Comparison of Loss of Bone Height Following Total Ankle Arthroplasty Versus Tibiotalocalcaneal Arthrodesis.

Ankle arthrodesis and total ankle arthroplasty are both well-accepted surgical treatment options for end-stage ankle arthrosis. However, total ankle arthroplasty has gained popularity as the survivability of implants is improving. It is understood that there is loss of bone height following tibiotalocalcaneal arthrodesis, but to our knowledge, this has not been investigated in the setting of total ankle arthroplasty. A retrospective radiographic review was conducted over a 5-year period. We investigated all patients who underwent a tibiotalocalcaneal arthrodesis or total ankle arthroplasty for treatment of ankle arthritis by a single fellowship-trained orthopedic surgeon. The anterior and posterior height measurements were measured on preoperative and postoperative lateral radiographs. Differences between preoperative and postoperative heights were analyzed through a series of analyses of covariance. One hundred and thirty-three patients and 143 operative extremities were included: 71 operative extremities in the tibiotalocalcaneal arthrodesis group (mean age 55.5 ± 13.3 years, BMI 32.2 ± 7.9) and 72 in the total ankle arthroplasty group (mean age 65.4 ± 9.5 years, BMI 30.7 ± 6.4). Statistical analysis demonstrated a loss of height in the tibiotalocalcaneal arthrodesis group, and an increased anterior and posterior height in the total ankle arthroplasty group. However, when comparing the arthroplasty group and arthrodesis group only the anterior height measurement reached statistical significance when stratified by gender (p < .001). The potential change in height is an important factor to consider during surgical planning as a limb length discrepancy may result.

Predictive Factors of Postoperative Pain in Patients With Tibiotalocalcaneal Arthrodesis With an Intramedullary Nail: A Retrospective Review.

Tibiotalocalcaneal arthrodesis has been shown in literature to have good results in regards to low complication rates and deformity correction. While previous studies have investigated functional outcomes and complication rates, no large-scale studies have looked at pain outcomes. The present study performed a retrospective review of 154 extremities to analyze how a patient's comorbidities and characteristics influence pain outcomes following a tibiotalocalcaneal arthrodesis. The present study found an average change of pain from 7.1 to 3.0 in at least a 6 month follow up. We found that a diagnosis of chronic pain and tobacco use had statistically significant less pain improvement compared to patients without chronic pain or current tobacco use. We determined no statistically significant difference in pain outcomes for patients with or without Charcot deformity. Lastly, we found that with older patients there was more pain improvement observed. We physicians can educate current tobacco users of the improved pain outcomes with tobacco cessation prior to surgery. We recommend a multidisciplinary approach for pain in patients with a pre-operative diagnosis of chronic pain and to educate patients on realistic postoperative pain outcomes.

Retrospective Comparison of Isolated Haglund's Deformity Surgery Versus Combined With Gastrocnemius Recession.

Insertional Achilles tendonitis is a common pathology treated by foot and ankle surgeons that may require surgical intervention. Literature has shown good outcomes following detachment and reattachment of the Achilles for removal of the exostosis. However, there is minimal literature showing the impact of adding a gastrocnemius recession to the Haglund's resection. The goal of the present study was to retrospectively review the outcomes of an isolated Haglund's resection versus a Haglund's resection combined with a gastrocnemius recession. A retrospective chart review of 54 operative extremities was performed: 29 with isolated Haglund's resection and 25 with a Strayer gastrocnemius recession. We found similar decreases in pain between the 2 groups, 6.1 to 1.5 and 6.8 to 1.8 in the isolated Haglund's and Strayer's group, respectively. We found decreased postoperative Achilles rupture and reoperation rates in the Strayer group but this did not reach statistical significance. We found a statistically significant decreased rate of wound healing complications in the Strayer group, 4% in the Strayer group and 24% in the isolated procedure. In conclusion, adding a Strayer to a Haglund's resection was found to have a statistically significant decrease in wound complications. We recommend future randomized controlled studies to compare the use of a Strayer procedure on postoperative complications.

