient achieved complete response, 18 patients (62.1%) achieved partial response, 8 patients (27.6%) had stable disease, and 3 patients (10.3%) experienced progressive disease. The corresponding objective response rate (ORR) was 18/29 (62.1%), and the disease control rate (DCR) was 26/29 (89.7%). The median overall survival (OS) was 16.9 months (95% confidence interval [CI]: 12.0 -21.8) and the median progress free survival (PFS) was 10.2 months (95% CI: 7.8- 12.6). The 1-year OS and PFS were 65% (95% CI: 0.479-0.864) and 41% (95% CI: 0.234-0.656), respectively. The incidence of adverse reactions was 27/29 (93.1%), and the incidence of grade III/IV adverse reactions was 5/29 (17.2%).ConclusionThe combination of chemotherapy, regorafenib, and immune checkpoint inhibitors as a first-line treatment for patients with advanced BTC may has good anti-tumor efficacy without causing serious adverse reactions, and can significantly improve the long-term prognosis.

An economic model to understand the cost-effectiveness of olanzapine orally dispersible tablets (ODT) and olanzapine film coated tablets as a group compared with other oral atypical antipsychotics for treating schizophrenia in Morocco

BackgroundAntipsychotic medications are the primary treatment for schizophrenia, with olanzapine being an effective medication for schizophrenia. The economic cost for each individual with schizophrenia is high, with antipsychotic medication being a major expense. This study aims to develop an economic decision model that compares different treatment options for schizophrenia patients, including olanzapine Orally Dispersible Tablets (ODT), olanzapine [ODT + Standard Oral Tablet (SOT)], risperidone (ODT + SOT), and aripiprazole (ODT + SOT), to determine their cost-effectiveness with an objective to optimize healthcare resource allocation in Morocco.MethodsThe study used published medical literature and a clinical expert panel to develop a decision analytic model. This model was designed to capture parameters such as adherence levels, treatment discontinuation, relapse with and without hospitalization, quality-adjusted life years (QALYs), treatment-related adverse events, healthcare resource utilization, and associated costs. The main outcomes of interest included the total annual direct cost per treatment, QALYs, and incremental cost-effectiveness ratio (ICER) per 1 QALY gained. One-way and probabilistic sensitivity analyses were employed to account for parameter uncertainty.ResultsAccording to the simulation model, the ODT and ODT + SOT as a group form of olanzapine was the most effective treatment option in terms of the lowest percentages of inpatient relapse, and patients who remained stable (11% and 79% respectively) than risperidone (19% and 62% respectively) and aripiprazole ODT (26% and 50% respectively) and ODT + SOT formulation groups. Olanzapine (ODT + SOT) therapy group was cost-effective when compared to the combined group of ODT + SOT forms of risperidone [ICER: Moroccan Dirham (MAD) 103,907], and aripiprazole (ICER: MAD 65,047). Additionally, olanzapine ODT was found to be cost-effective compared to olanzapine SOT with an ICER of MAD 3921, risperidone ODT with an ICER of MAD 1,02,298, risperidone SOT with an ICER of MAD 31,088, and aripiprazole ODT or SOT formulations. All the above ICERs fall under the willingness-to-pay threshold in Morocco of MAD 250,832.40. Sensitivity analyses confirmed the reliability of the findings.ConclusionsThe model concluded that olanzapine ODT is the most cost-effective first-line treatment option for schizophrenia in Morocco when compared to other atypical antipsychotic medications in ODT and SOT formulations.

2024 UK and Ireland modified Delphi consensus on myopia management in children and young people.

This work aimed to establish the largest UK and Ireland consensus on myopia management in children and young people (CYP). A modified Delphi consensus was conducted with a panel of 34 optometrists and ophthalmologists with expertise in myopia management. Two rounds of voting took place and 131 statements were agreed, including that interventions should be discussed with parents/carers of all CYP who develop myopia before the age of 13 years, a recommendation for interventions to be publicly funded for those at risk of fast progression and high myopia, that intervention selection should take into account the CYP's hobbies and lifestyle and that additional training for eye care professionals should be available from non-commercial sources. Topics for which published evidence is limited or lacking were areas of weaker or no consensus. Modern myopia management contact and spectacles are suitable first-line treatments. The role and provision of low-concentration atropine needs to be reviewed once marketing authorisations and funding decisions are in place. There is some evidence that a combination of low-concentration atropine with an optical intervention can have an additive effect; further research is needed. Once an intervention is started, best practice is to monitor non-cycloplegic axial length 6 monthly. Research is needed to identify those at risk of progression, the long-term effectiveness of individual and combined interventions, and when to discontinue treatment when myopia has stabilised. As further evidence continues to emerge, this consensus work will be repeated to ensure it remains relevant.

