Patients Receiving Combination Therapy Research Articles

TAS0313 plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma.

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/μL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/μL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824.

EVALUATION OF THE ANTIHYPERTENSIVE DRUGS IN PREECLAMPSIA PATIENTS TO CLINICAL OUTCOMES AT RSUD SEKARWANGI ON 2021 PERIOD

Preeclampsia is a pregnancy complication with several symptoms, such as hypertension, proteinuria, and edema. Such symptoms occur in pregnant women after the gestational age reaches 20 weeks. Preeclampsia is divided into mild preeclampsia (PER) and severe preeclampsia (PEB). Antihypertensive drugs are used to lower blood pressure and proteinuria levels in patients with preeclampsia. The purpose of this study was to obtain a profile of antihypertensive drugs and monitor changes in clinical outcomes in patients with preeclampsia. This was a retrospective cross-sectional study using secondary data from the medical records of preeclampsia patients. Of the 54 patients who met the inclusion criteria with the age at which most preeclampsia was 21–35 years old, 33 (61.11%) patients and 32 (59.62%) patients had PEB. The most widely used antihypertensive drug was a combination of methyldopa and nifedipine, with 27 (50%) patients receiving combination therapy. After treatment with antihypersensitive drugs, 50 (92.60%) patients experienced a decrease in blood pressure, 45 (83.33%) patients experienced a decrease in proteinuria levels, and 45 (83.33%) patients had normal birth conditions. Antihypertensive treatment for preeclampsia patients has a relationship with a decrease in the patient’s blood pressure (p-value = 0,007), but there was no relationship with a decrease in proteinuria levels (p-value = 0,660) and condition of baby birth (p-value = 0,446). Keyword: Preeclampsia; Antihypertensive Drugs; Clinical Outcomes

Ceftazidime-Avibactam in the Treatment of Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacteria in Hematological Patients: Experience in a Single Center

Background: Experience with ceftazidime-avibactam (CAZ-AVI) for bacteremia caused by carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) in hematological patients is limited. Methods: We performed a single-center, retrospective, observational study including patients receiving CAZ-AVI for bacteremia due to CRE or CRPA between 2018 and 2022. The primary outcome was 30-day survival. To identify predictors of survival, multivariable analysis was performed. Results: 56 patients were included and 57 (41 CRE and 16 CRPA) strains were isolated. 35 strains produced carbapenemase (25 MBL, 10 serine-beta-lactamase). 48 (85.7%) patients received combination therapy. All patients with MBL-CRE bacteremia (n=24) received combination therapy with aztreonam. The susceptibility rates to CAZ-AVI were only 25.0% (10/40) in CRE and 80.0% (8/10) in CRPA. The 30-day survival rates were 85.0% (34/40) and 81.3% (13/16) in CRE and CRPA group, respectively. In patients with MBL-CRE bacteremia, 30-day survival was high to 91.7% (22/24) due to combination with aztreonam. Ceftazidime did not influence the activity of aztreonam-avibactam against MBL-CRE in-vitro. Multivariable cox analysis revealed neutropenia &amp;gt; 14 days (P=0.002, HR: 0.029, 95%CI: 0.003~0.260) and higher Pitt bacteremia score (P=0.005, HR: 0.482, 95%CI: 0.291~0.798) were risk factors of 30-day survival. Conclusions: CAZ-AVI is highly effective for bacteremia due to CRPA and serine-beta-lactamase CRE. Avibactam in combination with aztreonam is highly active for bacteremia due to aztreonam-resistant MBL producers.

Small molecule multitarget antiangiogenic inhibitor treatments for advanced thymic epithelial tumors: A retrospective study.