Change in Height Following Tibiotalocalcaneal Arthrodesis: Retrospective Radiographic Analysis.

Tibiotalocalcaneal arthrodesis (TTCA) with an intramedullary rod is a viable treatment option for a myriad of pathologies involving the foot and ankle. While the current literature has focused on fixation techniques, deformity correction, and clinical outcomes, we are unaware of any studies specifically examining change in height following a TTCA. In the present study, we retrospectively analyzed radiographs with novel radiographic techniques to determine the change in height from preoperative to postoperative radiographs following TTCA. Patients were divided into 3 categories: Charcot, arthritis, and pes planus as the indication for surgical intervention. We found that Charcot and arthritis had an average decrease in height on anterior and posterior measurements of the height from the distal tibia to the calcaneus, while pes planus had an increase in height. The average Charcot change in height was -12.0 ± 24.4 mm anteriorly and -7.6 ± 15.5 mm posteriorly. The average change in height for the arthritis group was -6.9 ± 6.7 mm anteriorly and -3.8 ± 5.8 mm posteriorly. The pes planus group was found to have an average increase in height 0.5 ± 8.0 mm anteriorly and 2.9 ± 5.8 mm posteriorly. Overall, we found a statistically significant difference in height change between the 3 groups in anterior measurements (p = .012) and posterior measurement (p = .006). We recommend surgeons who perform this procedure to be aware of the potential change in height to better tailor surgical and postoperative care.

Incidence of Nonunion Following First Metatarsophalangeal Joint Arthrodesis for Hallux Valgus Deformity: A Retrospective Analysis of Four Different Constructs.

Arthrodesis of the great toe joint is a valuable procedure for hallux valgus deformities. The primary aim of this study was to determine nonunion rates of a first metatarsophalangeal joint (MTPJ) arthrodesis for bunion deformity. This was a retrospective review of 166 consecutive limbs that underwent a first metatarsal phalangeal joint arthrodesis at Wake Forest Baptist Medical Center (WFBMC). Procedures were performed using 4 different constructs for the arthrodesis. Incidence of nonunion, intermetatarsal correction, infection, and recurrence were measured. Overall, 20 patients (12%) experienced nonunion following a first metatarsophalangeal joint arthrodesis. Eighty-seven patients (86%) of plate and screw patients achieved union while 14 (78%) of crossing screw patients achieved union. The minimum time of follow-up was 3 months and the maximum time was 15.4 months. The mean change in intermetatarsal and hallux valgus angle correction was 3.4° and 20.3°, with no statistical difference based on hardware construct or being diabetic. First metatarsophalangeal joint arthrodesis is a viable option for hallux valgus. However, the results of the present study suggest that there is a lower fusion rate of the first MTPJ using crossing screws for bunion deformities.

Review of Achilles Tendon Reattachment Using Double-Row Knotted and Knotless Techniques in the Management of Insertional Achilles Tendinopathy.

Insertional Achilles tendinopathy represents a chronic degenerative condition affecting the insertion of the Achilles. Surgery is indicated in recalcitrant cases and often involves extensive debridement followed by subsequent repair of the insertion. In the present study, we evaluate the results of knotted and knotless double-row suture systems for Achilles reattachment. Despite the popularity of double-row repairs, there is a relative paucity of clinic data regarding efficacy of the available implants. In a retrospective cohort study, 38 patients (40 Achilles tendons) who received double-row repairs between November 2012 and December 2016 were evaluated. In addition to demographic information, preoperative pain scores and symptom duration were recorded. Perioperative and postoperative records were reviewed, and telephone interviews were conducted to assess patient satisfaction, functional status, postoperative pain, and information regarding surgical complications. At a mean follow-up of 32.5 months, 35 (92.1%) patients reported satisfaction with the outcome. Decreased pain levels were reported in 38 (95%) ankles, with 21 (52.5%) ankles being rated pain-free postoperatively. Of the patients working prior to surgery, 20 (95.2%) were able to return to normal work duties, and all 11 (100%) patients who engaged in sports preoperatively were able to return to the same level of activity. Two patients developed postoperative infections, one of which required operative debridement. No Achilles avulsions were encountered. No significant differences were noted between the 2 operative techniques. Considering the available biomechanical data, along with high patient satisfaction rates and low rate of complications, double-row repair offers a viable option for recalcitrant insertional Achilles tendinopathy.