Venetoclax-based salvage therapy as bridge-to-transplant is feasible and effective in patients with relapsed/refractory AML.

The BCL2-inhibitor Venetoclax (VEN) in combination with hypomethylating agents (HMA) has been approved for first-line treatment of acute myeloid leukemai (AML) patients ineligible for intensive treatment. Emerging Data suggest that VEN containing treatment strategies may also be effective in relapsed/refractory (R/R) AML, however, comparative studies with conventional treatment strategies for medically fit patients as a bridge-to transplant strategy are limited. Using propensity score matching (PSM) analysis, we compared 37 R/R AML patients, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic cell transplantation (allo-HCT) with 90 patients from the German Study Alliance Leukemia (SAL) AML registry, who were treated with non-VEN-containing salvage therapy according to their treating physician's choice (TPC) including intensive and non-intensive protocols. The overall response rate (ORR=CR+CRi) among all VEN patients was significantly higher compared to the TPC control cohort (62% vs. 42%; p=0.049). Overall, 73% of VEN-treated patients vs. 63% of TPC patients were successfully bridged to allo-HCT (p =0.41). After a median follow-up of 34.3 months for the VEN cohort and 21.0 months for the TPC cohort, the median overall-survival (OS) was 15.8 months (95%-CI, 10.6-NE) and 10.5 months (95%-CI, 6.8-19.6) (p=0.15), respectively. PSM revealed a trend towards improved OS for VEN patients (HR 0.70; 95%-CI, 0.41-1.22; p=0.20). Median event free survival (EFS) was significantly longer in the VEN cohort (8.0 months) compared to the TPC cohort (3.7 months) (p=0.006). In summary, our data suggests that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.

CRAFITY score as a predictive marker for refractoriness to atezolizumab plus bevacizumab therapy in hepatocellular carcinoma: a multicenter retrospective study.

Although atezolizumab plus bevacizumab (Atezo/Bev) therapy has been used as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC), up to 26% of patients do not achieve disease control, suggesting alternative treatments might be more beneficial for such patients. We investigated key predictors for refractoriness to Atezo/Bev therapy, particularly in the first-line setting. We retrospectively analyzed 302 patients with HCC who received Atezo/Bev therapy between October 2020 and September 2022 across nine hospitals in Japan. Refractoriness was defined as best overall response (BOR) of progressive disease or stable disease and a progression-free survival (PFS) of < 180days (RECIST v1.1). Clinical benefit was defined as BOR of partial/complete response or stable disease with PFS of ≥ 180days. Baseline characteristics and potential predictors, identified through literature review, were compared between these groups. Stratifications of overall survival (OS), and PFS were also assessed. Refractoriness was observed in 126 (41.7%) patients, while 154 (51.0%) achieved clinical benefit. Due to a significant association between the treatment line and refractory rate, the subsequent analysis focused on the first-line cohort (n = 214; 72 [33.6%] patients showed refractoriness). Among 13 potential predictors, the CRP and AFP in immunotherapy (CRAFITY) score had the best predictive performance, with refractory rates of 24.6%, 44.6%, and 57.9% in CRAFITY-0, 1, and 2 patients, respectively (p < 0.001). OS and PFS were also well-stratified by this scoring system. Approximately one-third of patients were refractory to first-line Atezo/Bev therapy. The CRAFITY score demonstrated superior performance in predicting refractoriness.

Emergency Department and Critical Care Use of Clevidipine for Treatment of Hypertension in Patients with Acute Stroke.

