4.7 Review

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance

Related references

Note: Only part of the references are listed.
Article Gastroenterology & Hepatology

Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification

Carla Montironi et al.

Summary: This study characterizes the immunogenomic contexture of hepatocellular carcinoma (HCC) and defines inflamed and non-inflamed tumors. Two distinct patterns of CTNNB1 are associated with differential immune evasion and may help predict immune response in HCC.
Article Gastroenterology & Hepatology

Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients

Zhiwu Tan et al.

Summary: A PD-1 isoform called Delta 42PD-1 plays an important role in the development and resistance to nivolumab immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC). We investigated the role of Delta 42PD-1 in HCC patients and found that Delta 42PD-1(+) T cells accounted for up to 71% of cytotoxic T lymphocytes in untreated HCC patients and were associated with HCC severity. These Delta 42PD-1(+) T cells were more exhausted than PD-1(+) T cells. HCC patients treated with anti-PD-1 ICB showed increased frequencies of Delta 42PD-1(+) T cells over time, especially in patients with progressive disease. Delta 42PD-1(+) T cells sustained HCC through toll-like receptor 4 signaling. An anti-Delta 42PD-1 antibody inhibited tumor growth in murine HCC models.
Article Gastroenterology & Hepatology

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma

Philipp K. Haber et al.

Summary: This study analyzed tumor samples from patients with advanced hepatocellular carcinoma (aHCC) treated with anti-PD1 and identified interferon signaling and major histocompatibility complex-related genes as key molecular features of HCCs responding to anti-PD1. The researchers developed an 11-gene signature that can predict treatment response and survival in frontline aHCC patients.

GASTROENTEROLOGY (2023)

Article Oncology

Tislelizumab in Patients with Previously Treated Advanced Hepatocellular Carcinoma (RATIONALE-208): A Multicenter, Non-Randomized, Open-Label, Phase 2 Trial

Zhenggang Ren et al.

Summary: Tislelizumab demonstrated durable antitumor activity and acceptable tolerability in previously treated advanced HCC patients, regardless of the number of prior lines of therapy.

LIVER CANCER (2023)

Article Gastroenterology & Hepatology

Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma

Ann-Lii Cheng et al.

Summary: The study demonstrated that atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma patients led to improved survival outcomes. After updated analysis, atezolizumab plus bevacizumab maintained its position as the first-line treatment option for advanced hepatocellular carcinoma.

JOURNAL OF HEPATOLOGY (2022)

Article Oncology

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

Thomas Yau et al.

Summary: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib in patients with advanced hepatocellular carcinoma, but clinical activity and a favorable safety profile were observed in some patients.

LANCET ONCOLOGY (2022)

Review Oncology

Immunotherapies for hepatocellular carcinoma

Josep M. Llovet et al.

Summary: Liver cancer, specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death globally. Traditional treatments involve specific drugs, but the emergence of immune checkpoint inhibitors has revolutionized the management of HCC.

NATURE REVIEWS CLINICAL ONCOLOGY (2022)

Article Oncology

Serum Concentration of CD137 and Tumor Infiltration by M1 Macrophages Predict the Response to Sintilimab plus Bevacizumab Biosimilar in Advanced Hepatocellular Carcinoma Patients

Wen Zhang et al.

Summary: This study aimed to investigate the biomarkers, safety, and efficacy of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) in advanced hepatocellular carcinoma (HCC). The results showed that sintilimab plus IBI305 was an effective therapy for advanced HCC. Serum concentrations of CD137 and tumor infiltration of M1 macrophages may serve as potential predictive biomarkers.

CLINICAL CANCER RESEARCH (2022)

Article Oncology

Alpha-Fetoprotein as a Potential Surrogate Biomarker for Atezolizumab plus Bevacizumab Treatment of Hepatocellular Carcinoma

Andrew X. Zhu et al.

