Iter-4360dd15-0054-transcript
第 54 轮执行轨迹
→ call search_memory({"limit":10,"query":"4360dd15 NEXT_FOCUS PMID 10 条候选 研究类型 保留 排除 理由"}) → call list_recent({"n":8})
→ call list_by_tag({"limit":20,"tag":"evidence-retrieval clinical-trials"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0051-transcript", "tags": "iteration transcript", "modified": "20260424194527000", "preview": "!! 第 51 轮执行轨迹
→ call search_memory({\"limit\":10,\"query\":\"4360dd15 10 条候选 PMID 题名 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0051-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424194527000\", \"preview\": \"!! 第 51 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 PMID 38310895 reference chain Crossref 75 references human trial rapamycin everolimus sirolimus\"}) → call list_recent({\"n\":8}) → call list_tools({}) 【too【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0053-reflection", "modified": "20260424194952000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424194952000", "tags": "pinned focus"}, {"title": "先定研究原始性再补 PMID", "modified": "20260424194952000", "tags": "lesson evidence-retrieval clinical-trials filtering"}, {"title": "Iter-4360dd15-0053-transcript", "modified": "20260424194945000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0053-final-audit-14-candidates", "modified": "20260424194939000", "tags": "4360dd15 knowledge fact audit clinical-trials"}, {"title": "Iter-4360dd15-0052-reflection", "modified": "20260424194723000", "tags": "iteration reflection"}, {"title": "先排除二次分析再做原始性归类", "modified": "20260424194723000", "tags": "lesson evidence-retrieval clinical-trials filtering"}, {"title": "Iter-4360dd15-0052-transcript", "modified": "20260424194718000", "tags": "iteration transcript"}]}
【tool:list_by_tag】
{"ok": true, "items": []}
→ call read_note({"title":"NEXT_FOCUS"})
【tool:read_note】
{"ok": true, "title": "NEXT_FOCUS", "tags": "pinned focus", "text": "!! 下轮焦点（来自 mission `4360dd15` · Iter-0053）\n\n下一轮必须把 10 条剩余候选逐条补齐 PMID、研究类型和保留/排除理由，优先清掉 extension、follow-up、secondary analysis。"}
→ call read_note({"title":"Iter-4360dd15-0053-final-audit-14-candidates"})
【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0053-final-audit-14-candidates", "tags": "4360dd15 knowledge fact audit clinical-trials", "text": "!! 第 53 轮：14 条候选的最终审计表（PMID、题名、研究类型、保留/排除理由）\n\n本轮目标：把上一轮留下的“剩余 10 条候选”补全为可审计表，并把 4 条已确认的非原始研究并入同一张表，形成完整 14 条清单。\n\n!! 结论\n- 保留：10 条，均可映射到原始临床研究\n- 排除：4 条，标题已明确为 ancillary / follow-up / extension / postextension\n\n!! 可审计表\n| PMID | 题名 | 研究类型 | 决策 | 理由 |\n|---|---|---|---|---|\n| 33977284 | Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. | phase 2b/3 randomized trials | 保留 | 原始随机试验 |\n| 22367193 | A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults. | 单次给药对照研究 | 保留 | 原始临床药理试验 |\n| 29408453 | A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. | randomized controlled trial | 保留 | 原始随机对照试验 |\n| 22115710 | A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. | dose-escalation study | 保留 | 原始剂量递增试验 |\n| 35040506 | mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis. | randomized double-blind placebo-controlled futility trial | 保留 | 原始试验 |\n| 25525171 | Intravitreal
→ call search_memory({"limit":10,"query":"4360dd15 29992557 4EVER trial single-arm original clinical trial"})
→ call search_memory({"limit":10,"query":"4360dd15 33977284 mTOR inhibitors older adults randomized trials original"})
→ call search_memory({"limit":10,"query":"4360dd15 22367193 temsirolimus cardiac repolarization healthy adults placebo moxifloxacin"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0001-transcript", "tags": "iteration transcript", "modified": "20260424173243000", "preview": "!! 第 1 轮执行轨迹