Clevidipine is a parenteral dihydropyridine calcium channel blocker that received Food and Drug Administration (FDA) approval in 2008 for the reduction of blood pressure (BP) when oral therapy is not feasible or not desirable. Soon after approval, our institution incorporated clevidipine into protocols for management of hypertension among acute stroke patients, based on the drug's rapid onset of action and straightforward titration to goal. A subsequent retrospective review of its use in otherwise alteplase-eligible ischemic stroke patients with BP greater than 185/110 mmHg (n=32, in 2014) revealed that clevidipine in that setting demonstrated the shortest median time to BP control, the shortest median door to alteplase administration time, and the lowest administered volume of any parenteral antihypertensive used. As a result, clinical protocols in our institution were modified to make clevidipine first-line antihypertensive in both ischemic and hemorrhagic acute stroke. In this study we report our institution's experience with clevidipine in acute stroke, comprising the largest such report to date. . We conducted a retrospective chart review of all acute stroke patients who received clevidipine in the Emergency Department (ED) or intensive care unit (ICU) (n=295) for the management of clinically significant hypertension between January 1, 2015 and December 31, 2017. Metrics analyzed included target (goal) BP for thrombolysis eligibility among patients intended for lytic therapy according to stroke management guidelines in effect at the time of care. The median time for initial parenteral antihypertensive Dose-to-Goal (DTG) BP for all ischemic stroke patients (both those intended for and those not intended for lytic therapy) with complete data (n= 71 of 204) was 15 minutes; median time for Door-to-IV-alteplase administration for ischemic stroke patients with complete data (n=14 of 34 treated patients) was 59 minutes. The median time for initial parenteral antihypertensive DTG BP for all hemorrhagic stroke patients with complete data (n=33 of 91 treated patients) was 39 minutes. We conclude that the salutary findings of the initial small study are valid across a larger patient sample of all acute stroke types. Based on these data, clevidipine is shown to be safe, consistent, and effective in the treatment of acute hypertension in ischemic and hemorrhagic stroke events, and is a reasonable first-line treatment option for acute hypertension in this setting.

Pharmacomechanical thrombectomy in management of pulmonary embolism

BackgroundAcute pulmonary embolism is recorded as one of the most common and critical medical conditions, resulting in a notable mortality rate requiring a multidisciplinary management. In this series, we address the management of massive and sub-massive pulmonary embolism utilizing catheter-based intervention, in particular the conjunction of mechanical thrombus disruption and aspiration with pharmacological thrombolysis (pharmacomechanical thrombectomy).Results37 patients were diagnosed with massive and sub-massive pulmonary embolism based on the clinical and radiological findings. Pre-procedural vital parameters were obtained, including oxygen saturation, pulse rate, and blood pressure. Under continuous monitoring and conscious sedation, a pulmonary angiography via right common femoral vein access was performed for pre-procedural assessment. Pharmacomechanical thrombectomy was performed using the AngioJet Ultra System (Boston Scientific). Using the power pulse option, a fibrinolytic agent was infused into the thrombus. After 5–10 min, mechanical thrombectomy is performed with a maximum 3 passes through the thrombus. This technique is performed in the main pulmonary artery and lower branch. The procedure is repeated on the other side. The maximum duration of thrombectomy is 2–3 min on each side. Procedure success was based on improvement of vital signs and not related to post-procedure angiographic findings. All patients showed immediate improvement of vital signs (blood pressure, 02 saturation, and pulse rate) with progressive improvement over the following days. There were no procedure-related complications.ConclusionPharmacomechanical thrombectomy is a safe and effective technique in the treatment of massive and submassive pulmonary embolism. It can be a first-line treatment even in patients without absolute contraindication to systemic thrombolysis.

ASO Author Reflections: The Gustave Roussy Immune Score May Be a Useful Biomarker for Conversion Surgery After Chemotherapy Plus Nivolumab as the First-Line Treatment for Gastric Cancer.

PAST: There are no reports of promising biomarkers that predict which cases can be transferred to conversion surgery (CS) after chemotherapy plus nivolumab as first-line treatment for unresectable advanced or recurrent gastric cancer (GC). The purpose of this multicenter retrospective study was to conduct an analysis of real-world data on CS after chemotherapy plus nivolumab as a first-line treatment and to identify predictive biomarkers. PRESENT: We showed the CS transition rate was 11.5%. All CS cases had R0 resection, and the postoperative short-term outcome was acceptable. There were no high-risk Gustave Roussy Immune Score (GRIm-s) cases among those who underwent CS. FUTURE: Although this study was a multicenter study, the number of patients was small. A randomized controlled trial should be conducted for a more detailed study of the significance of CS.

