Biomedical subjects

Steven K Libutti

Publications and source records attributed to Steven K Libutti.

At least 55 records · Page 3Linked to original sources

PubMed2003

Role of metastasectomy in the management of thyroid carcinoma: the NIH experience.

BACKGROUND AND OBJECTIVES: We studied the impact of metatasectomy on disease outcome in 29 advanced nonmedullary thyroid carcinoma (ThyrCa) patients who were operated on between 1969 and 2001 at NIH to further define its role in the management of this malignancy. METHODS: Data were extracted by retrospective chart review. A Kaplan-Meyer survival curve was constructed, and comparative stratification for various parameters was performed. RESULTS: During 47 surgeries, the following lesions were resected from mid-mediastinum/hila, 17; lung parenchyma, 12; skeleton, 14; kidneys, 2; and brain, 2. All patients received multiple radioiodine (RAI) treatments. External-beam radiotherapy, chemotherapy and other palliative measures were used in selected patients. Six patients (21%) died within 74.7 +/- 54.7 months after the first distant metastasectomy. The outcome of the remaining patients was as follows: complete remission, 3; partial remission, 10; and 10: progressive disease, 10, with a follow-up of 175 patient-years. Metastasectomy led to a decrease of 38% in thyroglobulin levels in 23 patients. Cumulative survival rates were 78.5 +/- 8.4% at 5 years and 50.2 +/- 12.5% at 10 years (mean +/-SEM) after initial distant metastasectomy. CONCLUSIONS: Our data show that extensive targeted metastasectomy in the setting of a tertiary center can be beneficial to patients with disseminated ThyrCa with persistent or recurrent distant disease, when used in conjunction with nonsurgical treatment modalities.

Adenocarcinoma, Follicular↗

PubMed2003

Peak stimulated insulin secretion is associated with specific changes in gene expression profiles in sporadic insulinomas.

BACKGROUND: The molecular pathways that are responsible for pathologic insulin secretion by insulinomas have not been characterized. We studied gene expression profiles from insulinomas and determined associations between these changes and preoperative peak serum insulin levels. METHODS: Ten patients with insulinomas underwent calcium-stimulated arteriography and surgical resection. Tumor RNA was isolated; corresponding complementary DNA was hybridized to 10K human complementary DNA arrays. Pooled human islet cell complementary DNA served as the control. Cluster analysis of gene expression and analysis of expression ratios was performed. RESULTS: Nineteen genes were up-regulated at least 3-fold in insulinomas compared with controls, which included the genes for islet amyloid polypeptide and proprotein convertase type 2. Cluster analysis revealed 2 groups of patients with insulinoma and with distinct patterns of gene expression. Mean peak serum insulin values between groups were 196 and 1100 (U/mL (P<.05), which demonstrates a significant difference in insulin response to calcium stimulation between these 2 groups. CONCLUSION: We show that genes that are relevant to the pathogenesis of hyperinsulinemia are expressed preferentially in insulinomas. In addition, patients with a distinct and common pattern of gene expression had significantly higher stimulated insulin secretion levels. The study of these genes may help to identify the biochemical pathways that are responsible for pathologic insulin secretion.

Adult↗

PubMed2003

Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1.

BACKGROUND: Hyperparathyroidism in patients with multiple endocrine neoplasia type 1 (MEN1) is characterized by multiglandular disease and a propensity for recurrence after parathyroidectomy (PTx). This study analyzes outcomes of a cohort of MEN1 patients undergoing initial PTx at one institution. METHODS: Between April 1960 and September 2002, 92 patients with MEN1 underwent initial PTx. Outcomes were analyzed based on extent of parathyroid resection. RESULTS: Fourteen percent had 2.5 or fewer glands resected, 69% had subtotal PTx, and 17% had total PTx (88% with immediate autotransplantation). The initial surgical cure rate was 98%. Excluding 6 patients lost to follow-up, 33% have developed recurrent hyperparathyroidism (in 46% after < or =2.5 PTx, in 33% after subtotal, and in 23% after total PTx). Median recurrence-free survival was not statistically significantly different between subtotal versus total PTx, but it was longer for subtotal and total PTx compared with lesser resection (16.5 vs 7.0 years, respectively, P=.03). The incidence of severe hypoparathyroidism was 46% after total versus 26% after subtotal PTx. CONCLUSIONS: Subtotal and total PTx result in durable control of MEN1-associated hyperparathyroidism and have longer recurrence-free intervals compared with lesser resection. The high incidence of severe hypoparathyroidism after total PTx suggests that subtotal PTx is the initial operation of choice in this setting.

