{"version":"2026.10.24.3","status":"Independent clinical and methodological review pending","reviewTasks":[["Oncology / clinical nutrition","Check cancer-trial interpretation, nutritional vulnerability, ketosis claims and treatment boundaries."],["Autophagy / metabolism research","Verify flux terminology, tissue differences, figure denominators and the absence of validated human timing milestones."],["Trial methodology / statistics","Complete outcome-specific bias signaling forms, registry-history comparisons and evidence-certainty judgments."],["Dietitian / patient communication","Assess readability, medication context, eating-disorder considerations and inappropriate extrapolation to vulnerable groups."]],"appraisals":[{"id":"bahrami","outcome":"Pathological response and chemotherapy toxicity","domains":[["Randomization / allocation","Block randomization stratified by receptor status and stage; 22 participants per arm. Concealment and independent assessor masking are not fully established here."],["Deviations from assignment","The diet arm also received omega-3. The comparison therefore estimates a treatment package, not fasting alone."],["Missing outcomes","Outcome tables use 22 per arm; full missing-data and adherence history still needs independent verification."],["Outcome measurement","Pathological and imaging response differ from survival. Toxicity grading and multiple endpoints require careful interpretation."],["Selective reporting","Table 5 reports P=.03 for response comparisons, while the prose reports .01. Raw event counts are retained; no silent reconciliation."]],"conclusion":"Encouraging small-trial signal, with cointervention and reporting concerns. Not confirmatory evidence of fasting-specific cancer efficacy."},{"id":"fit","outcome":"Medication use and HbA1c at 12 months","domains":[["Randomization / allocation","Randomized 51 versus 49; outcome assessors masked."],["Deviations from assignment","Usual-care comparator does not match diet-product provision or intervention intensity. Medication changes were part of the clinical program."],["Missing outcomes","Eight intervention and ten control participants lost to follow-up. Mixed-model intention-to-treat analysis depends on missing-data assumptions."],["Outcome measurement","HbA1c is objective; medication-effect scores and combined management categories require clinical interpretation."],["Selective reporting","Two primary outcomes and multiple secondary measures; historical registry changes not fully reconciled. Commercial co-funding disclosed."]],"conclusion":"Useful evidence for this supervised program in diet/metformin-treated diabetes, with limits on fasting-specific attribution and broader applicability."},{"id":"liu","outcome":"12-month weight change","domains":[["Randomization / allocation","Randomized active-control design; concealment details require second extraction."],["Deviations from assignment","Both groups prescribed calories; open-label behavior and achieved intake can differ."],["Missing outcomes","118/139 completed; missing-data assumptions remain relevant."],["Outcome measurement","Measured weight is less vulnerable to expectation bias than subjective symptoms."],["Selective reporting","Primary weight comparison reported with confidence interval; full registry history not independently reconciled."]],"conclusion":"Some unresolved concerns; useful evidence against a large extra benefit in this protocol."},{"id":"catenacci","outcome":"12-month weight change","domains":[["Randomization / allocation","165 randomized, 84 versus 81; source access here is primarily abstract/protocol."],["Deviations from assignment","Intensive behavioral program in both arms; achieved restriction and attendance can contribute."],["Missing outcomes","125/165 completed; intention-to-treat analysis reported."],["Outcome measurement","Objective weight endpoint; assessor procedures not fully extracted."],["Selective reporting","Primary result and 95% CI reported; all protocol amendments not audited."]],"conclusion":"Incomplete formal assessment; modest benefit with an interval near no difference."