Efficacy, reactogenicity, and safety of the adjuvanted recombinant zoster vaccine for the prevention of herpes zoster in Chinese adults ≥ 50 years: A randomized, placebo-controlled trial.

Phase III multi-country studies (ZOE-50/70) demonstrated that the adjuvanted recombinant zoster vaccine (RZV) was well tolerated and prevented herpes zoster (HZ) in healthy ≥ 50-year-olds, with a vaccine efficacy (VE) > 90% across age groups. These pivotal trials did not enroll participants from mainland China where RZV is licensed, therefore similar clinical data are missing for this population. In this phase IV observer-blind study (NCT04869982) conducted between 2021 and 2023 in China, immunocompetent and medically stable ≥ 50-year-olds were randomized 1:1 to receive two RZV or placebo doses, 2 months apart. This study assessed the VE (overall, as confirmatory objective, and descriptively by age category [50-69-year-olds/≥ 70-year-olds]), reactogenicity, and safety of RZV in this Chinese population. Of the 6138 enrolled participants, 99.2% completed the study. During a mean follow-up period of 15.2 (±1.1) months, 31 HZ episodes were confirmed (RZV = 0; placebo = 31) for an incidence rate of 0.0 vs 8.2 per 1000 person-years and an overall VE of 100% (89.82-100). The descriptive VE was 100% (85.29-100) for 50-69-year-olds and 100% (60.90-100) for ≥ 70-year-olds. Solicited adverse events (AEs) were more frequent in the RZV vs the placebo group (median duration: 1-3 days for both groups). Pain and fatigue were the most frequent local and general AEs (RZV: 72.1% and 43.4%; placebo: 9.2% and 5.3%). The frequencies of unsolicited AEs, serious AEs, potential immune-mediated diseases, and deaths were similar between both groups. RZV is well tolerated and efficacious in preventing HZ in Chinese ≥ 50-year-olds, consistent with efficacy studies including worldwide populations with similar age and medical characteristics.

What is the context? Herpes zoster, commonly known as shingles, is a painful rash resulting from the reactivation of the dormant virus causing chickenpox.Vaccines preventing shingles, such as Shingrix, were shown to be well tolerated and efficacious in healthy adults over 50 years of age from Europe, North and Latin America, Australia, and Asia (Taiwan, Hong Kong, Korea, Japan).However, data on real-world protective effect of Shingrix are limited in some regions where the vaccine is licensed for use, such as mainland China.What is new? We analyzed data from Chinese adults aged 50 years or older to determine the efficacy and safety of Shingrix.Around 6000 participants were divided in two equal groups to receive two doses of Shingrix or two doses of a placebo, given 2 months apart.We found that, during the study period, the vaccine was 100% efficacious in preventing shingles.We showed that the vaccine had an acceptable safety profile in this Chinese population.What is the impact? Shingrix is efficacious and well tolerated in Chinese adults over 50 years of age, as it is in similarly aged populations from other evaluated regions.

Immunogenicity, reactogenicity, and safety of two-dose adjuvanted herpes zoster subunit vaccine in patients with systemic lupus erythematosus in South Korea: a single-centre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: The adjuvanted herpes zoster subunit vaccine has shown good efficacy and safety in the general population. However, its effectiveness has not been comprehensively assessed in patients with systemic lupus erythematosus (SLE). This study aimed to evaluate the immunogenicity and safety of the adjuvanted herpes zoster subunit vaccine in patients with SLE. METHODS: This single-centre, randomised, double-blind, placebo-controlled, trial was done at the rheumatology outpatient clinic at Seoul National University Hospital, South Korea. Patients (aged ≥19 years) with clinically stable SLE and previous exposure (≥4 weeks) to immunosuppressive drugs were randomly assigned (4:1) via a central interactive web response system to receive herpes zoster subunit vaccine or placebo (0·5 mL intramuscular injection) at weeks 0 and 8. Investigators and participants were masked to intervention and group assignment. Anti-glycoprotein E antibody titres and glycoprotein E-specific cell-mediated vaccine responses were evaluated at baseline and at week 8 after the first dose, and at week 4, week 26, and week 52 after the second dose using enzyme-linked immunosorbent assay and flow cytometry, respectively. Reactogenicity, SLE disease activity, including Systemic Lupus Erythematosus Disease Activity Index 2000 and British Isles Lupus Assessment Group-flare rate, were examined. The primary outcome was the proportion of patients with a positive humoral vaccine response 4 weeks after the second dose. The primary and safety analyses were done in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT06001606. FINDINGS: Between June 14, and July 19, 2023, 65 patients with SLE were enrolled, of whom 52 were randomly assigned to the herpes zoster subunit vaccine and 13 to placebo. 49 patients in the vaccine group and 11 patients in the placebo group were included in the modified intention-to-treat population. 56 (93%) of 60 patients were women and four (7%) were men. Mean age was 48·7 years (SD 11·4). The proportion of participants with a humoral vaccine response at 4 weeks after the second dose was significantly higher in the vaccine group (48 [98%] of 49 participants) than the placebo group (none [0%] of 11 patients; p<0·0001). More patients in the vaccine group than placebo group reported injection site reactions (42 patients vs two patients), fever (ten vs none), and fatigue (26 vs two). There were no differences in Systemic Lupus Erythematosus Disease Activity Index 2000 and British Isles Lupus Assessment Group-flare rates between the groups. There were no treatment-related deaths. INTERPRETATION: The herpes zoster subunit vaccine induces humoral and cellular immunity against herpes zoster with a good safety profile in patients with SLE. A larger study is warranted to assess the efficacy of vaccines to prevent herpes zoster in patients with SLE. FUNDING: Ministry of Science and ICT, The Government of the Republic of Korea.