Thymic epithelial tumors (TETs) are rare malignant tumors with limited treatment options. No established second-line treatment regimen is available following the preferred first-line chemotherapy, resulting in unsatisfactory efficacy and poor prognosis for patients with advanced TETs. This study aimed to evaluate the efficacy of small molecule multitarget antiangiogenic inhibitors as well as the prognostic factors for advanced TETs. A retrospective study was conducted using data from a real-world database. Clinical information and survival follow-up data were collected from 52 patients with advanced TETs who received small molecule multitarget antiangiogenic inhibitors at Zhejiang Cancer Hospital between August 10, 2016 and August 10, 2022. The short-term efficacy of the treatments, survival time of the patients, and relevant prognostic factors of advanced TETs were analyzed. Out of the 52 patients included in this study, 16 had thymoma and 36 had thymic carcinoma. The 52 patients had an overall response rate of 21.1% and a disease control rate of 94.2%. In addition, the median progression-free survival (PFS) was 8.05 months, and the overall survival (OS) was 25.00 months. Apatinib was given to 33 patients, anlotinib to 15 patients, and sunitinib or lenvatinib to four patients. Only seven patients received antiangiogenic inhibitors as their first-line therapy, 27 patients as their second-line therapy, and 18 patients as third-line or subsequent therapy. Meanwhile, 42 patients received monotherapy with an antiangiogenesis inhibitor, while 10 patients received combination therapy. Univariate analysis indicated that the combined treatment was associated with a superior OS (p = 0.044); multivariate analysis indicated that the combined treatment was an independent prognostic factor for PFS (p = 0.014) and OS (p = 0.012). The findings suggest that small molecule multitarget antiangiogenic inhibitors are efficacious as second or post-line treatments as a viable alternative treatment option for patients with advanced TETs.

Safety and Efficacy of Second-Line TKI Plus Anti-PD1 in Metastatic Non-Clear Cell Renal Cell Carcinoma: A Real-World Study

ObjectivesGuidelines recommend clinical trials or tyrosine kinase inhibitor (TKI) as the first-line option for systemic therapy for non-clear cell renal cell carcinoma (nccRCC) with limited efficacy. However, the preferred subsequent options remain unclear when patients progress after first-line treatment. This study aimed to evaluate the efficacy and safety of anti-PD-1 plus TKI therapy as the second-line regimen in nccRCC. Patients and MethodsWe conducted a retrospective analysis of patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020. The baseline characteristics of the patients and adverse events (AEs) were collected. Efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). ResultsThe current study enrolled 65 patients, with a median age of 48 (interquartile 37–60) years. Among all patients, 21 received TKI monotherapy while 44 patients received combination therapy (TKI plus anti-PD1). The ORR and DCR for the whole cohort were 38.5% and 56.9%, respectively. ORR (50.0% vs. 14.3%, P = .006) and DCR (70.5% vs. 28.6%, P = .001) were improved in the combination group compared with the TKI group. The overall second-line PFS was 7.7 (95% CI: 6.1-9.3) months and OS was 25.2 (19.5-30.8) months. Patients receiving combination therapy had a longer PFS compared with those receiving TKI monotherapy [median PFS (95% CI): 9.2 (5.9-12.4) vs. 5.4 (2.6-8.2) m, Log-rank P = .002]. The incidence of treatment-related AEs of grade 3 or higher was comparable between the 2 groups (56.8% vs. 52.4%). ConclusionAnti-PD-1 plus TKI therapy appeared effective and safe in the treatment of patients with metastatic nccRCC who progressed after first-line TKIs.

Effectiveness and safety of vitamin U in patients with dyspepsia in real clinical practice

The relevance of improving treatment methods for patients with dyspepsia is important due to widespread prevalence, negative impact on the quality of life and regularly updated pathogenetic conception of this syndrome. Objective. To evaluate the effectiveness and safety of methylmethionine sulfonium chloride as part of combination therapy in patients with epigastric pain in real clinical practice. Materials and methods. An anonymous, retrospective, non-interventional clinical study of 408 patients with a primary diagnosis of dyspepsia (K30.0) treated with a combination of omeprazole (20 mg) and methylmethionine sulfonium chloride (300 mg) or omeprazole (20 mg) for 30 days for epigastric pain syndrome. Results. In patients receiving combination therapy, epigastric pain was relieved in 80.1% versus 68.3% in patients receiving monotherapy (p=0.007). Adverse effects of therapy in the group of patients receiving vitamin U occurred in 13.1% versus 6.9% in the group of patients receiving omeprazole monotherapy (p=0.03), but this did not affect patient adherence to treatment. Conclusion. The reliable effectiveness of methylmethionine sulfonium chloride as part of combination therapy in patients with dyspepsia in real clinical practice demonstrated.