It Is Time to Rethink Biomarkers for Surveillance of Small Bowel Neuroendocrine Tumors.

BACKGROUND: Tumor biomarkers (TBMs) reflect disease burden and correlate with survival for small bowel neuroendocrine tumors (SBNETs). This study sought to determine the performance of chromogranin A (CgA), pancreastatin (PST), neurokinin A (NKA), and serotonin (5HT) during follow-up assessment of resected SBNETs. METHODS: An institutional database identified patients undergoing surgery for SBNETs. Tumor biomarker levels were assessed as categorical (normal vs elevated) and continuous variables for association with progression-free survival (PFS) and overall survival (OS) via the Kaplan-Meier method with Cox multivariable models adjusted for confounders. Sensitivity, specificity, and predictive values of TBM levels in identifying imaging-confirmed progression were calculated. RESULTS: In 218 patients (44% female, 92% node + , 73% metastatic, 97% G1 or G2), higher levels of CgA, PST, NKA, and 5HT correlated with higher-grade and metastatic disease at presentation (p < 0.05). Elevated pre- and postoperative CgA, PST, and NKA correlated with lower PFS and OS (p < 0.05; median follow-up period, 49.6 months). Normal CgA, PST, and NKA were present in respectively 20.3%, 16.9%, and 72.6% of the patients with progression, whereas elevated levels were present in respectively 69.5%, 24.8%, and 1.3% of the patients without progression. Using TBMs to determine progression showed superiority of PST (78.9% accuracy) over CgA (63.3% accuracy) or CgA and PST together (60.3% accuracy). CONCLUSION: Although specific for progression, NKA was rarely elevated, limiting its usefulness. Pre- and postoperative PST and CgA correlated with disease burden and survival, with PST providing better discrimination of outcomes. During the follow-up period, use of PST most accurately detected progression. These results suggest that PST should replace CgA for SBNET surveillance.

Presacral neuroendocrine tumors associated with the Currarino syndrome.

Currarino syndrome (CS) is an autosomal dominant syndrome caused by mutations in MNX1 and characterized by anorectal abnormalities, partial sacral agenesis, and presacral masses. The presacral masses are typically benign; however, malignant degeneration can occur, and presacral neuroendocrine tumors (NETs) have been reported in six cases. We report three individuals from two families affected by CS in which multiple individuals developed presacral NETs. The first family, 491, had six members with features of CS, including two siblings who presented with presacral, Grade 2 NETs, one of which had metastasized to bone and lymph nodes. A germline c.874C>T (p.Arg292Trp) mutation was found in a highly conserved region of MNX1 in three affected members who underwent sequencing. A second somatic variant/deletion in MNX1 was not detected in either patient's tumor. In the second family, 342, the proband presented with an incidentally discovered presacral NET. The proband's father had previously undergone resection of a presacral NET, and so genetic testing was performed, which did not reveal an MNX1 mutation or copy number variants. The lack of a second, somatic mutation in the tumors from family 491 argues against MNX1 acting as a tumor suppressor, and the absence of a germline MNX1 mutation in family 342 suggests that other genetic and anatomic factors contribute to the development of presacral NETs. These cases highlight the variable presentation of CS, and the potential for malignancy in these patients.

Bone xenotransplantation: A review of the history, orthopedic clinical literature, and a single-center case series.