Adolescent↗

PubMed2003

Surgical management of multi-organ visceral tumors in patients with von Hippel-Lindau disease: a single stage approach.

PURPOSE: We assessed surgical feasibility of a 1-stage multi-organ approach for multiple visceral tumors in patients with von Hippel-Lindau disease. MATERIALS AND METHODS: A total of 14 men and 15 women with von Hippel-Lindau disease underwent simultaneous multi-organ surgery for multiple adrenal, renal and pancreatic tumors at the National Cancer Institute between 1988 and 2001. Perioperative and followup data were analyzed retrospectively. The Mann-Whitney U test was used for statistical analysis. RESULTS: Surgery involving 2 or more organs (mean 2.4 procedures per patient, range 2 to 4) was performed in all patients and concurrent pancreatic operations were performed in 12 (41%). Overall a combined 71 procedures, were performed including 4 cases (13%) treated laparoscopically. Mean +/- SD operative time and estimated blood loss were 464 +/- 142 minutes (range 206 to 830) and 2,798 +/- 4,285 cc (300 to 20,000), respectively. In 16 patients (55%) blood transfusion was administered intraoperatively. At a median followup of 21 months (range 5 to 151) renal tumors recurred in 8 patients (28%), requiring further kidney operations, but no patient had pancreatic or adrenal recurrence. The overall complication rate was 38%, and there was no operative mortality. CONCLUSIONS: A single stage surgical approach for multi-organ visceral tumors is a viable option for patients with von Hippel-Lindau disease. With careful patient selection and surgical planning combined procedures can be safely performed in 1 operative setting.

Adolescent↗

PubMed2003

Management and outcome of patients with sporadic gastrinoma arising in the duodenum.

BACKGROUND: Primary duodenal gastrinomas are now recognized as a common etiology for patients with sporadic Zollinger Ellison Syndrome (ZES); however, the clinical and pathologic features of this condition and long-term outcome after operation are not well characterized. METHODS: Between November 1982 and September 2000, 63 patients diagnosed with sporadic ZES underwent resection of a primary duodenal gastrinoma and regional nodal metastases with curative intent. Data from a prospectively maintained database were reviewed for clinical and pathologic parameters relating to primary tumor size, location, frequency of lymph node metastases, and disease-specific and disease-free survival. RESULTS: There were 41 males and 22 females (mean age, 48.6 years). The majority of duodenal gastrinomas were in the first or second portions of the duodenum (83%). Tumor size ranged from 0.2 to 2.0 cm with 62% measuring less than 1.0 cm. Sixty percent of individuals had regional lymph node metastases identified primarily in proximity to the primary tumor. At a median 10-year follow-up, the overall disease-specific and disease-free survivals were 100% and 60%, respectively. Actuarial 10-year disease-free survival was significantly higher for patients without lymph node metastases versus those with lymph node metastases (78% versus 48%, P = 0.0137). CONCLUSIONS: Duodenal gastrinomas in patients with sporadic ZES are frequently small, most commonly located in the proximal duodenum, and associated with regional lymph node metastases in 60%. Disease-free survival is lower for patients with regional lymph node metastases suggesting that a more systematic lymphadenectomy to extirpate occult disease may be indicated in this group.

Adolescent↗

PubMed2003

Current advances in molecular imaging: noninvasive in vivo bioluminescent and fluorescent optical imaging in cancer research.

Recently, there has been tremendous interest in developing techniques such as MRI, micro-CT, micro-PET, and SPECT to image function and processes in small animals. These technologies offer deep tissue penetration and high spatial resolution, but compared with noninvasive small animal optical imaging, these techniques are very costly and time consuming to implement. Optical imaging is cost-effective, rapid, easy to use, and can be readily applied to studying disease processes and biology in vivo. In vivo optical imaging is the result of a coalescence of technologies from chemistry, physics, and biology. The development of highly sensitive light detection systems has allowed biologists to use imaging in studying physiological processes. Over the last few decades, biochemists have also worked to isolate and further develop optical reporters such as GFP, luciferase, and cyanine dyes. This article reviews the common types of fluorescent and bioluminescent optical imaging, the typical system platforms and configurations, and the applications in the investigation of cancer biology.