Efficacy and safety of first-line treatments for advanced hepatocellular carcinoma patients: a systematic review and network meta-analysis

BackgroundThe first-line treatment for advanced hepatocellular carcinoma has evolved significantly. This study aimed to identify the most beneficial regimen.MethodsA systematic search was conducted from July 2012 to August 2024 across the following four databases: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. This search focused on phase III prospective randomized controlled trials that compared first-line treatment for advanced hepatocellular carcinoma.ResultsSeventeen studies involving 10322 patients were included in this network meta-analysis. Of the studies we included, twelve studies were global multicenter clinical studies, four were initiated in China, and one was initiated in Korea. The results of our statistical analysis suggest that Hepatic artery infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) demonstrated significant overall survival (OS) benefits compared with most treatments, including various immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). In terms of OS, HAIC had shown similar efficacy with sorafenib plus FOLFOX (HR, 0.88; 95% CI: 0.37-2.09) and transcatheter arterial chemoembolization (TACE) combined with lenvatinib (HR, 0.69; 95% CI: 0.30-1.56). Notably, immune-related treatments, such as ICIs combined with anti-VEGF therapies, also showed improved OS compared with anti-VEGF-TKIs alone. In terms of progression-free survival (PFS), HAIC-FO outperformed anti-VEGF-TKI monotherapy, ICI monotherapy, and several ICI combinations. However, it was not superior to lenvatinib plus TACE or lenvatinib plus pembrolizumab. Based on the Surface Under the Cumulative Ranking Curve (SUCRA) values, HAIC-FO was ranked the most effective in terms of OS (SUCRA = 0.961) and objective response rate (ORR) (SUCRA = 0.971). The results of the subgroup analysis suggested that HAIC-FO achieved the best OS benefit in the macrovascular invasion (MVI) and extrahepatic spread (EHS) subgroup (SUCRA = 0.99) and that tremelimumab combined with durvalumab achieved the best OS benefit in the Asian subgroup (SUCRA = 0.88).ConclusionThis systematic review and network meta-analysis suggest that HAIC-based therapies may become a potential first-line treatment option for advanced HCC, especially for patients in Mainland China with MVI and EHS. Additionally, immune-related treatments may be more suitable for Asian populations.

Pharmacokinetics-pharmacodynamics of first-line antitubercular drugs: a comparative study in tuberculosis patients with and without concomitant diabetes mellitus.

To observe the variability in the plasma concentrations and pharmacokinetic-pharmacodynamic (PK-PD) profiles of first-line antitubercular drugs in pulmonary tuberculosis (TB) patients with and without diabetes mellitus (DM). Newly diagnosed pulmonary TB patients aged 18-60years with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas group II (n = 20) included patients withboth TB and DM. After 2 weeks of therapy, plasma concentrations and other PK-PD parameters were determined. Improvements in clinical features, X-ray findings, sputum conversion, and adverse drug reactions (ADRs) were assessed after 2 months of therapy. Isoniazid displayed non-significantly higher plasma concentrations in diabetic patients, along with a significantly (P < 0.05) longer elimination half-life (t1/2). Rifampicin plasma concentrations at 4, 8, and 12 h were significantly (P < 0.05) lower, and it displayed significantly (P < 0.05) lower area underthe curve (AUC0-12 and AUC0-∞), shorter t1/2, higher clearance (Cl), and a lower AUC0-∞/MIC ratio in diabetic patients. Pyrazinamide and ethambutol showed non-significantly higher plasma concentrations, AUC0-12, AUC0-∞, and t1/2 in diabetic patients. The improvements in clinical features, X-ray findings, sputum conversion, and ADRs were comparable in both groups. The presence of DM in TB patients affects the PK-PD parameters of isoniazid, rifampicin, pyrazinamide, and ethambutol variably in the Indian population. Studies with a larger number of patients are required to further elucidate the role of DM on the PK-PD profile of first-line antitubercular drugs and treatment outcomes in TB patients with concomitant DM. CTRI/2021/08/035578 dated 11/08/2021.