BACKGROUND: One-half of all orthopedic surgeries require bone grafting for successful outcomes in fusions, reconstructive procedures, and the treatment of osseous defects resulting from trauma, tumor, infection, or congenital deformity. Autologous bone grafts are taken from the patient's own body and remain the "gold standard" graft choice but are limited in supply and impart significant patient morbidity. Xenograft bone is an attractive alternative from donors with controlled biology, in large supply and at a theoretically lower cost. Clinical results with xenograft bone for orthopedic applications have been mixed in the limited clinical trials published. METHODS: In the current review, we introduce fundamental principles of bone grafting, systematically review all orthopedic clinical studies reporting outcomes on patients transplanted with xenograft bone, and we present our own clinical results from patients grafted with bovine bone in foot and ankle reconstructive procedures. RESULTS: Thirty-one clinical studies were identified for review and the majority (47%) were from spine surgery literature. Favorable results were reported in 44% of studies while 47% of studies reported poor outcomes and discouraged use of xenograft bone products. In our own clinical series, xenograft failed to integrate with host bone in 58% of cases and persistent pain was reported in 83% of cases. CONCLUSIONS: This is the first systematic review of clinical results reported after bone xenotransplantation for orthopaedic surgery applications. Current literature does not support the use of xenograft bone products and our institution's results are consistent with this conclusion. Our laboratory has reported promising pre-clinical results with a xenograft product derived from porcine cancellous bone, but additional testing is required before considering clinical translation.

The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors.

BACKGROUND: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma.

PURPOSE: Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results. METHODS: Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals. CONCLUSION: Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.

Comparison of Anal Versus Rectal Staging in the Prognostication of Rectal Squamous Cell Carcinoma: A Population-Based Analysis.

BACKGROUND: Rectal squamous cell carcinoma is a rare malignancy with limited data regarding management and prognosis. It is also unknown whether a rectal squamous cell cancer staging system should be based on size, as for anal squamous cell carcinoma, or depth of invasion, as for rectal adenocarcinoma. OBJECTIVE: The aims of the current study were to determine the optimal management strategy, prognostic factors, and staging system for rectal squamous cell carcinoma. DESIGN: This was a population-based study. SETTINGS: The Surveillance, Epidemiology, and End Results database was used to identify patents diagnosed between 1988 and 2013. PATIENTS: Patients ≥18 years of age undergoing radiation or local excision alone, radiation with local excision, or radiation with radical resection were included. Patients were then staged according to both the American Joint Committee on Cancer classification for rectal adenocarcinoma (American Joint Committee on Cancer-rectum) and anal cancer (American Joint Committee on Cancer-anus). MAIN OUTCOME MEASURES: The main outcome was 5-year, disease-specific survival. RESULTS: In both univariate and multivariate survival analyses, the addition of local excision or radical resection to radiation resulted in similar-to-worse outcomes across all of the stages. Among patients staged according to American Joint Committee on Cancer-rectum (n = 1646), although a significant difference in 5-year survival was observed for stage I as compared with higher stages, no difference was noted between stages II and III (80% vs 61% and 62%). However, in the American Joint Committee on Cancer-anus classification (n = 1327), a significant difference was observed across all of the stages (87% vs 72% vs 59%; p < 0.001). In multivariate analysis, the prognostic discrimination based on HRs provided by the American Joint Committee on Cancer-anus was superior to that of the American Joint Committee on Cancer-rectum. LIMITATIONS: This study was limited by lack of data on chemotherapy and location of positive nodes. CONCLUSIONS: A treatment approach primarily based on radiation should be considered the optimal management strategy for rectal squamous cell carcinoma. Moreover, a staging system based on size (American Joint Committee on Cancer-anus) rather than on depth of invasion (American Joint Committee on Cancer-rectum) appears to be more accurate in predicting its prognosis. See Video Abstract at http://links.lww.com/DCR/A734.

Primary Arthrodesis versus Open Reduction and Internal Fixation for Lisfranc Joint Fracture-Dislocations in Adults: A Systematic Review.