},{"id":"lowe","outcome":"12-week weight and subgroup lean mass","domains":[["Randomization / allocation","141 randomized; analysis subset should not be called the randomized sample."],["Deviations from assignment","Open-label eating patterns; self-reported adherence cannot establish equal calories."],["Missing outcomes","25 supplied no weight data; substantial concern about missing outcomes."],["Outcome measurement","Weight and DXA are objective; lean mass is not a direct muscle-protein measure."],["Selective reporting","Lean-mass findings are from a small subgroup; corrected Figure 2C is noted."]],"conclusion":"Missingness and subgroup interpretation warrant caution; no primary weight advantage."},{"id":"trim","outcome":"12-week weight under isocaloric feeding","domains":[["Randomization / allocation","Randomized, small single-site trial; baseline weight imbalance reported."],["Deviations from assignment","Provided isocaloric meals help isolate timing; full adherence details need extraction."],["Missing outcomes","All 41 randomized participants completed."],["Outcome measurement","Objective weight; glucose endpoints secondary."],["Selective reporting","Primary weight outcome reported; historical protocol reconciliation incomplete."]],"conclusion":"Useful mechanistic human comparison; imprecision and incomplete full-text appraisal remain."},{"id":"carter","outcome":"12-month HbA1c equivalence","domains":[["Randomization / allocation","Two randomized active dietary arms; unequal group sizes are not evidence of failed randomization."],["Deviations from assignment","Medication adjustment was part of supervised care and can affect glycemic outcomes."],["Missing outcomes","97/137 completed; attrition matters especially in equivalence analyses."],["Outcome measurement","Laboratory HbA1c is objective; equivalence margin concerns clinical interpretation."],["Selective reporting","Prespecified 90% interval/margin used; weight equivalence should not be inferred."]],"conclusion":"Some concerns, especially missingness; follow-up no longer demonstrated equivalence."},{"id":"direct","outcome":"Chemotherapy toxicity and pathological complete response","domains":[["Randomization / allocation","131 randomized; 129 analyzed. Small phase II multicenter trial."],["Deviations from assignment","Only about one fifth adhered through every cycle; dexamethasone differed by arm."],["Missing outcomes","Exclusions and poor adherence make per-protocol estimates vulnerable to selection."],["Outcome measurement","Pathological response more objective than symptoms; assessor blinding not fully reconciled."],["Selective reporting","Primary toxicity null; favorable imaging/per-protocol findings are secondary, not a positive primary trial."]],"conclusion":"Some concerns for assignment effects; high selection concern for adherence-based claims."},{"id":"ergo","outcome":"Six-month progression-free survival","domains":[["Randomization / allocation","50 randomized; 25 per arm; small recurrent-brain-tumor population."],["Deviations from assignment","Four withdrew before diet; 20 completed the dietary protocol and 17 achieved ketosis."],["Missing outcomes","Attrition and small numbers constrain estimates; all survival censoring not independently audited."],["Outcome measurement","Radiological progression is clinically relevant but requires consistent assessment."],["Selective reporting","Primary endpoint was null; ketosis or responder subgroups should not replace it."]],"conclusion":"Imprecise trial with adherence concerns; no demonstrated primary benefit."},{"id":"jameson","outcome":"Progression-free and overall survival","domains":[["Randomization / allocation","36 randomized, 32 evaluable; very small groups."],["Deviations from assignment","Open-label ketogenic support alongside identical chemotherapy backbone; nutritional adherence varied."],["Missing outcomes","Four randomized participants excluded from evaluable population; potential selection concern."],["Outcome measurement","Survival relevant; radiological progression can depend on assessment schedules."],["Selective reporting","One-sided alpha .20 screening design; 95% hazard-ratio intervals include 1."]],"conclusion":"Exploratory evidence with substantial imprecision; not a confirmatory efficacy conclusion."},{"id":"harvie","outcome":"Progression-free survival","domains":[["Randomization / allocation","68 randomized, 35 versus 33; small advanced-breast-cancer sample."],["Deviations from assignment","Dietary package and professional support alongside exercise; cannot isolate fasting biology."],["Missing outcomes","Progression/censoring and all sensitivity analyses need independent full-text audit."],["Outcome measurement","Disease progression relevant; open-label behavior remains a limitation."],["Selective reporting","One-sided .20 screening threshold; HR 95% CI crosses 1."]],"conclusion":"Promising screening result, low certainty pending larger trials and independent appraisal."