Clinical characteristics and treatment patterns in patients with atherosclerotic cardiovascular disease with hypercholesterolemia: a retrospective analysis of a large US real-world database cohort

Objective Guidelines developed by the American College of Cardiology/American Heart Association (ACC/AHA) recommend lipid-lowering therapies (LLTs) to reduce low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. This study described LLT utilization patterns and LDL-C goal achievement (to <70 mg/dL) among patients with ASCVD in the United States. Methods This retrospective study was conducted using Optum’s de-identified Clinformatics Data Mart Database (CDM). Patients with their first ASCVD diagnosis (index date) in the CDM database between July 1, 2015, and December 31, 2018, were followed for ≥12 months to assess LLT utilization patterns and change in LDL-C. LLTs included were statins and non-statin LLTs (ezetimibe, fibrates, and proprotein convertase subtilisin/kexin type 9 inhibitors). Adherence was measured as the proportion of days covered (PDC), defined as the number of days with drug on-hand (or number of days exposed to drug) divided by the 12-month follow-up period. Patients with PDC ≥0.8 were considered adherent. Results Among the patients with ASCVD (N = 1,424,893) included in this study, only 621,978 (43.7%) had at least one LDL-C measurement at baseline (6 months prior to and 3 months after the index date). The mean age was 71.5 years, and almost half of the patients were female. Patients were followed for a mean (standard deviation [SD]) duration of 30.6 (11.4) months (median of 29.9 months). During the follow-up, about one-quarter of the patients did not receive any LLT. Among treated patients, 89.5% received statins and 10.5% received non-statin LLT. Less than half (47.6%) of the patients were adherent to the index treatment during the 12-month follow-up. Even in patients receiving combination therapy (statin + non-statin LLT), a sizable proportion (35.8%) showed an increase in LDL-C over the follow-up period. Conclusions This retrospective study highlighted limited LDL-C monitoring in patients with ASCVD, and unmet need in terms of suboptimal utilization of non-stain LLTs, limited adherence to LLTs, and inadequate lipid control after treatment (among those with LDL-C measurements during the follow-up period) need to be addressed to improve outcomes in this patient cohort.

IMMU-49. BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS

Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success.Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment with an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Further, using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

Abstract 18449: Myocarditis in Patients With Cancer Undergoing Combination Checkpoint Inhibitor Therapy

Introduction: Immune checkpoint inhibitors (ICI) have improved the clinical outcomes of several cancers but have also been associated with a greater risk of cardiovascular adverse effects. Hypothesis: The use of combination ICI therapy is associated with an increased risk of myocarditis, compared to use of a single ICI. Methods: A cohort study was conducted using medical and pharmacy claims data (2011 to 2022) in the Optum Clinformatics database. Cox regression models quantified the comparative risk of myocarditis between cancer patients receiving combination therapy (nivolumab and ipilimumab) and those taking a single ICI. Results: Among 53,018 patients to whom ICI were dispensed there were 148 cases of myocarditis (0.3%): 33 (0.7%) in patients on combination therapy and 115 (0.2%) in patients on monotherapy. The crude risk of myocarditis per 1,000 patients was 7.40 in the combination therapy group and 2.37 in the monotherapy group (risk ratio= 3.12; 95% CI: 2.12 to 4.60) over an average follow-up period of 226 days (IQR 93-495 days). After propensity score-matching the hazard ratio comparing myocarditis in the combination therapy versus monotherapy groups was 3.67 (1.76 to 7.67; p&lt;0.01). 76% of all myocarditis events in both groups occurred within six months of commencing treatment (figure). Conclusions: Simultaneous combination therapy with nivolumab and ipilimumab was associated with an increased risk of myocarditis compared to the use of single agents. Myocarditis was infrequent and occurred most often within six months of treatment start.