A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. MATERIALS AND METHODS: This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. RESULTS: Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. CONCLUSIONS: In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Safety profile of recombinant adjuvanted anti-herpes zoster vaccine (RZV) in high-risk groups: Data from active surveillance program. Puglia (Italy), 2021-23.

BACKGROUND: Since 2021 a recombinant adjuvanted anti-Herpes Zoster vaccine(Recombinant Zoster Vaccine, RZV) is offered in Italy to high-risk patients. Few real-life data about RZV safety are available in target populations. OBJECTIVES: This study investigates Adverse Events Following Immunization(AEFIs), baseline disease flare-ups, and Herpes Zoster (HZ) episodes occurring after RZV administration in a heterogeneous population of fragile patients to design its safety profile. METHODS: This is a retrospective population-based study. RZV-vaccinated patients at Bari Policlinico General Hospital vaccination clinic from October 1st, 2021, to March 31st, 2023, were enrolled. Subjects were screened for reason of RZV eligibility and baseline chronic pathologies. AEFIs occurred in the first 7-days post-vaccination period were collected, and baseline disease flare-ups and post-vaccination HZ episodes were assessed via a 3-month follow-up. RESULTS: Five-hundred-thirty-eight patients were included and total of 1,031 doses were administered. Most patients were vaccinated due to ongoing immunosuppressive therapy(54.65 %); onco-hematological and cardiovascular conditions were the most common chronic baseline pathologies. Out of 1,031 follow-ups, 441 AEFI cases were reported(42.7/100). The most common symptoms were injection site pain/itching(35.60/100), asthenia/malaise(11.44/100), and fever (10.09/100). Four serious AEFIs occurred(0.38/100). Older age, male sex, and history of cardiovascular diseases(OR:0.71; 95CI:0.52-0.98; p-value <0.05) were found to decrease AEFIs risk, while endocrine-metabolic illnesses(OR:1.61; 95CI:1.15-2.26; p-value <0.05) increased it. Twelve patients(2.23 %) reported a flare-up/worsening of their baseline chronic condition within the first three months after vaccination(mean interval 31.75 days, range 0-68 days). Patients with rheumatological illnesses had a higher risk of relapse(OR:16.56; 95CI:3.58-76.56; p-value <0.001), while male sex behaved as a protective factor. Twelve patients who completed the vaccination cycle(2.43%) had at least one HZ episode by the long-term follow-up. CONCLUSIONS: The study demonstrates RZV safety in a significant number of high-risk patients. Hence, RZV should be actively offered as part of tailored vaccination programs to decrease the burden of HZ in fragile populations.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

Stroke Risk After COVID-19 Bivalent Vaccination Among US Older Adults.

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

Fulminant myocarditis during postoperative adjuvant chemotherapy for lung cancer with atezolizumab: a case report.

