Exploratory Subgroup Analysis Research Articles

Comparison between talazoparib and conventional chemotherapy in the treatment of HER2-positive breast cancer patients: A retrospective study.

BackgroundThe benefits of talazoparib compared with conventional chemotherapy in HER2-negative advanced breast cancer (ABC) remain unclear.MethodsPatients older than 18 years, with a deleterious germline BRCA1/2 (gBRCA1/2) mutated, metastatic, or locally advanced and HER2-positive breast cancer were enrolled. Patient data including age, menostatus, tumor grade, pathologic tumor size, lymph node status, and whether they had received adjuvant radiation or chemotherapy was collected. The primary outcomes of the study were disease-free survival (DFS), which was defined as the time from randomization to death or recurrence due to any reason, and overall survival (OS), which was defined as the time from randomization to death due to any reason. P<0.05 was considered to be statistically significant.ResultsA total of 136 patients were finally enrolled in the present retrospective study, including 62 patients in the talazoparib group (group A) and 74 in the conventional chemotherapy group (group B). After a median follow-up of 70.9 months [95% confidence interval (CI): 68.3–78.5], both DFS and OS did not differ significantly between the two groups (P=0.658 and P=0.690, respectively). The exploratory subgroup analyses further validated the robustness of the primary results across the subgroups.ConclusionsTalazoparib was not better than conventional chemotherapy in terms of DFS and OS for the treatment of gBRCA1/2 mutated HER2-positive breast cancer patients.

The role of postoperative radiotherapy in patients with uterine sarcomas: A PSM-IPTW analysis based on SEER database.

ObjectiveThe optimal adjuvant therapy for uterine sarcomas remains poorly determined due to its rarity and histological diversity. The purpose of the study is to explore and characterize the association between utilization of radiotherapy and survival outcome in patients with surgically resected uterine sarcomas.MethodsWe collected data regarding uterine sarcomas which were confirmed after total hysterectomy between 2010 and 2018 period from the latest version of the Surveillance, Epidemiology, and End Results (SEER) database. Initially, 1-, 3- and 5-year survival rate were calculated to predict potential risk factors and possible role of adjuvant chemotherapy and radiotherapy. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) technique were employed to balance confounding factors in the utilization of additional therapy. Multivariate and exploratory subgroup analyses were respectively conducted to evaluate the impact of adjuvant therapy on overall survival (OS) and cause-specific survival (CSS).ResultsA total of 2897 patients were enrolled in the analysis. Survival benefit at 1-, 3-and 5-year after initial treatment was observed in the group of radiotherapy given, however, poorer prognosis in the group of chemotherapy administration. Accordingly, chemotherapy was enrolled as a confounding factor when stratifying and matching patients by receipt of radiotherapy. Prior to and after PSM-IPTW adjustment, radiotherapy both demonstrated beneficial effect on OS and CSS based on multivariate analysis. Further subgroup analysis indicated radiotherapy improved OS and CSS among a subset of patients in stage II-IV, particularly with uterine leiomyosarcoma, tumor grade IV, bigger tumor size than 100 mm and even with chemotherapy administration.ConclusionsAdjuvant radiotherapy in uterine sarcomas after hysterectomy might be underutilized, and proper use of adjuvant radiotherapy combined with chemotherapy after surgery in advanced-stage and high-risk patients might improve survival.

A 5-year community program in Singapore to prevent cognitive decline.

There is a scarcity of naturalistic follow-up studies on cognitive stimulating activities (CSAs), particularly in a real-world setting and over long-term. We thus investigated a pooled novel CSA intervention to prevent cognitive decline amongst community-dwelling older adults without dementia. Nested within a community-based longitudinal follow-up cohort study of community-dwelling and multi-ethnic older adults (N=991), a subset of the cohort (n=264) underwent four single-blinded randomized controlled trials involving four novel CSAs, including mindfulness, horticulture, art therapy, and choral singing. At the cohort's 5-year follow-up, we examined if involvements in the CSAs improved cognition, compared to controls (n=727). The primary outcomes were changes in global cognition and specific cognitive domain scores measured by the mini-mental state examination (MMSE). Exploratory subgroup analyses stratified by baseline cognitive status and the number of CSAs were also conducted. Compared to the control group, there was a small improvement in the CSA group on the total MMSE score (d=0.108) and MMSE-immediate recall score (d=0.199). Furthermore, subgroup analyses revealed medium effect sizes of improvements (d=0.420) in cognitive domains in mild cognitive impairment (MCI) (vs. cognitively healthy) and those involved in two CSAs (vs. one CSA). In summary, a CSA intervention improved cognition. MCI and those involved in two CSAs gained greater benefits from the CSAs. These sustained improvements in cognitive functions could have a significant impact on delaying or preventing dementia.