Summary: This study investigated the potential of on-treatment alpha-fetoprotein (AFP) response as a surrogate biomarker for prognosis in hepatocellular carcinoma patients receiving atezolizumab + bevacizumab. The results showed that AFP cutoffs of >= 75% decrease and <= 10% increase from baseline at 6 weeks could distinguish responders and patients with disease control. These AFP cutoffs were associated with longer overall survival and progression-free survival in patients, particularly those with hepatitis B virus etiology.

CLINICAL CANCER RESEARCH (2022)

Article Gastroenterology & Hepatology

CXCR2 inhibition enables NASH-HCC immunotherapy

Jack Leslie et al.

Summary: This study found that targeting neutrophils using a CXCR2 small molecule inhibitor can enhance the sensitivity of non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) to immune checkpoint inhibition therapy (ICI). The combination therapy can reprogram the tumor immune microenvironment, increase the number of anti-tumor immune cells, and improve treatment outcomes.
Article Biochemistry & Molecular Biology

Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial

Nazli Dizman et al.

Summary: Adding a live bacterial product to an immunotherapy combination can enhance the clinical outcome in patients with metastatic renal cell carcinoma, showing longer progression-free survival and higher response rate.

NATURE MEDICINE (2022)

Article Oncology

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312) : a multicentre, open-label, randomised, phase 3 trial

Robin Kate Kelley et al.

Summary: This study evaluated the combination of cabozantinib and atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma. The combination treatment group showed better progression-free survival compared to the sorafenib group, but overall survival did not reach statistical significance. Common adverse events in the combination group included liver enzyme elevation, hypertension, and skin reactions. The study suggests that cabozantinib plus atezolizumab may be a treatment option, but further research is needed.

LANCET ONCOLOGY (2022)

Article Oncology

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis

M. Rimini et al.

Summary: This study analyzed the effects of different treatment options in non-viral hepatocellular carcinoma patients. The results showed that lenvatinib treatment had better survival benefits compared to atezolizumab plus bevacizumab, particularly in patients with NAFLD/NASH-related HCC.

ESMO OPEN (2022)

Article Gastroenterology & Hepatology

Global burden of primary liver cancer in 2020 and predictions to 2040

Harriet Rumgay et al.

Summary: The burden of liver cancer varies across the world, and it is a major cause of death in many countries. The number of liver cancer cases and deaths is predicted to increase, with a significant rise expected by 2040.

JOURNAL OF HEPATOLOGY (2022)

Article Oncology

Association of High Levels of Antidrug Antibodies Against Atezolizumab With Clinical Outcomes and T-Cell Responses in Patients With Hepatocellular Carcinoma

Chan Kim et al.

Summary: This study found that highly elevated ADA levels may be associated with poor clinical outcomes in patients with advanced hepatocellular carcinoma treated with Atezo/Bev. High ADA levels may reduce atezolizumab exposure and attenuate the anticancer efficacy of the drug.

JAMA ONCOLOGY (2022)

Review Oncology

Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma

Stefania De Lorenzo et al.

Summary: This review provides important information on the mechanisms and therapeutic strategies for immune checkpoint inhibitor (ICI) resistance in hepatocellular carcinoma (HCC), aiming to guide clinicians and researchers.

CANCERS (2022)

Article Oncology

Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A for Nonrandomized, Open-label, Phase II Trial

Jianming Xu et al.

Summary: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced hepatocellular carcinoma, representing a novel treatment option for these patients.

CLINICAL CANCER RESEARCH (2021)

Article Gastroenterology & Hepatology

Qualification of tumour mutational burden by targeted next-generation sequencing as a biomarker in hepatocellular carcinoma

Ching Ngar Wong et al.

Summary: In this pilot study, targeted next-generation sequencing (tNGS) was optimized to estimate tumour mutational burden (TMB) in hepatocellular carcinoma (HCC). The results showed that FFPE samples had higher TMB values compared to FF samples, while UDG-treated samples had lower TMB values. TMB values from fresh HCC samples may limit its role as a predictor of response to immunotherapy in HCC.

LIVER INTERNATIONAL (2021)

Article Biochemistry & Molecular Biology

Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma

Johann von Felden et al.