4360dd15 起始时间：2026-04-25T01:22:08 !! 使用说明 这是 Sisyphus 的北极星。永远围绕这个目标展开。 其它 mis"}, {"title": "Iter-4360dd15-0010-transcript", "tags": "iteration transcript", "modified": "20260424175830000", "preview": "!! 第 10 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 rapamycin review 2024 trial endpoint remaining 11\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0007-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424174944000\", \"preview\": \"!! 第 7 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 10 条候选 PMID 题名 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"result【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0052-transcript", "tags": "iteration transcript", "modified": "20260424194718000", "preview": "!! 第 52 轮执行轨迹
→ call search_memory({\\\"limi"}, {"title": "Iter-4360dd15-0053-transcript", "tags": "iteration transcript", "modified": "20260424194945000", "preview": "!! 第 53 轮执行轨迹 → call search_memory({\\\""}, {"title": "Iter-4360dd15-0010-transcript", "tags": "iteration transcript", "modified": "20260424175830000", "preview": "!! 第 10 轮执行轨迹 【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0053-transcript", "tags": "iteration transcript", "modified": "20260424194945000", "preview": "!! 第 53 轮执行轨迹
→ call search_memory({\"limit\":10,\"query\":\"4360dd15 10 条候选 PMID 题名 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0051-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424194527000\", \"preview\": \"!! 第 51 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 14 候选 PMID 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0051-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424194527000\", \"preview\": \"!! 第 51 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 PMID 38310895 reference chain Crossref 75 references human trial rapamycin everolimus sirolimus\"}) → call list_recent({\"n\":8}) → call list_tools({}) 【t → call pubmed_search({"limit":5,"query":"29992557 everolimus exemestane 4EVER trial single-arm phase IIIB"})
【tool:pubmed_search】
{"ok": true, "query": "29992557 everolimus exemestane 4EVER trial single-arm phase IIIB", "results": [{"pmid": "29992557", "title": "Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial.", "source": "Int J Cancer", "pubdate": "2019 Feb 15", "authors": ["Tesch H", "Stoetzer O", "Decker T", "Kurbacher CM", "Marmé F", "Schneeweiss A", "Mundhenke C", "Distelrath A"], "url": "https://pubmed.ncbi.nlm.nih.gov/29992557/"}]}
→ call pubmed_search({"limit":5,"query":"33977284 mTOR inhibitors older adults phase 2b phase 3 randomised trials"})
【tool:pubmed_search】
{"ok": true, "query": "33977284 mTOR inhibitors older adults phase 2b phase 3 randomised trials", "results": [{"pmid": "33977284", "title": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.", "source": "Lancet Healthy Longev", "pubdate": "2021 May", "authors": ["Mannick JB", "Teo G", "Bernardo P", "Quinn D", "Russell K", "Klickstein L", "Marshall W", "Shergill S"], "url": "https://pubmed.ncbi.nlm.nih.gov/33977284/"}, {"pmid": "25361980", "title": "Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer.", "source": "Ann Oncol", "pubdate": "2015 Jan", "authors": ["Treilleux I", "Arnedos M", "Cropet C", "Wang Q", "Ferrero JM", "Abadie-Lacourtoisie S", "Levy C", "Legouffe E"], "url": "https://pubmed.ncbi.nlm.nih.gov/25361980/"}]}
→ call pubmed_search({"limit":5,"query":"22367193 temsirolimus cardiac repolarization healthy adults placebo moxifloxacin"})
【tool:pubmed_search】
{"ok": true, "query": "22367193 temsirolimus cardiac repolarization healthy adults placebo moxifloxacin", "results": [{"pmid": "22367193", "title": "A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults.", "source": "Cancer Chemother Pharmacol", "pubdate": "2012 Jun", "authors": ["Boni JP", "Leister C", "Hug B", "Burns J", "Sonnichsen D"], "url": "https://pubmed.ncbi.nlm.nih.gov/22367193/"}]}
→ call web_fetch({"max_chars":5000,"url":"https://pubmed.ncbi.nlm.nih.gov/29992557/"})
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://pubmed.ncbi.nlm.nih.gov/29992557/'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call search_memory({"limit":10,"query":"4360dd15 4EVER trial companion analysis secondary publication protocol"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0010-transcript", "tags": "iteration transcript", "modified": "20260424175830000", "preview": "!! 第 10 轮执行轨迹
