Long-term Clinical Benefit Research Articles

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial

S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Adjuvant therapy in biliary tract cancers: oral fluoropyrimidine as a beginning

Biliary tract cancer is a group of malignant tumours, mostly adenocarcinoma, arising from different sites of the biliary tract with diverse aetiology, molecular profiling, TNM classification, and surgical procedures and outcomes of resectable diseases. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Radical surgical resection remains the only curative treatment, but postoperative relapse is common. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Developing effective adjuvant therapy is mandatory. However, two modern observation-controlled phase 3 trials, the BCAT trial 2 Ebata T Hirano S Konishi M et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018; 105: 192-202 Crossref PubMed Scopus (192) Google Scholar and the PRODIGE 12-ACCORD 18 trial, 3 Edeline J Benabdelghani M Bertaut A et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019; 37: 658-667 Crossref PubMed Scopus (230) Google Scholar did not show the benefit of adjuvant gemcitabine-based chemotherapy in resected biliary tract cancers. BILCAP 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar was the first phase 3 study to support the role of adjuvant chemotherapy, with oral capecitabine, for resected biliary tract cancers. 5 Shroff RT Kennedy EB Bachini M et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019; 37: 1015-1027 Crossref PubMed Scopus (198) Google Scholar , 6 Yoo C Jeong H Kim KP et al. Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): a multicenter, open-label, randomized, phase 2 study (STAMP). Proc Am Soc Clin Oncol. 2022; 404019 Google Scholar , 7 Stein A Arnold D Bridgewater J et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015; 15: 564 Crossref PubMed Google Scholar The recommendation mainly relied on a significant improvement in overall survival by the prespecified sensitivity analysis (hazard ratio [HR]=0·71, 95% CI 0·55–0·92) but not on overall survival (ie, the primary endpoint; HR=0·81, 95% CI 0·63–1·04) in the primary, intention-to-treat analysis, 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar and is thus debatable. The adjusted HR for overall survival increased to 0·84 (95% Cl 0·67–1·06) and the HR for recurrence-free survival was 0·81 (95% Cl 0·65–1·01) in the extension report, 8 Bridgewater J Fletcher P Palmer DH et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. 2022; 40: 2048-2057 Crossref PubMed Scopus (11) Google Scholar which further weakened the recommendation. 9 Edeline J Malka D Capecitabine: still a standard option in the adjuvant setting of biliary tract cancer?. J Clin Oncol. 2022; 40: 3667-3668 Crossref PubMed Scopus (1) Google Scholar Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trialAlthough long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. Full-Text PDF

Patient Selection and Clinical Indication for Chronic Total Occlusion Revascularization-A Workflow Focusing on Non-Invasive Cardiac Imaging.

Percutaneous coronary intervention of chronic total occlusion (CTO PCI) is a challenging procedure with high complication rates and, as not yet fully understood long-term clinical benefits. Ischemic symptom relief in patients with high ischemic burden is to date the only established clinical indication to undergo CTO PCI, supported by randomized controlled trials. In this context, current guidelines suggest attempting CTO PCI only in non-invasively assessed viable CTO correspondent myocardial territories, with large ischemic areas. Hence, besides a comprehensive coronary angiography lesion evaluation, the information derived from non-invasive cardiac imaging techniques is crucial to selecting candidates who may benefit from the revascularization of the occluded vessel. Currently, there are no clear recommendations for a non-invasive myocardial evaluation or choice of imaging modality pre-CTO PCI. Therefore, selecting among available options is left to the physician's discretion. As CTO PCI is strongly recommended to be carried out explicitly in experienced centers, full access to non-invasive imaging for risk-benefit assessment as well as a systematic institutional evaluation process has to be encouraged. In this framework, we opted to review the current myocardial imaging tools and their use for indicating a CTO PCI. Furthermore, based on our experience, we propose a cost-effective systematic approach for myocardial assessment to help guide clinical decision-making for patients presenting with chronic total occlusions.

Characterization of a Novel Capsid Assembly Modulator for the Treatment of Chronic Hepatitis B Virus Infection.

