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Background After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. Methods We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. Results Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (−5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (−0.1 ± 5.5%, P = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and 2 ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 [odds ratio (OR) 2.9, interquartile range (IQR) 1.3-6.6, P =.009] and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, P =.014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. Conclusion In patients with uncontrolled CTX levels after Dmab withdrawal, 2 ZOL infusions 6 months apart do not prevent BMD loss and FX. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Helicobacter pylori infection is one of the most common bacterial infections affecting humans, causing gastroduodenal and extraintestinal diseases. Treatment of the infection remains challenging for the clinicians, and different factors are involved in the failure of the therapeutic approach. The importance of the intensity of acid secretion inhibition remains an unclear issue. The aim of this study is to assess whether 80 mg/day esomeprazole‐based 10‐day sequential therapy (esomeprazole‐ST) achieved different eradication rates when compared to 80 mg/day pantoprazole‐based analogous regimen (pantoprazole‐ST).This was a retrospective observational study where data of consecutive patients referred by their physicians to our unit to perform an upper gastrointestinal endoscopy were analyzed.Overall, 1,327 patients were available for the analysis: 599 and 728 patients received pantoprazole‐ST and esomeprazole‐ST, respectively. Eradication rate was significantly higher in patients receiving esomeprazole‐ST (92.6%, 95% CI: 91–94.5) than pantoprazole‐ST (89.3%, 95% CI: 86.7–91.7; difference: 3.3%; 95% CI: 0.2–6.5; P = 0.037). Even after a multivariate analysis, the esomeprazole‐ST achieved a significantly higher eradiation (OR: 1.44; 95% CI: 1.1–2.17).This study showed that esomeprazole‐ST achieved significantly higher H. pylori cure rates than pantoprazole‐ST. Prospective and well‐designed trials are demander to confirm this prelaminar finding. [ABSTRACT FROM AUTHOR]

Simple Summary: Relapse and treatment-related side effects pose significant challenges for older patients with high-risk blood cancers (myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)) undergoing hematopoietic stem cell transplants from HLA-haploidentical donors. We compared two preparative treatment regimens to identify the most tolerable and effective approach: one using fludarabine, cyclophosphamide, and melphalan, and the other using fludarabine, cyclophosphamide, and treosulfan. Our goal was to determine which treatment offers better survival rates and fewer side effects. We found that both regimens resulted in similar survival outcomes. However, the melphalan regimen was associated with fewer relapses but more treatment-related deaths, while the treosulfan regimen had fewer side effects but exhibited poorer disease control. These findings suggest that treosulfan may be safer, though higher doses might improve disease control, providing valuable insights for future treatments. Relapse and regimen-related toxicities remain major challenges in achieving long-term survival, particularly among older patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated the feasibility of treosulfan-based conditioning, noting stable engraftment and low non-relapse mortality (NRM) in patients undergoing HLA-matched allo-HSCT. However, data on treosulfan-based conditioning in the HLA-haploidentical transplantation (HaploT) setting are limited. We retrospectively compared conditioning with fludarabine–cyclophosphamide (FC)–melphalan (110 mg/m2) and FC-treosulfan (30 g/m2) prior to HaploT using post-transplantation cyclophosphamide (PTCy) in patients with high-risk MDS/AML patients ≥ 50 years, transplanted from 2009–2021 at our institution (n = 80). After balancing patient characteristics by a matched-pair analysis, we identified twenty-one matched pairs. Two-year OS and LFS were similar among the groups (OS 66% and LFS 66%, p = 0.8 and p = 0.57). However, FC-melphalan was associated with a significantly lower probability of relapse compared to FC-treosulfan (0% vs. 24%, p = 0.006), counterbalanced by a higher NRM (33% vs. 10%, p = 0.05). Time to engraftment and incidences of acute and chronic graft-versus-host disease (GvHD) did not differ significantly. In conclusion, HaploT using FC-treosulfan in combination with PTCy in patients aged ≥50 years with MDS/AML appears safe and effective, particularly in advanced disease stages. We confirm the favorable extramedullary toxicity profile, allowing for potential dose intensification to enhance antileukemic activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Although atezolizumab plus bevacizumab is the standard first-line treatment for patients with advanced HCC, the optimal second-line regimen remains unknown. In this meta-analysis, we examined the subsequent regimen after the failure of atezolizumab–bevacizumab and found that sequential multitargeted tyrosine kinase inhibitors, including sorafenib and lenvatinib, significantly prolonged the survival of patients, with a pooled OS of 11.45 months and a PFS of 3.78 months, respectively. Moreover, the subsequent use of sorafenib or lenvatinib has manageable toxicity. Therefore, our data indicate that sorafenib or lenvatinib treatment is a rational option for patients with advanced HCC after progression on atezolizumab–bevacizumab. Background: Although atezolizumab plus bevacizumab (hereinafter, atezolizumab–bevacizumab) is the standard first-line treatment for patients with advanced HCC, the optimal second-line regimen remains unknown. This study evaluated the efficacy and safety of sorafenib and lenvatinib in patients with advanced HCC that progressed under atezolizumab–bevacizumab treatment. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed, Embase, and the Cochrane Library for articles published before November 2023. Random-effects meta-analysis was performed to determine the pooled objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), comparing patients who received sorafenib versus lenvatinib. Results: Seven studies involving 387 patients were included. The pooled ORR, DCR, OS, and PFS for sorafenib and lenvatinib together were 26% (95% CI: 14–43%), 63% (95% CI: 47–77%), 11.45 months (95% CI: 7.12–15.77, I2 = 92%, p < 0.01), and 3.78 months (95% CI: 2.34–5.23, I2 = 67%, p = 0.02), respectively. Although lenvatinib users had a longer median OS (12.42 vs. 10.75 months) and PFS (5.15 vs. 2.58 months) than sorafenib users, the pooled ORR, DCR, median OS, and PFS for these medications were comparable. Additionally, the distributions of all-grade and grade ≥ 3 adverse events for sorafenib and lenvatinib were comparable to those for these two medications when used as first-line therapies. Conclusions: Sorafenib or lenvatinib can provide effective treatment with manageable toxicity in patients with advanced HCC after disease progression under atezolizumab–bevacizumab. [ABSTRACT FROM AUTHOR]