Summary: This study reveals the mutational landscape of advanced HCC and identifies predictive biomarkers for response to systemic therapies. Mutations in the PI3K/MTOR pathway are associated with shorter PFS after tyrosine kinase inhibitor treatment, while WNT pathway mutations are not predictive of response after CPI therapy.

ONCOGENE (2021)

Article Oncology

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

Carl M. Gay et al.

Summary: Despite the heterogeneity of small cell lung cancer (SCLC), four subtypes have been identified based on tumor expression data, each showing different responses to treatment. SCLC-I subtype benefits the most from immunotherapy, while other subtypes have vulnerabilities to different inhibitors. Matching tumor subtype to therapy and manipulating subtype switching during treatment may enhance response depth and duration for SCLC patients.

CANCER CELL (2021)

Article Oncology

Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice

David J. Pinato et al.

Summary: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in patients with hepatocellular carcinoma (HCC) receiving immune checkpoint inhibitors (ICI) in international clinical trials, indicating potential predictive value for treatment response.

EUROPEAN JOURNAL OF CANCER (2021)

Article Oncology

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung et al.

Summary: The global cancer burden in 2020 saw an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths. Female breast cancer surpassed lung cancer as the most commonly diagnosed cancer, while lung cancer remained the leading cause of cancer death. These trends are expected to rise in 2040, with transitioning countries experiencing a larger increase compared to transitioned countries due to demographic changes and risk factors associated with globalization and a growing economy. Efforts to improve cancer prevention measures and provision of cancer care in transitioning countries will be crucial for global cancer control.

CA-A CANCER JOURNAL FOR CLINICIANS (2021)

Article Biochemistry & Molecular Biology

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Kevin Litchfield et al.

Summary: Checkpoint inhibitors (CPIs) enhance adaptive immunity, with clonal tumor mutation burden (TMB) identified as the strongest predictor of CPI response. Dinucleotide variants may serve as a source of immunogenic epitopes, while copy-number alterations and HLA evolutionary divergence lack pan-cancer significance.
Article Multidisciplinary Sciences

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Dominik Pfister et al.

Summary: The study investigated the impact of NASH on immunotherapy response in HCC patients and found that NASH-HCC may be less responsive to immunotherapy. Aberrant T cell activation caused by NASH-related tissue damage led to impaired immune surveillance in HCC patients.

NATURE (2021)

Article Multidisciplinary Sciences

Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Michael Dudek et al.

Summary: Liver resident CD8 T cells play an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis. These cells display specific phenotypic and metabolic characteristics in the liver, making them susceptible to metabolic stimuli and leading to auto-aggressive responses. This study sheds light on the mechanisms underlying liver damage in NASH and highlights the distinction between auto-aggressive and protective T cell immunity.

NATURE (2021)

Article Oncology

Anti-angiogenic agents - overcoming tumour endothelial cell anergy and improving immunotherapy outcomes

Zowi R. Huinen et al.

Summary: Anti-angiogenic therapy has the potential to enhance antitumor immunity by inhibiting immunosuppressive features of angiogenesis. Combinations of anti-angiogenic agents and immunotherapy have shown success in clinical trials and have been approved by the FDA. The article discusses the impact of angiogenesis on antitumor immunity, the role of endothelial cells, and the progress in combining anti-angiogenic agents with immune checkpoint inhibitors.

NATURE REVIEWS CLINICAL ONCOLOGY (2021)

Article Oncology

Reductions in AFP and PIVKA-II can predict the efficiency of anti-PD-1 immunotherapy in HCC patients

Xuqi Sun et al.

Summary: This study demonstrated that early reductions in AFP and PIVKA-II can serve as predictors of the efficacy of PD-1 blockade in hepatocellular carcinoma patients. The study found a positive correlation between AFP and PIVKA-II reductions > 50% and better outcomes in terms of objective response rate, progression-free survival, and overall survival.

BMC CANCER (2021)

Review Gastroenterology & Hepatology

Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020)

Philipp K. Haber et al.