Animals↗

PubMed2003

Comparison of noninvasive fluorescent and bioluminescent small animal optical imaging.

Optical imaging is a modality that is cost-effective, rapid, easy to use, and can be readily applied to studying disease processes and biology in vivo. For this study, we used a green fluorescent protein (GFP)- and luciferase-expressing mouse tumor model to compare and contrast the quantitative and qualitative capabilities of a fluorescent reporter gene (GFP) and a bioluminescent reporter gene (luciferase). We describe the relationship between tumor volume, tumor mass, and bioluminescent/fluorescent intensity for both GFP and luciferase. Bioluminescent luciferase imaging was shown to be more sensitive than fluorescent GFP imaging. Luciferase-expressing tumors were detected as early as 1 day after tumor cell inoculation, whereas GFP-expressing tumors were not detected until 7 days later. Both bioluminescent and fluorescent intensity correlated significantly and linearly with tumor volume and tumor weight, as measured by caliper. Compared to bioluminescent imaging, fluorescent imaging does not require the injection of a substrate and may be appropriate for applications where sensitivity is not as critical. Knowing the relative strengths of each imaging modality will be important in guiding the decision to use fluorescence or bioluminescence.

Animals↗

PubMed2003

Antiangiogenic therapy: targeting vascular endothelial growth factor and its receptors.

Angiogenesis is an important natural process occurring in the body, both in health and in infirmity, that is controlled by angiogenesis-stimulating growth factors and angiogenesis inhibitors. Uncontrolled angiogenesis in a tumor can result in both tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) are major players in many human malignancies and contribute directly to disease outcome. There is compelling evidence indicating that the beneficial effects of VEGF and VEGFR can be targeted as antiangiogenic therapy. Many of the agents have shown promising results in cell culture preclinical and animal models. Some of these agents have been tested in clinical trials as well. This review discusses the clinical significance of VEGF/VEGFR in human cancer, summarizes the more recent progress in the field, and further emphasizes the current development of agents that block VEGFR/VEGFR as angiogenesis inhibitors and the therapeutic significance of these agents in clinical trials.

Angiogenesis Inhibitors↗

PubMed2002

Comparison of SUV and Patlak slope for monitoring of cancer therapy using serial PET scans.

The standardized uptake value (SUV) and the slope of the Patlak plot ( K) have both been proposed as indices to monitor the progress of disease during cancer therapy. Although a good correlation has been reported between SUV and K, they are not equivalent, and may not be equally affected by metabolic changes occurring during disease progression or therapy. We wished to compare changes in tumor SUV with changes in K during serial positron emission tomography (PET) scans for monitoring therapy. Thirteen patients enrolled in a protocol to treat renal cell carcinoma metastases were studied. Serial dynamic fluorodeoxyglucose (FDG) PET scans and computed tomography (CT) and magnetic resonance (MR) scans were performed once prior to treatment, once at 36+/-2 days after the start of treatment, and (in 7/13 subjects, 16/27 lesions) a third time at 92+/-9 days after the start of treatment. This resulted in a total of 33 scans, and 70 tumor Patlak and SUV values (one value for each lesion at each time point). SUV and K were measured over one to four predefined tumors/patient at each time point. The input function was obtained from regions of interest over the heart, combined, if necessary, with late blood samples. Over all tumors and scans, SUV and K correlated well ( r=0.97, P<0.0001). However, change in SUV with treatment over all tumor scan pairs was much less well correlated with the corresponding change in K ( r=0.73, P<0.0001). The absolute difference in % change was outside the 95% confidence limits expected from previous variability studies in 6 of 43 pairs of tumor scans, and greater than 50% in 2 of 43 tumor scan pairs. In four of the six cases, the two indices predicted opposing therapeutic outcomes. Similar results were obtained for SUV normalized by body weight or body surface area and for SUVs using mean or maximum count. Changes in CT and MR tumor cross-product dimensions correlated poorly with each other ( r=0.47, P=NS), and so could not be used to determine the "correct" PET index. Absolute values of SUV and K correlated well over the patient population. However, when monitoring individual patient therapy serially, large differences in the % changes in the two indices were occasionally found, sometimes sufficient to produce opposing conclusions regarding the progression of disease.

