Achieve Disease Control Research Articles

FRI300 Prolactinoma And Pregnancy: A Systematic Review And Meta-analysis

Abstract Disclosure: D.B. Bandeira: None. L.S. Alves: None. A. Glezer: None. C.L. Boguszewski: None. V.S. Nunes-Nogueira: None. Introduction: Prolactinomas are the most common pituitary tumors, being an important cause of irregular menses and infertility. However, fertility can be restored, making pregnancy possible, especially for women who have achieved disease control, mainly on dopamine agonist (DA) treatment. Although literature data demonstrate safety in maternal and fetal outcomes, the evidence has not been systematically synthesized. Purpose: To perform a systematic review evaluating disease control and fetal and maternal outcomes in pregnancy of women with prolactinoma. Methods: We conducted a systematic review according to the Joanna Briggs Institute methodology for systematic reviews of etiology and risk. We included observational studies that evaluated pregnant women with prolactinoma. The outcomes of interest were spontaneous miscarriage, preterm birth, worsening of preexisting diabetes/development of gestational diabetes, tumor growth during pregnancy, headache, visual impairment, perinatal mortality, low birth weight, congenital malformations. Embase, Medline, LILACS, and CENTRAL were our source databases. To perform proportional meta-analyses, we used Stata Statistical Software 17. Results: Fifty-one studies were included encompassing a total of 2513 pregnancies in 1903 women with prolactinoma. The overall frequency of the pregnant women on DA at conception was 97% (from 49 studies of 2493 pregnancies; 95% confidence interval (CI), 93–99%); there were 9% of spontaneous miscarriage (from 38 studies of 2073 pregnancies; 95% CI, 7–12%), 3% of prematurity (from 38 studies of 1584 pregnancies; 95% CI, 3–2%), 9% of symptomatic tumor growth during pregnancy (from 38 studies of 1584 pregnancies; 95% CI, 5–15%), 4% of visual impairment (from 33 studies of 1480 pregnancies; 95% CI, 2–7%), 6% of headache (from 31 studies of 1385 pregnancies; 95% CI, 3–11%) and 4% of worsening of preexisting diabetes/development of gestational diabetes (from 9 studies of 666 pregnancies; 95% CI, 3–7%). The overall frequency of congenital malformations was 2% (from 23 studies of 1212 newborns; 95% CI, 1–4%), 2% of perinatal mortality (from 18 studies of 1123 newborns; 95% CI, 1–3%) and 6% of low birth weight (from 17 studies of 843 newborns; 95% CI, 3–9%). Conclusion: Pregnancy in women with prolactinoma is frequently safe in relation to fetal and maternal outcomes, presenting low frequency of spontaneous miscarriage, prematurity, tumor growth, visual impairment, headache, congenital malformations, perinatal mortality and of low birth weight. Presentation: Friday, June 16, 2023

Reduced Asthma Exacerbations in Adult Patients Treated With Bronchial Thermoplasty.

Bronchial thermoplasty (BT) has been shown to be effective in randomized controlled trials of patients with severe asthma who failed to achieve disease control with high-dose inhaled corticosteroids combined with bronchodilators. However, the effectiveness of BT in real-world clinical settings, especially among the Asian population, has not been determined. To evaluate the effectiveness of BT using a nationwide database. Using the inpatient and outpatient data from the Japanese Diagnosis Procedure Combination database, we applied a self-controlled case series design to evaluate changes in the composite outcome of hospital admissions and emergency department visits, as well as systemic corticosteroid dose, between 1 year before and after BT. We also conducted subgroup analyses based on patients' profiles. Among the 561 patients with asthma who underwent BT treatment between September 2014 and March 2020, 102 patients with at least 1 outcome were analyzed. Bronchial thermoplasty was significantly associated with an improvement in the composite outcome of hospital admission and emergency department visits (incidence rate ratio 0.53; 95% CI 0.44-0.64). Systemic corticosteroid use was reduced after BT sessions (1931.5 mg [1,341.2-3,725.3 mg] to 641.3 mg [134.2-1,691.1 mg] per person-year; P < .001). Although all groups showed a significant improvement in the composite outcome in the subgroup analyses, BT tended to be less effective among people older than 65 years and those with higher body mass index (>25 kg/m2). The present study using real-world data suggests that BT may improve asthma control; however, the effectiveness of BT can vary depending on patient baseline profiles.

