Biography
Dr. Nakakura earned a medical degree at Stanford Medical School and a doctorate degree in cellular and molecular medicine at the Johns Hopkins University. He completed a residency in general surgery at the Johns Hopkins Medical Institutions and was a specialist registrar in surgery at the John Radcliffe Hospital in Oxford, England. He also completed a fellowship in surgical oncology at the Johns Hopkins Medical Institutions.
Neuroendocrine tumors (NETs) of the small intestine and pancreas frequently spread throughout the body (i.e., metastasize). Surgery is often not possible for patients with advanced disease, and current therapies are ineffective for shrinking tumors and durable palliation of debilitating symptoms, often caused by the release of hormones into the blood. Dr. Nakakura and his colleagues' long-term goal is to find the causes of NETs of the small intestine and pancreas, which can lead to earlier diagnosis and ultimately a cure.
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Education
Institution | Degree | Dept or School | End Date |
---|---|---|---|
Stanford University | M.D. | School of Medicine | 1995 |
Board Certifications
- American Board of Surgery, 2004
Clinical Expertise
Ampullary Cancer
Bile Duct Cancer (Cholangiocarcinoma)
Borderline Resectable Pancreatic Cancer (BRPC)
Chronic Pancreatitis
Gallbladder Cancer
Gastrointestinal Neuroendocrine (Carcinoid) Tumors
Gastrointestinal Stromal Tumor (GIST)
Liver Cancer (Hepatocellular Carcinoma)
Liver Cysts
Liver Metastases
Pancreatic Cancer
Pancreatic Neuroendocrine (Islet Cell) Tumors
Pancreatic Pseudocysts
Retroperitoneal Neoplasms
Small Intestine Cancer
Soft Tissue Sarcoma
Stomach (Gastric) Cancer
Whipple Procedure (Pancreaticoduodenectomy)
Program Affiliations
- GI Oncology Program
- Member, UCSF Helen Diller Family Comprehensive Cancer Center
- Surgical Oncology Laboratory
- Sarcoma Program at UCSF
In the News
Research Narrative
Neuroendocrine tumors (NETs) of the small intestine and pancreas frequently spread throughout the body (i.e., metastasize). Surgery is often not possible for patients with advanced disease, and current therapies are ineffective for shrinking tumors and durable palliation of debilitating symptoms, often caused by the release of hormones into the blood. Dr. Nakakura and his colleagues’ long-term goal is to find the causes of NETs of the small intestine and pancreas, which can lead to earlier diagnosis and ultimately a cure.
How And Why Neuroendocrine Tumors Develop
In collaboration with Matthew Meyerson (Broad Institute, Dana-Farber Cancer Institute) and Chrissie Thirwell ( University College London Cancer Institute), Dr. Nakakura is studying the causes of small intestine neuroendocrine tumors utilizing state-of-the art genetic and epigenetic technologies of primary tumors and single cell analyses of precursor lesions.
Funding: Neuroendocrine Tumor Research Foundation (NETRF) Accelerator Grant
Novel Neuroendocrine Tumor Models
A particular interest and focus of Dr. Nakakura’s translational research is the development of novel neuroendocrine tumor models. His laboratory successfully developed a patient-derived pancreatic neuroendocrine tumor (PNETs) xenograft model--the onlysuch model in the world--that faithfully retains the pathologic and genetic aberrations typical of human PNETs. Dr. Nakakura’s laboratory is collaborating with investigators worldwide, studying mechanisms of resistance to current therapies, novel small molecule targeted therapies, CAR T cell therapy, peptide receptor radionucleotide therapy, and the unfolded protein response.
Funding: Neuroendocrine Tumor Research Foundation (NETRF), American Association for Cancer Research (AACR)
Identification of Regulators of NET growth and Hormone Production
Dr. Nakakura’s laboratory has a long-term interest to elucidate the transcriptional and signaling events critical to the pathogenesis of NETs of the small intestine and pancreas, which can identify novel targets for diagnosis and treatment. His approach has been to turn to developmental biology for clues. Dr. Nakakura and collegues have found that the same transcription factors (Ascl1, Nkx2.2, Fev, Scratch)1-4 and signaling pathways (Notch)2 that function in the normal development of endocrine cells throughout the body also act to regulate NET hormone production and growth, as well as metastasis. These findings that conserved pathways of neuroendocrine differentiation function in cancer have also shed important insight into normal gut endocrine cell development.