Objective To investigate the difference in the efficacy of sequent teriparatide with denosumab and sequent teriparatide with zoledronic acid in the treatment of osteoporosis in patients with osteoporotic vertebral compression fracture after percutaneous vertebroplasty. Methods A retrospective selection was conducted on 60 postmenopausal osteoporosis patients who underwent percutaneous vertebroplasty at the Nanjing First Hospital from December 2020 to December 2023 and were treated with terlipide for 12 months postoperatively. According to the sequential medication situation， the patients were divided into the denosumab group and the zoledronic acid group，with 30 cases in each group. The changes of serum P1NP，serum β-CTX，lumbar spine BMD，hip BMD and the occurrence of refracture were compared between the two groups before treatment， at 6th month and at 12th month，and the differences of curative effect between the two groups were evaluated. Results The BMD growth rate of hip in the denosumab group was higher than that in the zoledronic acid group after 12 months of treatment (P<0.05). The BMD of lumbar spine and hip in the two groups at 12th month was higher than that before treatment (P<0.05). The BMD of lumbar spine in the denosumab group and the zoledronic acid group at 12th month was 8.7 % and 6.7 % higher than that before treatment， respectively. The BMD of hip in the denosumab group and the zoledronic acid group at 12th month was 6.6 % and 2.9 % higher than that before treatment，respectively. The levels of serum P1NP and serum β-CTX in the denosumab group were lower than those in the zoledronic acid group at 6th month and at 12th month (P<0.05). There was no significant difference in the incidence of refracture between the two groups during treatment (P>0.05). Conclusion In postmenopausal osteoporosis patients with OVCF，teriparatide sequent with denosumab is more effective than sequent with zoledronic acid in increasing bone mineral density in the hip and reducing bone metabolism markers. The two treatment regimens have no significant effect on the incidence of recurrent fractures. [ABSTRACT FROM AUTHOR]

Abstract Background and aim Bismuth and non-bismuth quadruple therapy are the guideline-recommended first-line therapy in children with Helicobacter pylori infection in areas with high antibiotic resistance. However, their efficacy in children is uncertain and there are few well-designed studies. Here, we evaluated the eradication rates of standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection. Methods A randomised controlled trial was conducted in children infected with H. pylori in West China Second Hospital. They were randomly assigned to 14-day standard triple therapy (omeprazole + amoxicillin + clarithromycin), 14-day bismuth quadruple therapy (bismuth + omeprazole + amoxicillin + clarithromycin) and 10-day sequential therapy (omeprazole + amoxicillin for 5 days followed by omeprazole + clarithromycin + metronidazole for 5 days). The eradication rate was assessed by a 13C-urea breath test 4 to 6 weeks after therapy completion. Symptom improvement and adverse events were compared among the groups. Results In total, 132 patients were enrolled. The eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0%, 78.9% and 50.0% in per-protocol analysis and 63.6%, 68.2% and 43.2% in intention-to-treat analysis, respectively. Symptom improvement and adverse drug event rates were similar in the three groups. Conclusion The three therapeutic regimens evaluated in this study are equally not recommendable for H. pylori infection treatment due to unsatisfactory eradication rates. The high prevalence of clarithromycin resistance makes the use of clarithromycin-based quadruple therapy not advisable, even in combination with amoxicillin and bismuth salts.

BACKGROUND: Bibliometrics and visual analyses based on thematic literature are particularly important for understanding the foundation and frontiers of postmenopausal osteoporosis research. OBJECTIVE: To perform bibliometric, citation, and visualization analyses of highly cited SCI papers in postmenopausal osteoporosis research over the last 20 years. METHODS: The top 100 highly cited papers on postmenopausal osteoporosis published between 2003 and 2022 included in SCI-EXPANDED catalog of the Web of Science database were obtained for bibliometric measure and visual analysis using CiteSpace software. RESULTS AND CONCLUSION: The top 100 highly cited papers have a total of 67 377 citations in the Web of Science Core Collection, with an annual average of 49.17 citations per paper. Postmenopausal osteoporosis research primarily involves medical, engineering, biological, and multidisciplinary fields. The subcategories are dominated by endocrinology and metabolism, and medicine: internal medicine. Stable and close cooperative network relationships have been formed globally. United States, University of California System, Cummings, and Steven R are the country, research institution, and author, respectively, with the most highly-cited publications. The frontiers of postmenopausal osteoporosis research mainly include calcium and vitamin D supplementation and fracture risk, clinical studies of bisphosphonates in the treatment of postmenopausal osteoporosis, atypical femur fracture, clinical studies of new drugs and sequential treatment of postmenopausal osteoporosis, predictors of fracture risk, mid- and long-term follow-up of osteoporotic vertebral compression fractures, genetic polymorphisms and hereditary factors, formulation and updating of clinical practice guidelines for postmenopausal osteoporosis. Large cohort studies, high-quality randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines are the great engines that drive the development of clinical research in postmenopausal osteoporosis. We should make efforts in the above areas to improve China’s international influence in the field of osteoporosis. [ABSTRACT FROM AUTHOR]