The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

Response to programmed cell death protein 1 antibody in patients with Epstein–Barr virus-associated intrahepatic cholangiocarcinoma

AimEpstein–Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3+ and CD8+ T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC. MethodsPatients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured. ResultsA total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months. ConclusionsThis study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody.

Osimertinib early dose reduction as a risk to brain metastasis control in EGFR-mutant non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) mutation is a risk factor associated with brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the impact of osimertinib early dose reduction on BM worsening. We retrospectively analyzed EGFR-mutant NSCLC patients treated with osimertinib as first-line treatment between August 2018 and October 2021. To evaluate the impact of osimertinib early dose reduction, we performed a landmark analysis of patients who achieved disease control at 4 months. Patients were divided into two groups according to whether the osimertinib dose was reduced or not, within 4 months after the start of treatment. We evaluated the time to BMs onset or progression, progression-free survival, and overall survival. In total, 62 NSCLC patients with EGFR mutations were analyzed. Thirteen patients experienced early dose reduction of osimertinib treatment. Seven patients received osimertinib 40 mg daily, and six received 80 mg every other day. The most common reason for dose reduction was gastrointestinal toxicity (n = 4), followed by skin rashes (n = 3). The time to BMs onset or progression was significantly shorter in patients who experienced early dose reduction than in those who continued regular treatment (Hazard ratio 4.47, 95% confidence interval, 1.52-13.11). The 1-year cumulative incidence of BM onset or progression was 23.1% in the reduced-dose group and 5.0% in the standard dose group. The risk of worsening BMs with early dose reduction of osimertinib treatment was higher in patients who had BMs before treatment and in younger patients. Early dose reduction of osimertinib was a risk factor for the worsening of BMs. A higher risk was associated with younger patients and those presenting BMs before treatment.

Correlation of Baseline Tumor Burden with Clinical Outcome in Melanoma Patients Treated with Ipilimumab

Introduction: Tumor burden is a frequently mentioned parameter; however, a commonly accepted definition is still lacking. Methods: In this double-center prospective and retrospective study, 76 patients with unresectable stage III or stage IV melanoma treated with ipilimumab were included. We defined the baseline tumor burden (BTB) as the global sum of all metastases’ longest diameters before treatment started and correlated the calculated BTB with disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and with the baseline levels of LDH, S100B, and sULPB2. Results: BTB correlated significantly with DCR (p = 0.009), PFS (p = 0.002), OS (p = 0.032), and the occurrence of NRAS mutation (p = 0.006). BTB was also correlated to baseline serum levels of LDH (p = 0.011), S100B (p = 0.027), and SULBP (p < 0.0001). Multivariate analysis revealed that BPB and LDH were independently correlated with PFS and OS. With increasing BTB, disease control was less likely; no patient with a BTB >200 mm achieved disease control. For patients with brain metastasis, no correlation of BTB with DCR (p = 0.251), PFS (p = 0.059), or OS (p = 0.981) was observed. Conclusion: Calculated BTB is an independent prognostic factor for patients with metastatic melanoma treated with ipilimumab. Using calculated BTB as a definition of tumor burden may help increase comparability of outcome of therapies in future studies.

