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ABSTRACT: Neuroendocrine tumors (NETs) can have indolent clinical courses and patients with metastatic disease may live many years after the initial diagnosis. Recent studies have suggested that aggressive treatments may extend survival. In this review, we assess the recent literature regarding management of well-differentiated NETs from the gastrointestinal (GI) tract metastatic to the liver. We focus on studies regarding surgical resection, embolization, or ablation of hepatic lesions. We also present a management algorithm for patients who present with metastatic lesions but the primary lesion cannot be located. Since NETs are rare, all of the available evidence is based on retrospective studies that have limited sample size. As a result, recommendations are offered with caution.
Seminars in Oncology 02/2013; 40(1):69-74. · 3.50 Impact Factor
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ABSTRACT: The decision to perform pancreas-preserving procedures or standard resections for pancreatic neuroendocrine tumors (PNETs) is often based on the perceived risk of malignancy, including potential nodal involvement. We sought to identify clinicopathological factors that predict nodal disease.
This is a retrospective review of pathology database for PNET resections from January 1, 1988, to March 15, 2010. Univariate analysis and multivariate logistic regression were used to identify predictors of nodal metastasis.
A total of 149 patients were identified. Enucleations had lower lymph node sampling rates compared to major resections. Excluding enucleations, 23% of patients had no lymph nodes sampled. For patients who did have lymph nodes evaluated, a median of 5 lymph nodes were examined. On multivariate analysis, only distant disease predicted nodal metastasis (odds ratio = 3.80, P = 0.02); tumor size did not (P = 0.48). One third of patients with lymph node metastasis had tumors less than 3 cm.
Lymph nodes are not evaluated in many major pancreatic resections for PNET, and preoperative prediction of nodal metastasis is difficult, even when tumor size is considered. Consequently, many patients may be understaged and undergo potentially inadequate resection. Inconsistent lymph node sampling may explain conflicting conclusions in the literature regarding the prognostic value of lymph node involvement in PNET patients.
Pancreas 08/2012; 41(6):840-4. · 2.39 Impact Factor
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Margaret A Tempero,
J Pablo Arnoletti,
Stephen W Behrman,
Edgar Ben-Josef,
Al B Benson,
Ephraim S Casper,
Steven J Cohen,
Brian Czito,
Joshua D I Ellenhorn,
William G Hawkins, [......],
Jorge Obando,
Martha B Pitman,
Aaron R Sasson,
Anitra Tally,
Sarah P Thayer,
Samuel Whiting,
Robert A Wolff,
Brian M Wolpin,
Deborah A Freedman-Cass,
Dorothy A Shead
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ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.
Journal of the National Comprehensive Cancer Network: JNCCN 06/2012; 10(6):703-13. · 4.41 Impact Factor
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ABSTRACT: Retroperitoneal tumors are often massive and can involve adjacent organs and/or vital structures, making them difficult to resect. Completeness of resection is within the surgeon's control and critical for long-term survival, particularly for malignant disease. Few studies directly address strategies for complete and safe resection of challenging retroperitoneal tumors.
Fifty-six patients representing 63 cases of primary or recurrent retroperitoneal tumor resection between 2004-2009 were identified and a retrospective chart review was performed. Rates of complete resection, use of adjunct procedures, and perioperative complications were recorded.
In 95% of cases, complete resection was achieved. Fifty-eight percent of these cases required en bloc multi-organ resection, and 8% required major vascular resection. Complete resection rates were higher for primary versus recurrent disease. Adjunct procedures (ureteral stents, femoral nerve monitoring, posterior laminotomy, etc.) were used in 54% of cases. Major postoperative complications occurred in 16% of cases, and one patient died (2% mortality).
Complete resection of challenging retroperitoneal tumors is feasible and can be done safely with important pre- and intraoperative considerations in mind.
World Journal of Surgical Oncology 11/2011; 9:143. · 1.12 Impact Factor
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ABSTRACT: This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.