The standard of care for the treatment of chronic hepatitis B (CHB) is typically lifelong treatment with nucleos(t)ide analogs (NAs), which suppress viral replication and provide long-term clinical benefits. However, infectious virus can still be detected in patients who are virally suppressed on NA therapy, which may contribute to the failure of these agents to cure most CHB patients. Accordingly, new antiviral treatment options are being developed to enhance the suppression of hepatitis B virus (HBV) replication in combination with NAs ("antiviral intensification"). Here, we describe GS-SBA-1, a capsid assembly modulator (CAM) belonging to class CAM-E, that demonstrates potent inhibition of extracellular HBV DNA in vitro (EC50 [50% effective concentration] = 19 nM) in HBV-infected primary human hepatocytes (PHHs) as well as in vivo in an HBV-infected immunodeficient mouse model. GS-SBA-1 has comparable activities across HBV genotypes and nucleos(t)ide-resistant mutants in HBV-infected PHHs. In addition, GS-SBA-1 demonstrated in vitro additivity in combination with tenofovir alafenamide (TAF). The administration of GS-SBA-1 to PHHs at the time of infection prevents covalently closed circular DNA (cccDNA) formation and, hence, decreases HBV RNA and antigen levels (EC50 = 80 to 200 nM). Furthermore, GS-SBA-1 prevents the production of extracellular HBV RNA-containing viral particles in vitro. Collectively, these data demonstrate that GS-SBA-1 is a potent CAM that has the potential to enhance viral suppression in combination with an NA.

Real-World Pain Relief Outcomes Using an Interspinous Spacer for Treatment of Lumbar Spinal Stenosis

In patients with Lumbar Spinal Stenosis (LSS), long-term clinical benefit can be achieved using Indirect Decompression Systems (IDS) or lnterspinous Spacers (ISS) as demonstrated by sustained pain relief, improved quality of life, and medication reduction for up to 5-years post-implant (Nunley PD, et al. 2017; Nunley PD, et al. 2018). In addition, in patients implanted with an ISS out to 12-months post-operation, effective leg pain responder rate and pain severity (75% and 60%, respectively) have been demonstrated (Tekmyster G, et al.

HTA227 A Cross-Stakeholder Approach to Support the Acceptance of Non-Os Endpoints in Reimbursement Decision Making

Use of non-overall survival (OS) endpoints in HTA assessments is limited by the difficulty in reliably proving long-term clinical and economic benefits. Using early breast cancer (EBC; stages 1 and 2) and multiple myeloma (MM; all stages) as examples, this research aims to identify the specific actions that must be taken to ensure that non-OS endpoints are fit-for-purpose for use in reimbursement decisions.

49P Exploiting multi-omic integrated data from DC-vaccinated melanoma patients for the generation of an advanced adoptive T cell therapy

Dendritic Cells (DCs) account for the best adaptive immune stimulators promoting their usage as advanced therapy medicinal products (ATMP). Despite the well tolerated profile and the ability to induce anti-tumor immunity, DC vaccine has nowadays failed to translate into prolonged long-term clinical benefit, requiring an update of its therapeutic application.

Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes

Despite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) in type 1 diabetes using high-resolution single-cell multiomics and flow cytometry on longitudinally-collected peripheral blood samples. Our results confirm that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+ regulatory T cells and CD56bright NK cells, and show that the treatment reduces the frequency of IL-21-producing CD4+ T cells and of two innate-like mucosal-associated invariant T and Vγ9Vδ2 CD8+ T cell subsets. The cellular changes induced by iLD-IL-2 associate with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. These findings warrant investigations into the potential longer-term clinical benefits of iLD-IL-2 in immunotherapy.

Impact of treatment compliance in chronic hepatitis B

The incidence rate of chronic hepatitis B remains high in China. Antiviral therapy can significantly reduce the risk of progressive liver disease and hepatocellular carcinoma in patients with chronic hepatitis B. However, all current antiviral treatments can only inhibit HBV replication and not completely eliminate the hepatitis B virus, so antiviral therapy for chronic hepatitis B is probably a long-term or even lifelong treatment. Antiviral therapy compliance is essential for achieving long-term clinical benefits and preventing nucleot(s)ide drugs resistance. Herein, we analyzed the relevant factors of antiviral therapy compliance and their impact on CHB treatment and explored feasible programs that can improve compliance with nucleot(s)ide drug treatment by conducting a literature search using PubMed and Scopus with search terms including hepatitis B, compliance, nucleot(s)ide drugs, antiviral therapy, viral suppression, and drug resistance.