Bullous Pemphigus: A Comprehensive Review of a Complex Autoimmune Disease of the Skin and Mucous Membranes

Pemphigus bullosus, also known as pemphigus vulgaris, is a rare and potentially serious autoimmune disease affecting the skin and mucous membranes, characterized by the formation of intraepidermal blisters due to the loss of cellular cohesion at desmosomal junctions. In this article, we present a comprehensive review of the entity, covering its epidemiology, etiopathogenesis, clinical manifestations, diagnosis and therapeutic options. We highlight the complexity and diagnostic challenges associated with bullous pemphigus, emphasizing the importance of careful clinicopathologic and immunofluorescent correlation for its proper identification. We also discuss in detail the multidisciplinary therapeutic approach required to achieve disease control, emphasizing the use of systemic immunosuppressants and biological therapies. In addition, we highlight the relevance of local therapy and care management, along with the need for close medical follow-up to assess response to treatment and minimize adverse effects. Finally, we highlight the importance of continued research in this complex clinical entity, in order to improve the understanding of its immunopathological mechanisms and to develop more specific and personalized therapies. In conclusion, this article provides a comprehensive and updated view of bullous pemphigus, with the aim of improving its clinical management and promoting a more efficient and effective therapeutic approach.

Evaluation of Dupilumab in Patients With Bullous Pemphigoid

Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study. To assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes. A retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded. The primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed. Among 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02). In this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.

Severe acute respiratory syndrome coronavirus 2 infection in patients with autoimmune bullous diseases in China.

Patients with autoimmune bullous diseases (AIBDs) are considered to be immunocompromised and, consequently, they may be more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and have poorer outcomes. However, the risk and repercussions of SARS-CoV-2 infection in patients with AIBDs have not been fully understood. Therefore, we aimed to investigate the risk factors of SARS-CoV-2 infection and the impact of SARS-CoV-2 on patients with AIBDs. From December 2022 to January 2023, all patients with AIBDs who visited our clinic were enrolled in this study. Meanwhile, web-based questionnaires and telesurveys were used as supplements. Information about patients' demographics, comorbidities, SARS-CoV-2 infection, and vaccination, as well as AIBD status and treatments were collected and analyzed. The diagnosis of SARS-CoV-2 infection was based on a positive polymerase chain reaction test, and/or an antigen test, or the presence of typical symptoms in conjunction with an epidemiological history. Finally, 95 patients with AIBDs were enrolled, including 47 cases of pemphigus and 48 cases of pemphigoid cases, and 73 had symptoms consistent with coronavirus disease 2019. Common symptoms after SARS-CoV-2 infection were fever (80.8%), fatigue (75.0%), cough (71.2%), muscle/joint pain (49.3%), and sore throat (45.2%). No significant differences were found between SARS-CoV-2-infected and asymptomatic patients. Patients who had hypertension (p = 0.034), hyperlipidemia (p = 0.017), or more than two comorbidities (p = 0.011) were more likely to develop pneumonia after infection. Patients with pemphigus who did not achieve disease control (p = 0.045) or had an oral corticosteroid dose ≥15 mg/day (p = 0.024) and patients with pemphigoid with a disease duration ≥2 years (p = 0.037) were more prone to AIBDs aggravation. In conclusion, patients with AIBDs are generally susceptible to SARS-CoV-2 infection. Individuals with newly diagnosed AIBDs, uncontrolled disease, and a higher corticosteroid dose are more susceptible to disease exacerbation.

Organ sparing treatment for penile cancer using a 3D-printed high-dose-rate brachytherapy applicator

PURPOSEWe present a case study of the treatment of localized squamous cell carcinoma on the glans penis with a custom-fabricated high-dose-rate (HDR) brachytherapy applicator. METHODS AND MATERIALSA cylindrically shaped applicator was fabricated with eight embedded channels suitable for standard plastic brachytherapy catheters. An additional custom silicone bolus/sleeve was designed to be used with the 3D-printed applicator to provide an additional offset from the source to skin to reduce the surface dose and for patient comfort. RESULTSThe patient (recurrent cT1a penile cancer) underwent CT simulation, and the brachytherapy plan was created with a nominal prescription dose of 40 Gy in 10 fractions given bidaily to the surface, and 35 Gy at 5 mm depth. Dose coverage to the clinical target volume was 94% (D90). Most fractions were treated with only 5-10 min of setup time. Follow up visits up to 1 year showed no evidence of disease with no significant changes in urinary and sexual function and limited cosmetic detriment to the patient. CONCLUSIONSPatient-specific organ-sparing HDR plesiotherapy using 3D printing technology can provide reliable and reproducible patient setup and may be effective in achieving disease control for superficial penile cancer, although preserving patient quality of life.