},{"id":"bensalem","outcome":"Blood-cell autophagic flux at six months","domains":[["Randomization / allocation","Substudy of a randomized parent trial; 121 selected, 114 with baseline samples."],["Deviations from assignment","Intermittent early eating combines timing and energy restriction; not a single continuous fast."],["Missing outcomes","Substudy availability and time-specific samples can introduce selection."],["Outcome measurement","Flux assay is closer to the process than static markers, but blood is not whole-body tissue."],["Selective reporting","Six-month difference was post hoc; two-month comparison and within-arm change did not establish an increase."]],"conclusion":"Exploratory mechanistic evidence; insufficient for universal timing or clinical-benefit claims."},{"id":"tread","outcome":"12-week weight","domains":[["Randomization / allocation","61 randomized; original sequence/concealment details not independently re-extracted."],["Deviations from assignment","Behavioral intervention with self-monitoring; equal achieved intake not established."],["Missing outcomes","52 completed; missingness may influence results."],["Outcome measurement","Weight objective; not the originally registered primary mechanistic endpoint."],["Selective reporting","Primary outcome changed after final participant visit, reportedly before analysis; original history needs reconciliation."]],"conclusion":"Reporting concern lowers confidence; retain the finding with its amendment history visible."},{"id":"pietzner","outcome":"Blood-protein changes during seven-day fasting","domains":[["Randomization / allocation","No randomization or independent control group."],["Deviations from assignment","Supervised water-only exposure; behavior/time effects cannot be separated."],["Missing outcomes","Only 12 volunteers; no broad clinical outcome population."],["Outcome measurement","Proteomic measurements are molecular outcomes, not measured disease prevention."],["Selective reporting","Thousands of proteins and genetically inferred disease associations; not a clinical benefit trial."]],"conclusion":"Very low certainty for causal health benefit; useful descriptive physiology."}],"evidenceProfiles":[{"question":"Does fasting help adults lose weight?","judgment":"Supported for several structured programs","certainty":"Moderate, provisional","refs":["trepanowski","helena","lin","liu","catenacci","hajek"],"explanation":"Repeated randomized comparisons support weight loss relative to usual behavior. Average advantages over active calorie restriction are usually small or uncertain; support, energy intake and adherence differ. Most follow-up is one year or less."},{"question":"Is fasting better than calorie restriction?","judgment":"No consistent overall advantage","certainty":"Moderate, provisional","refs":["liu","lin","helena","trim","catenacci","jamshed2022"],"explanation":"Several larger or longer active-control trials are null; some supported regimens produce additional loss. A single pooled number would conceal different schedules, calorie targets and comparators. “Not significant” does not mean proven equivalent."},{"question":"Can it improve diabetes measures or remission?","judgment":"Possible benefit under clinical management","certainty":"Low to moderate, provisional","refs":["yang","pavlou","carter","carterfollow","teong","early","parr","fit"],"explanation":"HbA1c improvements and remission signals are clinically relevant, but small studies, dietary packages, medication management and limited durability reduce confidence in a fasting-specific effect. Remission is not permanent cure."},{"question":"Does it prevent heart attacks or extend human life?","judgment":"Not established by this trial library","certainty":"Insufficient direct trial evidence","refs":["cramer","sutton","chen","lifespan"],"explanation":"Blood pressure, lipids and glucose are intermediate outcomes. The selected trials do not establish fewer cardiovascular events or longer human survival. Observational mortality associations cannot settle causality; mouse lifespan cannot answer the human question."