What Patients with Bipolar Disorder Need to Know about Lithium

Lithium is the superior first-line treatment for bipolar disorder (BD). Yet the percentage of patients receiving lithium is abysmally low, especially in the US. Since psychiatrists have failed to place lithium in its appropriate role, we make the case that patients with BD themselves need to be better educated about the unique characteristics and pre-eminence of the drug so that it can be used more often and appropriately. Lithium has a highly unfavorable popular reputation among would-be patients and many psychiatrists. Thus, a direct appeal to patients with BD appears appropriate to try to remediate this situation. The unique assets of lithium are underappreciated or not well known. Conversely, the side effects profile of lithium are overestimated. Here, we make the case that lithium’s image needs to be revised not only with better and more accurate information but also with a wholesale renaming and rebranding of the drug. We will not only outline the unique qualities and new information about the side effects of the drug but attempt to change some of the terminology conventionally used to refer to lithium so that its use may be appropriately applied earlier and at an increased frequency for patients with BD.

Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health

The phosphodiesterases type 5 (PDE5) are catalytic enzymes converting the second messenger cyclic guanosine monophosphate (cGMP) to 5’ GMP. While intracellular cGMP reduction is associated with several detrimental effects, cGMP stabilization associates with numerous benefits. The PDE5 specific inhibitors, PDE5i, found their explosive fortune as first-line treatment for erectile dysfunction (ED), due to their powerful vasoactive properties. The favorable effect for ED emerged as side-effect when PDE5i were originally proposed for coronary artery disease (CAD). From that point on, the use of PDE5i captured the attention of researchers, clinicians, and companies. Indeed, PDE5-induced intracellular cGMP stabilization offers a range of therapeutic opportunities associated not only with vasoactive effects, but also with immune regulatory/anti-inflammatory actions. Chronic inflammation is acknowledged as the common link underlying most non-communicable diseases, including metabolic and cardiac diseases, autoimmune and neurodegenerative disorders, cancer. In this scenario, the clinical exploitation of PDE5i is undeniably beyond ED, representing a potential therapeutic tool in several human diseases. This review aims to overview the biological actions exerted by PDE5i, focusing on their ability as modulators of inflammation-related human diseases, with particular attention to inflammatory-related disorders, like cardiac diseases and cancer.

Highly Efficient Synergistic Chemotherapy and Magnetic Resonance Imaging for Targeted Ovarian Cancer Therapy Using Hyaluronic Acid-Coated Coordination Polymer Nanoparticles.

The diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin-based chemotherapy is the first-line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt-COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt-COOH, and Gossypol from HA@PFG NPs. Pt-COOH with GSH consumption and cisplatin-basedchemotherapy plus Gossypol with pro-apoptotic effects displays asynergisticeffect forkillingtumorcells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. Inthe patient-derived tumor xenograft (PDX)model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL-6 signal pathways. This work combines MRI imaging with cisplatin-based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy.

Late Subcutaneous Infection Caused by Serratia marcescens Following Hyaluronic Acid Injection: A Case Report and Systemic Review.

The field of cosmetic filler injection has experienced rapid development over the past two decades, especially in facial augmentation utilizing hyaluronic acid (HA) fillers. Gram-negative bacteria are found to be the main pathogens of infective nodules after HA injection. The occurrence of cutaneous infections attributed to Serratia marcescens is exceedingly rare and predominantly noted in patients with compromised immune systems. To summarize the clinical features, diagnosis, and treatment of subcutaneous infection caused by Serratia marcescens following hyaluronic acid injection. A rare case of cutaneous Serratia marcescens infection following hyaluronic acid injection was presented. A comprehensive review of the published literature describing the management of skin infection caused by S. marcescens in immunocompetent patients was then conducted, which encompassed three case series and eight case reports published between 1999 and 2017. Data extraction included information on authors, gender, age, signs and symptoms, previous treatment, corresponding management strategies, and follow-up duration. Serratia marcescens were isolated in abscesses (n = 6, 35.29%), painful nodules (n = 2, 11.76%), ulcers (n = 6, 35.29%), and others (n = 3, 17.65%). In cases providing salvage plans (n = 11), quinolones were shown to be the most effective antibiotics for salvage, with eight full recoveries (72.73%), and trimethoprim-sulfamethoxazole was the second most useful antibiotic (18.18%). With the help of pathogen examination and drug-sensitive tests, sensitive aminoglycosides, quinolone (especially moxifloxacin), or TMP-SMX for at least 2 weeks can be considered as the first-line treatment of late subcutaneous infection caused by Serratia marcescens following hyaluronic acid injection.