Cost-Effectiveness of Surgical Weight-Loss Interventions for Patients With Knee Osteoarthritis and Class III Obesity.

Class III obesity (body mass index [BMI] ≥40 kg/m2 ) is associated with worse knee pain and total knee replacement (TKR) outcomes. Because bariatric surgery yields sustainable weight loss for individuals with BMI ≥40 kg/m2 , our objective was to establish the value of Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) in conjunction with usual care for knee osteoarthritis (OA) patients with BMI ≥40 kg/m2 . We used the Osteoarthritis Policy model to assess long-term clinical benefits, costs, and cost-effectiveness of RYGB and LSG. We derived model inputs for efficacy, costs, and complications associated with these treatments from published data. Primary outcomes included quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs), all discounted at 3%/year. This analysis was conducted from a health care sector perspective. We performed sensitivity analyses to evaluate uncertainty in input parameters. The usual care + RYGB strategy increased the quality-adjusted life expectancy by 1.35 years and lifetime costs by $7,209, compared to usual care alone (ICER=$5,300/QALY). The usual care + LSG strategy yielded less benefit than usual care + RYGB and was dominated. Relative to usual care alone, both usual care + RYGB and usual care + LSG reduced opioid use from 13% to 4%, and increased TKR usage from 30% to 50% and 41%, respectively. For cohorts with BMI between 38 and 41 kg/m2 , usual care + LSG dominated usual care + RYGB. In the probabilistic sensitivity analysis, at a willingness-to-pay threshold of $50,000/QALY, usual care + RYGB and usual care + LSG were cost-effective in 70% and 30% of iterations, respectively. RYGB offers good value among knee OA patients with BMI ≥40 kg/m2 , while LSG may provide good value among those with BMI between 35 and 41 kg/m2 .

Transfusion Independence Response As a Potential Surrogate for Overall Survival in Jaki-Experienced Patients with Myelofibrosis from Momentum