→ cal"}, {"title": "Iter-4360dd15-0052-transcript", "tags": "iteration transcript", "modified": "20260424194718000", "preview": "!! 第 52 轮执行轨迹 → call search_memory({\\\"limi"}, {"title": "Iter-4360dd15-0053-transcript", "tags": "iteration transcript", "modified": "20260424194945000", "preview": "!! 第 53 轮执行轨迹 → call web_search({"limit":8,"query":"29992557 4EVER trial secondary analysis everolimus exemestane companion paper"})
【tool:web_search】
{"ok": true, "query": "29992557 4EVER trial secondary analysis everolimus exemestane companion paper", "results": [{"title": "Efficacy and safety of everolimus plus exemestane in ... - PubMed", "url": "https://pubmed.ncbi.nlm.nih.gov/29992557/", "snippet": "The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://www.semanticscholar.org/paper/Efficacy-and-safety-of-everolimus-plus-exemestane-Tesch-Stoetzer/5ddc51835d665716e433f6e561c7f88ee3fc68c9", "snippet": "The 4EVER trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2− aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI. In BOLERO‐2, adding everolimus to exemestane resulted in a twofold increase in median progression‐free survival (PFS) vs exemestane in postmenopausal women ..."}, {"title": "(PDF) Efficacy and safety of everolimus plus exemestane in ...", "url": "https://www.academia.edu/90580953/Efficacy_and_safety_of_everolimus_plus_exemestane_in_postmenopausal_women_with_hormone_receptor_positive_human_epidermal_growth_factor_receptor_2_negative_locally_advanced_or_metastatic_breast_cancer
→ call web_search({"limit":8,"query":"4EVER trial everolimus exemestane companion analysis follow-up secondary publication"})
【tool:web_search】
{"ok": true, "query": "4EVER trial everolimus exemestane companion analysis follow-up secondary publication", "results": [{"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6587781/", "snippet": "The patient population was broader than that evaluated in previous major trials , and thus more reflective of real‐world practice. Overall, the results confirm the clinical benefits and known safety profile of everolimus plus exemestane in this patient population."}, {"title": "(PDF) Efficacy and safety of everolimus plus exemestane in ...", "url": "https://www.researchgate.net/publication/326330427_Efficacy_and_safety_of_everolimus_plus_exemestane_in_postmenopausal_women_with_hormone_receptor-positive_human_epidermal_growth_factor_receptor_2-negative_locally_advanced_or_metastatic_breast_cancer_", "snippet": "Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast ..."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://cris.fau.de/publications/220855577/", "snippet": "The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal w
→ call web_search({"limit":10,"query":"\"Efficacy and safety of everolimus plus exemestane\" 4EVER trial final efficacy analysis primary results"})
【tool:web_search】
{"ok": true, "query": "\"Efficacy and safety of everolimus plus exemestane\" 4EVER trial final efficacy analysis primary results", "results": [{"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6587781/", "snippet": "Here, the authors report on the phase IIIB 4EVER trial , which evaluated the efficacy , safety and quality of life effects of everolimus plus exemestane in postmenopausal women with pretreated, HR+, HER2- advanced breast cancer."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.31738", "snippet": "Here, we report the final efficacy , safety and quality of life (QoL) results from the phase IIIB 4EVER trial , which evaluated the use of everolimus plus exemestane in a broader population compared with BOLERO-2 and is thus more reflective of real-world practice."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://www.researchgate.net/publication/326330427_Efficacy_and_safety_of_everolimus_plus_exemestane_in_postmenopausal_women_with_hormone_receptor-positive_human_epidermal_growth_factor_receptor_2-negative_locally_advanced_or_metastatic_breast_cancer_", "snippet": "Real-Life Analysis of Efficacy and Safety of Everolimus Plus Exemestane in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cance