Genetic markers of children asthma: predisposition to disease course variants.

Asthma is a heterogeneous and often difficult to treat condition that results in a disproportionate cost to healthcare systems. Children with severe asthma are at increased risk for adverse outcomes including medication-related side effects, life-threatening exacerbations, and impaired quality of life. An important therapeutic focus is to achieve disease control, which is supposed to involve a personalized approach to treatment of asthma of any severity. Asthma is a multifactorial disease with a significant genetic determinant, however, the inheritance of asthma has not been fully elucidated. Polymorphic genes of inflammatory mediators, including cytokines, play an important role in developing various disease forms. In the current study, large-scale original data on the prevalence of cytokine gene genotypes (IL2, IL4, IL5, IL6, IL10, IL12, IL13, IL17A, IL31, IL33, IFNG, TNFA) among Russian children with asthma in Krasnoyarsk region have been obtained. Genotyping was carried out using real-time PCR. We identified markers predisposing to the development of different variants of the course of childhood asthma: the CT genotype and T allele of IL4 rs2243250 are associated with asthma (p < 0.05), especially in mild asthma and in controlled asthma. The TT genotype and allele T of IL13 rs1800925 are associated with severe and uncontrolled asthma (p < 0.05). The AA genotype of IL17A rs2275913, the TT genotype of IFNG rs2069705 and allelic A variants of TNFA rs1800629 are associated with mild asthma, and the TT genotype of IFNG rs2069705 is additionally associated with controlled asthma. The results obtained will supplement information on the prevalence of polymorphic variants of the cytokine genes in the Russian population and in asthma patients with different disease courses, which is likely to be used in order to shape a plan for Public Health Authority to prevent the development of severe uncontrolled asthma and to optimize personalized therapy.

Sonidegib in Locally Advanced Basal Cell Carcinoma: A Monocentric Retrospective Experience and a Review of Published Real-Life Data.

Basal cell carcinoma (BCC) represents the most common skin cancer and locally advanced BCC (laBCC) refers to an aggressive, large, infiltrative BCC that cannot be treated by surgery or radiotherapy. Sonidegib is a Hedghehog inhibitor (HHi) indicated for laBCC. This is a monocentric retrospective real-life study of laBCCs receiving Sonidegib treatment. Although Sonidegib is widely used, since its approval by Food and Drug Administration in 2015, only a limited number of real-life experiences have been reported. Eleven patients, including four patients diagnosed with Basal Cell Naevus syndrome, received treatment with Sonidegib for laBCCs. Seven (63.6%) patients experienced adverse events (AEs) but only three had to discontinue treatment and were therefore excluded from the following results. Four patients (50%) achieved complete clinical remission (CR); in all cases the remission was confirmed by biopsy. Partial response (PR) was found in three patients out of eight (37.5%). One patient out of eight (12.5%) showed a steady disease (SD). None of the patients showed signs of progression during treatment with HHi. Sonidegib showed the same efficacy in treating laBCCs as already seen in trials. All four patients suffering from Basal Cell Naevus syndrome achieved disease control by being treated with Sonidegib. Consequently, we strongly advise the joint management of laBCCs through a multidisciplinary team whenever feasible.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Semaglutide versus tirzepatide for people with type 2 diabetes: cost of glycemic control in Austria, the Netherlands, Lithuania, and the United Arab Emirates