BACKGROUND: Postoperative adjuvant systemic therapy with atezolizumab for lung cancer has been reported to be effective. Although myocarditis is a rare immune adverse event associated with atezolizumab, it can have a serious course and should be treated with caution. We herein report a case of fulminant myocarditis during adjuvant systemic therapy with atezolizumab. CASE PRESENTATION: The patient was a 49-year-old Asian woman. She was diagnosed with pT2aN1M0 stage IIB (Programmed Death Ligand 1(PD-L1), 50%) after surgery for right upper lobe lung adenocarcinoma. Atezolizumab was administered following platinum-based adjuvant chemotherapy. On day 14, the patient was hospitalized because of deterioration in her general condition caused by fever. On day 16, she developed dyspnea, which worsened, and on day 17, she experienced shock. Blood tests, echocardiography, and cardiac catheterization were performed, and the patient was diagnosed with cardiogenic shock due to myocarditis. Initial measures did not improve the patient's shock state. The patient was transferred to hospital for the use of an assistive circulatory system. Pulse steroid therapy was administered, and myocarditis showed a tendency toward improvement. A retrospective review of the patient's history revealed a decreased lymphocyte count and an increase in the neutrophil/lymphocyte ratio, which may be useful for detecting severe immune-related adverse events. The troponin levels were elevated, but creatine phosphokinase level remained within the normal range. CONCLUSION: Myocarditis can be fatal due to the rapid progression of symptoms. Close follow-up, a prompt diagnosis, and therapeutic intervention are important. Decreased lymphocyte counts, increased neutrophil/lymphocyte ratios, and the measurement of multiple myocardial biomarkers are considered useful for the early diagnosis of myocarditis.

Intratumoral administration of the immunologic adjuvant AS01B in combination with autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells plus ipilimumab and intravenous nivolumab in patients with refractory advanced melanoma.

BACKGROUND: Patients with advanced melanoma who progress after treatment with immune checkpoint-inhibitors (ICI) and BRAF-/MEK-inhibitors (if BRAF V600 mutated) have no remaining effective treatment options. The presence of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment correlates with pre-existing immune recognition and responsiveness to immune checkpoint blockade. The synthetic saponin-based immune adjuvant AS01B enhances adaptive immunity through the involvement of myDC. METHODS: In this first-in-human phase I clinical trial, patients with metastatic melanoma refractory to ICI and BRAF-/MEK inhibitors (when indicated) were recruited. Patients received an intravenous administration of low-dose nivolumab (10 mg, every 2 weeks) plus an intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01B (every 2 weeks). All myDC, isolated from blood, were injected on day 2 into the same metastatic lesion. Tumor biopsies and blood samples were collected at baseline and repeatedly on treatment. Multiplex immunohistochemistry (mIHC) was performed on biopsy sections to characterize and quantify the IT and peritumoral immune cell composition. RESULTS: Study treatment was feasible and well tolerated without the occurrence of unexpected adverse events in all eight patients. Four patients (50%) obtained a complete response (CR) in the injected lesions. Of these, two patients obtained an overall CR, and one patient a partial response. All responses are ongoing after more than 1 year of follow-up. One additional patient had a stable disease as best response. The disease control rate was 50%. Median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration, with a reduced mean distance between T cells and tumor cells. Peripheral blood immune cell composition did not significantly change during study treatment. CONCLUSIONS: Combining an intratumoral injection of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myDC with repeated IT administration of ipilimumab and AS01B and systemic low-dose nivolumab is safe, feasible with promising early results, worthy of further clinical investigation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03707808.

Difference in the cellular response following THP-1 derived phagocytic monocyte cells exposure to commercial aluminum-based adjuvants and aluminum-containing vaccines.

BACKGROUND: Aluminum-based adjuvants (ABAs) enhance the immune response following vaccine injection. Their mechanisms of action are not fully understood, and their bio-persistency have been described associated with long-term adverse effects. METHODS: We evaluated and compared the cellular effects of the two main ABAs and whole vaccines on ATP production, ROS generation and cytokines production (IL-6 and IL-10), using THP-1 cells. RESULTS: ABAs altered the cell energy metabolism by increasing ROS production after 24 h and reducing ATP production after 48 h. In addition, both ABAs and whole vaccines induced different kinetics of IL-6 production, whereas only ABAs induced IL-10 secretion. CONCLUSION: This study showed clearly, for a first time, a difference in cellular response to the ABAs and whole vaccines which should be taken into consideration in future studies focusing on the effect of ABA in vaccines. Future studies on ABAs should also pay attention to mitochondrial function alterations following exposure to ABA-containing vaccines.

Influvac Tetra: clinical experience on safety, efficacy, and immunogenicity.