Summary: A review of 49 high-quality phase III randomized controlled trials in hepatocellular carcinoma conducted between 2002 and 2020 found that 9 had positive results, suggesting that immunotherapies may be more effective in viral etiologies.

GASTROENTEROLOGY (2021)

Article Oncology

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study

Robin Kate Kelley et al.

Summary: This study evaluated the treatment regimens for patients with hepatocellular carcinoma and found that all regimens were tolerable and clinically active, with the T300 + D regimen showing the most favorable benefit-risk profile. Early expansion of CD8+ lymphocytes was associated with treatment response across arms.

JOURNAL OF CLINICAL ONCOLOGY (2021)

Article Oncology

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study

Zhenggang Ren et al.

Summary: The study aimed to assess the efficacy of sintilimab plus IBI305 versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma in China, showing significant overall survival and progression-free survival benefits with acceptable safety profiles.

LANCET ONCOLOGY (2021)

Review Oncology

Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion

Suchit Jhunjhunwala et al.

Summary: This review discusses the importance of antigen presentation in the success of immune checkpoint inhibition therapy and mechanisms by which tumors evade immune recognition. Tumors evade immune recognition by modulating antigen expression and altering antigen presentation.

NATURE REVIEWS CANCER (2021)

Article Multidisciplinary Sciences

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Dominik Pfister et al.

Summary: The text discusses the impact of NASH on the development of HCC and the effect of immunotherapy, revealing the accumulation of exhausted and unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, anti-PD1 treatment led to an increase in HCC, with CD8(+) T cells contributing to this increase.

NATURE (2021)

Article Gastroenterology & Hepatology

Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-titer HBV Carrier Mice

Thomas Michler et al.

GASTROENTEROLOGY (2020)

Review Gastroenterology & Hepatology

Gut microbiome in HCC - Mechanisms, diagnosis and therapy

Robert F. Schwabe et al.

JOURNAL OF HEPATOLOGY (2020)

Article Gastroenterology & Hepatology

Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma

Liang-qing Dong et al.

JOURNAL OF HEPATOLOGY (2020)

Article Medicine, Research & Experimental

Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy

Jing Li et al.

JOURNAL OF CLINICAL INVESTIGATION (2020)

Article Gastroenterology & Hepatology

Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma

Robert Montal et al.

JOURNAL OF HEPATOLOGY (2020)

Article Medicine, General & Internal

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

Richard S. Finn et al.

NEW ENGLAND JOURNAL OF MEDICINE (2020)

Article Multidisciplinary Sciences

Neoantigen-directed immune escape in lung cancer evolution

Rachel Rosenthal et al.

NATURE (2019)

Review Gastroenterology & Hepatology

Biology and significance of alpha-fetoprotein in hepatocellular carcinoma

Peter R. Galle et al.

LIVER INTERNATIONAL (2019)

Article Genetics & Heredity

Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Robert M. Samstein et al.

NATURE GENETICS (2019)

Article Biochemistry & Molecular Biology

Translation control of the immune checkpoint in cancer and its therapeutic targeting

Yichen Xu et al.

NATURE MEDICINE (2019)

Review Oncology

The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy

Jonathan J. Havel et al.

NATURE REVIEWS CANCER (2019)

Review Oncology

Liquid Biopsies and Cancer Immunotherapy

Jonathan R. Thompson et al.

CANCER JOURNAL (2018)

Article Immunology

The Immune Landscape of Cancer

Vesteinn Thorsson et al.

IMMUNITY (2018)

Article Medicine, Research & Experimental

β-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas

Jeremie Nsengimana et al.

JOURNAL OF CLINICAL INVESTIGATION (2018)

Article Oncology

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Dal Fukurnura et al.

NATURE REVIEWS CLINICAL ONCOLOGY (2018)

Article Multidisciplinary Sciences

Role of PD-1 during effector CD8 T cell differentiation

Eunseon Ahn et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2018)

Review Multidisciplinary Sciences

Cancer immunotherapy using checkpoint blockade

Antoni Ribas et al.