Postoperative tegafur-uracil for stage I lung adenocarcinoma: first real-world data with an exploratory subgroup analysis.

The effect of postoperative tegafur-uracil on overall survival (OS) after resection of stage I adenocarcinoma has been shown in clinical trials. The purpose of this study was to investigate whether findings from randomized trials of adjuvant tegafur-uracil are reproducible in a real-world setting. A retrospective cohort study was performed using a multi-institutional database that included all patients who underwent complete resection of pathological stage I adenocarcinoma between 2014 and 2016. Survival outcomes for patients managed with and without tegafur-uracil were analyzed using the Kaplan-Meier method and a Cox proportional hazards model for the whole patient cohort and in a selected cohort based on eligibility criteria of a previous randomized trial. Propensity score matching was used to adjust for confounding effects. After propensity score matching, the hazard ratios for OS were 0.57 (95% confidence interval (CI) 0.29-1.14, P = 0.11) in the whole cohort and 0.69 (95% CI 0.32-1.50, P = 0.35) in the selected cohort. The effects of tegafur-uracil in this retrospective study appear to be consistent with those found in randomized clinical trials. These effects may be maximized in patients aged from 45 to 75years.

The association between Mediterranean diet adherence and allostatic load in older adults

Allostatic load (AL) is a multisystemic index of biological wear and tear which is associated with poor health outcomes. In recent years, researchers have examined the association between dietary pattern intake and AL; however, no studies to date have examined the relationship between AL and consumption of a Mediterranean diet. Blood and urine samples were collected from 201 community-dwelling older adults who completed a Food Frequency Questionnaire (FFQ). A Mediterranean Diet Score (MDS) was calculated based on previous recommendations and a sex-based AL index was calculated using a count-based approach for 16 biomarkers associated with neuroendocrine, immune, cardiovascular, or metabolic function. It was hypothesized that a higher MDS would be associated with lower AL, and that this association would be particularly robust for the immune and metabolic subcomponents of the AL index. In support of the primary study hypotheses, generalized linear models revealed a significant inverse relationship between MDS and AL (ß = −0.03, P = 0.037). However, subcomponents of the AL model were not significantly associated with MDS. Exploratory sub-group analyses by sex suggested that the association between AL and MDS was more robust in male than in female participants. The current findings are interpreted with caution given the study design and sample characteristics. Nonetheless, these findings contribute to the literature supporting the Mediterranean diet as an important lifestyle behavior that may minimize AL, and therefore support healthy aging.

Age-Limited Effects of Low-Frequency Transcutaneous Electric Nerve Stimulation on Insomnia: A 4-Week Multi-Center, Randomized Controlled Study.

Objective Insomnia disorder is a common condition with considerable harmful effects on health. We investigated the therapeutic efficacy and safety of low-frequency transcutaneous electric nerve stimulation (LF-TENS) as an alternative treatment option for insomnia disorder. Methods A 4-week, multi-center, randomized controlled study was conducted. A total of 160 individuals aged 40 to 80 years with insomnia disorder were included and randomized to the experimental group receiving active device (n=81) or control group receiving sham device (n=79). Both groups used the device for four weeks, more than five days a week. The participants also completed pre- and post-intervention assessment with questionnaires, sleep diaries, wrist actigraphy, and blood tests. Results There was no significant between-group difference in the changes of mood and sleep parameters and blood test results among the two study groups. Meanwhile, in the exploratory sub-group analysis of patients aged over 60 years, the experimental group showed better improvement after intervention in the change of Pittsburgh Sleep Quality Index (PSQI) score (-2.63±3.25 vs. -1.20±2.28, p=0.039; Cohen’s d=0.99 vs. 0.45) and blood cortisol level (-1.65±3.37 μg/dL vs. -0.16±3.49 μg/dL, p=0.007; Cohen’s d=0.56 vs. 0.05). In addition, no serious adverse reaction occurred during the study period in both groups. Conclusion The effect of LF-TENS was limited to older patients aged over 60 years, which might be related to the modulation of hypothalamic-pituitary-adrenal axis activity.