→ call web_fetch({"max_chars":7000,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6587781/"})
【tool:web_fetch】
{"ok": true, "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6587781/", "status": 200, "content_type": "text/html; charset=utf-8", "text": "Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative locally advanced or metastatic breast cancer: Results of the single‐arm, phase IIIB 4EVER trial - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Int J Cancer . 2018 Oct 30;144(4):877–885. doi: 10.1002/ijc.31738 Search in PMC Search in PubMed View in NLM Catalog Add to search Efficacy and safety of everolimus plus exemestane
→ call web_search({"limit":8,"query":"33977284 full text phase 2b phase 3 randomised trials pooled analysis mTOR inhibitors older adults"})
→ call web_search({"limit":8,"query":"\"33977284\" PMC full text mTOR inhibitors older adults"})
→ call web_search({"limit":8,"query":"\"Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults\" methods phase 2b phase 3"})
【tool:web_search】
{"ok": true, "query": "33977284 full text phase 2b phase 3 randomised trials pooled analysis mTOR inhibitors older adults", "results": [{"title": "Targeting the biology of ageing with mTOR inhibitors to improve immune ...", "url": "https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00062-3/fulltext", "snippet": "The results of the phase 2b and phase 3 trials done in over 1500 adults aged at least 65 years confirm the results of the previous phase 2a trial that mTOR inhibition with RTB101 was well tolerated and consistently upregulated IFN-induced antiviral gene expression in older adults ."}, {"title": "Targeting the biology of ageing with mTOR inhibitors to improve immune ...", "url": "https://www.researchgate.net/publication/351374712_Targeting_the_biology_of_ageing_with_mTOR_inhibitors_to_improve_immune_function_in_older_adults_phase_2b_and_phase_3_randomised_trials", "snippet": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults : phase 2b and phase 3 randomised trials May 2021 The Lancet Healthy Longevity 2 (5):e250-e262"}, {"title": "Targeting the biology of ageing with mTOR inhibitors to improve immune ...", "url": "https://www.unboundmedicine.com/medline/citation/33977284/Targeting_the_biology_of_ageing_with_mTOR_inhibitors_to_improve_immune_function_in_older_adults:_phase_2b_and_phase_3_randomised_trials_", "snippet": "The COVID-19 pandemic highlights the need for therapies that improve immune function in ol
【tool:web_search】
{"ok": true, "query": "\"33977284\" PMC full text mTOR inhibitors older adults", "results": [{"title": "Grace Katzschmann - Author profile - Europe PMC", "url": "https://europepmc.org/authors/0000-0001-6205-4125", "snippet": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults : phase 2b and phase 3 randomised trials. Mannick JB, Teo G, Bernardo P, Quinn D, Russell K, Klickstein L, Marshall W, Shergill S Lancet Healthy Longev, 2 (5):e250-e262, 06 May 2021 Cited by: 5 articles | PMID: 33977284 | PMCID: PMC8102040 Free to ..."}, {"title": "Mis12m - coViki", "url": "https://coviki.org/cov/index.php?title=Mis12m", "snippet": "IFIT Proteins Are Involved in CXCL10 Expression in Human Glomerular Endothelial Cells Treated with a Toll-Like Receptor 3 Agonist. 33977284 2021. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults : phase 2b and phase 3 randomised trials. 33915103 2021."}]}
【tool:web_search】
{"ok": true, "query": "\"Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults\" methods phase 2b phase 3", "results": []}
【assistant】
本轮结论（严审版）：
1. **PMID 29992557** 不应被误判为二次分析。
证据显示它是 **4EVER 试验的原始主报告**：
- open-label
- single-arm
- phase IIIB
- 主要终点是前 24 周 ORR
因此应继续放在**保留**集合，而不是排除。
2. **PMID 33977284** 也应保留。
它是 **phase 2b + phase 3 randomized t
```