Anti-Btla Antibody Tifcemalimab As a Single Agent or in Combination with Toripalimab in Relapsed/Refractory Lymphomas

Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Using Peripheral Blood Mononuclear Cell (PBMC) derived from cancer patients, co-blockade of the BTLA and PD-1 pathways improved antigen specific T cell response compared to either blockade alone. Tifcemalimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand Herpesvirus Entry Mediator (HVEM). Tifcemalimab is the first BTLA antibody to enter the clinical development stage. Here, we report the safety and efficacy of tifcemalimab as a single agent or in combination with toripalimab (anti-PD-1) in patients with relapsed/refractory (R/R) lymphoma after long term follow-up. Methods: Eligible patients with R/R lymphoma were enrolled in this open-label, multicenter phase 1 study (NCT04477772). Tifcemalimab was administered as a monotherapy at escalating doses of 1, 3 and 10 mg/kg intravenously Q3W, followed by 3 mg/kg and 200 mg monotherapy dose expansion until disease progression or intolerable toxicity. During combination dose escalation, patients received ascending doses of tifcemalimab (100mg and 200mg) plus toripalimab (240mg). Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, and efficacy. Results: By the cutoff date of July 19, 2023, a total of 71 patients were enrolled, including 25 in the monotherapy and 46 in the combination cohorts. The median follow-up time was 57 weeks. The median age was 38 (range 19-70) years with 50 (70%) male patients. The median prior line of therapy was 4 with 54 (76%) progressed upon prior anti-PD-1/L1 therapy. No DLT was observed in either monotherapy or combination dose escalation. Recommended phase 2 dose (RP2D) was determined to be 200 mg tifcemalimab as monotherapy or in combination with toripalimab. Sixty-seven (94%) patients experienced treatment emergent adverse events (TEAEs), 22 (31%) of whom experienced grade 3 or above TEAEs. The most common TEAEs were COVID-19 infection (30%), anemia (30%) and Infusion related reaction (27%). Four treatment-related adverse events led to the discontinuation of the study drug. Among 25 patients receiving monotherapy, 1 PR (follicular lymphoma) and 7 SD were observed with median progression-free survival (PFS) 2.1 months. Among 46 patients receiving combination therapy, 1 CR,16 PR (ORR 37.0%) and 20 SD (DCR 80.4%) were observed and estimated median PFS was 14.7 months. Thirty-four patients with Hodgkin's Lymphoma received RP2D of combination therapy and all of them had received previous chemotherapy and anti-PD-1 or anti-PD-L1 antibody, and 12 PR (ORR 35.3%) and 17 SD (DCR 85.3%) were observed with estimated median progression-free survival was 16.2 months. Conclusions: Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination regimen showed favorable safety and durable efficacy in lymphoma patients with heavily pretreatment, providing evidence for future investigation.

Total and treatment-related costs of care associated with in patients with metastatic renal cell carcinoma receiving targeted or immune therapy.