With increasing focus on novel targeted therapies for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), this longitudinal claims-based study evaluated real-world CLL/SLL treatment sequences, particularly sequential targeted therapy. Among patients with first-line (1 L) treatment in 2014-2017 (N = 2,612; median follow-up = 3 years), the most common 1 L treatment was chemoimmunotherapy (CIT; 44.6%), followed by CD20 (25.2%) and Bruton's tyrosine kinase inhibitors (BTKi; 21.7%). Among those with 1 L in 2018-2021 (N = 4,534; median follow-up = 1 year), these were BTKi (45.5%), CD20 (20.4%), CIT (17.5%), and B-cell lymphoma 2 inhibitor (8.3%). In 2014-2017, the proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 11.2% (80.2% was BTKi→BTKi); in 2018-2021, this proportion was 34.3% (66.4% was BTKi→BTKi). Over time, there was a substantial increase in targeted therapy use in 1 L and sequential targeted therapy, particularly with BTKi→BTKi. Future studies should assess clinical outcomes to determine optimal sequences for CLL/SLL and reasons for restarting BTKi. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of early sequential enteral nutrition (EN) support on the nutritional status, complication rate and prognosis of acute hemorrhagic stroke patients. Methods 69 patients with acute hemorrhagic stroke admitted to Department of Neurosurgery, the Affiliated Hospital of Inner Mongolia Medical University from September 2017 to July 2019 were randomly divided into two groups. 35 patients in the experimental group received sequential EN therapy with gradual transition from EN preparation to whole protein, while 34 patients in the control group were treated with whole protein-based EN preparation throughout the whole course of treatment. The treatment program was implemented according to the nutritional technology route developed by Department of Neurosurgery, the Affiliated Hospital of Inner Mongolia Medical University. The average daily time to obtain the target amount of EN, the rate of combined parenteral nutrition (PN) therapy, the incidence of hypoalbuminemia, the complications after feeding, and the average number of days in the neurosurgical intensive care unit (NICU) in the two groups were observed. Results Both groups were able to achieve the EN treatment target. The mid-arm muscle circumference (MAMC) and serum prealbumin (PAB) concentration of the experimental group were higher than that of the control group on the 7th and 14th day after treatment (P＜0. 05), and the incidence of infections was less than that of the control group (P＜0. 05), and the prognosis of the experimental group was not significantly different from that of the control group (P＞0. 05) . There was no statistically significant difference in complications related to other feeding modalities and mean length of stay in the NICU between the two groups (P＞0. 05) . Conclusions Sequential EN can significantly improve the systemic nutritional status of patients with acute hemorrhagic stroke, improve the body's immune function, significantly reduce the risk of other comorbidities, and shorten the length of hospitalization of the patients, but it has no significant effect on the prognosis (P＞0. 05) . Sequential EN has a better therapeutic effect than whole protein EN and has some clinical application value. [ABSTRACT FROM AUTHOR]

Background: The use of additional treatment after surgery for stage IIIC endometrial cancer (EC) according to the Federation of Gynecology and Obstetrics (FIGO) is still a topic of discussion. This meta-analysis examined the effects of sandwich treatment and sequential treatment on the survival of individuals diagnosed with stage IIIC EC. Methods: We examined the literature from various databases regarding the overall survival (OS) and adverse effects of the two additional therapies following surgery in individuals diagnosed with stage IIIC EC. Revman 5.4.1 was utilized to combine hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) for OS and toxicities. Results: The findings comprised of five retrospective investigations involving a combined total of 800 individuals. The patients who underwent sandwich treatment did not demonstrate a notable improvement in survival rates over a period of 3 years. Upon eliminating the impact of extensive samples, it was discovered that sandwich therapy exhibited a superior 5-year overall survival compared to patients receiving sequential therapy. The effectiveness of sandwich therapy was superior to sequential therapy in terms of a 3-year OS for non-endometrioid histology, although the outcome did not reach statistical significance. The toxicities of both treatments were similar. Conclusions: In terms of long-term survival, sandwich therapy was found to be more advantageous than sequential therapy for patients with stage IIIC EC, with no significant disparity observed in the 3-year OS and toxicities between the two treatments. Sandwich therapy exhibited a tendency towards improved effectiveness in patients with histology other than endometrioid. [ABSTRACT FROM AUTHOR]

Purpose: To explore pre-treatment risk factors for overall survival (OS) in advanced urothelial carcinoma (UC) patients treated with first-line (1L) chemotherapy in sequential therapy (ST) era. Additionally, to evaluate the proportion of patients who were not able to undergo subsequent immune checkpoint inhibitor (ICI) therapy according to the subgroups stratified by the risk factors. Methods: A multicenter retrospective study was conducted. Metastatic or locally advanced UC patients treated between 2017 and 2022 were included. The Kaplan–Meier method with the log-rank test and multivariate Cox regression models were used to address OS. Results: Three hundred and fourteen patients treated with 1L chemotherapy were included in the study and 57 (18.2%) patients were not able to proceed to subsequent ICI therapy. Pre-chemotherapy risk factors for OS in 314 patients were ECOG-PS 1 or more, having no primary site resection, C-reactive protein (CRP) level of 3 mg/dL or more, and non-cisplatin-based regimen. Patients having 3 or 4 risk factors had higher risk for not being able to receive ST (Mann–Whitney U test, P < 0.001). As risk factors for OS in 230 patients who were able to receive ST, having no primary site resection, a neutrophil to lymphocyte ratio of 3 or more, and the presence of liver metastasis were identified. Conclusion: We reported the risk factors for OS in advanced UC patients treated with 1L chemotherapy in ST era. Patients with high risk for OS may not be able to proceed to subsequent ICI therapy even in the ST era. [ABSTRACT FROM AUTHOR]

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25–57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach. Methods: A panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches. Results: The panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment. Conclusions: This consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management.

Background: Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk. Objective: A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines. Design: Systematic review and meta-analysis. Data sources and methods: PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change. Results: In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab versus placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates versus placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate versus the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site. Conclusion: The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or 'bone builders' in patients with very high or imminent risk of fracture. Plain language summary: A systematic review to evaluate the sequential therapy of antiresorptive (denosumab and bisphosphonate, such as alendronate, minodronate, risedronate, and etidronate), anabolic treatment (such as romosozumab, teriparatide), or placebo in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines Subjects with previous fragility fractures should promptly receive effective strategies to prevent the risk of subsequent events. Indeed, patients with a fragility fracture have a doubled risk of a new fracture. For this reason, it is essential to provide adequate sequential therapy based on the mechanisms and the rapidity of action. A systematic review was performed to identify the sequential strategy in patients at high- or imminent-risk of (re)fracture and to support the Panel of the Italian Fragility Fracture Guideline in formulating recommendations. Our systematic review included seventeen studies mostly focused on women and enabled us to strongly recommend the anabolic drugs as first-line treatment. Specifically, for the sequential therapy from anabolic to antiresorptive treatment, there was a significant reduction in the risk of different types of fractures after the switch from romosozumab to denosumab versus placebo to denosumab. These findings were confirmed at 24 months after the switch. Considering the sequential treatment from antiresorptive to anabolic medications, there was a decreased risk of fracture 12 months after the switch from placebo to teriparatide versus bisphosphonate or antiresorptive to teriparatide. Moreover, a greater bone mineral density increase after the switch from anabolic to antiresorptive medications was shown in the lumbar spine, total hip, and femoral neck. The results of this systematic review and meta-analysis confirm that initial treatment with anabolic drugs produces substantial bone mineral density improvements, and the transition to antiresorptive drugs can preserve or even amplify the acquired benefit. These findings support the choice to treat very high-risk individuals with anabolic drugs first, followed by antiresorptive drugs. [ABSTRACT FROM AUTHOR]