1 Nakakura EK, Watkins DN, Schuebel KE, Sriuranpong V, Borges MW, Nelkin BD, Ball DW. Mammalian Scratch: a neural-specific Snail family transcriptional repressor. Proc Natl Acad Sci U S A, Mar/27/2001;98(7):4010-5. PMID: 11274425
2 Nakakura EK, Sriuranpong VR, Kunnimalaiyaan M, Hsiao EC, Schuebel KE, Borges MW, Jin N, Collins BJ, Nelkin BD, Chen H, Ball DW. Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by Notch signaling. J Clin Endocrinol Metab, Jul/2005;90(7):4350-6. PMID: 15870121
3 Wang YC, Gallego-Arteche E, Iezza G, Yuan X, Matli MR, Choo SP, Zuraek MB, Gogia R, Lynn FC, German MS, Bergsland EK, Donner DB, Warren RS, Nakakura EK. Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors. Endocr Relat Cancer, Mar/2009;16(1):267-79. PMID: 18987169
4 Wang YC, Zuraek MB, Kosaka Y, Ota Y, German MS, Deneris ES, Bergsland EK, Donner DB, Warren RS, Nakakura EK. The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine. Endocr Relat Cancer, 2010;17(1):283-91. PMID: 20048018
Neuroendocrine Tumors of Unknown Primary
Dr. Nakakura and colleagues have found a straightforward solution to a challenging issue for patients with NETs. Often patients are diagnosed with a NET; however, the primary site remains elusive. Based on the small size, submucosal location, and outward growth pattern of ileum NETs, they hypothesized that most patients with NET of unknown primary tumor have an ileal primary tumor.1 Indeed, despite a negative preoperative evaluation, surgical exploration identifies an ileal primary tumor in most cases.1-3 Their studies show that the routine use of many other tests, such as capsule endoscopy, enteroclysis, double-balloon enteroscopy, and endoscopic ultrasonography, is unnecessary because they will not affect patient care and will only delay treatment.
1 Wang SC, Parekh JR, Zuraek MB, Venook AP, Bergsland EK, Warren RS, Nakakura EK. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg. 2010 Mar; 145(3):276-80. PMID: 20231629
2 Wang SC, Fidelman N, Nakakura EK. Management of well-differentiated gastrointestinal neuroendocrine tumors metastatic to the liver. Seminars in Oncology. 2013 Feb; 40(1):69-74. PMID 23391114
3 Bergsland EK, Nakakura EK. Neuroendocrine tumors of unknown primary: Is the primary site really not known? JAMA Surg. 2014 Sep; 149(9):889-90. PMID: 25029597
Predictors of Lymph Node Metastases in Pancreatic Neuroendocrine Tumors
The significance of lymph node metastases in PNETs is controversial. Consequently, the role and extent of lymph node sampling in PNETs is not standardized. Therefore, there is no consensus regarding the optimal surgical approach for PNETs. Surgical options include pancreas-preserving procedures (enucleation, central pancreatectomy) versus standard resections (pancreaticoduodenectomy, distal pancreatectomy).