Introduction: Momelotinib (MMB), an oral ACVR1, JAK1 and JAK2 inhibitor, has previously demonstrated clinical activity on symptoms, anemia and spleen volume in JAK inhibitor (JAKi)-naïve and JAKi -experienced patients with myelofibrosis (MF). A commonly used anemia endpoint, transfusion independence response (TI-R), is defined as the absence of transfusions and no hemoglobin (Hgb) measurements below 8 g/dL during the 12 weeks preceding Week 24 (W24). As previously reported from the SIMPLIFY-1 Phase 3 study of JAKi-naïve patients with MF, patients receiving MMB who achieved TI-R experienced prolonged overall survival (OS) compared to those who were non-TI-R. Hence, TI-R can provide a surrogate for long-term clinical benefit (Mesa et al. Leukemia. 2022). The TI-R endpoint, however, does not fully describe transfusion burden outcomes for patients not meeting the definition of TI-R. Dynamic and time-to-event analyses have previously demonstrated MMB can reduce overall transfusion burden compared to ruxolitinib (RUX) in JAKi-naïve patients including in those who do not achieve TI-R (Mesa et al. Leuk Lymphoma. 2022). To better understand the impact of MMB on TI-R, OS and transfusion burden in JAKi-experienced patients, similar analyses were applied to the ongoing Phase 3 MOMENTUM study which is investigating MMB vs danazol (DAN) in anemic, symptomatic patients with MF who have previously been treated with a JAKi. Methods: MOMENTUM is a double-blind, randomized (2:1) study of MMB 200 mg daily (130 patients) vs DAN 600 mg daily (65 patients) with a randomized treatment (RT) period of 24 weeks, after which patients could receive open-label (OL) MMB. Eligible patients had primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1 MF; MFSAF total symptom score ≥10; Hgb <10 g/dL; prior JAKi for ≥90 days or ≥28 days with RBC transfusions ≥4 units in 8 weeks or Grade 3/4 thrombocytopenia, anemia, or hematoma; and palpable spleen ≥5 cm. Anemia benefit was evaluated by TI-R, Kaplan-Meier (KM) estimates of the proportion of patients who required zero units transfused during RT, hazard ratio (HR) of RBC units transfused as recurrent events, HR of time to 1st, 3rd and 5th transfusion unit and odds ratio (OR) of having zero units transfused estimated by a zero-inflated negative binomial model. Survival was estimated using KM analysis. Transfusion dependence (TD) was defined as requiring ≥4 units of RBC transfusions in the 8 weeks immediately prior with each transfusion in response to a Hgb assessment of ≤9.5 g/dL. Transfusion requiring (TR) was defined as neither TD nor TI. Results: Mean duration of prior JAKi therapy was 139 weeks in the MMB arm and 125 weeks in the DAN arm. The study population was highly anemic with a mean Hgb of 8.1 g/dL in the MMB arm and 7.9 g/dL in the DAN arm; 48% and 49% of MMB and DAN patients respectively had baseline Hgb <8 g/dL. At baseline, 13% and 15% of MMB and DAN patients were TI, respectively, whereas a majority (49% MMB; 52% DAN) were TD. The rate of W24 TI-R was 31% and 20% for the MMB and DAN arms, respectively (non-inferiority p=0.0064). Over the 24-week RT period, 35% of MMB patients had zero units transfused compared to 17% of DAN patients (OR=2.7; p=0.0107). Regardless of baseline transfusion status (TD, TI, or TR), patients randomized to MMB received fewer mean cumulative RBC units during RT compared to those randomized to DAN. Time-to-event-analyses showed median days to 1st, 3rd, and 5th transfusion on MMB was >2 times that on DAN (MMB:40, 106 and not reached; DAN:15, 52, 109). Of the 63 MMB patients with baseline TD, 9 (14%) were TI at the end of W24 and 19 (30%) were TR. Of the 34 DAN patients with baseline TD, 9% were TI at the end of W24 and 9% were TR. Interim OS analysis of both study arms shows that patients who achieve W24 TI-R have prolonged OS compared to those who were non-TI-R; MMB arm shown in Figure 1 (HR=0.15; p=0.0364). Discussion: Anemia is a major unmet need in MF that is associated with poor prognosis and frequently managed with recurrent transfusions, which are costly in terms of reduced quality of life and OS as well as increased healthcare resource utilization. The analyses presented herein demonstrate that patients receiving MMB benefitted from increased likelihood of becoming TI and lower transfusion burden compared with patients receiving DAN. These findings are consistent with previously reported data from the SIMPLIFY studies of MMB and suggest that TI-R at W24 is a potential surrogate for improved OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Results from UKALL60+ (NCT01616238), a UK National Cancer Research Institute Trial for Older People with De Novo Acute Lymphoblastic Leukaemia