SCIENCE (2018)

Editorial Material Oncology

Combination Cancer Immunotherapy in Hepatocellular Carcinoma

Masatoshi Kudo

LIVER CANCER (2018)

Review Oncology

Molecular therapies and precision medicine for hepatocellular carcinoma

Josep M. Llovet et al.

NATURE REVIEWS CLINICAL ONCOLOGY (2018)

Article Gastroenterology & Hepatology

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features

Daniela Sia et al.

GASTROENTEROLOGY (2017)

Letter Medicine, General & Internal

Tumor Mutational Burden and Response Rate to PD-1 Inhibition

Mark Yarchoan et al.

NEW ENGLAND JOURNAL OF MEDICINE (2017)

Article Biochemistry & Molecular Biology

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Nadeem Riaz et al.

Review Oncology

Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer

Khinh Ranh Voong et al.

ANNALS OF TRANSLATIONAL MEDICINE (2017)

Article Oncology

PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer

Jennifer H. Yearley et al.

CLINICAL CANCER RESEARCH (2017)

Review Oncology

Predictive biomarkers for checkpoint inhibitor-based immunotherapy

Geoffrey T. Gibney et al.

LANCET ONCOLOGY (2016)

Article Biochemistry & Molecular Biology

Classification and characterization of microsatellite instability across 18 cancer types

Ronald J. Hanse et al.

NATURE MEDICINE (2016)

Article Medicine, General & Internal

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer

Martin Reck et al.

NEW ENGLAND JOURNAL OF MEDICINE (2016)

Review Oncology

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

Suzanne L. Topalian et al.

NATURE REVIEWS CANCER (2016)

Article Oncology

Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy

Suzanne L. Topalian et al.

CANCER CELL (2015)

Article Pharmacology & Pharmacy

PD-1/PD-L1 inhibitors

Joel Sunshine et al.

CURRENT OPINION IN PHARMACOLOGY (2015)

Article Medicine, General & Internal

Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer

Edward B. Garon et al.

NEW ENGLAND JOURNAL OF MEDICINE (2015)

Article Multidisciplinary Sciences

Immunogenicity of somatic mutations in human gastrointestinal cancers

Eric Tran et al.

SCIENCE (2015)

Article Multidisciplinary Sciences

Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer

Naiyer A. Rizvi et al.

SCIENCE (2015)

Article Multidisciplinary Sciences

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens

Matthew M. Gubin et al.

NATURE (2014)

Article Multidisciplinary Sciences

PD-1 blockade induces responses by inhibiting adaptive immune resistance

Paul C. Tumeh et al.

NATURE (2014)

Article Medicine, General & Internal

Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

Alexandra Snyder et al.

NEW ENGLAND JOURNAL OF MEDICINE (2014)

Review Oncology

Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy

Pierre G. Coulie et al.

NATURE REVIEWS CANCER (2014)

Review Immunology

Oncology Meets Immunology: The Cancer-Immunity Cycle

Daniel S. Chen et al.

IMMUNITY (2013)

Article Biotechnology & Applied Microbiology

Potentiating Functional Antigen-specific CD8+ T Cell Immunity by a Novel PD1 Isoform-based Fusion DNA Vaccine

Jingying Zhou et al.

MOLECULAR THERAPY (2013)

Article Medicine, General & Internal

Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer

Suzanne L. Topalian et al.

NEW ENGLAND JOURNAL OF MEDICINE (2012)

Review Oncology

The immune contexture in human tumours: impact on clinical outcome

Wolf Herman Fridman et al.

NATURE REVIEWS CANCER (2012)

Article Oncology

Focal gains of VEGFA and molecular classification of hepatocellular carcinoma

Derek Y. Chiang et al.

CANCER RESEARCH (2008)

Article Medicine, General & Internal

Sorafenib in advanced hepatocellular carcinoma

Josep M. Llovet et al.

NEW ENGLAND JOURNAL OF MEDICINE (2008)

Article Multidisciplinary Sciences

The response of autologous T cells to a human melanoma is dominated by mutated neoantigens

V Lennerz et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2005)