Dr. Nakakura and colleagues hypothesized that the conflicting prognostic value of PNET lymph node metastasis might be due to inadequate evaluations of lymph nodes and difficulties predicting metastasis. They found that lymph nodes are not evaluated in many major pancreatic resections for PNET and preoperative prediction of nodal metastasis is difficult.1 Their findings suggest that enucleation of PNETs should be reserved for small insulinomas. For other PNETs, surgeons should routinely sample lymph nodes, working closely with pathologists to maximize the number of lymph nodes identified in each specimen. As a result of their study and that of others, the most recent NCCN guidelines for the management of PNETs have incorporated our recommendations and have affected patient management.2
1 Parekh JR, Wang SC, Bergsland EK, Venook AP, Warren RS, Kim GE, Nakakura EK. Lymph Node Sampling Rates and Predictors of Nodal Metastasis in Pancreatic Neuroendocrine Tumor Resections: The UCSF Experience With 149 Patients. Pancreas. 2012 Aug; 41(6):840-4. PMID: 22781907
2 http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf (login/password required)
Research Interests
- Neuroendocrine (NE) tumors of the gastrointestinal (GI) Tract
- The role of proendocrine transcription factors and signaling pathways in normal and neoplastic gut
- Early detection of neuroendocrine tumors
- Targeted therapy for treatment of neuroendocrine tumors
- Concurrent EGFR and mTOR blockade in patients with pancreatic neuroendocrine tumors
- Translational studies of cancers of the pancreas and gastrointestinal tract
Publications
- ASO Visual Abstract: Long-term Survival Outcomes After Minimally Invasive Surgery for Ileal Neuroendocrie Tumors.| | View in PubMed
- Graft choice in pancreatectomy with vascular resection: equivalent safety in selected patients.| | View in PubMed
- ASO Visual Abstract: Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.| | View in PubMed
- Distinct Indications for Adjuvant Therapy in Resected Invasive Mucinous Cystic Neoplasms of the Pancreas Compared with Pancreatic Ductal Adenocarcinoma.| | View in PubMed
- Enucleation of Neuroendocrine Liver Metastases.| | View in PubMed
- ASO Author Reflections: Total Neoadjuvant Therapy with Chemotherapy Alone for Pancreatic Cancer?| | View in PubMed
- Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.| | View in PubMed
- ASO Author Reflections: Minimally Invasive Surgery for Prototypical Small Intestinal Neuroendocrine Tumors.| | View in PubMed
- Long-Term Survival Outcomes After Minimally Invasive Surgery for Ileal Neuroendocrine Tumors.| | View in PubMed
- National practice patterns in the use of endoscopic ultrasound biopsy for resectable Pancreatic Neuroendocrine Tumors: Insights into the role of DOTATATE PET/CT in diagnosis.| | View in PubMed
- Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.| | View in PubMed
- Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.| | View in PubMed
- Robotic-assisted endoluminal gastric leiomyoma resection: a novel surgical technique for benign gastroesophageal junction tumors.| | View in PubMed
- Improved survival of patients receiving immunotherapy and chemotherapy following curative-intent resection of colorectal liver metastases.| | View in PubMed
- A Machine Learning Approach to Predict Postoperative Pancreatic Fistula After Pancreaticoduodenectomy Using Only Preoperatively Known Data.| | View in PubMed
- ASO Visual Abstract: National Practice Patterns in Malignant Peritoneal Mesothelioma-Updates in Management and Survival.| | View in PubMed
- Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms.| | View in PubMed
- Residual Tumor Volume, Not Percent Cytoreduction, Matters for Surgery of Neuroendocrine Liver Metastasis.| | View in PubMed
- Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.| | View in PubMed
- National Practice Patterns in Malignant Peritoneal Mesothelioma: Updates in Management and Survival.| | View in PubMed
- Laparoscopic Gastrectomy for Gastric Cancer.| | View in PubMed
- Metastatic colorectal adenocarcinoma tumor purity assessment from whole exome sequencing data.| | View in PubMed
- Baseline tumor growth rate highlights the heterogeneity of well differentiated gastroenteropancreatic neuroendocrine tumors and predicts for increases in Ki67 index over time.| | View in PubMed
- Hypertension Requiring Medication Use: a Silent Predictor of Poor Outcomes After Pancreaticoduodenectomy.| | View in PubMed
- Contemporary Trends in Malignant Peritoneal Mesothelioma: Incidence and Survival in the United States.| | View in PubMed