28 Background: Oral anticancer agents (OAA) and immunotherapy (IO) as initial treatments in metastatic renal cell carcinoma (mRCC) have yielded substantial improvements in disease control and survival but may increase costs. OAA monotherapy has decreased in recent years and use of IOs has increased dramatically, however, their impact on costs in patients with mRCC has not been examined at the population level. Methods: Retrospective cohort study of Medicare beneficiaries over age 65 diagnosed with mRCC from 2015 through 2019, who were enrolled in Medicare Part D for at least 1 year after diagnosis and received OAA or IO within a year of diagnosis. We summarized Medicare payments and out-of-pocket (OOP) responsibility in the year following diagnosis stratified by type of initial treatment and cost component (Treatment, Inpatient, and Outpatient). Dollar amounts were adjusted to 2019 using the Urban All Consumers Price Index. We used multivariate generalized linear models with a gamma distribution to assess the relationship between demographic and treatment variables and costs. All reported differences were significant with p &lt; 0.001. Results: The study sample included 6183 patients. Initial therapy was an OAA in 3630 patients (59%), IO in 2034 patients (33%), and combined OAA+IO in 519 patients (8%). Total mean Medicare payments were substantially higher in patients receiving combination therapy (OAA+IO $149,200) vs. monotherapy with IO ($104,800) or OAAs ($109,900). Direct treatment costs composed at least half of all costs for all patients, including those undergoing first line OAA (56%), IO (50%), or combination OAA+IO (69%) therapy. Costs increased over the study period, with metastatic diagnosis in 2019 vs. 2015 being associated with roughly 33% higher costs [aCRR1.33(1.26-1.40)]. Older age (≥ 81 vs age 66-70 [aCRR 0.74 (0.71-0.77)] and female sex [aCRR 0.93(0.90-0.95] were associated with lower total payments. Total OOP responsibility was higher for individuals who received IO ($18,500) compared to an OAA ($12,200). Those receiving OAA+IO had the highest OOP costs ($21,800). OAA+IO combination therapy was also associated with higher total Medicare payments compared to OAA [adjusted Cost Relative Ratio (aCRR) 1.36 (95% CI; 1.29-1.43)]. Conclusions: Direct costs of treatment are the primary drivers of costs in patients with mRCC initiating therapy during the first year of diagnosis, with half or more of total costs derived from treatment. OOP responsibility remained relatively steady from 2015 to 2019, while total costs to Medicare increased by a third. The recently passed Inflation Reduction Act may impact future total costs in patients with mRCC given the substantial contribution of direct treatment costs to overall costs in this population.

Characteristics of patients with non-specific aortoarteritis and arterial hypertension based on retrospective analysis

The aim was to study the medical history, laboratory and instrumental data, the trends of arterial hypertension (AH), risk factors for cardiovascular events, target organ damage (TOD), and the development of cardiovascular complications in patients with NSAA (Non-Specific Aortoarteritis).Materials and Methods. The study included 33 women with confirmed NSAA who had been treated at the 5th Cardiology Department of the E.I. Chazov National Medical Research Center of Cardiology since 2005. Complete blood count, biochemical blood analysis, urine analysis, the following instrumental examinations, such as, ECG, echocardiography, ultrasound of the brachial, femoral, aortic, and renal arteries, MRA or CT angiography with contrast, blood pressure measurement in the arms and legs were performed for all patients. Telephone interviews were conducted to assess some patient's condition over time.Results. The most common symptom (84% of patients) was AH, the average age of AH onset was 30 [19; 40] years and the AH average duration is 7,5 [2; 13] years. Nearly half of the patients (45%) had AH as the leading symptom that led them to perform the examination that helped to the diagnosis of NSAA. The average systolic and diastolic blood pressure values were 123±35 mmHg and 66±17 mmHg in the upper extremities, and 166±31 mmHg and 78±18 mmHg in the lower extremities, respectively. About half of patients (51%) had stage 3 AH, and almost all of them had type 3 according to E. Lupi-Herrera classification. The most common risk factors for cardiovascular events were dyslipidemia (82%), a family history of early cardiovascular events (51%), resting heart rate above 80 bpm (25%), and carbohydrate metabolism disorders (21%). When assessing cardiovascular risk, moderate risk of developing cardiovascular events was observed in 3 patients (10,7%), high risk in 16 patients (57,1%), and very high risk in 9 patients (32,1%). The most common TODs were nervous system damage (53%), including cerebrovascular ischemic events (14%) and left ventricular hypertrophy (42%). This group of patients was characterized by resistant hypertension, and combination with other risk factors for cardiovascular events, it leds to severe TOD and influenced survival rate. In terms of antihypertensive therapy, 61% of patients received combination therapy, with CCB, beta-blockers, and imidazoline receptor agonist being the most prescribed. Two fatal cases were identified in the long-term follow-up, and cardiovascular events, most frequently stroke, were the main complications observed. Additionally, AH progression and its uncontrolled course despite going through multiple drug therapy were characteristic.Conclusion: AH is often difficult to diagnostic in patients with NSAA, and it significantly contributes to the structure of complications and mortality in this patient cohort, progressively worsening over time. It is important to measure blood pressure in both arms and legs to detect elevated values early. The main goals of treatment are achieving NSAA remission and blood pressure control and preventing cardiovascular events.

