Eric Nakakura, MD, PhD

Neuroendocrine tumors (NETs) and cancers of the gastrointestinal tract (small intestine, pancreas, and liver)

Minimally Invasive Surgery for Small Intestine Neuroendocrine Tumors

Because patients with small intestine NETs often present with small, multifocal primary tumors and bulky lymphadenopathy/mesenteric masses, an open surgical approach has been the standard of care. We developed a minimally invasive surgical approach utilizing a hand-access port, which allows surgeons to palpate the entire jejunum-ileum to identify multifocal primary tumors and facilitates resection of regional lymph nodes/mesenteric masses with favorable short- and long-term outcomes.^1-4 As a result of our findings, the NCCN guidelines has, for the first time, recognized minimally invasive surgery as a viable option for ileum NETs.⁵

¹Kasai Y, Mahuron K, Hirose K, Corvera CU, Kim GE, Hope TA, Shih BE, Warren RS, Bergsland EK, Nakakura EK. A novel stratification of mesenteric mass involvement as a predictor of challenging mesenteric lymph node dissection by minimally invasive approach for ileal neuroendocrine tumors. PMID: 32291778.

²Mahuron KM, Kasai Y, Javeed ZA, Bergsland EK, Hirose K, Corvera CU, Nakakura EK. Minimally Invasive Surgery for Ileal Neuroendocrine Tumors. PMID: 33742361.

³Yogo A, Paciorek A, Kasai Y, Moon F, Hirose K, Corvera CU, Bergsland EK, Nakakura EK. Long-Term Survival Outcomes After Minimally Invasive Surgery for Ileal Neuroendocrine Tumors. Ann Surg Oncol. PMID: 38797790.

⁴Yogo A, Nakakura EK. ASO Author Reflections: Minimally Invasive Surgery for Prototypical Small Intestinal Neuroendocrine Tumors. PMID: 38822170.

⁵www.NCCN.org 

Residual Tumor Volume is Most Prognostic After Surgery for Neuroendocrine Tumor Liver Metastases (NELMs)

Historically, at least 70-90% cytoreduction has been associated with favorable overall survival and used to select patient for surgery of NELMs. However, using objective measurement of tumor volume, we showed that residual tumor volume, rather than the percent cytoreduction, was prognostic after surgery for NELMs.^1-3

¹Kasai Y, Hirose K, Corvera CU, Kim GE, Hope TA, Shih BE, Harun N, Kim MO, Warren RS, Bergsland EK, Nakakura EK. Residual tumor volume discriminates prognosis after surgery for neuroendocrine tumor liver metastasis. PMID: 31828813.

²Kasai Y, Nakakura EK, Yogo A, Nagai K, Masui T, Hatano E. Residual Tumor Volume, Not Percent Cytoreduction, Matters for Surgery of Neuroendocrine Liver Metastasis. PMID: 37394668.

³Yogo A, Kasai Y, Nakakura EK. Enucleation of Neuroendocrine Liver Metastases. PMID: 39032553.

Outcomes After Complex Pancreatic Surgery

At UCSF, we our incredibly proud of our superior outcomes for patients who undergo complex surgery for pancreatic cancer and other pancreatic diseases. Our multidisciplinary team has a long track record of successfully guiding patients with challenging disease processes through their diagnosis, medical management, and surgery.^1-2   

¹Miller PN, Romero-Hernandez F, Calthorpe L, Wang JJ, Kim SS, Corvera CU, Hirose K, Kirkwood KS, Hirose R, Maker AV, Alseidi AA, Adam MA, Kim GE, Tempero MA, Ko AH, Nakakura EK. Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer. PMID: 38879670.

²Hoffman D, Ganjouei AA, Hernandez FR, Ifuku K, Miller P, Glencer A, Corvera C, Kirkwood K, Alseidi A, Adam M, Maker A, Hirose K, Hirose R, Nakakura EK. Graft choice in pancreatectomy with vascular resection: equivalent safety in selected patients. PMID: 39181231.

How And Why Neuroendocrine Tumors Develop

In collaboration with Matthew Meyerson (Broad Institute, Dana-Farber Cancer Institute) and Chrissie Thirwell (Bristol Medical School), Dr. Nakakura is studying the causes of small intestine NETs utilizing state-of-the art genetic and epigenetic technologies of primary tumors and single cell analyses of precursor lesions.^1-3 

¹Zhang Z, Mäkinen N, Kasai Y, Kim GE, Diosdado B, Nakakura E, Meyerson M. Patterns of chromosome 18 loss of heterozygosity in multifocal ileal neuroendocrine tumors. PMID: 32291827. 

²Mäkinen N, Zhou M, Zhang Z, Kasai Y, Perez E, Kim GE, Thirlwell C, Nakakura E, Meyerson M. Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors. PMID: 35922826. 

³Lee IT, Dolman A, Gao T, Zhang Z, Kasai Y, Kim GE, Thirwell C, Nakakura E, Meyerson M, Makinen N. Characterization of tumor-associated microbiome in multifocal small intestinal neuroendocrine tumors (SI-NETs). ESMO Gastrointestinal Oncology. 2025 Sept.

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. PMID: 20231629 

² Wang SC, Fidelman N, Nakakura EK. Management of well-differentiated gastrointestinal neuroendocrine tumors metastatic to the liver. PMID 23391114

³ Bergsland EK, Nakakura EK. Neuroendocrine tumors of unknown primary: Is the primary site really not known? PMID: 25029597

Predictors of Lymph Node Metastases in Pancreatic Neuroendocrine Tumors

The significance of lymph node metastases in pancreatic NETs (PNETs) was controversial. Consequently, the role and extent of lymph node sampling in PNETs was 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. PMID: 22781907  

²www.NCCN.org 

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. 

¹Nakakura EK, Watkins DN, Schuebel KE, Sriuranpong V, Borges MW, Nelkin BD, Ball DW. Mammalian Scratch: a neural-specific Snail family transcriptional repressor. PMID: 11274425 

²Nakakura 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. PMID: 15870121  

³Wang 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. PMID: 18987169 

⁴Wang 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. PMID: 20048018