BACKGROUND: The Lisfranc joint is an intricate podiatric medical structure that when injured can prove difficult to treat. No consensus has been established on optimal surgical management for this injury. It is widely debated whether open reduction and internal fixation or primary arthrodesis provides better outcomes for patients. Although literature has been published on this subject, no generalized guidelines have been created. The goal of this study was to analyze high-level meta-analyses to draw conclusions about surgical interventions for Lisfranc joint injuries. METHODS: A literature review was conducted to analyze outcomes of meta-analyses from January 1, 2016, to August 31, 2021. Only high-level evidence that reported at least one of the following outcomes was included: American Orthopaedic Foot and Ankle Society scale score, visual analog scale score, total complication rate, hardware removal rate, revision surgery rate, and secondary procedure rate. RESULTS: Six articles met the inclusion and exclusion criteria and were then analyzed. For all of the outcome measures, primary arthrodesis was equal or superior to open reduction and internal fixation. CONCLUSIONS: We recommend primary arthrodesis over open reduction and internal fixation for adult Lisfranc injuries.

Talar neck fractures: a systematic review of the literature.

Considerable controversy surrounds the management of talar neck fractures regarding the rate of post-traumatic arthrosis, secondary procedures, avascular necrosis, and the effect of the interval to surgery on these variables. A data search using PubMed was performed with the keywords "talus" and "fracture." The search found 1280 studies. Ultimately, 21 reports involving 943 talar neck fractures were analyzed. Data concerning open fractures, the interval to surgery and its relationship to the incidence of avascular necrosis, and the rates of malunion and nonunion, post-traumatic arthrosis, secondary salvage procedures, and functional outcomes were collected and analyzed. The variables examined were not uniformly reported in all studies. The overall rate of avascular necrosis was 33%, with no demonstrated relationship between the interval to surgery and the rate of avascular necrosis. Malunion occurred approximately 17% of the time, with nonunion occurring approximately 5% of the time. Post-traumatic arthrosis occurred in 68% of patients, although secondary salvage procedures were only performed in 19% of patients. Functional outcomes were difficult to assess, given the variability of reported outcomes and unvalidated measures. The optimal management of talar neck fractures has yet to be determined. Although the present review has improved understanding of these difficult fractures, additional studies that use validated outcomes measures are warranted to determine the effect of delayed surgery on final outcomes and optimal treatment methods.

Intermediate to Long-Term Follow-up of the Salto Talaris Fixed-Bearing Total Ankle Prosthesis.

BACKGROUND: Total ankle arthroplasty (TAA) remains a viable option for recalcitrant, end-stage ankle arthritis. Among the various Food and Drug Administration (FDA)-approved prosthetic options is the fixed-bearing Salto Talaris implant. The aim of the present study was to evaluate the intermediate to long-term clinical outcomes and radiographic complications following implantation of the Salto Talaris TAA. METHODS: Nineteen Salto Talaris total ankle implants were included in the present retrospective study. Medical records were reviewed to determine pre- and postoperative visual analog scale (VAS) pain scores, and both medical records and radiographs were utilized to assess for complications. Telephone interviews were then conducted to assess for overall patient satisfaction. RESULTS: At a mean follow of 6.9 years (range, 3.5-12 years), there was a 21% complication rate according to the classification system described by Glazebrook et al. The reoperation rate was low at 10.5%, and there was 100% survivorship of the total ankle implant. The average pain decreased from 9.1 (range, 7-10) preoperatively to 2.6 (range, 0-10) postoperatively. Patients reported a 95% satisfaction rate, and 16% of patients reported using a brace postoperatively. CONCLUSION: The Salto Talaris arthroplasty was associated with low complication and reoperation rates, and a high survivorship at intermediate to long-term follow-up. LEVELS OF EVIDENCE: 4.

Liver-Directed Therapy in Neuroendocrine Neoplasms Metastatic to Both Liver and Bone.