Possibilities of combined PET/CT with 18F-FDG in evaluating the effectiveness of targeted therapy in patients with non-small cell lung cancer

Introduction. Early assessment of the effect of targeted therapy in patients with non-small cell lung cancer (NSCLC) and a mutation in the EGFR gene is important for the timely correction of antitumor therapy.Aim: To study the possibilities of combined positron emission and computed tomography with 18F-fluorodeoxyglucose (PET/ CT with 18F-FDG) using the RECIST 1.1 and PERCIST 1.0 criteria. In a comparative assessment of the effect of various targeted therapy options in patients with NSCLC and a mutation in the EGFR gene.Material and Methods. The study included 86 patients with stage II-IV NSCLC, including 56 patients with a mutation in the EGFR gene. Of these, 32 patients received targeted monotherapy with tyrosine kinase inhibitors (TKI) – gefitinib or erlotinib and 24 patients received combination therapy (TKI + bevacizumab). The control group consisted of 30 patients who received platinum-containing chemotherapy drugs in combination with bevacizumab. The effect of antitumor therapy was evaluated using the combined PET method/CT with 18F-FDG using RECIST 1.1 and PERCIST 1.0 criteria. The results of the study were compared before the start of treatment and after 4-6 weeks of treatment.Results. In the repeated study of PET/CT with 18F-FDG, a partial positive response to the treatment of both tumor foci and affected regional lymph nodes according to the metabolic criteria PERCIST 1.0. was observed 1.3–1.8 times more often than when using the anatomical criteria RECIST 1.1. (p = 0,049). The frequency of а positive response to treatment in patients receiving targeted monotherapy was quite comparable to that in patients in the control group (43.7 and 40.0%, respectively). Based on 18F-FDG repeat PET/CT and PERCIST 1.0 metabolic criteria in patients receiving combined targeted therapy, a partial positive effect of treatment (58.3%) was observed 1.4 times more often, and disease progression was 4 times less common than in the subgroup of targeted monotherapy and in the control group (p = 0,043).Conclusions. Possibilities of early assessment of the effect of antitumor therapy using PET/CT with 18F-FDG increase when using the metabolic criteria PERCIST 1.0 – more sensitive than the anatomical criteria RECIST 1.1. According to PET/CT with 18F-FDG in patients with NSCLC and a mutation in the EGFR gene, the effect of combined therapy of TKI in combination with bevacizumab significantly exceeds not only the result of targeted monotherapy, but also the effect of chemotherapeutic treatment of patients in the control group.

Monitoring Tekanan Darah Pada Pasien Diabetes Melitus Tipe Dengan Hipertensi Di Puskesmas Tlogosari Kulon Kota Semarang

Diabetes Mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia that occurs due to abnormalities in insulin secretion, insulin action, or both. DM is a risk factor for hypertension. Hypertension in DM increases the risk of complications so it is necessary to monitor whether blood pressure targets are achieved. This study aims to determine the achievement of blood pressure targets in type 2 DM patients with hypertension at the Tlogosari Kulon Health Center, Semarang City. This research is a descriptive observational study. Data collection uses purposive sampling technique. Data were obtained from medical records of type 2 DM patients with hypertension aged ≥ 45 years, who had blood pressure examination results on 2 consecutive visits in September 2022 – February 2023, use antihypertensives for at least 1 year. It was found 47 patients, consisting of 25 male patients and 22 female patients. A total of 26 patients were aged between 60-69 years. A total of 36 patients (76.59%) had taken antihypertensives for 1-5 years and 42 patients (89.40%) received single therapy, namely amlodipine. Only 1 patient received combination therapy of 2 drugs (amlodipine and candesartan). There were 14 patients who achieved the target blood pressure &lt;140/90 mmHg (29.78%).