Real-world outcomes associated with bevacizumab combined with chemotherapy in platinum-resistant ovarian cancer.

5555 Background: In the pivotal Aurelia study, addition of bevacizumab (bev) to physician’s choice chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) for platinum-resistant (PL-R) ovarian cancer (OC) was associated with improved progression-free survival (PFS; 6.7 vs 3.4 mos; hazard ratio (HR) 0.48, p = 0.001) but not overall survival (OS; 16.6 vs 13.3 mos HR 0.85, p = 0.174); the latter finding may relate to extensive crossover. In an exploratory subgroup analysis by treatment arm, benefits were particularly marked for bev + paclitaxel where median PFS (mPFS) increased from 3.9 to 10.4 mos (HR 0.46; 95%CI 0.30-0.71) and increases in OS approached statistical significance (HR 0.65; 95%CI, 0.42-1.02; 22.4 v 13.2 mos). Here we describe utilization of bev for PL-R OC and outcomes in routine clinical practice. Methods: The Ontario Cancer Registry and the New Drug Funding Program databases were utilized to identify all patients treated with bev plus chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) for PL-R OC following its approval in 2017. Time on treatment (ToT) was defined as time from first to last bev treatment; this was used as a surrogate for PFS in routine practice. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with ToT and OS were identified using a Cox proportional hazard model. A before and after comparison analysis was performed to determine mOS for patients treated pre- (2011-2017) and post-bev (2017-2019) approval. Results: From Oct 2017 to Dec 2019, 180 patients received bev + chemotherapy for first-line PL-R OC. Mean age was 63 years old, and 80% had serous OC. Bev was most often combined with liposomal doxorubicin (64 %) followed by paclitaxel (34%) and topotecan (2%). Median ToT was 3 months and OS was 11 months. ToT and OS were longer in patients who received paclitaxel as chemotherapy backbone (5 mos [ToT]; 14 mos [OS]) than those who received bev with liposomal doxorubicin (2 mos; 9 mos) or topotecan (2 mos; 6 mos). In multivariable models, ToT was superior in patients who received bev + paclitaxel than bev + liposomal doxorubicin (HR 0.40; 95%CI 0.28-0.57; p &lt; 0.0001), and worse with longer time from diagnosis to bev start (1.03; 1.01-1.05; p = 0.0120). OS was also significantly longer in those who received paclitaxel vs liposomal doxorubicin (HR 0.54; 95%CI 0.30-0.98; p = 0.043). In a before and after analysis, patients treated in the pre- (n = 1290) and post-bev (n = 360) era had mOS of 8 and 9 months respectively. Post mOS increased for patients receiving paclitaxel (7 vs 12 months) but not with liposomal doxorubicin (9 vs 7 months). Conclusions: ToT and OS associated with bev for PL-R OC are shorter in a real-world population compared to results reported in AURELIA. ToT and OS were longer with bev + paclitaxel than with other chemotherapy agents.

Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC—a systematic review and meta-analysis

BackgroundThe ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study.MethodsA systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2).ResultsInformation by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03).ConclusionIn advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

The immunosuppressive landscape of the NOTCH gene family in hepatocellular carcinoma (HCC).

e16139 Background: Despite the recent addition of atezolizumab to advanced HCC first-line treatment, response biomarkers are not well studied. The involvement of the NOTCH gene family in HCC tumorigenesis has been previously discussed, yet insights on its effect on the immune microenvironment are still lacking. Methods: We systematically analyzed differentially expressed genes (DEGs) in the KEGG NOTCH pathway across HCC transcriptomics datasets from the HCCDB platform. Immune and prognostic analyses were done using The Cancer Genomic Atlas (TCGA) HCC cohort (n = 372). The TIMER 2.0 tool was used to assess immune infiltration. cBioportal was used for tumor mutational burden (TMB) and microsatellite instability (MSI) correlations. The TIDE tool assessed T cell dysfunction and DEGs efficacy predictive value using the only trial administering atezolizumab (IMvigor210, n = 348). Results: Four DEGs were identified: NCSTN, APH1A, NOTCH3, HDAC2. All four genes were significantly directly associated (spearman’s ρ &gt; 0.1, P &lt; 0.05) with immunosuppressive cells: Tregs, macrophage M2 cells, cancer-associated fibroblasts (CAF), and myeloid-derived suppressor cells (MDSC). HDAC2 was associated with higher T cell dysfunction (z score = 2.07, P = 0.04). High NOTCH3 and low HDAC2 expression served as favorable overall survival (OS) prognostic markers (HR: 0.66, 95% CI: 0.48 - 0.90, P = 0.008 &amp; HR: 1.52, 95% CI: 1.12–2.07, P = 0.006, respectively). Stratification based on the expression of these two genes and strongly associated immunosuppressive cells’ infiltration levels (ρ &gt; 0.5), revealed two unique patients’ subsets with worse OS marked by “low NOTCH3 expression with high CAF levels” and “high HDAC2 expression with high MDSC levels”. Regarding immune checkpoint genes expression, NOTCH3 and HDAC2 expression levels were directly correlated with CTLA-4, PD-1, and TIM-3, whereas NCSTN and APH1A were inversely related with PD-L1, LAG-3, and TIM-3 after correction for multiple hypothesis testing (ρ &gt; 0.2, Q value &lt; 0.05). TMB count was inversely associated with NOTCH3 expression (ρ = - 0.2, P &lt; 0.001), as for the MSI sensor score, NOTCH3 (ρ = -0.29) and APH1A (ρ = 0.29) expression had inverse and direct significant associations, respectively (P &lt; 0.0001). Exploratory subgroup analysis from the IMvigor210 trial on metastatic urothelial carcinoma patients on atezolizumab showed a significant difference in OS favoring low NOTCH3 expression (P = 0.003) and high APH1A expression (P = 0.049). Conclusions: DEGs from the NOTCH family seem to impose an immunosuppressive effect on HCC’s microenvironment. High NOTCH3 and low HDAC2 expression were identified as potential favorable prognostic markers. Interestingly, high NOTCH3 expression translated into worse OS in patients on anti-PD-L1 which could be owed to the inverse relation with TMB and MSI described in our study, thus deserving further translational investigations.

PD-8 Outcomes by disease status in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study