},{"question":"Does multiday water-only fasting improve long-term health?","judgment":"Short-term changes; comparative benefit unresolved","certainty":"Very low, provisional","refs":["goldhamer","pietzner","scharf","commissati","gabriel","finnell"],"explanation":"Mostly uncontrolled, selected residential cohorts with refeeding and subsequent dietary changes. Fluid/lean loss, adverse markers, attrition and limited follow-up prevent strong conclusions about net benefit, optimal duration or home safety."},{"question":"Do ketones starve and kill cancers?","judgment":"Universal claim is not supported","certainty":"Direct mechanistic counterexamples; clinical efficacy unproven","refs":["glycogen","xieglycogen","zhuogys1","kaluba","wangketones","bhb","zengbladder","ergo"],"explanation":"Some tumors use alternative fuels, including ketones; effects differ by tumor and ketone. A specific glycogen pathway is not a universal nutrient dependency. No selected human trial establishes fasting or ketosis alone as a cancer cure."},{"question":"Can fasting improve cancer treatment?","judgment":"Investigational adjunct, not established treatment","certainty":"Low to very low, provisional","refs":["direct","ergo","harvie","jameson","bahrami","ligoriosurvival","swift"],"explanation":"Small heterogeneous trials, adherence problems and wide intervals. Some response or symptom signals coexist with null primary outcomes. New survival screening trials use permissive one-sided thresholds and need confirmatory replication."},{"question":"When does beneficial autophagy begin and end?","judgment":"No validated universal human schedule","certainty":"Insufficient direct timing/outcome evidence","refs":["jamshed","bensalem","espinoza","vendelbo","pfeifer","mizushima","hoferspermidine","karahanautophagy"],"explanation":"Genes, static proteins and tissue-specific flux are different measurements. Sparse or chronic sampling cannot identify a universal onset, peak, duration or health benefit. Basal recycling already occurs in fed cells."},{"question":"Can autophagy contribute to an anticancer response?","judgment":"Yes in some models; the direction depends on context","certainty":"Experimental evidence; human treatment implications unresolved","refs":["pietrocola","buono","guo","gates","liupersisters","wangthyroid"],"explanation":"Tumor autophagy was necessary for a fasting-plus-chemotherapy benefit in one mouse model, while inhibiting it helped another treatment combination. Cell extrusion in the Gates preprint is distinct from ordinary intracellular digestion. None establishes universal cancer clearance through fasting-induced autophagy in people."},{"question":"Does fasting preserve muscle?","judgment":"Depends on regimen and population","certainty":"Low, provisional","refs":["moro","lowe","vendelbo","gabriel","hallo"],"explanation":"Short resistance-training studies and supervised multiday studies test very different exposures. Fat-free mass includes water; neither a stable DXA result nor later fluid recovery establishes preserved muscle function in every setting."},{"question":"Does it improve cognition or reset immunity?","judgment":"Preliminary and population-specific","certainty":"Very low, provisional","refs":["wang","mcleod","cheng","choi","arthritis","bahrms","jamesnight"],"explanation":"Small cognitive pilots conflict across populations. Animal regeneration, immune-cell changes and multi-component dietary trials do not establish general human rejuvenation, infection prevention or a timed immune reset."},{"question":"Does it eliminate fatty liver?","judgment":"Liver fat can improve; universal elimination unproven","certainty":"Low to moderate for measured liver fat","refs":["liver","ohmasld"],"explanation":"A 12-month active-control trial found similar liver-fat reductions with and without time restriction. It did not establish that fasting invariably resolves the disease or prevents liver complications."}],"corrections":[{"id":"xieglycogen","kind":"Coverage correction · 24 October 2026","note":"Added a direct counterexample to universal tumor glycogen dependence, alongside an earlier positive kidney-cancer study and the 2026 GYS1 signaling study. The subsequent assessment pass documents all 928 retained candidates, including explicit source-access limitations."},{"id":"bahrami","kind":"Source discrepancy and cointervention","note":"The intervention included omega-3 and four dietary days per cycle. Table 5 response counts are 16/22 versus 9/22 and 15/22 versus 8/22, with P=.03; prose gives .01. The discrepancy is retained rather than resolved by assumption."