Journal of Surgical Oncology 05/2011; 103(6):607-14. · 2.10 Impact Factor
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Margaret A Tempero,
J Pablo Arnoletti,
Stephen Behrman,
Edgar Ben-Josef,
Al B Benson,
Jordan D Berlin,
John L Cameron,
Ephraim S Casper,
Steven J Cohen,
Michelle Duff, [......],
Mokenge P Malafa,
Peter Muscarella, Eric K Nakakura,
Aaron R Sasson,
Sarah P Thayer,
Douglas S Tyler,
Robert S Warren,
Samuel Whiting,
Christopher Willett,
Robert A Wolff
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ABSTRACT: Overview An estimated 36,800 people will die of pancreatic cancer in the United States in 2010.1 This disease is the fourth most common cause of cancer-related death among men and women in the United States.(1) Its peak incidence occurs in the seventh and eighth decades of life. Although incidence is roughly equal for the sexes, African Americans seem to have a higher incidence of pancreatic cancer than white Americans.(2) These guidelines only discuss tumors of the exocrine pancreas; neuroendocrine tumors are not included. By definition, these NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. Exceptions to the rule were discussed among the panel members during development of these guidelines. A 5% rule (omitting clinical scenarios that constitute fewer than 5% of all cases) was used to eliminate uncommon clinical occurrences or conditions from these guidelines. The panel unanimously endorses participation in a clinical trial as the preferred option over standard or accepted therapy. Risk Factors and Genetic Predisposition Although the associated increase in risk is small, the development of pancreatic cancer is firmly linked to cigarette smoking.(3-5) Some evidence shows that increased consumption of red meat and dairy products is associated with an elevation in pancreatic cancer risk,(6) although other studies have failed to identify dietary risk factors.(4) An increased body mass index is also associated with increased risk.(7-9) Occupational exposure to chemicals, such as beta-naphthylamine and benzidine, is also associated with an increased risk of pancreatic...
Journal of the National Comprehensive Cancer Network: JNCCN 10/2010; 8(9):972-1017. · 4.41 Impact Factor
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ABSTRACT: Patients with neuroendocrine tumors (NETs) may have metastatic disease and unknown primary site. NETs commonly arise from the bronchopulmonary (BP) and gastrointestinal (GI) tract. The largest subgroups of well-differentiated BP-NETs are typical carcinoids (TCs). The homeodomain transcription factor NKX2.2 regulates development of gut serotonin cells and is a marker of GI-NETs. Previous work on a limited number of samples suggested that BP-TCs do not express NKX2.2. We hypothesized that lack of NKX2.2 expression in BP-TCs might be useful to distinguish BP- from GI-NETs, and evaluated NKX2.2 expression in a larger number of BP-TCs.
Archived formalin-fixed, paraffin-embedded tissues were obtained from 13 previously undescribed patients with BP-TCs. Expression of NKX2.2, serotonin, and the NE marker chromogranin A (CgA) were assessed by immunohistochemistry.
CgA expression was robust in all 13 BP-TCs, confirming the NE phenotype. Serotonin expression was less frequent (9/13; 69%). Two patients with BP-TCs in which serotonin expression was absent exhibited Cushing's syndrome due to ectopic ACTH production. NKX2.2 expression was not observed in any of the 13 tumors.
Bronchopulmonary TCs uniformly express CgA but not NKX2.2. Because most of these tumors express serotonin, our findings suggest that NKX2.2 may not be required for serotonin production by BP-TCs. We conclude that the presence or absence of NKX2.2 expression may assist in the determination of the primary tumor site in patients with NET metastases of unknown origin. NET metastases that are CgA-positive/NKX2.2-negative would suggest a BP primary, whereas those that are CgA-positive/NKX2.2-positive would suggest a GI primary.
Journal of Surgical Research 09/2010; 163(1):47-51. · 2.25 Impact Factor
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ABSTRACT: For patients with neuroendocrine tumor (NET) liver metastases, resection of the primary tumor may prevent local complications (obstruction, ischemia, and bleeding) and improve survival. Despite preoperative evaluation, the primary tumor location may remain unknown.
Retrospective cohort analysis of pathology database from January 1, 1993, to August 15, 2008.
Academic medical center.
One hundred twenty-three patients with NET liver metastases.
Successful identification and resection of the primary tumor.
Fifteen patients underwent surgical exploration. The primary tumor was located in 13 patients (86.7%) in the small intestine and resected in 12 patients. Primary tumors in the small intestine found during surgical exploration were significantly smaller than those identified preoperatively (1.38 vs 1.91 cm, P = .03) and were often multifocal (54.2% [n = 15]). Computed tomography (34.6% [n = 78]) and somatostatin receptor scintigraphy (26.2% [n = 42]) were not sensitive in locating a primary NET in the gastrointestinal tract. Colonoscopy was sensitive in detecting colonic NETs (86.7% [n = 15]).
For patients with NET liver metastases and unknown primary tumor, surgical exploration effectively identifies and resects occult primary tumors that are often located in the small intestine. Primary tumors are usually small and multifocal, so careful palpation of the small intestine is essential. Before patients are considered for surgery, a multidisciplinary team assessment and evaluation consisting of computed tomography, somatostatin receptor scintigraphy, and upper and lower endoscopy should be done.