INTRODUCTION: This paper summarizes the safety and immunogenicity data of Influvac Tetra across all age groups starting from 6 months of age, obtained during its clinical development program. AREAS COVERED: The article covers the clinical development program of Influvac Tetra based on five registration studies that included different age groups, different comparators, and participants from Europe and Asia. Safety and immunogenicity were assessed in all studies and in one study, the efficacy of Influvac Tetra was assessed. EXPERT OPINION: Seasonal influenza is a vaccine-preventable disease that can cause serious complications. Several types of influenza vaccines are available, including egg-based (standard dose, high dose, and adjuvanted), cell-based, and recombinant. The COVID-19 pandemic has stimulated innovation in the development such as mRNA vaccines. However, these vaccines are still in development and the true value still has to be proven. Regardless of the type of vaccine, it is also important to increase overall vaccination coverage. ECDC recommends that EU Member States implement action plans and policies aimed at reaching 75% coverage in at-risk groups and healthcare workers. Even so, vaccine coverage is still far from recommended.

The "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) after COVID-19 infection: A case report.

The term "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) describes a variety of autoimmune conditions triggered by exposure to substances with adjuvant activity. We present the case of a patient with a history of biopolymer infiltration in both glutes, who years later experienced progressive weakness and pain in the lower limbs, myalgias, cramps, and progressive functional impotence following a mild COVID-19 infection. Laboratory test results were not consistent with any autoimmune disease. Physical examination revealed diffuse bilateral subcutaneous nodules. After an extensive etiological study, a gluteal biopsy was performed, which showed findings compatible with sclerosing lipogranuloma. Our patient required treatment with high-dose glucocorticoids and showed significant improvement in symptoms during long-term follow-up. We suggest the role of COVID-19 infection as a possible trigger for ASIA, as it has already been described as a trigger for several other autoimmune diseases.

Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment.

Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate-lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague-Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI - 0.6 to 1.2). Plasma glucose levels were reduced by 36% (- 4.5 mmol/L), p < 0.05 (95% CI - 6.7 to - 2.5). Standard base excess was increased from - 3.5 mmol/L (IQR - 4 to - 2) to 0.5 mmol/L (IQR - 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.

Real-world efficacy of adjuvant single-agent intravesical gemcitabine for non-muscle invasive bladder cancer.

INTRODUCTION: Failure, intolerance, or shortage of bacillus Calmette-Guerin (BCG) treatment for patients with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) leave many facing the prospect of radical cystectomy (RC). However, despite the lack of large-scale randomized controlled studies with single-agent intravesical gemcitabine (Gem), it has emerged as a popular salvage agent after BCG failure or even a treatment alternative to BCG. AREAS COVERED: 1. Characterization of treatment regimen details pertaining to single-agent intravesical adjuvant Gem use among disease states of NMIBC characterized by risk and BCG exposure. 2. Comparison of safety and efficacy of Gem according to risk category, type of tumor (papillary vs. carcinoma in situ (CIS)), and tumor grades. EXPERT OPINION: Two randomized studies in early BCG failure disease demonstrate that single-agent Gem has superior efficacy versus repeated BCG therapy or mitomycin C. Studies enrolling patients with predominantly papillary disease without CIS, intermediate-risk (IR) disease, and less BCG exposure appear to derive the highest benefits from adjuvant Gem in terms of recurrence and progression. However, studies with cohorts enriched for a predominance of CIS, HR disease and/or more extensive BCG failure have poorer 2-year recurrence free survival and a somewhat higher risk of progression and RC.

Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guérin-unresponsive High-risk Non-muscle-invasive Bladder Cancer: SWOG S1605.

BACKGROUND: Although radical cystectomy (RC) is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), many patients are ineligible for surgery or elect bladder preservation. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab in BCG-unresponsive high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined RC. INTERVENTION: Intravenous atezolizumab every 3 wk for 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the pathological complete response (CR) rate for patients with carcinoma in situ (CIS) determined via mandatory biopsy at 6 mo. Event-free survival (EFS) at 18 mo for patients with non-CIS tumors and treatment-related adverse events (TRAEs) were key secondary endpoints. RESULTS AND LIMITATIONS: Of 172 patients enrolled in the trial, 166 received at least one dose of atezolizumab (safety analysis) and 129 were eligible (efficacy analysis). Of the 74 patients with CIS, 20 (27%) experienced a CR at 6 mo. The median duration of response was 17 mo, and 56% (95% confidence interval [CI] 34-77%) of the responses were durable to at least 12 mo. The 18-mo actuarial EFS rate among 55 patients with Ta/T1 disease was 49% (90% CI 38-60%). Twelve of 129 eligible patients experienced progression to muscle-invasive or metastatic disease. Grade 3-5 TRAEs occurred in 26 patients (16%), including three treatment-related deaths. The study was limited by the small sample size and a high rate of patient ineligibility. CONCLUSIONS: The efficacy of atezolizumab observed among patients with BCG-unresponsive NMIBC is similar to results from similar trials with other agents, but did not meet the prespecified efficacy threshold. Modest efficacy needs to be balanced with a significant rate of TRAEs and the risk of disease progression when considering systemic immunotherapy in early-stage bladder cancer. PATIENT SUMMARY: We tested intravenous immunotherapy (atezolizumab) in patients with high-risk non-muscle-invasive bladder cancer that recurred after BCG (bacillus Calmette-Guérin) treatment. Although we found similar outcomes to previous trials, the benefit of this therapy is modest and needs to be carefully balanced with the significant risk of side effects. This trial is registered on ClinicalTrials.gov as NCT02844816.