Borderline Resectable Pancreatic Cancer: Impact on Neoadjuvant Response Post Integration of MRI Guided Adaptive Radiation Therapy

The optimal neoadjuvant therapy regimen for patients with borderline resectable pancreas cancer (BRPC) remains to be defined, with a recent ALLIANCE study reporting that chemotherapy alone prior to resection is an acceptable standard of care. However, pathologic differences in response between patients receiving chemotherapy alone and chemotherapy with radiation with stereotactic technique is not clear. In this study, we sought to compare differences in pathologic outcomes between patients undergoing surgery in 2018 compared with 2021 at our comprehensive cancer center, after the new data of chemotherapy alone had been reported and after our center integrated stereotactic MRI guided online adaptive radiotherapy (SMART). Newly diagnosed BRPC patients were included on this IRB approved study if they were treated on our institutional clinical pathway with initial chemotherapy (FOLFIRINOX or Gemcitabine based) followed by 5 fraction stereotactic body radiation therapy (SBRT) with the intention of primary tumor resection. After surgical resection, tumor response was classified by the Tumor Regression Grading (TRG) System of the College of American Pathology on a scale from 0 (complete response) to 3 (poor response). In 2018 when patients were treated on a conventional Linac, the median SBRT dose was 40.5 Gy compared with 46.1 Gy in 2021 after SMART integration. In 2018, 54 BRPC patients were treated and 52% were explored. Of those, 72% were resected with a 95% (19/20) rate of R0 resection. In 2021, 66 BRPC patients were treated and 45% were explored. Of those, 74% were resected with a 100% (22/22) rate of R0 resection. In 2018, pathological results showed that 55% (11/20) had lymphovascular invasion (LVI) and 90% (18/20) had perineural invasion (PNI) with a median tumor size of 2.5 cm. The average lymph node ratio in 2018 was 0.06 in 2018 and 0.05 in 2021. In 2021, pathological results showed that 36% (8/22) had LVI and 64% (14/22) had PNI with a median tumor size of 2.2 cm. In 2018, 43% of surgeries required portal vein (PV) resection compared with 27% in 2021. In 2018, of those patients who underwent surgery, 65% (13/20) received both chemotherapy and SBRT compared to 10% (2/20) with chemotherapy alone. In 2021, 73% (16/22) received chemotherapy and SBRT prior to surgery compared with 27% (6/22) who received chemotherapy only. Patients who received chemotherapy only (n = 8) had an average TRG of 2.1 compared to the patients receiving combination therapy (29) with an average TRG of 1.8. This data suggests that higher ablative dose delivery with SMART following systemic therapy may be associated with improved pathologic outcomes, with less LVI, PNI, portal vein resection and improved TRG scores. Further prospective study is needed to confirm improved pathologic outcomes with SMART and to optimize patient selection regarding which patients benefit the most from the combination of chemotherapy and SBRT.

Current Evidence for Combined Targeted Therapy for the Treatment of Inflammatory Bowel Disease.

Biologicals and small molecules have revolutionized the medical management of inflammatory bowel diseases (IBD), yet they are only effective in a proportion of patients, and their impact on changing the natural history of the disease is still debatable. Recently, the concept of combining targeted biologics and small-molecule therapies has been introduced to the treatment of IBD. Dual-targeted therapy (sequential and combined), which is the combination of two targeted therapies, might be a reasonable choice for patients to break through the therapeutic ceiling. A recent randomized clinical trial (VEGA) provided the first controlled evidence that the short-term combination of two biological agents may lead to superior disease control than either of the agents alone in patients with ulcerative colitis (UC) without jeopardizing safety. Multiple studies are underway in both Crohn's disease and UC. Additionally, real-world evidence is accumulating in IBD patients receiving combination therapies with concomitant IBD and extraintestinal manifestations or in patients with medically refractory IBD. Of note, the majority of these patients were exposed to multiple biological agents earlier and lost response to at least one of the agents in the combination. This review summarizes current knowledge regarding this attractive novel therapeutic option in IBD. Clearly, more controlled data are needed to evaluate optimal timing, efficacy, and mitigation of safety concerns.