Background Improvements in outcome for older patients with Acute Lymphoblastic Leukaemia (ALL) have not kept pace with those for younger persons. Whether there is a survival benefit to more 'intensive’ chemotherapy for older patients and what is the 'pay-off’ in terms of adverse events and duration of inpatient hospitalisation is unclear. Few ALL trials recruit older individuals, with 55 or 60 years being common upper age limits. UKALL60+ (NCT 01616238) a UK National Cancer Research Institute Adult ALL subgroup study, was designed to investigate the safety, tolerability and outcomes of varied intensity chemotherapy protocols for patients ≥ 60 years (y) (55y with comorbidities, no upper age limit) with de novo ALL. Methods Physicians/patients with BCR::ABL1 negative ALL chose freely between three trial chemotherapy pathways; B: based on the UKALL14 adult ALL regimen, but modified to reduce common toxicities eg asparaginase was excluded and dose intensity of certain drugs eg anthracyclines, intravenous (IV) methotrexate were reduced C: the intensive in-patient regimen as used in HOVON100 and D: a regimen designed to be delivered as an 'outpatient', wherein vincristine was the only IV-administered agent. A, tyrosine kinase inhibitor combined with modest intensity chemotherapy was offered for patients with BCR::ABL+ ALL. Regimens A-D all included two full years of maintenance therapy. E was a registration-only pathway with free choice of therapy. Baseline characteristics collected included Charlson index, ECOG, Karnofsky, IADL and CRASH scores. The primary end point was complete remission (CR) rate. Secondary end points included EFS and OS at 1 year, treatment related mortality (TRM), minimal residual disease (MRD) response (patient-specific Ig/TCR quantification by PCR, performed in a central laboratory), adverse event (AE) rates, duration of inpatient hospitalisation and assessment of the relationship between baseline characteristics and treatment option chosen. Quality of life was assessed throughout; data are not yet analysed. Results Between 01/2013 and 11/2018, 126 patients aged 55-83y were recruited, of whom 5 were ineligible (misdiagnosis) leaving 121 analysable. Fifteen pursued registration only, whereas 106/121 elected treatment pathways A-D. Patient characteristics as well as main outcome measures are shown in panel (i). Those receiving regimen D were significantly older than those allocated to B (73 vs 67y p=0.0001). They were moderately more dependent (IADL score 27 vs 28, p =0.04) with slightly higher Charlson index (8 vs 7, p=0.038), suggesting a mix of drivers for therapy selection. Induction CR rate was 92% for pathway A recipients (BCR::ABL1+), 70.6% for B (intermediate intensity), 55.6% for C (most intensive) and 47.6% for D (least intensive), with the latter low rates being due to TRM and lack of disease response, respectively. Strikingly few (N=22, 18.2%, overall) patients achieved an MRD negative remission, with zero complete MRD responses in the low intensity pathway D. Median EFS (mo) was A 23.0 (11.8 - 54.3), B 18.1 (11.3 - 24.2), C not reached, and D 10.9 (5.0 - 13.2). AE forms were available for 102/106 patients. Grade 3/4 AEs rates were equivalent across the pathways; A 22/25 (88%), B 45/49 (91.8%), C 7/8 (87.5%) and D 19/20 (95%), although febrile neutropenia was uncommon in A 3/23(12%) and D 3/20 (15%) but common in B 23/49 (46.9%) and C 6/8(75%). Duration of hospitalisation as a percentage of total time on therapy was A 6%, B 14%, C 24%, and D 8% (p=0.026). Most inpatient days were during induction: 23%, 62%, 76% and 32% respectively (p<0.001). We compared the survival of all UKALL60+ participants to the N=65 patients >60 y treated on the UKALL14 study for patients aged 25-65 y between 05/2012 and 07/2017. Although remission rates were higher for those >60y treated on UKALL14 (87.3%), neither EFS (panel ii) nor OS differed between the trials, suggesting that outcome after chemotherapy treatment is poor across the board for older patients with ALL. Conclusion Our prospective trial data suggest that maximising chemotherapy intensity in older patients with ALL does not confer long-term clinical benefit for the majority of patients. Older patients should be counselled carefully as to the likely outcome of treatment with chemotherapy alone and offered novel therapies or trials of those agents as de novo therapy, wherever possible. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 9543: Cilostazol Improves Symptom Scores and Lowers NT-proBNP in HFpEF Preliminary Results From the CLIP-HFpEF N-of-1 Study

Introduction: Although heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly common, targeted HFpEF therapies remain limited. Current evidence-based treatment options are modestly effective and provide limited symptom relief. Hypothesis: Cilostazol, a generic and oral phosphodiesterase type 3 (PDE-3) inhibitor, rapidly improves HF symptoms and serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in HFpEF patients with an ejection fraction of 50% or higher. Methods: A prospective, double-blind, n-of-1 study with three crossovers with unblinding at the 1-month endpoint was designed. Stable outpatients with HFpEF received either placebo twice daily or Cilostazol 100mg twice daily for one week followed by three weekly crossovers. HF symptoms were assessed each week using the Kansas City Heart Failure Questionnaire (KCCQ-12) and NT-proBNP levels were measured at the end of weeks one and four. Results: Preliminary data from the initial 11 participants are presented (six men and five women, mean age 67±13 years). The mean KCCQ-12 score was eight points higher with Cilostazol than placebo (47±12 vs. 39±12; p&lt;0.05) (Figure 1A). Median NT-proBNP levels were lowered by 22% with Cilostazol compared to placebo (412 [293-1066] pg/dL vs. 659 [323-897] pg/dL; p&lt;0.05) (Figure 1B). Conclusions: In this preliminary analysis of CLIP-HFpEF, treatment with Cilostazol led to a rapid alleviation of HF symptoms and a decline in NT-proBNP levels when compared to placebo. The results of CLIP-HFpEF suggest a marked benefit of Cilostazol in HFpEF patients. Further studies are needed to elucidate the mechanism and long-term clinical benefits of Cilostazol in patients with HFpEF.

Hypergammaglobulinemia before Starting DAA Therapy Is A Strong Predictor of Disease Progression in Cirrhotic Patients Even after HCV Clearance.