Objectives The glucagon-like peptide-1 agonist semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide have proven to significantly reduce glucose levels in people with type 2 diabetes. However, the costs needed to achieve a sustained decrease in HbA1c level and disease control with semaglutide and tirzepatide, respectively, are unclear. Therefore, this study aimed to compare the cost of treatment with semaglutide with the cost of treatment with tirzepatide for type 2 diabetes in Austria, the Netherlands, Lithuania, and the United Arab Emirates in order to determine their respective value for money. Methods The primary outcome of this analysis was the cost in euros needed to achieve disease control in one person with type 2 diabetes based on the composite endpoint of HbA1c <7%, ≥5% weight loss, and no hypoglycemic events. In addition, analyses regarding the cost needed to reach relevant HbA1c endpoints were performed. Clinical data were obtained from the SURPASS 2 trial, registered at clinicaltrials.gov (NCT03987919), and drug cost was based on wholesale acquisition cost or pharmacy purchase prices from public domains obtained in Q1 of 2023. Results The cost needed to achieve disease control in one person with type 2 diabetes (HbA1c <7%, ≥5% weight loss, and no hypoglycemic events) was up to three times lower using semaglutide compared with all three doses of tirzepatide in most markets. In the HbA1c analyses, semaglutide was also found to be the least expensive treatment option. Conclusion Semaglutide provides better value for money than tirzepatide for HbA1c-lowering endpoints.

Economic Burden and Quality of Life of Patients With Moderate to Severe Atopic Dermatitis in a Tertiary Care Hospital in Helsinki, Finland: A Survey-Based Study.

We investigated medical costs and quality of life (QOL) in 167 patients with moderate to severe atopic dermatitis (AD) at a tertiary health care hospital in Helsinki, Finland. In the studied cohort, AD caused a substantial economic burden to the patients and health care system. Most patients with AD in Finland can achieve disease control with topical treatments, but it is important to efficiently manage the patients who require additional supportive measures and specialist consultations, which may be challenging in the primary health care system due to the relapsing and remitting nature of the disease.

Hopf Bifurcation Analysis and Optimal Control of an Infectious Disease with Awareness Campaign and Treatment

Infectious diseases continue to be a significant threat to human health and civilization, and finding effective methods to combat them is crucial. In this paper, we investigate the impact of awareness campaigns and optimal control techniques on infectious diseases without proper vaccines. Specifically, we develop an SIRS-type mathematical model that incorporates awareness campaigns through media and treatment for disease transmission dynamics and control. The model displays two equilibria, a disease-free equilibrium and an endemic equilibrium, and exhibits Hopf bifurcation when the bifurcation parameter exceeds its critical value, causing a switch in the stability of the system. We also propose an optimal control problem that minimizes the cost of control measures while achieving a desired level of disease control. By applying the minimum principle to the optimal control problem, we obtain analytical and numerical results that show how the infection rate of the disease affects the stability of the system and how awareness campaigns and treatment can maintain the stability of the system. This study highlights the importance of awareness campaigns in controlling infectious diseases and demonstrates the effectiveness of optimal control theory in achieving disease control with minimal cost.

Improving the Accuracy of Biologic Drug Survival Data: The Increasing Prevalence of Off-Label Dosing Must Be Considered when Reporting Drug Effectiveness and Safety

Improving the Accuracy of Biologic Drug Survival Data: The Increasing Prevalence of Off-Label Dosing Must Be Considered when Reporting Drug Effectiveness and Safety

Prognostic role of TP53 variants in the phase III study of FOLFIRI/cetuximab versus FOLFIRI/cetuximab followed by cetuximab (Cet) alone in first-line therapy of patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) (ERMES study).