TOPAZ-1 (NCT03875235) was a randomised, double-blind, global, phase 3 study evaluating the efficacy and safety of durvalumab plus gemcitabine and cisplatin (durvalumab) as first-line treatment for patients with advanced biliary tract cancer (BTC; Oh D-Y, et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Durvalumab significantly improved overall survival (OS) versus placebo plus gemcitabine and cisplatin (placebo) and represents a potential new treatment option for patients with advanced BTC. In BTC, disease status at baseline (initially unresectable vs recurrent [>6 months after surgery with curative intent or >6 months after adjuvant therapy]) may impact response to treatment. The aim of this exploratory subgroup analysis of TOPAZ-1 was to assess efficacy outcomes by disease status at baseline in patients receiving durvalumab versus placebo. Patients with BTC were randomised 1:1 to receive durvalumab (1500 mg) or placebo on Day 1 Q3W, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and 8 Q3W, for up to 8 cycles, followed by durvalumab or placebo monotherapy until disease progression, unacceptable toxicity or other discontinuation criteria were met. Randomisation was stratified by disease status and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Subgroup analysis of OS, progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) per RECIST v1.1 by disease status at baseline (initially unresectable or recurrent) was performed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for OS and PFS using a Cox proportional hazards model, and odds ratios (ORs) and 95% CIs for ORR were calculated using the Cochran-Mantel Haenszel test. The study included more patients with initially unresectable than recurrent disease (durvalumab, n=274 [80.4%] vs n=67 [19.6%]; placebo, n=279 [81.1%] vs n=64 [18.6%]). HRs for OS favoured durvalumab for both initially unresectable (0.84; 95% CI, 0.69–1.03) and recurrent (0.56; 95% CI, 0.32–0.96) disease; HRs for PFS also favoured durvalumab in both subgroups (0.79; 95% CI 0.66–0.95 and 0.63; 95% CI 0.42–0.94, respectively). ORs for ORR favoured durvalumab for both initially unresectable (1.61; 95% CI, 1.06–2.45) and recurrent (1.52; 95% CI 0.73–3.18) disease. Median DoR for durvalumab versus placebo was 6.0 versus 5.1 months for initially unresectable, and 9.7 versus 7.9 months for recurrent disease. Percentage of responders with a DoR of at least 9 and 12 months was numerically higher with durvalumab versus placebo for both initially unresectable (9-month, 21.5% vs 20.3%; 12-month, 16.7% vs 10.7%) and recurrent (9 months, 58.8% vs 38.1%; 12 months, 48.1% vs 25.4%) disease. In TOPAZ-1, addition of durvalumab to GemCis improved efficacy outcomes both in patients with initially unresectable and patients with recurrent disease at baseline, though the relative benefit versus placebo appears greater for recurrent compared with initially unresectable disease. These findings support the use of durvalumab plus GemCis as a potential new treatment option for patients with advanced BTC, irrespective of disease status.

Randomized phase III study of maintenance selinexor versus placebo in endometrial cancer (ENGOT-EN5/GOG-3055/SIENDO): Impact of subgroup analysis and molecular classification.

5511 Background: Endometrial cancers (ECs) are stratified into four molecular categories: wild type TP53 with non-specific molecular profile typically with microsatellite stability (NSMP, p53wt/MSS), DNA polymerase ε exonuclease domain-mutated (POLEmut), microsatellite instability high (MSI) and TP53 abnormal (p53abn). These are associated with specific prognoses. Selinexor (SEL) is a specific XPO1 inhibitor that leads to the nuclear retention and activation of tumor suppressor proteins (TSP) including p53. SEL showed improved progression-free survival (PFS) over placebo (PLB) in the stratification adjusted results of the ENGOT-EN5/GOG-3055/SIENDO study (NCT03555422; ESMO 2022). Methods: The SIENDO study is a prospective, multicenter, double-blind, placebo-controlled, phase 3 study of SEL (80 mg once weekly) vs. PLB (2:1 randomization) as maintenance therapy in 263 patients (pts) with advanced or recurrent EC after one line of taxane-platinum therapy with partial or complete remission. TP53 mutations and MSI were assessed by centralized targeted sequencing and local immunohistochemistry. Classification was based on sequencing 648 genes on tumor samples from 172 pts (107 on SEL), assigned first by POLEmut, then MSI, then p53abn or p53wt (NSMP). Preliminary exploratory analyses based on molecular classification were prespecified in the trial. Results: The SIENDO study resulted in a median progression-free survival (PFS) of 5.7 months (SEL) vs. 3.8 months (PLB), with a stratification adjusted (eCRF) hazard ratio (HR) of 0.70 (p =.024; and a stratification non-adjusted (IRT) HR of 0.76 (p=0.063). Among the 172 patients who underwent molecular classification, those on SEL (107 pts) were classified as follows: 37 (35%) NSMP, 2 (2%) POLEmut, 18 (17%) MSI, and 50 (46%) p53abn. A similar distribution was seen in those on PLB (65 pts): 20 (31%) NSMP; 4 (6%) POLEmut; 8 (12%) MSI; 33 (51%) p53abn. Subgroup analysis of pts with TP53wt showed a PFS of 13.7 mo with SEL vs. 3.7 mo with PLB (HR 0.375; 95% CI, 0.210-0.670; nominal p =.0003) and pts with MSS/pMMR disease had a PFS of 6.9 mo with SEL vs. 5.4 with PLB (HR 0.593; 95% CI, 0.388-0.905, nominal p =.007). An analysis of patients with NSMP (p53wt, MSS) showed a substantial difference in PFS for SEL vs. PLB: medians NR and 3.71 months, respectively (HR 0.163; 95% CI, 0.060-0.444; nominal p &lt;.0001). Analyses of the other 3 molecular categories did not show significant differences in PFS between SEL and PLB. Additional biomarker identification studies assessing tumor genetics and epigenetics are ongoing. Conclusions: SEL showed improved PFS over PLB in the SIENDO study based on the stratification adjusted analysis. As an indirect p53 activator, preliminary exploratory subgroup analyses of SEL showed improvement over PLB amongst the patients with TP53wt, MSS, and the NSMP EC comprising approximately 50% of patients with advanced/recurrent EC. Clinical trial information: NCT03555422.