The predictive factors of long-term clinical benefits in patients with hepatitis C virus (HCV)—related liver cirrhosis after Direct Antiviral Agents (DAA) treatment are still undefined. The aim of this study was to identify any predictors of liver failure, hepatocellular carcinoma (HCC) and/or death in patients with compensated liver cirrhosis who achieved the sustained virological response (SVR). To this purpose, 324 consecutive cirrhotic patients who started DAA treatment from 1 April 2015 to 31 December 2016 were retrospectively analyzed. All patients were followed up for a median time of 63 months (range 19−77) through clinical/biochemical/instrumental examinations performed at baseline and after stopping the DAA treatment. At the end of the evaluation, 230 (71%) individuals showed stable clinical liver disease over time, 43 (13.3%) developed HCC, and 24 (7.4%) developed hepatic decompensation without HCC. Overall, 49 (15,1%) patients died. Multivariate regression analysis showed that hepatic decompensation was significantly associated with at baseline older age, higher liver stiffness, higher spleen longitudinal size values and hypergammaglobulinemia (p = 0.003, p = 0.005, p = 0.001, p = 0.029, respectively). HCC development was significantly associated with hypergammaglobulinemia (p < 0.001). Death was associated with older age and hypergammaglobulinemia (p < 0.001 and p = 0.007, respectively). Finally, survival analysis confirmed that patients with gamma globulin levels ≥ 1.8 gr/dl had a significantly higher risk of death compared to those with gamma globulin levels < 1.8 gr/dl (p < 0.001). In conclusion, hypergammaglobulinemia before starting DAA therapy represents a strong predictor of hepatic decompensation, HCC and death in cirrhotic patients even after HCV clearance.

Role of Inhalational Aztreonam Lysine in Lower Airway Infections in Cystic Fibrosis: An Updated Literature Review.

Cystic fibrosis (CF) is an inherited disorder most prevalent in the Caucasian population, characterized by a functional abnormality of the transmembrane conductance regulator protein that leads to a wide array of complications, including chronic lung infections. Pseudomonas aeruginosa (PA) is a frequently acquired microbe in CF patients and is associated with deterioration in pulmonary function and increased mortality. Inhaled anti-infective agents are an established curative therapy for CF airway infections, especially with chronic PA lung disease. Amongst them, aztreonam lysine for inhalation (AZLI) is an aerosolized monobactam antibiotic aztreonam, approved for use in CF patients nearly a decade ago. This literature review aims to explore studies based on the efficacy, safety, and tolerability of AZLI use in CF patients with pulmonary infections. We searched for all the relevant articles present in PubMed, Google Scholar, Cochrane Library, EMBASE, ClinicalTrials.gov, and Journal of Cystic Fibrosis for our data collection from 2000 to 2020. The use of AZLI has substantially improved lung function, respiratory symptoms, and remarkably reduced sputum PA density in CF patients, thereby improving the patient's overall quality of life. The adverse effects reported were compatible with CF lung disease. Hence, inhalational therapy with AZLI is highly efficacious and safe in the management of chronic airway infections. More clinical trials need to be conducted in the future to assess its long-term clinical benefits and adverse events as well as to explore the role of AZLI in the setting of acute lung infections.

Development of the Novel Bifunctional Fusion Protein BR102 That Simultaneously Targets PD-L1 and TGF-β for Anticancer Immunotherapy.

