Empiric “Three-in-One” Bismuth Quadruple Therapy for Second-Line Helicobacter pylori Eradication: An Intervention Study in Southern Italy

The eradication of Helicobacter pylori (H. pylori) may be difficult due to antibiotic resistance. Indeed, after one failure, a second-line therapy is needed and a bismuth containing quadruple therapy (BQT) with a three-in-one capsule formulation is becoming very popular. Therefore, we aimed to evaluate effectiveness and safety of BQT as a second-line therapy. We recruited consecutive patients with one therapy failure. For ten days patients received the three-in-one BQT Pylera® therapy, in combination with a proton-pump inhibitor (PPI), decided at the choice of the investigator, at full dose bid. The eradication rate was calculated by intention-to-treat (ITT) and per-protocol (PP)analyses and 95% confidence intervals (CI) were calculated. Seventy-three patients were recruited, 41 females and 32 males (mean age 53.0±13.1 years). Fifty-five patients failed triple therapy with amoxicillin and clarithromycin and the remaining 18 received sequential therapy. Seventy-two patients consumed at least 90% of the capsules, while only one did not complete the therapy due to adverse events (nausea and diarrhea). By ITT analysis, BQT was successful in 62 subjects (eradication rate 84.9%, 95%CI 76.7–93.1%). By PP analysis, the eradication rate was 86.1% (95%CI 78.1–94.1%).Adverse events were observed in 14 subjects (20.5%).In conclusion, our report confirmed that BQT is effective as an empiric second-line regimen.

Incidence And Predictors of Relapse After Stopping Antiviral Therapy In Pediatric Chronic Hepatitis B

Objective: The objective was to evaluate the incidence of relapse after stopping antiviral therapy and to identify the predictors of relapse. Methods: All HBsAg positive children with who had been on antivirals for at least 2 years with undetectable HBV-DNA and normal alanine-aminotransferase (ALT) on three consecutive occasions over last 12 months were included. Antivirals were stopped if liver biopsy showed histological activity index <5 and fibrosis (metavir) <3. Children were monitored for virological relapse (elevation of HBV-DNA >2000 IU/mL) and biochemical relapse (ALT levels >2 × upper limit of normal (ULN)). Those having biochemical relapse were started on pegylated interferon alpha-2b based sequential therapy. Results: Antivirals were stopped in 31 HBsAg positive children. Virological and biochemical relapse was seen in 12 (38.7%) and 5 (16.1%) children within 12 months of stopping antiviral treatment. Majority of virological relapse occurred within a month and biochemical relapses within 6 months of stopping therapy. HBeAg positive status at the time of stopping antiviral therapy (HR: 7.206, p =0.005) and longer time taken for HBV-DNA to become undetectable while on antivirals (HR: 1.030, p=0.037) were found to be the 2 independent predictors of relapse after stopping antiviral treatment. Conclusion: Discontinuation of antiviral treatment in children with CHB resulted in relapse in one third of the patients. Relapse was more common in those with HBeAg positivity at the time of stopping therapy and in those with longer time taken for HBV-DNA to become undetectable on antivirals.

Fourteen-Day Sequential Therapy Containing Rabeprazole Versus 10 And 14-Day Concomitant Therapy in The First Line Treatment of Helicobacter Pylori Infection: A Randomized, Open-Label Clinical Trial

Aims:To compare an optimized sequential therapy to 10 and 14-day non-Bismuth quadruple therapies currently recommended, in terms of efficacy, incidence of adverse effects and cost.Patients and methods:This open-label prospective study randomized patients with confirmed Helicobacter pylori (H.Pylori) infection to 3 groups (1:1:1): The first group received quadruple therapy of twice-daily (bid) Omeprazole 20mg, Amoxicillin 1g, Clarithromycin 500mg and Metronidazole 500mg for 10days (QT-10), the second group received a 14 day quadruple therapy following the same regimen (QT-14), and the third received an optimized sequential therapy consisting on a bid Rabeprazole 20 mg plus amoxicillin 1g for 7 days, followed by bid Rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500mg for the next 7 days (OST-14). Adverse events (AEs) were recorded throughout the study, and the H.Pylori eradication rate was determined 4 to 6 weeks after treatment using the 13C urea breath test.Results:In intention to treat analysis, eradication rate was 85,5%, 91,8% and 95,4% respectively in QT-10, QT-14 and OST-14 groups (p=0,03). In the per protocol analysis, the eradication rate was significantly higher in the OST- 14 group compared to the QT-14 and QT-10 groups (98,1%, 94,4% and 89,5% respectively, p=0,02).The overall incidence of AEs was significantly lower in the OST-14 group (p=0,01). Furthermore, the OST-14 was the most cost-effective among the three groups.Conclusion:14-day optimized sequential therapy is a safe and effective alternative that allows a higher eradication rate compared to 10 and 14-days quadruple therapies while causing less adverse effects and allowing a gain in term of cost.