Bone metastases from gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) have been associated with poor prognosis, but it is unclear whether patients with concurrent bone metastases who receive liver-directed therapy (LDT) would derive survival benefit. The California Cancer Registry dataset, merged with data from the California Office of Statewide Health Planning and Development, was used to perform a retrospective study of GEPNENs metastatic to both liver and bone between 2000 and 2012. A total of 203 patients were identified. Of these, 14.8% underwent LDT after bone metastasis diagnosis, 22.1% received LDT prior to that diagnosis, and 63.1% never received LDT. The median overall survival from the time of bone metastasis diagnosis was significantly longer in those that received LDT after diagnosis when compared with those that never received LDT (p = 0.005) and was not significantly different from the median overall survival of those that had received LDT prior to diagnosis (p = 0.256). LDT may still be associated with improved survival even after a diagnosis of bone metastasis.

First metatarsophalangeal arthrodesis: a biomechanical comparison of three fixation constructs.

First metatarsophalangeal joint arthrodesis is utilized in the treatment of severe arthritis and hallux valgus. Successful fusion relies on limiting motion at the fusion site and may be achieved through numerous methods. Use of locking plates has recently generated considerable interest, but whether they provide any biomechanical advantage over other available constructs is unclear. Utilizing cyclic loading intended to mimic early weight bearing, the stiffness of three fixation methods for first metatarsophalangeal arthrodesis was compared using Sawbones. The one-third tubular plate completed 1.8 and 2.4 times more cycles before failure than the X-type locking plate or crossed screws, respectively. No difference was detected in cycles to failure between the X-type locking plate and crossed screws. One-third tubular plate mean stiffness was 49% greater than crossed screws at all cycles and greater than X-type locking plate by an average of 25%, beginning at cycle 50.

Metastatic pancreatic neuroendocrine tumors have decreased somatostatin expression and increased Akt signaling.

BACKGROUND: Patients with pancreatic neuroendocrine tumors often present with metastases, which reduce survival. Molecular features associated with pancreatic neuroendocrine tumor tumorigenesis have been reported, but mechanisms of metastasis remain incompletely understood. METHODS: RNA sequencing was performed on primary and metastatic pancreatic neuroendocrine tumors from 43 patients. Differentially expressed genes were identified, and quantitative polymerase chain reaction used to confirm expression differences. BON cells were transfected with short interfering RNAs and short hairpin RNAs to create knockdowns. Expression changes were confirmed by quantitative polymerase chain reaction, cell viability assessed, and protein levels evaluated by Western blot and immunofluorescence. RESULTS: Nodal and hepatic metastases had decreased expression of somatostatin compared with primary tumors (P = .003). Quantitative polymerase chain reaction in a validation cohort confirmed 5.3-fold lower somatostatin expression in hepatic metastases (P = .043) with no difference in somatostatin receptor, synaptophysin, or chromogranin A expression. Somatostatin knockdown in BON cells increased cell metabolic activity, viability, and growth. Somatostatin-knockdown cells had significantly higher levels of phosphorylated Akt protein and higher mTOR compared with controls. CONCLUSION: Pancreatic neuroendocrine tumor metastases have lower expression of somatostatin than primary tumors, and somatostatin knockdown increased growth in pancreatic neuroendocrine tumor cell lines. This was associated with increased activation of Akt, identifying this pathway as a potential mechanism by which loss of somatostatin expression promotes the metastatic phenotype.

Management of Small Bowel Neuroendocrine Tumors.

Small bowel neuroendocrine tumors (SBNETS) are slow-growing neoplasms with a noted propensity toward metastasis and comparatively favorable prognosis. The presentation of SBNETs is varied, although abdominal pain and obstructive symptoms are the most common presenting symptoms. In patients with metastases, hypersecretion of serotonin and other bioactive amines results in diarrhea, flushing, valvular heart disease, and bronchospasm, termed carcinoid syndrome. The treatment of SBNETs is multimodal and includes surgery, liver-directed therapy, somatostatin analogues, targeted therapy, and peptide receptor radionuclide therapy.

Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors.

PURPOSE: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed. EXPERIMENTAL DESIGN: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). RESULTS: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds. CONCLUSIONS: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.