- Hand-Assisted Versus Pure Minimally-Invasive Distal Pancreatectomy: Is There a Downside to Lending a Hand?| | View in PubMed
- Minimally Invasive Distal Pancreatectomy Techniques: A Contemporary Analysis Exploring Trends, Similarities, and Differences to Open Surgery.| | View in PubMed
- Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors.| | View in PubMed
- ASO Visual Abstract: Determining Hospital Volume Threshold for the Safety of Minimally Invasive Pancreaticoduodenectomy: A Contemporary Cutpoint Analysis.| | View in PubMed
- Optimal Staging for Gastric Cancer Starts With High-Resolution Computed Tomography.| | View in PubMed
- Determining Hospital Volume Threshold for Safety of Minimally Invasive Pancreaticoduodenectomy: A Contemporary Cutpoint Analysis.| | View in PubMed
- Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.| | View in PubMed
- Evidence-Based Guidelines for Branch-Duct Intraductal Papillary Mucinous Neoplasm Management: Still a Lot of Room to Grow.| | View in PubMed
- Outcomes after high-dose radiation in the management of neuroendocrine neoplasms.| | View in PubMed
- Burden of Ionizing Radiation in the Diagnosis and Management of Necrotizing Pancreatitis.| | View in PubMed
- Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.| | View in PubMed
- Recurrence Patterns After Surgical Resection of Gastroenteropancreatic Neuroendocrine Tumors: Analysis From the National Comprehensive Cancer Network Oncology Outcomes Database.| | View in PubMed
- Minimally Invasive Surgery for Ileal Neuroendocrine Tumors.| | View in PubMed
- Contemporary Management of Hepatic Cyst Disease: Techniques and Outcomes at a Tertiary Hepatobiliary Center.| | View in PubMed
- Hybrid Low-Grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma of the Pancreas.| | View in PubMed
- Randomized Clinical Trial of Nasogastric Tube Placement After Pancreaticoduodenectomy.| | View in PubMed
- Synchronous Versus Metachronous Colorectal Liver Metastasis Yields Similar Survival in Modern Era.| | View in PubMed
- Awareness of a mesenteric mass as a common manifestation of ileal neuroendocrine tumor.| | View in PubMed
- Patterns of chromosome 18 loss of heterozygosity in multifocal ileal neuroendocrine tumors.| | View in PubMed
- Ampullary stenosis and choledocholithiasis post Roux-En-Y gastric bypass: challenges of biliary access and intervention.| | View in PubMed
- A novel stratification of mesenteric mass involvement as a predictor of challenging mesenteric lymph node dissection by minimally invasive approach for ileal neuroendocrine tumors.| | View in PubMed
- Residual tumor volume discriminates prognosis after surgery for neuroendocrine liver metastasis.| | View in PubMed
- Prognostic impact of a large mesenteric mass >2 cm in ileal neuroendocrine tumors.| | View in PubMed
- Adjuvant Therapy for Ampullary Cancer.| | View in PubMed
- High thymidylate synthase gene expression predicts poor outcome after resection of hepatocellular carcinoma.| | View in PubMed
- Periprocedural Management of Patients Undergoing Liver Resection or Embolotherapy for Neuroendocrine Tumor Metastases.| | View in PubMed
- Comparison of Tumor Regression Grading of Residual Pancreatic Ductal Adenocarcinoma Following Neoadjuvant Chemotherapy Without Radiation: Would Fewer Tier-Stratification Be Favorable Toward Standardization?| | View in PubMed
- Pancreatic Adenocarcinoma, Version 1.2019.| | View in PubMed
- Mitogen Inducible Gene-6 Is a Prognostic Marker for Patients with Colorectal Liver Metastases.| | View in PubMed
- A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors.| | View in PubMed
- Outcomes of arterial bypass preceding resection of retroperitoneal masses involving major vessels.| | View in PubMed
- Progress in the March to Precision Cancer Medicine: Left, Right, Left.| | View in PubMed
- Challenges Staging Neuroendocrine Tumors of the Pancreas, Jejunum and Ileum, and Appendix.| | View in PubMed
- Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.| | View in PubMed
- Gastrocutaneous Fistula in a Patient with Locally Recurrent MSI-High Colorectal Cancer: Local Complications Arising from Therapeutic Response to Immune Checkpoint Blockade.| | View in PubMed
- The Surgical Management of Small Bowel Neuroendocrine Tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society.| | View in PubMed
- Complicated Case Presentation: Management of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1.| | View in PubMed
- Preoperative FOLFIRINOX for borderline resectable pancreatic cancer: Is radiation necessary in the modern era of chemotherapy?| | View in PubMed
- Finding the Common Thread in Rare Diseases.| | View in PubMed