Osteoporosis is a chronic condition characterized by decreased bone mass, loss of skeletal integrity, and increased susceptibility to fracture. Drugs used to treat osteoporosis can be classified as those that block bone resorption (antiresorptive), stimulate bone formation (anabolic), or do both. While all currently approved medications reduce the risk of fragility fractures in high-risk populations, they are generally unable to fully restore bone strength in most patients with established disease. Thus, the majority of patients require disease management over many years. Unfortunately, the continuous use of a single drug has limitations, both in terms of efficacy and safety, and so sequential therapy is commonly required. Given the expanding list of pharmacological agents currently available, careful consideration needs to be given as to which drugs to use and in what sequence. This review will evaluate the differential effects of antiresorptive, bone-forming, and dual-acting drugs when used in specific sequences and will explore the current evidence favoring the initial use of bone-forming/dual-acting drugs followed by antiresorptive medications. This review will also examine the notion that long-term treatment with an antiresorptive drug may diminish the efficacy of subsequent treatment with a bone-forming/dual-acting drug. Finally, this review will explore the current evidence pertaining to the specific issue of how to best prevent the clinical ramifications of denosumab cessation. [ABSTRACT FROM AUTHOR]

Background: non-bismuth sequential therapy (SEQ) was suggested as a first-line anti-Helicobacter pylori treatment alternative to standard triple therapy (STT). Methods: We conducted a systematic review with a meta-analysis of randomized controlled trials (RCTs) comparing the efficacy of 10-day SEQ vs. STT (of at least 7 days) using bibliographical searches up to July 2021, including treatment-naïve adult or children. The intention-to-treat (ITT) eradication rate and the risk difference (RD) were calculated. Results: Overall, 69 RCTs were evaluated, including 19,657 patients (9486 in SEQ; 10,171 in STT). Overall, SEQ was significantly more effective than STT (82% vs. 75%; RD 0.08; p < 0.001). The results were highly heterogeneous (I2 = 68%), and 38 studies did not demonstrate differences between therapies. Subgroup analyses suggested that patients with clarithromycin resistance only and all geographical areas but South America could benefit more from SEQ. Both therapies have evolved over the years, showing similar results when STT lasted 14 days; however, a tendency toward lower SEQ efficacy was noted from 2010 onwards. Conclusions: Prior to 2010, SEQ was significantly more effective than STT, notably when 7-day STT was prescribed. A tendency toward lower differences between SEQ and STT has been noted, especially when using 10-day STT. None of the therapies achieved an optimal efficacy and therefore cannot be recommended as a valid first-line H. pylori treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE). Methods We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance. Results Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5–17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient). Conclusions The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance.

Objectives: Due to its long half-life, dalbavancin offers benefits for long-duration treatments, especially osteoarticular and infective endocarditis (IE). We evaluated the efficacy and costs of IE treatment, comparing dalbavancin with standard of care (SOC). Methods: Retrospective multicenter cohort study of adult patients with Gram-positive cocci definite IE. Dalbavancin was used as a sequential therapy before discharge. Efficacy was a combined variable of clinical cure and absence of recurrence in 12-month follow-up. Length of hospital stay and the associated costs were analyzed in both groups of treatment. Results: Twenty-two patients received dalbavancin and 47 SOC. The efficacy was similar between the groups (dalbavancin 18 [72%] vs SOC 44 [94%], P = 0.198). Hospital stay was shorter in the dalbavancin group (dalbavancin 22 days [16-34] vs SOC 37 days [23-49], P = 0.001), especially in those with E. faecalis IE (dalbavancin 30 days [20-36] vs SOC 65 days [46-74], P

Objectives The incidence of treatment failures following standard triple therapy (STT) for Helicobacter pylori eradication (HPE) has reached an unacceptable level. Sequential therapy (SQ) has emerged as a promising approach to counteract the escalation of antibiotic resistance. In this study, we used a chronological cohort dataset to conduct a comparative analysis of the eradication rates, compliance, and adverse events associated with the 7-day STT and SQ. Methods A total of 789 patients underwent HPE treatment at Asan Medical Center between July 2013 and August 2017. Among them, 378 received a 7-day STT and 411 received a 10-day SQ. Baseline clinical data and treatment parameters were compared between the two treatment groups. Results SQ demonstrated an eradication rate of 84.7% (348/411), which was superior to that of the 7-day STT (74.1%; p

Background: Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE). Methods: We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance. Results: Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5–17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient). Conclusions: The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance. [ABSTRACT FROM AUTHOR]

Study question: In infertile women with polycystic ovary syndrome (PCOS), is the sequential use of letrozole 2.5 mg/follicle stimulating hormone(FSH) more effective than letrozole 5 mg/FSH in stimulating ovulation and promoting pregnancy? Research design and methods: The study was designed as a prospective, single-center, randomized, controlled pragmatic clinical trial. 220 infertile women between the ages of 20 and 40, who matched the Rotterdam criteria for PCOS and had no other identified reasons for infertility were enrolled from April 2023 to July 2023. The participants were randomly assigned to two groups in a 1:1 ratio. One group received 2.5 mg of letrozole on cycle days 3-7 with a sequential injection of 75 IU FSH on cycle days 8-10 (n = 110), while the other group received 5 mg of letrozole on cycle days 3-7 with a sequential injection of 75 IU FSH on cycle days 8-10 (n = 110). The duration of FSH treatment varied depending on the follicular development stage. Each participant underwent one to three treatment cycles until achieving pregnancy. The primary outcome was the cumulative pregnancy rate of all the participants. Secondary outcomes included characteristics and clinical pregnancy rates of all the intervention cycles. Results: For all 220 participants, the sequential letrozole 2.5 mg/FSH treatment group had a significantly higher cumulative pregnancy rate compared to the letrozole 5 mg/FSH treatment group (72.7% versus 59.1%, RR (95%CI) = 1.23 (1.02, 1.49), P-value = 0.033). For all 468 intervention cycles, letrozole 2.5 mg/FSH group had a significantly higher clinical pregnancy rate than the letrozole 5 mg/FSH group (36.2% versus 26.3%, Pvalue = 0.021), no statistically significant differences were observed in ovulation rates or adverse effects. Conclusions: The data indicate that the sequential letrozole 2.5mg/FSH protocol may be more effective than the sequential letrozole 5mg/FSH protocol for promoting pregnancy in infertile women with PCOS. [ABSTRACT FROM AUTHOR]