TLR-2 agonist Pam3CSK4 has no therapeutic effect on visceral leishmaniasis in BALB/c mice and may enhance the pathogenesis of the disease.

Most of the existing Leishmania-related research about TLR-2 agonists was focusing on their role as adjuvants in the vaccine, few studied its therapeutic effect. This paper aims to explore the therapeutic effect of TLR-2 agonist Pam3CSK4 on Leishmania-infected mice and the underlying immune molecular mechanisms. In L. donovani-infected BALB/c mice, one group was treated with Pam3CSK4 after infection and the other group was not treated. Normal uninfected mice treated with Pam3CSK4 or untreated were used as controls. Parasite load, hepatic pathology and serum antibodies were detected to assess the severity of the infection. The expression of immune-related genes, spleen lymphocyte subsets and liver RNA-seq were employed to reveal possible molecular mechanisms. The results showed that the liver and spleen parasite load of infected mice in Pam3CSK4 treated and untreated groups had no statistical difference, indicating Pam3CSK4 might have no therapeutic effect on visceral leishmaniasis. Infected mice treated with Pam3CSK4 possessed more hepatic inflammation focus, lower IgG and IgG2a antibody titers, and a lower proportion of spleen CD3+CD4+ T cells. Transcriptome analysis revealed that Th1/Th2 differentiation, NK cells, Th17 cell, complement system and calcium signaling pathways were down-regulated post-treatment of Pam3CSK4. In this study, TLR-2 agonist Pam3CSK4 showed no therapeutic effect on visceral leishmaniasis in BALB/c mice and might enhance the pathogenesis of the disease possibly due to the down-regulation of several immune-related pathways, which can improve our understanding of the role of TLR-2 in both treatment and vaccine development.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA), medical treatment of severe systemic compromise: case report.

Case description: A 42-year-old woman with severe pulmonary and mediastinal inflammatory involvement, secondary to infiltration of a silicone-related allogenic material with systemic migration. Clinical findings: The patient developed esophageal and bronchial stenosis, recurrent infections, malnutrition, and respiratory deterioration, making surgical removal of the allogenic material impossible. Treatment and outcome: Clinical and radiological improvement was achieved after treatment with multiple intravenous and oral immunomodulators. Clinical relevance: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a heterogeneous disease resulting from exposure to allogenic substances in a susceptible subject. These substances cause autoimmune or autoinflammatory phenomena. Since ASIA was described ten years ago, its diagnostic criteria are still under discussion, with an uncertain prognosis. The ideal therapy is based on eliminating the causative substance, but this is not always possible. Therefore, it is necessary to start an immunomodulatory treatment, using it in this patient, a scheme that had not been previously reported in the literature.

Descripción del caso: Mujer de 42 años con compromiso inflamatorio pulmonar y mediastinal severo, secundario a infiltración de un material alogénico relacionado con la silicona con migración sistémica. Hallazgos clínicos: La paciente desarrolló estenosis esofágica y bronquial, infecciones recurrentes, desnutrición y deterioro respiratorio, imposibilitando la extracción quirúrgica del material alogénico. Tratamiento y resultado: Mejoría clínica y radiológica lograda tras un tratamiento con múltiples inmunomoduladores intravenosos y orales. Relevancia clínica: El síndrome autoinmune / inflamatorio inducido por adyuvantes (ASIA) es una enfermedad heterogénea que resulta de la exposición a sustancias alógenas en un sujeto con susceptibilidad genética. Estas sustancias inducen fenómenos autoinmunitarios o autoinflamatorios. Desde que ASIA fue descrito hace 10 años, sus criterios diagnósticos continúan en discusión, con un pronóstico incierto. El tratamiento idóneo se basa en eliminar la sustancia causante, pero no siempre es posible, por lo cual se hace necesario iniciar un tratamiento inmunomodulador, empleándose en esta paciente un esquema que no había sido reportado previamente en la literatura.