Fatal Tumour Lysis Syndrome Induced by Brigatinib in a Lung Adenocarcinoma Patient Treated With Sequential ALK Inhibitors: A Case Report

Tumour lysis syndrome (TLS) represents a group of fatal metabolic derangements resulting from the rapid breakdown of tumour cells. TLS typically occurs soon after the administration of chemotherapy in haematologic malignancies but is rarely observed in solid tumours. Here, we report a case of brigatinib-induced TLS after treatment with sequential anaplastic lymphoma kinase (ALK) inhibitors in a patient with advanced ALK-rearranged lung adenocarcinoma. The patient was treated sequentially with crizotinib, alectinib, and ensartinib. High-throughput molecular profiling after disease progression indicated that brigatinib may overcome ALK resistance mutations, so the patient was administered brigatinib as the fourth-line treatment. After 22 days of therapy, he developed oliguria, fever, and progressive dyspnoea. Clinical manifestations and laboratory findings met the diagnostic criteria for TLS. The significant decrease in the abundance of ALK mutations in plasma indicated a therapeutic response at the molecular level. Consequently, the diagnosis of brigatinib-induced TLS was established. To the best of our knowledge, this is the first case of TLS induced by sequential targeted therapy in non-small cell lung cancer. With the extensive application of sequential therapy with more potent next-generation targeted therapeutic drugs, special attention should be given to this rare but severe complication.

A Sequential Therapeutic Hydrogel With Injectability and Antibacterial Activity for Deep Burn Wounds’ Cleaning and Healing

As a severe clinical challenge, escharotomy and infection are always the core concerns of deep burn injuries. However, a usual dressing without multifunctionality leads to intractable treatment on deep burn wounds. Herein, we fabricated a sequential therapeutic hydrogel to solve this problem. Cross-linked by modified polyvinyl alcohol (PVA-SH/ε-PL) and benzaldehyde-terminated F127 triblock copolymers (PF127-CHO), the hydrogel demonstrated excellent mechanical properties, injectability, tissue adhesiveness, antibacterial activity, biocompatibility, and satisfactory wound cleaning through both in vitro and in vivo assays. Additionally, based on the conception of “sequential therapy,” we proposed for the first time to load bromelain and EGF into the same hydrogel in stages for wound cleaning and healing. This work provides a strategy to fabricate a promising wound dressing for the treatment of deep burn wounds with injectability and improved patients’ compliance as it simplified the process of treatment due to its “three in one” characteristic (antibacterial activity, wound cleaning, and healing effects); therefore, it has great potential in wound dressing development and clinical application.

Changes in Blood Biomarkers of Angiogenesis and Immune Modulation after Radiation Therapy and Their Association with Outcomes in Thoracic Malignancies

The effects of radiotherapy on systemic immunity remain to be fully characterized in a disease-specific manner. The aim of the study was to examine potential biomarkers of systemic immunomodulation when using radiotherapy for thoracic malignancies. Serial blood samples were collected from 56 patients with thoracic malignancies prior (RTbaseline), during (RTduring) and at the end of radiotherapy (RTend), as well as at the first (FU1) and second follow-up (FU2). The changes in serum levels of IL-10, IFN-γ, IL-12p70, IL-13, IL-1β, IL-4, IL-6, IL-8, TNF-α, bFGF, sFlt-1, PlGF, VEGF, VEGF-C, VEGF-D and HGF were measured by multiplexed array and tested for associations with clinical outcomes. We observed an increase in the levels of IL-10, IFN-γ, PlGF and VEGF-D and a decrease in those of IL-8, VEGF, VEGF-C and sFlt-1 during and at the end of radiotherapy. Furthermore, baseline concentration of TNF-α significantly correlated with OS. IL-6 level at RTend and FU1,2 correlated with OS (RTend: p = 0.039, HR: 1.041, 95% CI: 1.002–1.082, FU1: p = 0.001, HR: 1.139, 95% CI: 1.056–1.228, FU2: p = 0.017, HR: 1.101 95% CI: 1.018–1.192), while IL-8 level correlated with OS at RTduring and RTend (RTduring: p = 0.017, HR: 1.014, 95% CI: 1.002–1.026, RTend: p = 0.004, HR: 1.007, 95% CI: 1.061–1.686). In conclusion, serum levels of TNF-α, IL-6 and IL-8 are potential biomarkers of response to radiotherapy. Given the recent implementation of immunotherapy in lung and esophageal cancer, these putative blood biomarkers should be further validated and evaluated in the combination or sequential therapy setting.