Summary: Background: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. Aims: To assess the treatment and renal/bone safety outcomes following the switch to TAF. Methods: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T‐scores (L‐spine) by bone absorptiometry by 24 months after switch to TAF. Results: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T‐score improved significantly from −1.43 ± 1.36 to −1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9–89.5 ± 16.3 mL/min/1.73 m2, p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T‐score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T‐score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). Conclusions: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable. [ABSTRACT FROM AUTHOR]

• Dalbavancin has been shown to be a safe option in the therapy of infective endocarditis. • A lower hospital stay was observed in patients who received dalbavancin. • Dalbavancin use was associated with a reduction in costs and hospital stay. Due to its long half-life, dalbavancin offers benefits for long-duration treatments, especially osteoarticular and infective endocarditis (IE). We evaluated the efficacy and costs of IE treatment, comparing dalbavancin with standard of care (SOC). Retrospective multicenter cohort study of adult patients with Gram-positive cocci definite IE. Dalbavancin was used as a sequential therapy before discharge. Efficacy was a combined variable of clinical cure and absence of recurrence in 12-month follow-up. Length of hospital stay and the associated costs were analyzed in both groups of treatment. Twenty-two patients received dalbavancin and 47 SOC. The efficacy was similar between the groups (dalbavancin 18 [72%] vs SOC 44 [94%], P = 0.198). Hospital stay was shorter in the dalbavancin group (dalbavancin 22 days [16-34] vs SOC 37 days [23-49], P = 0.001), especially in those with E. faecalis IE (dalbavancin 30 days [20-36] vs SOC 65 days [46-74], P <0.001). A reduction of cost was observed between both groups (dalbavancin, 12,206 € [8998-17,283] vs SOC 16,249 € [11,496-22,367], P = 0.032). Dalbavancin could be a safe and effective option in the sequential treatment of patients with IE. Also, a cost reduction was detected, due to a significant shortness of hospital stay. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis management often involves a sequential treatment approach to optimize patient outcomes and minimize fracture risks. This strategy is tailored to individual patient characteristics, treatment responses, and fracture risk profiles. Methods: A thorough literature review was systematically executed using prominent databases, including PubMed and EMBASE. The primary aim was to identify original articles and clinical trials evaluating the effectiveness of sequential therapy with anti-osteoporosis drugs, focusing on the period from 1995 to 2023. The analysis encompassed an in-depth examination of osteoporosis drugs, delineating their mechanisms of action, side effects, and current trends as elucidated in the literature. Results and Discussion: Our study yielded noteworthy insights into the optimal sequencing of pharmacologic agents for the long-term treatment of patients necessitating multiple drugs. Notably, the achievement of optimal improvements in bone mass is observed when commencing treatment with an anabolic medication, followed by the subsequent utilization of an antiresorptive drug. This stands in contrast to initiating therapy with a bisphosphonate, which may potentially diminish outcomes in the post-anabolic intervention period. Furthermore, it has been discerned that caution should be exercised against transitioning from denosumab to PTH homologs due to the adverse effects of heightened bone turnover and sustained weakening of bone structure. Despite the absence of fracture data substantiating the implementation of integrated anabolic/antiresorptive pharmacotherapy, the incorporation of denosumab and teriparatide presents a potential avenue worthy of consideration for individuals at a heightened vulnerability to fragility fractures. Conclusions: A judiciously implemented sequential treatment strategy in osteoporosis offers a flexible and tailored approach to address diverse clinical scenarios, optimizing fracture prevention and patient outcomes. [ABSTRACT FROM AUTHOR]

EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance.

Abstract Introduction Synergistic effects have been discussed for tyrosine kinase (TKI) and immune checkpoint inhibitors (ICI). Primary resistance to TKI might disturb subsequent ICI effectiveness. The objective was to investigate, if primary resistance to 1st line TKI monotherapy predicts response to ICI in subsequent therapy lines and impacts overall survival (OS) in advanced renal cell carcinoma (aRCC). Materials and methods Retrospectively, aRCC patients which received front-line TKI from 2016 to 2019 were analyzed for the outcomes primary resistance (1LR), response to sequential ICI therapy, progression free survival (PFS) and overall survival (OS). Kaplan–Meier-estimates, Cox proportional hazards and logistic regression were used. Results Primary resistance to front-line TKI was observed in 27 (53%) of 51 patients. Groups with disease control (DC) and 1st line TKI resistance (1LR) were not different at baseline with regard to clinicopathological features. Median duration on 1st line therapy was significantly shorter in the 1LR (5.1 months) than in the DC (14.7 months) group (p = 0.01). Sequential therapy was started in 21 (75%) and 12 (52%) patients of 1LR and DC groups using nivolumab in 16 (76%) vs. 11 (92%) cases (p > 0.05). Logistic regression revealed that 1LR status, neutrophil-to-lymphocyte ratio

Abstract Introduction Hybrid therapy (HT) is a non-bismuth quadruple therapy created to surpass Helicobacter pylori’s (H. pylori) resistance rates to antibiotics. HT has excellent eradication rates, as well as a very good compliance and safety profile. We aim to compare HT with sequential therapy (ST) and concomitant therapy (CT) for the eradication of H. pylori. Methods This systematic review was conducted following the principles of the PRISMA guidelines. Literature was electronically searched on the CENTRAL library, PubMed, Embase, Scopus, LILACS, and ClinicalTrials.gov. Only randomized controlled trials were included. The primary outcome evaluated was eradication rate of H. pylori. The secondary outcomes evaluated were adverse events and compliance rates. Meta-analyses were performed with Cochrane Review Manager 5.4. The Mantel–Haenszel method was used to estimate the pooled relative risk and 95% confidence interval of the eradication rates between HT and other regimens, as well as the secondary outcomes. Results 10 studies were included, comprising 2993 patients. The mean eradication rates achieved by HT with intention-to-treat (ITT) and per-protocol (PP) analyses were, respectively, 86% (range: 79.2–90.8%) and 91.7% (range: 82.6–96.1%). No statistically significant difference was found in ITT eradication rate between HT and CT (relative risk: 1; 95% CI: 0.96- 1.03) and between HT and ST (relative risk: 1.02; 95% CI: 0.92–1.14). PP analysis revealed similar results. HT was associated with higher compliance rates than CT and slightly lower than ST. As far as adverse events are concerned, this meta-analysis demonstrated a higher occurrence of adverse events on the group of patients treated with CT when compared with HT. HT and ST showed similar results. Conclusion HT has similar eradication, compliance and adverse event rates when compared to ST, but a better safety profile than the CT.

EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance. [ABSTRACT FROM AUTHOR]

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Introduction: Synergistic effects have been discussed for tyrosine kinase (TKI) and immune checkpoint inhibitors (ICI). Primary resistance to TKI might disturb subsequent ICI effectiveness. The objective was to investigate, if primary resistance to 1st line TKI monotherapy predicts response to ICI in subsequent therapy lines and impacts overall survival (OS) in advanced renal cell carcinoma (aRCC). Materials and methods: Retrospectively, aRCC patients which received front-line TKI from 2016 to 2019 were analyzed for the outcomes primary resistance (1LR), response to sequential ICI therapy, progression free survival (PFS) and overall survival (OS). Kaplan–Meier-estimates, Cox proportional hazards and logistic regression were used. Results: Primary resistance to front-line TKI was observed in 27 (53%) of 51 patients. Groups with disease control (DC) and 1st line TKI resistance (1LR) were not different at baseline with regard to clinicopathological features. Median duration on 1st line therapy was significantly shorter in the 1LR (5.1 months) than in the DC (14.7 months) group (p = 0.01). Sequential therapy was started in 21 (75%) and 12 (52%) patients of 1LR and DC groups using nivolumab in 16 (76%) vs. 11 (92%) cases (p > 0.05). Logistic regression revealed that 1LR status, neutrophil-to-lymphocyte ratio < 3, IMDC favorable prognosis and clear cell histology had no significant impact on responsiveness to ICI in subsequent therapy lines. Cox proportional hazards demonstrated no significant association of 1LR status with PFS and OS in patients who received subsequent ICI treatment. Conclusion: Primary TKI resistance of aRCC was neither significantly associated with responsiveness to ICI during sequential therapy nor with PFS and OS. This adds the evidence for ICI based sequential therapy in primary TKI resistant aRCC. [ABSTRACT FROM AUTHOR]

The aim of this study is to analyze the efficacy and safety of sequential therapy with bortezomib-based triplet regimens without lenalidomide (PXD, including VTD, PAD, and VCD) followed by continuous lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone (Vd) treatment. The main objective is to evaluate the advantages of PXD followed by Rd compared to the combinations of bortezomib–lenalidomide–dexamethasone (VRd) in newly diagnosed multiple myeloma (NDMM). Fifty-eight nontransplant NDMM patients who were admitted to our department from 2017 to 2019 were included in this study. Bortezomib-based triplet regimens were initially selected and followed by Rd or Vd as continuous treatment once the patients achieved partial remission (PR) or better response. The efficacy and safety of the patients were observed. The Rd continuous treatment cohort was compared with historical data from the EVOLUTION trial on continuous VRd treatment. In our cohort, the overall survival rate was 100%, and progression-free survival (PFS) was 38.5% after a median of 19 (4–36) cycles of Rd continuous therapy was applied. During the follow-up period, the best outcome assessments achieved were 53.8% complete response (CR) and 84.6% excellent partial response (VGPR). A total of 23.1% had grade 3–4 or higher drug-related adverse reactions, mainly hematological toxicity, and no patients died of adverse reactions. Compared with the Vd group, the Rd group had a better PFS and VGPR rate (2-year PFS: 92.3% vs. 56.3%, P = 0.002; 3-year PFS: 69.2% vs. 8.0%, P < 0.001; VGPR: 84.6% vs. 69.2%, P = 0.02). No significant differences were found in ORR (100% vs. 92.3%) or CR (53.8% vs. 35.7%, P = 0.082). Compared with the EVOLUTION study, patients in the Rd group had a more advanced disease stage (stage III rate of 40% vs. 19%, P = 0.039) and worse physical status (KPS 50–60 rate of 25.0% vs. 2.0%, P = 0.000). However, a higher proportion of ORR (100% vs. 73.0%, P < 0.001), VGPR or better (75.0% vs. 32.0%, P < 0.001), and PFS at 12 months (90.0% vs. 68%, P = 0.011) were achieved. Sequential administration of bortezomib-based triplet regimens without lenalidomide as an initial therapy followed by Rd as a continuous treatment may not be inferior to VRd for first-line treatment in NDMM patients. [ABSTRACT FROM AUTHOR]

Purpose: EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated lung cancer is limited by acquired resistance. In half of the patients treated with first/second-generation (1st/2nd gen) TKI, resistance is associated with EGFR p.T790M mutation. Sequential treatment with osimertinib is highly active in such patients. Currently, there is no approved targeted second-line option for patients receiving first-line osimertinib, which thus may not be the best choice for all patients. The present study aimed to evaluate the feasibility and efficacy of a sequential TKI treatment with 1st/2nd gen TKI, followed by osimertinib in a real-world setting. Methods: Patients with EGFR-mutated lung cancer treated at two major comprehensive cancer centers were retrospectively analyzed by the Kaplan–Meier method and log rank test. Results: A cohort of 150 patients, of which 133 received first-line treatment with a first/second gen EGFR TKI, and 17 received first-line osimertinib, was included. Median age was 63.9 years, 55% had ECOG performance score of ≥ 1. First-line osimertinib was associated with prolonged progression-free survival (P = 0.038). Since the approval of osimertinib (February 2016), 91 patients were under treatment with a 1st/2nd gen TKI. Median overall survival (OS) of this cohort was 39.3 months. At data cutoff, 87% had progressed. Of those, 92% underwent new biomarker analyses, revealing EGFR p.T790M in 51%. Overall, 91% of progressing patients received second-line therapy, which was osimertinib in 46%. Median OS with sequenced osimertinib was 50 months. Median OS of patients with p.T790M-negative progression was 23.4 months. Conclusion: Real-world survival outcomes of patients with EGFR-mutated lung cancer may be superior with a sequenced TKI strategy. Predictors of p.T790M-associated resistance are needed to personalize first-line treatment decisions. [ABSTRACT FROM AUTHOR]