},{"id":"jamesnight","kind":"Source discrepancy","note":"The paper reports 49 completers from 58 randomized, alongside an inconsistent retention percentage. The record uses the raw overall and arm-specific counts."},{"id":"breakfast","kind":"Comparator clarification","note":"The current primary registry specifies FMD plus chemotherapy in both experimental arms, with metformin added in one. A randomized label does not create a usual-diet comparator. Full published arm-specific outcomes and historical amendments remain to be reconciled.","url":"https://clinicaltrials.gov/study/NCT04248998"},{"id":"pietrocola","kind":"Coverage update · 24 October 2026","note":"Added previously omitted evidence that tumor autophagy can be required for fasting-assisted chemotherapy response in mice. The explanation now explicitly distinguishes this from universal tumor clearance and from models in which autophagy supports cancer survival."},{"id":"gates","kind":"New evidence · 24 October 2026","note":"Added the September 2026 cell-extrusion preprint, explicitly labeled as not peer reviewed. Its laboratory time course is not presented as a human fasting or autophagy timeline. Song 2026 and Buono 2023 were also added; four additional original-source leads remain partly assessed."},{"id":"bauersfeld","kind":"Source discrepancy","note":"Used original Figure 1: 50 randomized and 34 analyzed. The abstract describes 34 as randomized."},{"id":"wilhelmi","kind":"Source discrepancy","note":"Used Table 1 duration groups (659/530/196/37), which sum to 1,422; the conflicting methods count is not propagated."},{"id":"yang","kind":"Source discrepancy","note":"Conflicting long-term HbA1c values in abstract and body are omitted; remission denominators are retained."},{"id":"lowe","kind":"Published correction","note":"Figure 2C was corrected in 2020; a 2021 notice clarifies messages sent to participants. Both notices are linked in the source audit; the complete message history is not independently reconstructed."},{"id":"cheng","kind":"Published correction","note":"The 2016 correction changes flow-cytometry labels in Figures 2D and 3G from MPP to HSC+MPP. Original Figure 1 denominators were inspected separately.","url":"https://doi.org/10.1016/j.stem.2016.01.018"},{"id":"tread","kind":"Outcome amendment","note":"The primary outcome changed after the final participant visit; the paper says this occurred before analysis. Historical registration remains a review task."},{"id":"finnell","kind":"Source discrepancy","note":"Visits and unique people are distinguished. Event counts are preferred to an internally inconsistent serious-event percentage."}],"cohortLinks":[{"ids":["cramer","maifeld"],"text":"Maifeld reports a 71-person substudy of the 145-person Cramer program (NCT02099968)."},{"ids":["teong","bensalem"],"text":"Bensalem is an autophagy substudy of the Teong trial (NCT03689608)."},{"ids":["carter","carterfollow"],"text":"Carter’s 12- and 24-month reports follow the same randomized cohort (ACTRN12615000383561)."},{"ids":["cheng","dorff"],"text":"Cheng’s preliminary human blood findings and Dorff’s later pilot concern NCT00936364; they are not independent clinical replications."},{"ids":["vernieri","ligoriosurvival"],"text":"Ligorio’s 14-patient survival comparison is a subanalysis of NCT03340935, the broader trial reported by Vernieri; these are overlapping publications."}],"requestedChecks":["Verify source figures, denominators and outcome hierarchy.","Reconcile corrections and historical registry versions.","Complete validated outcome-specific bias signaling forms and certainty grading.","Check safety and applicability wording.","Declare expertise and relevant conflicts; return dated, source-linked corrections."],"reviewerResponseTemplate":{"specialty":"","qualifications":"","conflicts":"","reviewDate":"","studiesReviewed":[],"findings":[],"decision":"pending"},"unresolved":["Single-database structured search supplemented by targeted primary-source discovery; no duplicate independent screening.","All 928 retained candidates have assessments or documented access limitations; most assessments are based on original abstracts.","Not all supplements, historical protocols or publications have complete denominator extraction.","No external expert approval or automatic update schedule has been completed."]}