Carcinoma, Renal Cell↗

PubMed2002

Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma.

BACKGROUND: The aim of the current study was to assess circulating levels of endogenous endostatin in patients with renal carcinoma and to determine the relationship of these levels to circulating levels of vascular endothelial growth factor (VEGF) and prognosis. METHODS: The authors prospectively studied 66 patients (48 male, 18 female; mean age, 50 years) undergoing nephrectomy for renal carcinoma on clinical trials at the National Cancer Institute. Metastases were present in 51 of 66 patients (77%) at the time of nephrectomy. Preoperative and followup serum endostatin and VEGF levels were determined using competitive enzyme immunoassays and compared to a group of 32 age- and gender-matched healthy controls. Associations between circulating endostatin levels and clinicopathologic variables, including survival, were determined. RESULTS: Preoperative endostatin levels were higher in renal carcinoma patients than in healthy controls (P = 0.05). There was a weak to moderate correlation between pretreatment serum endostatin levels and serum VEGF levels (r = 0.47; P = 0.001), and levels of both proteins increased significantly following nephrectomy (P < 0.0001 and P < 0.0001, respectively; n = 41). In addition, patients whose endostatin levels increased more than twofold after nephrectomy had significantly poorer prognoses than patients without such an increase (P = 0.018). This association was more pronounced when patients without metastases were excluded (P = 0.0037). CONCLUSIONS: Circulating endostatin levels are elevated in patients with renal carcinoma and correlate with circulating VEGF levels. Endostatin levels increase after nephrectomy, and patients with the greatest increases experience shortened survival times. These findings suggest an association between tumor aggressiveness and the production of endogenous endostatin in patients with renal carcinoma.

Adult↗

PubMed2002

Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin.

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model.

Adenocarcinoma↗

PubMed2002

Hepatic vascular isolation and perfusion for patients with progressive unresectable liver metastases from colorectal carcinoma refractory to previous systemic and regional chemotherapy.

BACKGROUND: Many patients with colorectal carcinoma develop unresectable metastases confined to the liver that remain the life-limiting component of disease despite best available systemic or regional chemotherapy. In the current study, the authors present their results using vascular isolation and perfusion of the liver for individuals with progressive, unresectable liver metastases from colorectal carcinoma that were refractory to both previous systemic and regional chemotherapy. METHODS: Seven patients with refractory, progressive, unresectable colorectal carcinoma metastases confined to the liver underwent a 60-minute hyperthermic (39-40 degrees C) isolated hepatic perfusion (IHP) and were followed for toxicity, response, and survival. RESULTS: There was no surgical- or treatment-related mortality; all patients experienced transient Grade 3-4 (according to National Cancer Institute common toxicity criteria) hepatic toxicity. At a median potential follow-up of 16 months, the overall objective radiographic response rate (all partial responses) was 71% (5 of 7 assessable patients). It is interesting to note that two patients who were treated with tumor necrosis factor (TNF) alone demonstrated no response to therapy compared with all five patients who were treated with melphalan and TNF (three patients) or melphalan alone (two patients). For the 5 patients who responded to treatment, the median duration of response was 10 months (range, 10-13 months) and in all 7 patients the mean overall survival was 19.7 months (range, 2-33 months), including 5 months and 7.5 months, respectively, for the 2 patients treated with TNF alone. CONCLUSIONS: The results of the current study demonstrate that IHP using melphalan with or without TNF has significant antitumor activity in this patient population. IHP deserves continued clinical evaluation as a therapeutic modality for patients with unresectable colorectal carcinoma metastases to the liver.

Aged↗

PubMed2002

Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF.