Safety of Provocative Testing With Intracoronary Acetylcholine and Implications for Standard Protocols

BackgroundHeterogeneity in diagnostic criteria and provocation protocols has posed challenges in understanding the safety of coronary provocation testing with intracoronary acetylcholine (ACh) for the contemporary diagnosis of epicardial and microvascular spasm. ObjectivesWe examined the safety of testing and subgroup differences in procedural risks based on ethnicity, diagnostic criteria, and provocation protocols. MethodsPubMed and Embase were searched in November 2021 to identify original articles reporting procedural complications associated with intracoronary ACh administration. The primary outcome was the pooled estimate of the incidence of major complications including death, myocardial infarction, ventricular tachycardia/fibrillation, and shock. ResultsA total of 16 studies with 12,585 patients were included in the meta-analysis. The overall pooled estimate of the incidence of major complications was 0.5% (95% CI: 0.0%-1.3%) without any reports of death. Exploratory subgroup analyses revealed that the pooled incidence of major complications was significantly higher in the studies that followed the contemporary diagnosis criteria for epicardial spasm defined as ≥90% diameter reduction (1.0%; 95% CI: 0.3%-2.0%) but significantly lower in Western populations (0.0%; 95% CI: 0.0%-0.45%). The rate of positive epicardial spasm and the incidence of major complications were similar between provocation protocols using the maximum ACh doses of 100 μg and 200 μg. ConclusionsIntracoronary ACh administration for the contemporary diagnosis of epicardial and microvascular spasm is a safe procedure. Moreover, excellent safety records are observed in Western populations primarily presenting with myocardial ischemia and/or infarction with nonobstructive coronary arteries. This study will help standardize ACh testing to improve clinical diagnosis and ensure procedural safety.

177Lu]Lu-PSMA-617 in PSMA-positive metastatic castration-resistant prostate cancer: Prior and concomitant treatment subgroup analyses of the VISION trial.

5001 Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]

Effectiveness of the Sanyin Formula Plus Chemotherapy on Survival in Women With Triple-Negative Breast Cancer: A Randomized Controlled Trial.

PurposeTo evaluate the efficacy of the Sanyin formula (SYF) plus conventional standard chemotherapy in operable triple-negative breast cancer (TNBC) patients, a randomized controlled trial was implemented at 5 hospitals and cancer centers in China between May 23, 2016, and October 31, 2019.Materials and MethodsFemale patients aged 18 to 80 years with operable TNBC after definitive surgery were screened and enrolled. The exclusion criteria included metastatic disease, other tumors, or locally advanced disease. Patients were randomly divided into groups SYF plus conventional standard chemotherapy and placebo plus conventional standard chemotherapy at a ratio of 1:1. The primary endpoint of the investigation was disease-free survival (DFS), and secondary endpoints included overall survival (OS) and toxicity.ResultsA total of 252 operable female TNBC patients were randomized to receive SYF plus conventional standard chemotherapy (N = 127) or a placebo plus conventional standard chemotherapy (N = 125). At a median follow-up of 51 months, 5-year DFS time was longer in those assigned to SYF plus conventional standard chemotherapy compared with placebo plus conventional standard chemotherapy (94.2%vs 85.5%, hazard ratio [HR] = 0.40; 95%CI, 0.17-0.97; P = 0.034). The absolute benefit for 5-year DFS was 8.7% in the SYF plus conventional standard chemotherapy group. No statistically significant difference was observed in OS between the two groups (P = 0.23). Patients with negative node status benefited more from SYF plus conventional standard chemotherapy treatment (HR = 0.21, P-interaction = 0.013) in accordance with the exploratory subgroup analyses of DFS.ConclusionsThe results of the present study suggest that the traditional Chinese medicine SYF plus conventional chemotherapy regimens is an effective alternative adjuvant chemotherapy strategy for female operable TNBC patients.Clinical Trial Registrationhttps://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR-IPR-16008590.