Simple SummaryImmune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, have revolutionized the therapy landscape of cancer immunotherapy. However, poor clinical response to ICIs and drug resistance are the main challenges for ICIs immunotherapy. TGF-β produced in the TME was found to confer resistance to PD-1/PD-L1-targeted immunotherapy. The independent and complementary immunosuppressive role of PD-L1 and TGF-β in cancer progression provides a rationale for simultaneously targeting TGF-β and PD-L1 to improve anti-PD-L1 therapy. Consequently, we develop and characterize a novel anti-PD-L1/TGF-β bifunctional fusion protein termed BR102. The data suggest that BR102 could simultaneously disrupt TGF-β- and PD-L1-mediated signals and display high antitumor efficacy and safety. The data support further clinical advancement of BR102 as a promising approach to cancer immunotherapy.Immune checkpoint inhibitors (ICIs) are remarkable breakthroughs in treating various types of cancer, but many patients still do not derive long-term clinical benefits. Increasing evidence shows that TGF-β can promote cancer progression and confer resistance to ICI therapies. Consequently, dual blocking of TGF-β and immune checkpoint may provide an effective approach to enhance the effectiveness of ICI therapies. Here, we reported the development and preclinical characterization of a novel bifunctional anti-PD-L1/TGF-β fusion protein, BR102. BR102 comprises an anti-PD-L1 antibody fused to the extracellular domain (ECD) of human TGF-βRII. BR102 is capable of simultaneously binding to TGF-β and PD-L1. Incorporating TGF-βRII into BR102 does not alter the PD-L1 blocking activity of BR102. In vitro characterization further demonstrated that BR102 could disrupt TGF-β-induced signaling. Moreover, BR102 significantly inhibits tumor growth in vivo and exerts a superior antitumor effect compared to anti-PD-L1. Administration of BR102 to cynomolgus monkeys is well-tolerated, with only minimal to moderate and reversing red cell changes noted. The data demonstrated the efficacy and safety of the novel anti-PD-L1/TGF-β fusion protein and supported the further clinical development of BR102 for anticancer therapy.

PO181 / #567 REAL-WORLD PAIN RELIEF OUTCOMES USING AN INTERSPINOUS SPACER FOR TREATMENT OF LUMBAR SPINAL STENOSIS: E-POSTER VIEWING

In patients with Lumbar Spinal Stenosis (LSS), Indirect Decompression Systems (IDS) or Interspinous Spacers (ISS) can be used to achieve long-term clinical benefit with sustained pain relief, improved quality of life, and medication reduction up to 5-years post-implant.1-3 In addition, in patients implanted with an ISS out to 12-months post-operation, effective leg pain responder rate and pain severity (75% and 60%, respectively) have been demonstrated.4 We sought to examine real-world outcomes derived from acohort of patients who used an Indirect Decompression System for LSS post one-year implant as part of a multicenter, oberservational study.

Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label, Randomized Controlled Trial

IntroductionThe phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses. MethodsA total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m2 every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile. ResultsAt the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1–4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified. ConclusionsTislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.

Patients are Most Interested in Which Hip Arthroplasty Approach? A 15-year Google Trends Analysis

BackgroundThe purpose of this analysis was to assess the public interest in total hip arthroplasty (THA) based on approach by analyzing Google Trends online search volume trends between 2007 and 2021. MethodsData were obtained by querying the Google Trends online search tool for key terms and phrases relating to anterior, posterior, lateral, and minimally invasive approaches to THA. Data from January 2007 to December 2021 were utilized. Relative search volume (RSV) was generated for each THA approach group based on historical search volume trends in the United States. ResultsOver the 15-year period, Google Trends Search Data demonstrated a statistically significant increase (P < .001) in the RSV for all 4 major hip arthroplasty approaches. The growth in public interest for anterior hip arthroplasty was significantly greater than the growth for posterior (P = .02) and minimally invasive hip arthroplasty (P = .02). The difference in RSV growth between lateral and anterior approaches was not significant (P = .88). The average RSV for anterior hip arthroplasty was 59.0, which was significantly greater than the average RSV of all other groups. ConclusionsThe anterior approach to hip arthroplasty has demonstrated a consistent and statistically significant increase in RSV over the past 15 years that has outpaced the increases observed in the posterior and minimally invasive approaches. Despite the increase in public awareness and interest for anterior approach hip arthroplasty, it is yet to demonstrate any long-term clinical benefits over other approaches.

Mechanisms of resistance to tyrosine kinase inhibitors in liver cancer stem cells and potential therapeutic approaches.

The administration of tyrosine kinase inhibitors (TKIs) for the treatment of advanced-stage patients is common in hepatocellular carcinoma (HCC). However, therapy resistance is often encountered, and its emergence eventually curtails long-term clinical benefits. Cancer stem cells (CSCs) are essential drivers of tumor recurrence and therapy resistance; thus, the elucidation of key hallmarks of resistance mechanisms of liver CSC-driven HCC may help improve patient outcomes and reduce relapse. The present review provides a comprehensive summary of the intrinsic and extrinsic mechanisms of TKI resistance in liver CSCs, which mediate treatment failure, and discusses potential strategies to overcome TKI resistance from a preclinical perspective.