Archives of surgery (Chicago, Ill.: 1960) 03/2010; 145(3):276-80. · 4.32 Impact Factor
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ABSTRACT: Patients with renal cell carcinoma (RCC) involving the gastrointestinal (GI) tract may present with hemorrhage. Eight arterial embolization procedures were performed to treat five upper GI lesions and one ileal metastatic RCC lesion in five patients with GI bleeding. Control of GI hemorrhage for at least 30 days was achieved following six of the eight embolizations (75%) in four of the five patients (80%). Duration of response ranged from 1 to 26 months. Complications including GI ischemia and nontarget embolization were not encountered. Arterial embolization can be used safely for palliation of hemorrhage from RCC metastases to the GI tract.
Journal of vascular and interventional radiology: JVIR 03/2010; 21(5):741-4. · 1.81 Impact Factor
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ABSTRACT: Neuroendocrine (NE) or carcinoid tumors of the small intestine (SI) frequently metastasize and produce the hormone serotonin, causing significant morbidity and mortality. A member of the ETS oncogene family of transcription factors, Fev, acts with the homeodomain transcription factor Nkx2.2 in the development of serotonin neurons in mice. In this study, we investigated the role of Fev in normal and neoplastic SI. In NE tumors (NETs) of the SI, serotonin stimulates tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and right-sided valvular heart disease (i.e. carcinoid syndrome). Compared with those in the matched normal human SI, FEV expression levels were significantly elevated in primary NETs (20-fold, P<0.0001), lymph node metastases (35-fold, P=0.004), and NET liver metastases (22-fold, P<0.0001) resected from patients with serotonin excess. Fev is expressed in the wild type but not in Nkx2.2 (-/-) mouse SI, in which cells producing serotonin are absent. Using recombination-based cell lineage tracing, we found that FEV-positive cells give rise to serotonin-producing cells in the SI. In Fev (-/-) mouse SI, we observed no difference in the number of cells producing serotonin or other hormones. We conclude that FEV expression identifies serotonin-producing cells in normal and neoplastic SI and is a novel target for diagnosis of patients with NETs of the SI.
Endocrine Related Cancer 03/2010; 17(1):283-91. · 4.36 Impact Factor
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ABSTRACT: While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.
Genes & development 09/2009; 23(18):2152-65. · 12.08 Impact Factor
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ABSTRACT: Resection of large retroperitoneal neoplasms may injure the femoral nerve, thereby causing a permanent neurological deficit. We used electrical neurophysiological monitoring to identify, map, and preserve the femoral nerve during surgical resection to reduce the risk of neurological deficit.
Seven patients with retroperitoneal neoplasms underwent eight resections. Compound muscle action potentials (CMAPs) were recorded from needle electrodes placed in the iliacus, quadriceps, and sartorius muscles. Spontaneous electromyography (EMG) was continuously monitored from the same muscle groups. A handheld monopolar stimulator was used to elicit evoked EMG responses to identify and map the course of the femoral nerve. A stimulating strength of 10 mA was used to map the nerve. The stimulation threshold was tested after neoplasm resection to predict postoperative femoral nerve function.
Electrical stimulation with CMAP recording and a stimulating strength of 10 mA successfully localized the femoral nerve in six cases. Monitoring with a stimulating threshold between 0.6 and 1.6 mA predicted postoperative femoral nerve preservation after tumor resection in four of the six cases.
Neurophysiological monitoring using CMAP and spontaneous EMG can protect the femoral nerve during resection of large retroperitoneal neoplasms.
Annals of Surgical Oncology 07/2008; 15(6):1594-9. · 4.17 Impact Factor
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ABSTRACT: Dedifferentiated liposarcoma can be readily diagnosed by the juxtaposition of a well-differentiated liposarcoma to a nonlipogenic sarcoma. However, if the lipogenic component is not abundant due to surgical sampling or small biopsy, dedifferentiated liposarcoma can be difficult to distinguish from other poorly different sarcomas. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nuclear hormone receptor that plays a critical role in adipocyte differentiation. Prior studies have not only demonstrated PPAR-gamma mRNA in various subtypes of liposarcoma but have also shown that adipocyte differentiation can be induced in some liposarcomas by a PPAR-gamma agonist. In the present study, we investigated whether immunostaining for PPAR-gamma can be used to distinguish dedifferentiated liposarcoma from other retroperitoneal sarcomas. We examined a series of 40 dedifferentiated liposarcoma and compared the staining for PPAR-gamma to a series of 24 retroperitoneal sarcomas that lacked lipogenic differentiation. A monoclonal antibody against PPAR-gamma was used to stain formalin-fixed paraffin-embedded tissue. Specific nuclear immunostaining was present in 37/40 (93%) of the dedifferentiated liposarcoma and 6/24 (25%) of the other sarcomas (two leiomyosarcomas and four undifferentiated sarcomas). Interestingly, immunostaining for CDK4 and/or MDM2 was identified in three of the four PPAR-gamma-positive undifferentiated sarcomas, raising the possibility that these may represent dedifferentiated liposarcoma. This is the first study demonstrating the utility of PPAR-gamma immunohistochemistry in the diagnosis of dedifferentiated liposarcoma in tissue sections. Although not completely specific, the presence of PPAR-gamma staining, in combination with histologic findings and other markers, can aid in the diagnosis of dedifferentiated liposarcoma, particularly on small biopsies that may not sample the well-differentiated component.