Objective: To explore the efficacy of Saccharomyces boulardii and sequential therapy to eradicate Helicobacter pylori (Hp) infection in children. Methods: 100 children with Hp infection who visited Foshan Maternal and Child Health Hospital from January 2020 to June 2022 were selected, and the pathological changes of gastric mucosa were scored under gastroscope. According to the random number table method, the children were divided into an observation group (n=50, sequential therapy combined with Saccharomyces boulardii) and a control group (n=50, sequential therapy), both treated for 10 days. Immune function related indicators, inflammatory factor indicators, and incidence of adverse reactions in the two groups before treatment and 10 d after treatment were compared, the eradication rate of Hp 4 weeks after treatment and the lesion degree score of gastric mucosa before and 4 weeks after treatment were compared.Results: The total clinical effective rate and Hp eradication rate of the observation group were higher than those of the control group, and the gastric mucosa lesion degree score was better than that of the control group (P＜0.05). 10 d after treatment, the levels of CD3+, CD4+, CD4+/CD8+increased in both groups, and the observation group was higher than that of the control group, while CD8+decreased, and the observation group was lower than that of the control group (P＜0.05). 10 d after treatment, the levels of interleukin-10 (IL-10) in both groups increased, and the observation group was higher than that of the control group. IL-6 and tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) decreased, and the observation group was lower than that of the control group (P＜0.05). There was no difference in the incidence of adverse reactions between the two groups (P＞0.05). Conclusion: Sequential therapy combined with Saccharomyces boulardii for the eradication of Hp infection in children can reduce the degree of pathological changes in gastric mucosa, improve the immune function and inflammatory factor level of children, and increase the eradication rate of Hp. [ABSTRACT FROM AUTHOR]

Acute severe colitis (ASUC) remains a significant cause of morbidity in up to 25% of patients with ulcerative colitis during their disease course. We present the outcomes out to 12 months following the use of high‐dose tofacitinib, 10 mg three times daily (TDS), in patients with steroid and infliximab refractory ASUC. A total of 11 patients with ASUC who were treated with high‐dose tofacitinib after failing sequential infliximab therapy between 2019 and 2021 were identified at an Australian tertiary centre. Ten of 11 patients demonstrated clinical and biochemical response to treatment during admission. Two of 11 patients required colectomy, one during the index admission and the other during re‐admission 10 days after the index presentation. Nine of the initial responders had a median Mayo score of 1 (IQR 0–4) at both 6 and 12 months, and all remained colectomy‐free out to 12 months. Neither venous thromboembolic events nor major infective complications were observed. Tofacitinib may be a safe and effective induction and maintenance agent in the treatment of steroid and infliximab refractory ASUC. Prospective studies with long‐term follow‐up are required to explore the use of tofacitinib in ASUC before it can be routinely recommended as salvage therapy. [ABSTRACT FROM AUTHOR]

Background: Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown. Methods: We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0. Results: Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7–698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55). Conclusion: The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs. [ABSTRACT FROM AUTHOR]

Background and Aim: There is regional variation in the eradication rates of Helicobacter pylori (H. pylori) regimens depending on the local antibiotic resistance patterns. The aim of this study was to compare the efficacies of triple, quadruple and sequential antibiotic therapy in eradicating H. pylori infection. Methods: A total of 296 H. pylori-positive patients were randomized to receive one of the three regimens (triple, quadruple or sequential antibiotic therapy) and eradication rate was assessed by H. pylori stool antigen test. Results: The eradication rates of standard triple therapy, sequential therapy and quadruple therapy were 93%, 92.9% and 96.4%, respectively (p = 0.57). Conclusion: Fourteen days of standard triple therapy, 14 days of bismuth-based quadruple therapy and 10 days of sequential therapy are equally efficacious in eradicating H. pylori and all regimens have optimum H. pylori eradication rates. Trial registration: ClinicalTrials.gov Identifier: CTRI/2020/04/024929 [ABSTRACT FROM AUTHOR]

Background. First-line therapy does not always provide a high level of Helicobacter pylori eradication due to the increase of H. pylori resistance to antibiotics; therefore, it remains necessary to identify the most effective rescue treatments. The purpose of this study was to evaluate the efficacy and safety of empirical H. pylori furazolidone-containing regimens. Materials and methods. Adult H. pylori infected patients empirically treated with furazolidone-containing eradication regimens were registered in an international, prospective, multicenter non-intervention European registry on H. pylori management (Hp-EuReg). Data were collected at AEG-REDCap e-CRF from 2013 to 2021 and the quality was reviewed. Modified intention-to-treat (mITT) effectiveness analyses were performed. Results. Overall 106 patients received empirical furazolidone-containing therapy in Russia. Furazolidone was prescribed in a sequential scheme along with amoxicillin, clarithromycin and a proton pump inhibitor in 68 (64%) cases, triple regimens were prescribed in 28 (26%) patients and quadruple regimens in 10 (9.4%). Treatment duration of 7 days was assigned to 2 (1.9%) patients, 10-day eradication therapy in case of 80 (75%) and 14 days in 24 (23%) patients. Furazolidone was mainly used in first- (79%) and second-line (21%) regimens. The methods used to diagnose H. pylori infection were: histology (81%), stool antigen test (64%), 13C-urea breath test (6.6%), and rapid urease test (1.9%). The mITT effectiveness of sequential therapy was 100%; 93% with the triple therapy and 75.5% with quadruple therapy. Compliance was reported in 98% of cases. Adverse events were revealed in 5.7% of patients, mostly nausea (3.8%). No serious adverse events were reported. Conclusion. Furazolidone containing eradication regimens appear to be an effective and safe empirical therapy in Russia.