Tumor necrosis factor (TNF) has marked effects on permeability and procoagulant activity on tumor-associated neovasculature when used in isolation perfusion, the latter effect primarily mediated via induction of cell surface expression of tissue factor (TF) on endothelial tissue. However, the cellular events that result in rapid alterations in endothelial cell (EC) permeability after intravascular TNF administration in isolation perfusion are not well characterized. We demonstrate that short exposure intervals to TNF induces TF expression on ECs but has no effect on permeability as assessed by flux of Evans blue-bound albumin across confluent EC monolayers using a 2-compartment model under basal culture conditions. However, a rapid and significant increase in EC permeability occurred with TNF in the presence of factor VIII-deficient plasma. Permeability was induced only with luminal versus abluminal TNF exposure and was blocked by antithrombin III, TF pathway inhibitor, or anti-TF antibody cotreatment. These data indicate that EC surface expression of TF and extrinsic clotting factors are critical in augmenting capillary leak following intravascular TNF administration. Alterations in permeability were associated with intercellular gap formation at sites of down-regulation of vascular endothelial (VE)-cadherin expression, the primary endothelial intercellular adhesion molecule, and intracellular contraction and alignment of F-actin cytoskeletal elements. Rapid induction of TF by TNF may be the primary EC response that results in alterations in permeability and procoagulant activity observed following intravascular TNF administration in isolation perfusion.

Antibodies, Monoclonal↗

PubMed2002

Adenovirus-mediated endostatin delivery results in inhibition of mammary gland tumor growth in C3(1)/SV40 T-antigen transgenic mice.

We demonstrate the efficacy of systemic administration of a replication-defective adenovirus expressing endostatin (Ad-mEndo) administered during the preinvasive stage of mammary tumor development in C3(1)/T antigen transgenic mice. Mean serum levels of endostatin increased about 8-fold above that of controls and resulted in a significant decrease in tumor growth and an increase in survival. The inhibitory effect of endostatin occurred during or after the progression to invasive carcinoma. Reduced levels of vascular endothelial growth factor mRNA were found in association with high levels of endostatin. Our results demonstrate that the adenoviral induction of high levels of circulating endostatin significantly inhibits mammary tumor growth during the period when the "angiogenic switch" occurs.

Adenoviridae↗

PubMed2002

Retroviral gene transfer of interferon-inducible protein 10 inhibits growth of human melanoma xenografts.

Interferon-inducible protein 10 (IP-10) is an immunomodulatory chemokine recently recognized to have potent antiangiogenic activity in vivo. Due to difficulties in the stability, manufacture and chronic administration of recombinant forms of endogenous antiangiogenic proteins, antiangiogenic gene therapy has emerged as a promising new form of cancer treatment. We retrovirally transduced A375 human melanoma cells with the human IP-10 gene and injected cells subcutaneously into nude mice. IP-10-transduced cells also were mixed with null-transduced cells in varying proportions before injection. In vivo growth of IP-10-transduced melanoma cells was markedly diminished compared to parental or null-transduced cells (p = 0.0002, Kruskal-Wallis test). This growth inhibition was associated with a marked reduction in microvessel density. The degree of growth inhibition of tumors following injection of a mixed population of null- and IP-10-transduced cells was directly associated with the fraction of IP-10-transduced cells present. We conclude that retroviral transduction of human melanoma cells with the IP-10 gene leads to sufficient protein secretion to inhibit angiogenesis and tumor growth. These findings suggest that IP-10 gene therapy might be an effective therapy in patients with cancer.

Animals↗

PubMed2002

Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer.

BACKGROUND: Drug resistance in breast cancer is a major obstacle to successful chemotherapy. In this study we used cDNA microarray technology to examine gene expression profiles obtained from fine needle aspiration (FNA) of primary breast tumors before and after systemic chemotherapy. Our goal was to determine the feasibility of obtaining representative expression array profiles from limited amounts of tissue and to identify those expression profiles that correlate with treatment response. METHODS: Repeat presurgical FNA samples were taken from six patients who were to undergo primary surgical treatment. Additionally, a group of 10 patients who were to receive neoadjuvant chemotherapy underwent two FNAs before chemotherapy (adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2) followed by another FNA on day 21 after the first cycle. Total RNA was amplified with T7 Eberwine's procedure and labeled cDNA was hybridized onto a 7600-feature glass cDNA microarray. RESULTS: We identified candidate gene expression profiles that might distinguish tumors with complete response to chemotherapy from tumors that do not respond, and found that the number of genes that change after one cycle of chemotherapy was 10 times greater in the responding group than in the non-responding group. CONCLUSION: This study supports the suitability of FNA-derived cDNA microarray expression profiling of breast cancers as a comprehensive genomic approach for studying the mechanisms of drug resistance. Our findings also demonstrate the potential of monitoring post-chemotherapy changes in expression profiles as a measure of pharmacodynamic effect and suggests that these approaches might yield useful results when validated by larger studies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Molecular imaging of tumor angiogenesis.