Sequential Therapy with Fitcy Preparative Regimen for Patients with Primary Refractory AML - a Single Center Retrospective Analysis

Introduction - primary refractory AML is associated with a dismal prognosis. Only 30% of patients will respond to salvage chemotherapy and continue to allogeneic hematopoietic cell transplantation (HCT) with a 10-20% long- term overall survival. Following from the FLAMSA protocol, we implemented a modified RIC regimen - FITCy (fludarabine, cytarabine +/- idarubicin and 4 Gy TBI) in all primary refractory patients with a donor available for transplant. Methods - all patients who were admitted with AML, were identified by the transplantation coordinator nurse and underwent donor evaluation within 2 days from diagnosis. Patients who received induction chemotherapy had a day 14 marrow examination and where leukaemia blasts were identified, donor search was prioritized. These patients went on to have a day 28 bone marrow examination to confirm refractory disease. Patients who were treated with azacitidine ±venetoclax had a 2-month BM evaluation and donor search was prioritized in case of refractory disease. All consecutive patients, diagnosed with primary refractory AML, underwent HCT with the FITCy regimen in the Tel Aviv Sourasky Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) or a second HCT were excluded from this analysis. The protocol was amended on January 2018 to include ATG for all patients after interim analysis showed a high rate of GVHD. Results - Between January 2014 and June 2021, 48 patients were identified with primary refractory disease and were eligible for the protocol. Median age was 63 (range, 22-75) years (Table). Median follow-up for surviving patients was 33 (range, 1-81) months. Prior to HCT, 12 (25%) patients had ongoing documented infections (either microbiology or clinically). Median days to engraftment of neutrophils (&gt;500/dL) and to complete engraftment of platelets (&gt;20000/dL) were 10 (range, 7-20) days, and 16 (9-35) days, respectively. 7 patients with early progression/non relapse mortality were not evaluated for this outcome. No patient had primary/secondary graft rejection. Severe mucositis was observed in only 7 patients (15%) and was mostly observed in the upper gut. 18 patients (38%) developed microbiology documented infections during the neutropenic period and in 7 (40%) this directly contributed to mortality. Only 2 patients (4%) developed sinusoidal obstruction syndrome. Complete remission was documented on day 30, in all but 1 patient with a median whole marrow donor chimerism of 98% (range, 73-100%).Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 55% and 15%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 64% and 24%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 24% and 30%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 13%, 20%, and 32%, respectively. Cumulative incidences of 1, 2, and 3 years overall survival were 50%, 42%, and 42%, Figure. Cox regression analysis for overall survival identified increased time from diagnosis (HR-1.03, p=.046), mismatched donor (HR-1.4, p=.05) and the use of ATG (HR=.33, p=.006) to impact survival, while age, sex and comorbidity index were not predictive. Conclusions - Sequential therapy in patients with primary refractory AML provides a remarkable anti- leukemic effect. A timely donor search program is essential for the succession of this approach. Nevertheless, infection control and GVHD prophylaxis is still suboptimal and future protocols should focus on these domains while preserving graft vs. leukemia function. Figure 1 Figure 1. Disclosures Moshe: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Ram: Novartis: Honoraria; Gilead: Honoraria. OffLabel Disclosure: Off label Cellcepet for prophylaxis of GVHD

Сombined (anti-VEGF and laser) treatment for operated secondary refractory neovascular glaucoma

Purpose. To develop an optimal algorithm for the management of patients with operated neovascular uncompensated glaucoma. Material and methods. 2 patients with operated secondary neovascular glaucoma of stage III-c. In the combined sequential therapy, the anti-VEGF medication Ranibizumab (0.5 mg) was used, laser coagulation of residual newly formed vessels, laser reconstruction in the surgical area, contact transcleral cyclolazercoagulation, and laser coagulation of the peripheral parts of the retina were performed. Results. The combined sequential treatment, combined with the appointment of antihypertensive drugs in drops, allowed to stabilize the level of IOP. IOP indicators remained at the level of normal values during 1 year of follow-up. Conclusion. The use of combined laser technologies and anti-VEGF therapy makes it possible to potentiate and prolong the hypotensive effect in the treatment of patients with operated secondary refractory neovascular glaucoma. Key words: operated neovascular glaucoma, anti-VEGF, combined laser treatment.