Secondary Prevention Risk Interventions via Telemedicine and Tailored Patient Education (SPRITE): A randomized trial to improve post myocardial infarction management

ObjectiveWe evaluated the impact of a low intensity web-based and intensive nurse-administered intervention to reduce systolic blood pressure (SBP) among patients with prior MI. MethodsSecondary Prevention Risk Interventions via Telemedicine and Tailored Patient Education (SPRITE) was a three-arm trial. Patients were randomized to 1) post-MI education-only; 2) nurse-administered telephone program; or 3) web-based interactive tool. The study was conducted 2009–2013. ResultsParticipants (n = 415) had a mean age of 61 years (standard deviation [SD], 11). Relative to the education-only group, the 12-month differential improvement in SBP was − 3.97 and − 3.27 mmHg for nurse-administered telephone and web-based groups, respectively. Neither were statistically significant. Post hoc exploratory subgroup analyses found participants who received a higher dose (>12 encounters) in the nurse-administered telephone intervention (n = 60; 46%) had an 8.8 mmHg (95% CI, 0.69, 16.89; p = 0.03) differential SBP improvement versus low dose (<11 encounters; n = 71; 54%). For the web-based intervention, those who had higher dose (n = 73; 53%; >1 web encounter) experienced a 2.3 mmHg (95% CI, −10.74, 6.14; p = 0.59) differential SBP improvement versus low dose (n = 65; 47%). ConclusionsThe main effects were not statistically significant. Practical ImplicationsCompleting the full dose of the intervention may be essential to experience the intervention effect. Clinical Trial RegistrationThe unique identifier is NCT00901277 (http://www.clinicaltrials.gov/ct2/show/NCT00901277?term=NCT00901277&rank=1).

First-line gemcitabine plus nab-paclitaxel versus FOLFIRINOX for metastatic pancreatic cancer in a real-world population.

Aim: To compare the overall survival (OS) among patients who received first-line modified gemcitabine plus nab-paclitaxel (G/nab-P) or 5-fluorouracil, leucovorin, irinotecanand oxaliplatin (mFOLFIRINOX) for metastatic pancreatic cancer. Methods: Asingle-center, retrospective, real-world study was conducted. Results: The median OS was 9.4months versus 7.5months in the mFOLFIRINOX and modified G/Nab-P groups, respectively (p=0.16). An exploratory subgroup analysis excluding patients who received one infusion and had an Eastern Cooperative OncologyGroup performance score of 2 demonstrated similarOS of 11.3months and 8.9months, respectively. Median progression-free survival and time-to-treatment failure were not significantly different. Higher rates of adverse events were noted with mFOLFIRINOX. Conclusion: mFOLFIRINOX did not significantly prolong OS compared with modified G/nab-P and was associated with increased toxicities.

Nightshift Work and Nighttime Eating Are Associated With Higher Insulin and Leptin Levels in Hospital Nurses.

BackgroundCircadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modulates these effects in nightshift workers.MethodsFemale nurses (N=18; 8 dayshift and 10 nightshift) completed daily diet records for 8 consecutive days. The nurses then completed a 24-h inpatient stay, during which blood specimens were collected every 3 h (beginning at 09:00) and meals were consumed at regular 3-h intervals (09:00, 12:00, 15:00, and 18:00). Specimens were analyzed for insulin and leptin levels, and generalized additive models were used to examine differences in mean insulin and leptin levels.ResultsMean insulin and leptin levels were higher in nightshift nurses by 11.6 ± 3.8 mU/L (p=0.003) and 7.4 ± 3.4 ng/ml (p=0.03), respectively, compared to dayshift nurses. In an exploratory subgroup analysis of nightshift nurses, predominately eating at night (21:00 – 06:00) was associated with significantly higher insulin and leptin levels than consuming most calories during the daytime (06:00 – 21:00).ConclusionsIn our study of hospital nurses, working the nightshift was associated with higher insulin and leptin levels, and these effects were driven by eating predominately at night. We conclude that although nightshift work may raise insulin and leptin levels, eating during the daytime may attenuate some of the negative effects of nightshift work on metabolic health.

Impact of Brain Metastases on Treatment Patterns and Outcomes With First-Line Durvalumab Plus Platinum-Etoposide in Extensive-Stage SCLC (CASPIAN): A Brief Report

IntroductionIn the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone (p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases. MethodsPatients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of durvalumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophylactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020. ResultsAt baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radiotherapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44–1.41) or without (0.76, 0.62–0.92) brain metastases, with similar PFS results (0.73, 0.42–1.29 and 0.80, 0.66–0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophylactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%). ConclusionsThe OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use.

Latent Profile/Class Analysis Identifying Differentiated Intervention Effects.

The randomized clinical trial is generally considered the most rigorous study design for evaluating overall intervention effects. Because of patient heterogeneity, subgroup analysis is often used to identify differential intervention effects. In research of behavioral interventions, such subgroups often depend on a latent construct measured by multiple correlated observed variables. The purpose of this article was to illustrate latent class analysis/latent profile analysis as a helpful tool to characterize latent subgroups, conduct exploratory subgroup analysis, and identify potential differential intervention effects using clinical trial data. After reviewing different approaches for subgroup analysis, latent class analysis/latent profile analysis was chosen to identify heterogeneous patient groups based on multiple correlated variables. This approach is superior in this specific scenario because of its ability to control Type I error, assess intersection of multiple moderators, and improve interpretability. We used a case study example to illustrate the process of identifying latent classes as potential moderators based on both clinical and perceived risk scores and then tested the differential effects of health coaching in improving health behavior for patients with elevated risk of developing coronary heart disease. We identified three classes based on one clinical risk score and four perceived risk measures for individuals with high risk of developing coronary heart disease. Compared to other classes we assessed, individuals in the class with low clinical risk and low perceived risk benefit most from health coaching to improve their physical activity levels. Latent class analysis/latent profile analysis offers a person-centered approach to identifying distinct patient profiles that can be used as moderators for subgroup analysis. This offers tremendous opportunity to identify differential intervention effects in behavioral research.

The Role of Chemotherapy in the Treatment of Adult Medulloblastoma

The role of chemotherapy (CT) in the treatment of adult patients with medulloblastoma (MB) is unclear. The aim of this study is to compare the survival difference between adult patients with MB treated with and without chemotherapy. Data were derived from the SEER (Surveillance Epidemiology and End Results) database from 2010 to 2018. The Kaplan-Meier method with log-rank tests, univariate and multivariate Cox proportional hazard analyses, and propensity score matching (PSM) were used to investigate the association between chemotherapy and survival. We further conducted an exploratory subgroup analysis. The outcomes of interest were cancer-specific survival (CSS) and overall survival (OS). We included 333 patients in this study, with 227 patients in the CT cohort and 106 in the nonchemotherapy cohort. The median follow-up time and the median age of the study population were 61 months and 30 years, respectively. The 5-year CSS of the CT cohort was superior to the nonchemotherapy cohort, whereas the 5-year OS was not. Kaplan-Meier curves after PSM supported the survival benefit of CT on CSS but not on OS. In the multivariate analysis after PSM, CT was the only prognostic factor for CSS, whereas there were no independent prognostic factors for OS. The survival of patients receiving CT who were diagnosed between 2010 and 2018 was better than that of previous patients. The subgroup analysis showed that there were interaction effects between CT and sex. CT improved CSS for adult patients with MB. With therapeutic advances, adult patients with MB might benefit from the use of CT.