The emergence of angiogenesis as an important target for cancer therapy has led to increased research aimed at understanding the mechanisms underlying the development, maintenance, and destruction of tumor vasculature. Concurrently, molecular imaging technologies have been developed and are being incorporated as integral components of biomedical research due to their ability to noninvasively monitor in vivo molecular events. With the evaluation of numerous anti-angiogenic agents in clinical trials, the adaptation and validation of molecular imaging modalities for monitoring angiogenesis is actively being pursued. The importance of selecting appropriate molecular targets in the study of angiogenesis has become increasingly complex due to the pleiotropy of vascular phenotypes. Furthermore, due to both the relatively low abundance of endothelial cells in tumor tissue and the inherent difficulties of detecting molecular events, molecular imaging of vasculature necessitates continued improvements in achieving higher sensitivity. While several studies have been published that set the groundwork for imaging angiogenesis, much has yet to be accomplished. Various tumor models and transgenic mice provide an excellent resource for developing molecular imaging technologies for the understanding of angiogenesis. This research may play a particularly crucial role in evaluating mechanism and efficacy during pre-clinical testing of anti-angiogenic drugs. Due to practical limitations, however, the implementation of angiogenesis-directed molecular imaging may not extend beyond highly specialized clinical trials. That is, imaging modalities that evaluate angiogenesis at a functional level may prove more appropriate. Despite future technical challenges, molecular imaging will become an important research and clinical tool in evaluating tumor angiogenesis.

Animals↗

PubMed2002

Blind distal pancreatectomy for occult insulinoma, an inadvisable procedure.

BACKGROUND: Fasting hypoglycemia with neuroglycopenic symptoms corrected by administration of glucose are the hallmarks for the diagnosis of insulinoma. Surgical resection is the treatment of choice for insulinomas, but localization of these lesions can be challenging. Blind distal pancreatectomy has been advocated for occult insulinomas not detected on imaging studies or during abdominal exploration. With the advent of newer localization techniques, we challenge the wisdom of this approach. STUDY DESIGN: The records of patients (multiple endocrine neoplasia excluded) with pathologically proved insulinoma who were screened at our institution or referred to us after a failed blind distal pancreatectomy were reviewed. All records included patient history and results of physical examination and routine blood and urine tests. The diagnosis of insulinoma was confirmed during a supervised fast. Patients with biochemically proved insulinoma underwent localization studies and operation. Studies included CT scans, MRI, transabdominal ultrasound, intraoperative ultrasonography, angiography (more recently, Ca++-stimulated arteriography), and venous sampling. RESULTS: From 1970 to 2000, 99 patients (34 men, 65 women; mean age 43 years) underwent operation. All patients with benign tumors (92) were cured after operation. Seventeen patients were referred to the NIH after a failed blind distal pancreatectomy. Of these, 5 were diagnosed as having factitious hypoglycemia. In the other 12 patients a tumor was localized in the pancreatic head. Two patients incorrectly diagnosed with nesidioblastosis after initial surgery were subsequently cured by resection of an insulinoma. CONCLUSIONS: The use of preoperative imaging studies, most notably Ca++-stimulated arteriography, and intraoperative ultrasonography permits detection of virtually all insulinomas, including reopcrated cases. When a tumor is not detected, the procedure should be terminated and the patient referred to a center capable of performing advanced preoperative and intraoperative localization techniques. With the preoperative and intraoperative imaging strategies currently available, the use of blind distal pancreatectomy for occult insulinoma should be abolished.

Adolescent↗