Abstract Background Ziprasidone mesylate injection is an atypical antipsychotic drug which is recently approved in China. In combination with its oral formulation, sequential therapy with ziprasidone brings new interventions to patients with agitation in the acute phase of schizophrenia. The purpose of this 7-day multicenter study conducted in China was to evaluate the efficacy and safety of ziprasidone sequential treatment through intramuscular/oral routes in agitated patients with schizophrenia. Methods A total of 95 patients were enrolled from three centers in this study. The study duration was 7 days. In the first 3 days, subjects were administered an intramuscular injection of ziprasidone 10–40 mg daily and started sequentially with oral ziprasidone 40–80 mg at dinner (or lunch) from the day of the last intramuscular injection. In the following 4 days, according to the severity of the symptoms and the drug response, 120–160 mg of ziprasidone was orally administered daily. In total, six visits were scheduled to assess the Positive and Negative Syndrome Scale (PANSS), the Behavioral Activity Rating Scale (BARS), the Clinical Global Impression of Severity (CGI-S), and Improvement (CGI-I) scores throughout the procedure. Lastly, adverse events were recorded during treatment. Results Out of the 95 patients that were enrolled, 83 cases were effectively completed. Visits 3, 4, 6, PANSS, and PANSS-excited component (PANSS-EC) subscale points, and Visit 2–Visit 6 viewpoints, BARS scale points, and baseline scores denote a progressive downward trend (P

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25–57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Introduction: Hybrid therapy (HT) is a non-bismuth quadruple therapy created to surpass Helicobacter pylori's (H. pylori) resistance rates to antibiotics. HT has excellent eradication rates, as well as a very good compliance and safety profile. We aim to compare HT with sequential therapy (ST) and concomitant therapy (CT) for the eradication of H. pylori. Methods: This systematic review was conducted following the principles of the PRISMA guidelines. Literature was electronically searched on the CENTRAL library, PubMed, Embase, Scopus, LILACS, and ClinicalTrials.gov. Only randomized controlled trials were included. The primary outcome evaluated was eradication rate of H. pylori. The secondary outcomes evaluated were adverse events and compliance rates. Meta-analyses were performed with Cochrane Review Manager 5.4. The Mantel–Haenszel method was used to estimate the pooled relative risk and 95% confidence interval of the eradication rates between HT and other regimens, as well as the secondary outcomes. Results: 10 studies were included, comprising 2993 patients. The mean eradication rates achieved by HT with intention-to-treat (ITT) and per-protocol (PP) analyses were, respectively, 86% (range: 79.2–90.8%) and 91.7% (range: 82.6–96.1%). No statistically significant difference was found in ITT eradication rate between HT and CT (relative risk: 1; 95% CI: 0.96- 1.03) and between HT and ST (relative risk: 1.02; 95% CI: 0.92–1.14). PP analysis revealed similar results. HT was associated with higher compliance rates than CT and slightly lower than ST. As far as adverse events are concerned, this meta-analysis demonstrated a higher occurrence of adverse events on the group of patients treated with CT when compared with HT. HT and ST showed similar results. Conclusion: HT has similar eradication, compliance and adverse event rates when compared to ST, but a better safety profile than the CT. [ABSTRACT FROM AUTHOR]

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens. [ABSTRACT FROM AUTHOR]

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Objective: Psoriasis is an autoimmune disease that causes rapid turnover of skin cells. It is a chronic disease that affects a patient's quality of life significantly and frequently requires long-term treatment. The study on sequential therapy with tazarotene 0.1% and calcitriol 0.0003% has not been tried so far; hence, we designed this study to compare the safety and efficacy of sequential therapy with tazarotene 0.1% cream and calcitriol 0.0003% ointment versus monotherapy in mild-to-moderate stable plaque psoriasis (SPP). The objective of this study was to compare the safety and efficacy of topical sequential treatment with tazarotene followed by calcitriol, topical calcitriol followed by tazarotene, tazarotene monotherapy, calcitriol monotherapy, and compare the safety and efficacy of the sequential therapies with monotherapies. Methods: The study was a single center, prospective parallel-group, active control, randomized study of 16 weeks duration (treatment for 8 weeks and follow-up for 16 weeks), randomized to either of the four groups, i.e., tazarotene 0.1% for 4 weeks followed by calcitriol 0.0003% for 4 weeks or calcitriol 0.0003% for 4 weeks followed by tazarotene 0.1% for 4 weeks or tazarotene 0.1% for 8 weeks or calcitriol 0.0003% for 8 weeks. Both tazarotene and calcitriol were applied once daily in all the groups. Findings: There was no significant difference with regard to age and duration of illness among the four treatment groups. Statistically significant improvement was observed in erythema, scaling, and induration scores, and Physician's global assessment scale at 8 weeks and 16 weeks as compared to baseline in tazarotene – calcitriol, calcitriol – tazarotene, and calcitriol versus tazarotene groups. Conclusion: This study concluded that topical treatment with tazarotene 0.1% and calcitriol 0.003% was efficacious in treating mild-to-moderate SPP as both sequential and monotherapy. However, topical treatment with tazarotene as monotherapy was the least efficacious.

Objective To assess the clinical efficacy and safety of sequential therapy for nodular cystic acne. Methods Forty three patients with nodular cystic acne were divided into sequential and control groups. In the sequential group, 22 patients were treated with ALA-PDT every two weeks for 3 times, and oral antibiotics in the first stage, followed by chemical peeling once every two weeks for 3 times, and oral isotretinoin in the second stage. Finally, oral isotretinoin alone was given in the last stage. While 21 patients in the control group were treated with isotretinoin alone. The treatments lasted for 16 weeks. After each treatment course, the efficacy and adverse effect were compared between the two therapies. The patients in both groups were followed up for 6 months, and the relapse rate and adverse reactions were recorded. Results In the first stage of treatment, effective rates after the second and the third treatment course were 9.09% and 22.73%, respectively, in the sequential group, and 0 and 4.76%, respectively, in the controls. In the second stage, the effective rates after each treatment course were higher in sequential groups than in the controls (1st treatment course: 50.00% vs. 23.81%; 2nd treatment course: 90.90% vs. 42.86%, and the 3rd treatment course: 100% vs. 66.67%. P

Qingqing Li,1,&ast; Tong Su,2,&ast; Xu Zhang,3,&ast; Yanfeng Pan,1,&ast; Shengli Ma,4 Lu Zhang,4 Xianqiang Zhang,1 Xiaojuan Gao1 1Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 2Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China; 4Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email panfirstfeng@163.comPurpose: To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment.Patients and Methods: Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety.Results: Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88– 8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥ 3 AEs was 38.7%.Conclusion: Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.Keywords: hepatocellular carcinoma, anlotinib, sequential therapy, real world