Nivolumab in the treatment of thoracic cancer — new possibilities

Immune checkpoint inhibitors have significantly changed the treatment of patients with advanced non-small cell lung cancer in recent years. The value of nivolumab was initially assessed in patients previously treated with systemic therapy. The association of nivolumab with ipilimumab and the interaction of these antibodies on different immune checkpoints have proven effective in solid tumors (melanoma and renal cell carcinoma). The CheckMate-9LA study assessed the value of dual immunotherapy combined with platinum-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer. A clinical benefit – prolonged overall survival in patients receiving combination therapy – was documented. The results of the CheckMate743 trial for patients with pleural mesothelioma provide a basis for changing the current management algorithm for patients with this diagnosis. Patients diagnosed with mesothelioma of a non-epithelioid type particularly benefit from two-drug immunotherapy compared to chemotherapy. Maintaining the safety of treatment using immunotherapy targeting two immune checkpoints remains the challenge.

Serum metabolomics probes the molecular mechanism of action of acupuncture on metabolic pathways related to glucose metabolism in patients with polycystic ovary syndrome-related obesity.

Polycystic ovary syndrome (PCOS) is a common endocrine syndrome, and obesity is the most common clinical manifestation. Acupuncture is effective in treating PCOS, but the differences in the biological mechanisms of acupuncture therapy and Western medicine treatment have not been determined. Thus, the purpose of this study was to find glucose metabolism-related pathways in acupuncture treatment and differentiate them from Western medical treatment. Sixty patients with PCOS-related obesity were randomly distributed into three groups: patients receiving (1) acupuncture treatment alone, (2) conventional Western medicine treatment, and (3) acupuncture combined with Western medicine treatment. A targeted metabolomics approach was used to identify small molecules and metabolites related to glucose metabolism in the serum of each group, and ultra-high-performance liquid chromatography-tandem mass spectrometry was used to analyze different metabolic fractions. The results showed acupuncture treatment modulates the activity of citric and succinic acids in the tricarboxylic acid cycle, regulates glycolytic and gluconeogenesis pathways, and improves the levels of sex hormones and energy metabolism. The intervention effects on the metabolic pathways were different between patients receiving combination therapy and patients receiving acupuncture therapy alone, suggesting that the dominant modulatory effect of Western drugs may largely conceal the efficacy of acupuncture intervention.

SYST-05 BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS

Abstract Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just at the tumor but also outside the CNS. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with metastatic disease, represent a patient population that is on the rise and in need of targeted treatment approaches. Through this work we present a novel axis of immunosuppression in brain tumor patients and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study

Background & AimsCheckpoint inhibitors (CPI) account for increasing numbers of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI). MethodsPrescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading, and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPI-naive patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterisation and outcomes of ChILI. ResultsOut of 432 patients who received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 person-months (95% CI 8.2–15.8). Probability of ChILI was highest in combination therapy (32%) and no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres. Although Common Terminology Criteria for Adverse Events classified 20 patients (20.2%) to have ‘life-threatening’ grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases. ConclusionsThe real-world risk of ChILI is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after 4.5 months. As Common Terminology Criteria for Adverse Events overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care. Impact and implicationsUsing prescription event monitoring over a 10-year period, the incidence rate of checkpoint inhibitor induced liver injury (ChILI) based on established case definitions for drug-induced liver injury (DILI) is 11.5 per 1,000 person-months. Formal causality assessment identified an alternative cause in 19% of patients with suspected ChILI highlighting the importance of systematic evaluation by clinicians to minimise unnecessary immunosuppression. Intensity of monitoring in patients receiving combination therapy regime after 4.5 months of therapy can be reduced as the risk of new onset ChILI beyond this point is minimal. Current Common Terminology Criteria for Adverse Events (CTCAE) grading overestimates clinical severity of ChILI and hence contributes to avoidable hospitalisation.