3544 Background: The ERMES study explored the optimal intensity of anti-EGFR-based first line therapy for RAS/BRAF wt mCRC once achieved disease control. Although the study did not demonstrate non-inferiority of maintenance with Cet alone versus standard treatment, preliminary results suggested that a strategy of de-escalation treatment with only Cet might be effective in selected patients. Conflicting results have been previously reported for the predictive and prognostic role of TP53 variants in mCRC patients receiving anti-EGFR monoclonal antibody therapy. Here we describe the role of TP53 mutations within the ERMES study. Methods: Patients with untreated RAS/BRAF wt mCRC were randomly assigned (1:1) to receive either FOLFIRI/Cet until PD/toxicity (arm A) or FOLFIRI/Cet for 8 cycles followed by Cet alone (arm B). Tumor tissue samples were tested using the Oncomine Solid Tumor DNA kit covering hot spot mutations in 22 genes, including KRAS, NRAS, BRAF and TP53. Variant calling was performed using the Variant Caller Ion Torrent suite 5.16 software. The prognostic value of TP53 variants was assessed in the intention-to-treat (ITT) patients’ population with available sequencing data. Results: Tumor tissue specimens were available for 418/593 (70.5%) patients of the ITT population. Testing failed in 29 cases, whereas KRAS/NRAS/BRAF V600E variants were found in 36/389 (9.2%) patients, who were enrolled on the basis of local testing. Progression free survival (PFS) data were not available for 4 cases. Therefore, the final population in analysis was 349 cases. TP53 variants were detected in 165/349 (47.3%) patients, of which 86/165 (52.1%) in arm A and 79/165 (47.9%) in arm B. The median PFS (mPFS) of TP53 wild type patients in the overall population was 9.4 months versus 10.4 months in the TP53 mutant subgroup (HR 0.8439; 95%CI, 0.673-1.058; p = 0.142). In arm A, the mPFS of TP53 wild type patients was 10.8 months versus 10.7 months in TP53 mutant patients, with an HR 1.053 (95%CI, 0.7582-1.462; p = 0.76). The mPFS of TP53 wild type patients in arm B was 8.3 months versus 10.2 months in the TP53 mutant cohort, with an HR 0.7 (95%CI, 0.5087-0.9657; p = 0.0298). No significant difference was observed for the overall response rate (ORR) in both arms between TP53 mutant and wild type patients. Conclusions: These preliminary data suggest a possible prognostic role of TP53 variants in RAS/BRAF wild type mCRC patients receiving first line FOLFIRI/cetuximab followed by Cet alone. Comprehensive genomic profiling is ongoing to identify genomic signatures associated with sensitivity to Cet.

LUNG-IST-127: A pilot phase II study of maintenance cabozantinib plus pembrolizumab for patients with metastatic squamous non-small cell lung cancer (sqNSCLC) with disease control following induction therapy.

TPS9151 Background: First-line combination chemotherapy with pembrolizumab followed by maintenance pembrolizumab is the standard of care treatment for patients with metastatic sqNSCLC. This was established by the phase III KEYNOTE-407 trial, which demonstrated a median progression-free survival (PFS) of 6.4 months in the experimental arm. Despite these advances, there remains a need to continue to improve upon survival outcomes for these patients. Cabozantinib is a small-molecule inhibitor of multiple tyrosine kinsases including MET, VEGFRs, AXL, RET, and ROS, which are receptors involved in tumor cell-proliferation, angiogenesis, and immune cell regulation. Preclinical studies have demonstrated the ability of cabozantinib to modulate both adaptive and innate immune cells and to exhibit synergistic activity when used in combination with immune checkpoint inhibitors. We hypothesize that cabozantinib in combination with pembrolizumab in the maintenance phase of first-line treatment of metastatic sqNSCLC will prolong median PFS with a tolerable toxicity profile. Methods: LUNG-IST 127 is a pilot phase II, single-arm clinical trial of maintenance cabozantinib in combination with pembrolizumab for patients with metastatic sqNSCLC who achieved disease control following standard 1L induction therapy with chemotherapy and pembrolizumab. Thirty-six patients will be enrolled at 2 US sites to receive first-line induction therapy with carboplatin, nab-paclitaxel or paclitaxel, and pembrolizumab for four cycles. After induction therapy, those who have achieved disease control based on re-staging imaging will continue onto maintenance therapy with cabozantinib 40mg PO daily in combination with pembrolizumab 200mg IV every 3 weeks. The primary endpoint is PFS estimated by Kaplan-Meier methods with associated 95% confidence intervals. Based on an exploratory power analysis using an elevated one-sided alpha level of 0.40, we hypothesize that the proposed therapy will prolong median PFS from 6.4 to 9 months. Key secondary endpoints include overall survival (OS), overall response rate (ORR), and characterizing the safety and tolerability of cabozantinib in combination with pembrolizumab. Quality of life will also be measured with the EORTC QLQ-C30. Correlative endpoints include characterizing cfDNA from biofluids and assessing the change in circulating immune cells in different phases of treatment in association with PFS and OS. This trial would be the first to address whether there is clinical benefit in utilizing combination cabozantinib and pembrolizumab in the maintenance phase of treatment in metastatic sqNSCLC. Clinical trial information: NCT05613413 .