Modern Pathology 06/2008; 21(5):517-24. · 4.79 Impact Factor
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ABSTRACT: The patient described here exemplifies the feasibility and potential benefits of rapid, sequential pre-operative embolization and surgical resection of a large, functional abdominal paraganglioma. This combination of immediate pre-operative embolization and surgical resection may help decrease operative complications, including hypertensive crisis, improve the surgical outcome in patients with large secretory vascular tumors, may provide palliation for patients with unresectable tumors. Normetanephrines >24,478 nmol/d (Normal <2,738 nmol/d) Total metanephrines >49,209 nmol/d (Nl <3,498 nmol/d) Epinephrine 38.22 nmol/d (Nl <591 nmol/d) Norepinephrine 9113 nmol/d (Nl <131 nmol/d) Dopamine 4087 nmol/d (Nl <3139 nmol/d) The patient's plasma fractionated metanephrine, catecholamine, and serum chromogranin A levels are presented in Table 1. The patient described here exemplifies the feasibility and potential benefits of rapid, sequential pre-operative embolization and surgical resection of a large, functional abdominal paraganglioma. This combination of immediate pre-operative embolization and surgical resection may help decrease operative complications, including hypertensive crisis, improve the surgical outcome in patients with large secretory vascular tumors, may provide palliation for patients with unresectable tumors.
Journal of Human Hypertension 05/2008; 22:S20. · 2.80 Impact Factor
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Surgical Oncology 01/2008; 16(4):235. · 2.44 Impact Factor
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ABSTRACT: Because most patients with pancreatic and biliary cancer have advanced disease, the palliation of debilitating symptoms is critically important in patient management. A multidisciplinary team consisting of representatives from surgery, medical oncology, gastroenterology, radiology, and palliative care medicine is essential for the optimal palliation of symptoms. In this article, the key issues in palliative care for patients with advanced pancreatic and biliary cancer are discussed. In particular, the prevention and amelioration of suffering due to obstructive jaundice, gastric outlet obstruction, cancer-related pain, pancreatic enzyme insufficiency, and thromboembolic disease is addressed. To this end, an algorithm for the multidisciplinary management of these challenging patients is proposed with the goal of providing clinicians with a useful framework for providing palliative care for patients with advanced pancreatic and biliary cancer.
Surgical Oncology 01/2008; 16(4):293-7. · 2.44 Impact Factor
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Margaret Tempero,
J Pablo Arnoletti,
Edgar Ben-Josef,
Pankaj Bhargava,
Ephraim S Casper,
Paula Kim,
Mokenge P Malafa, Eric K Nakakura,
Stephen Shibata,
Mark Talamonti,
Hanlin Wang,
Christopher Willett
Journal of the National Comprehensive Cancer Network: JNCCN 12/2007; 5(10):998-1033. · 4.41 Impact Factor
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ABSTRACT: A multidisciplinary team is essential for the optimal management of patients with metastatic neuroendocrine tumors. In this article, the systemic and regional nonsurgical therapeutic options for metastatic neuroendocrine cancers are discussed. In particular, the roles of biotherapy, chemotherapy, and hepatic artery embolization/chemoembolization are reviewed. A proposed treatment algorithm is provided with the aim of providing clinicians with a useful framework for managing these challenging patients. Finally, the rationale for promising investigational therapies is described.
Surgical Oncology Clinics of North America 08/2007; 16(3):639-51, x. · 1.12 Impact Factor
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ABSTRACT: Most patients who have islet cell tumors, except those who have insulinomas, present with locally advanced or metastatic disease. In contrast with patients who have adenocarcinoma of the pancreas, those who have islet cell carcinomas can achieve long-term survival even if their disease is advanced. Liver-directed therapies, somatostatin analogs, and interferon are not curative but can be used to relieve tumor-associated symptoms. Similarly, palliative chemotherapy has been used with limited success. Advances in our understanding of the molecular mechanisms underlying tumor progression have translated into intense interest in biologically based strategies to treat this disease.
Hematology/Oncology Clinics of North America 07/2007; 21(3):457-73; viii. · 2.64 Impact Factor
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ABSTRACT: We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than one-fourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer.
Cancer Research 09/2006; 66(15):7509-15. · 7.86 Impact Factor