- Correcting for respiratory motion in liver PET/MRI: preliminary evaluation of the utility of bellows and navigated hepatobiliary phase imaging.| | View in PubMed
- Solid pseudopapillary neoplasm of the pancreas head in a pregnant woman: safe pancreaticoduodenectomy postpartum.| | View in PubMed
- Simultaneous (68)Ga-DOTA-TOC PET/MRI with gadoxetate disodium in patients with neuroendocrine tumor.| | View in PubMed
- A patient with cholangiocarcinoma demonstrating pathologic complete response to chemotherapy: exploring the role of neoadjuvant therapy in biliary tract cancer.| | View in PubMed
- Bone metastases and skeletal-related events from neuroendocrine tumors.| | View in PubMed
- Neuroendocrine tumors of unknown primary: is the primary site really not known?| | View in PubMed
- Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines.| | View in PubMed
- Time to put another surgical dogma to sleep?| | View in PubMed
- Home, sweet home, after surgery.| | View in PubMed
- Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.| | View in PubMed
- Management of well-differentiated gastrointestinal neuroendocrine tumors metastatic to the liver.| | View in PubMed
- Reply to P.H. Sugarbaker.| | View in PubMed
- Can CT features differentiate between inferior vena cava leiomyosarcomas and primary retroperitoneal masses?| | View in PubMed
- Lymph node sampling rates and predictors of nodal metastasis in pancreatic neuroendocrine tumor resections: the UCSF experience with 149 patients.| | View in PubMed
- Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines.| | View in PubMed
- Pseudomyxoma peritonei: more questions than answers.| | View in PubMed
- Complete and safe resection of challenging retroperitoneal tumors: anticipation of multi-organ and major vascular resection and use of adjunct procedures.| | View in PubMed
- Unique patterns of metastases in common and rare types of malignancy.| | View in PubMed
- Pancreatic adenocarcinoma.| | View in PubMed
- Lack of NKX2.2 expression in bronchopulmonary typical carcinoid tumors: implications for patients with neuroendocrine tumor metastases and unknown primary site.| | View in PubMed
- Arterial embolization for the management of gastrointestinal hemorrhage from metastatic renal cell carcinoma.| | View in PubMed
- Identification of unknown primary tumors in patients with neuroendocrine liver metastases.| | View in PubMed
- The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine.| | View in PubMed
- MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer.| | View in PubMed
- Mitogen-inducible gene-6 expression correlates with survival and is an independent predictor of recurrence in BRAF(V600E) positive papillary thyroid cancers.| | View in PubMed
- Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors.| | View in PubMed
- Compound muscle action potentials and spontaneous electromyography can be used to identify and protect the femoral nerve during resection of large retroperitoneal tumors.| | View in PubMed
- Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas.| | View in PubMed
- Introduction.| | View in PubMed
- Pancreatic adenocarcinoma. Clinical Practice Guidelines in Oncology.| | View in PubMed
- Palliative care for patients with advanced pancreatic and biliary cancers.| | View in PubMed
- Systemic and regional nonsurgical therapy--what is the optimal strategy for metastatic neuroendocrine cancer?| | View in PubMed
- Islet cell carcinoma: neuroendocrine tumors of the pancreas and periampullary region.| | View in PubMed
- Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells.| | View in PubMed
- Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling.| | View in PubMed
- Notch signaling induces rapid degradation of achaete-scute homolog 1.| | View in PubMed
- Mammalian Scratch participates in neuronal differentiation in P19 embryonal carcinoma cells.| | View in PubMed
- Mammalian Scratch: a neural-specific Snail family transcriptional repressor.| | View in PubMed
- Management of hepatocellular carcinoma.| | View in PubMed
- Long-term survival of solid organ allografts by brief anti-lymphocyte function-associated antigen-1 monoclonal antibody monotherapy.| | View in PubMed
- A non-lymphocyte-depleting monoclonal antibody to the adhesion molecule LFA-1 (CD11a) prevents sensitization to alloantigens and effectively prolongs the survival of heart allografts.| | View in PubMed
- Potent and effective prolongation by anti-LFA-1 monoclonal antibody monotherapy of non-primarily vascularized heart allograft survival in mice without T cell depletion.| | View in PubMed