Retreatment with EGFR inhibitor in non-small cell lung cancer patients previously exposed to EGFR-TKI: A systematic review and meta-analysis.

e21159 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard therapy for EGFR-mutated non-small cell lung cancer (NSCLC) patients. Unfortunately, patients eventually develop resistance to EGFR-TKI and disease progression. Re-exposure after a drug-free interval may be an alternative to overcome tumor resistance. We performed a systematic review and meta-analysis to assess EGFR-TKI retreatment’s efficacy in advanced NSCLC. Methods: We systematically searched PubMed, Embase, and Cochrane databases for clinical trials and observational cohort studies evaluating EGFR-TKI retreatment in advanced NSCLC patients. We aimed to assess the objective response rate (ORR), disease control rate (DCR), and survival outcomes. Subgroup analyses were performed according to the type of EGFRmutation and the TKI drug used in retreatment. We further stratified studies to assess the efficacy of rechallenging with the same drug used initially or a different one. Heterogeneity was assessed using the Cochran Q test, and I2 statistics and random effects models were fitted. Results: We included 16 studies (7 prospective clinical trials, and 9 retrospective cohorts) with 806 patients. Most of them had adenocarcinoma (70.8%), were females (58.1%), and were non-smokers (74.5%). The most frequently TKI given as the initial treatment was gefitinib (58.1%), whereas in the rechallenge it was erlotinib (36.6%) followed by gefitinib (31.6%). In a pooled analysis of patients who were retreated with TKI, the median PFS was 4.1 months (95%CI 3.0 - 4.4), and OS was 12.6 months (95%CI 10.2 - 12.6). ORR was 16% (95%CI 10 - 22%) and DCR was documented in 63% (95%CI 0.54 - 0.72%). Patients harboring a sensitive EGFR mutation had a significantly higher DCR, compared to patients with EGFRT790M mutation, and those with unknown mutational status, (DCR: 70%, 62%, and 48%, respectively, p = 0.02). Patients rechallenged with gefitinib, erlotinib, or afatinib had a similar DCR of 60%, while patients re-exposed to osimertinib had a greater DCR of 70% (95%CI 59 - 80%), (p &lt; 0.01). Regarding ORR, no significant difference was observed amongst the groups defined by the type of EGFR mutation (p = 0.74) or type of TKI used (p = 0.05). Rechallenge using the same versus a different TKI resulted in similar ORR and DCR. In a subgroup analysis of 102 patients who had disease control with the first TKI, 62% (95%CI 45 – 79%) achieved disease control with TKI rechallenge. Conclusions: Our meta-analysis suggests that a subgroup of advanced EGFR-mutated NSCLC patients who failed TKI treatment benefit from rechallenge with an EGFR-TKI after a TKI-free interval. Re-exposure with either the same or a different TKI was shown to be equally effective. Patients treated with osimertinib and those with EGFR-sensitive mutations have better responses to the treatment.