Progression of Femoral Osteolytic Metastases after Intramedullary Nailing and Subsequent Salvage Techniques.

Intramedullary nailing insertion from the proximal-to-distal femur is frequently performed for impending and complete pathological femur fractures due to osteolytic metastases. After nailing through cancer-laden bone, residual chemotherapy- and/or radiation-resistant tumor may progress. Progression of osteolysis risks future nail failure or pathological fractures. This study assesses the incidence of cancer progression following intramedullary nailing in a femur-only cohort and describes a percutaneous rod-retaining salvage technique. A single-institution, retrospective study was conducted to identify adult patients who underwent intramedullary nailing for femoral osteolytic lesions for complete or impending nail failure from 2016 to 2023. Progression was defined as enlargement of the pre-existing lesion and/or appearance of new lesions on radiographs. Surgical outcomes were assessed with a combined pain and functional score. A total of 113 patients (median age 66.8 years (IQR = 16.4); median follow-up 6.0 months (IQR = 14.5)) underwent intramedullary nailing. Sixteen patients (14.2%) exhibited post-nailing cancer progression. Pre- and postoperative radiation and chemotherapy did not decrease the odds of cancer progression. Three patients underwent initial open surgical salvage consisting of proximal femur replacement arthroplasty, and six patients did not receive salvage due to poor surgical candidacy or patient choice. Seven patients (median follow-up 10.7 months (IQR = 12.9)) received percutaneous salvage. In this group, pain and functional scores improved by 4.0 points (p = 0.0078) at two-week postoperative follow-up and 2.0 points (p = 0.0312) at the most recent follow-up (mean follow-up 13.0 ± 9.4 months). All three nonambulatory patients became ambulatory, and six patients were able to ambulate independently without walking aids. No major complications were reported 30 days postoperatively. Progression of femoral osteolytic metastases may occur following intramedullary nailing. Continued monitoring of the entire femur is needed to maintain improved functional status and to prevent catastrophic progression of pre-existing lesions or appearance of new lesions. In patients with more proximal metastases only, the customary practice of bringing a long nail from the proximal femur to distal metaphysis should be reconsidered. Furthermore, there is concern of mechanical transport of cancer cells during guide wire insertion, reaming, and rod insertion through cancer laden bone to cancer free distal bone.

Recent Advances in Minimally Invasive Management of Osteolytic Periacetabular Skeletal Metastases.

Painful skeletal osteolytic metastases, impending pathological fractures, and nondisplaced fractures present as a devastating clinical problem in advanced stage cancer patients. Open surgical approaches provide excellent mechanical stabilization but are often associated with high complication rates and slow recovery times. Percutaneous minimally invasive interventions have arisen as a pragmatic and logical treatment option for patients with late-stage cancer in whom open surgery may be contraindicated. These percutaneous interventions minimize soft tissue dissection, allow for the immediate initiation or resumption of chemotherapies, and present with fewer complications. This review provides the most up-to-date technical and conceptual framework for the minimally invasive management of osseous metastases with particular focus on periacetabular lesions. Fundamental topics discussed are as follows: (1) pathogenesis of cancer-induced bone loss and the importance of local cytoreduction to restore bone quality, (2) anatomy and biomechanics of the acetabulum as a weight-bearing zone, (3) overview of ablation options and cement/screw techniques, and (4) combinatorial approaches. Future studies should include additional studies with more long-term follow-up to better assess mechanical durability of minimally invasive interventions. An acetabulum-specific functional and pain scoring framework should be adopted to allow for better cross-study comparison.

Bone Mass Changes Following Percutaneous Radiofrequency Ablation, Osteoplasty, Reinforcement, and Internal Fixation of Periacetabular Osteolytic Metastases.

BACKGROUND: The success of orthopedic interventions for periacetabular osteolytic metastases depends on the progression or regression of cancer-induced bone loss. PURPOSE: To characterize relative bone mass changes following percutaneous radiofrequency ablation, osteoplasty, cement reinforcement, and internal screw fixation (AORIF). METHODS: Of 70 patients who underwent AORIF at a single institution, 21 patients (22 periacetabular sites; average follow-up of 18.5 ± 12.3 months) had high-resolution pelvic bone CT scans, with at least one scan within 3 months following their operation (baseline) and a comparative scan at least 6 months post-operatively. In total, 73 CT scans were measured for bone mass changes using Hounsfield Units (HU). A region of interest was defined for the periacetabular area in the coronal, axial, and sagittal reformation planes for all CT scans. For 6-month and 1-year scans, the coronal and sagittal HU were combined to create a weight-bearing HU (wbHU). Three-dimensional volumetric analysis was performed on the baseline and longest available CT scans. Cohort survival was compared to predicted PathFx 3.0 survival. RESULTS: HU increased from baseline post-operative (1.2 ± 1.1 months) to most recent follow-up (20.2 ± 12.1 months) on coronal (124.0 ± 112.3), axial (140.3 ± 153.0), and sagittal (151.9 ± 162.4), p < 0.05. Grayscale volumetric measurements increased by 173.4 ± 166.4 (p < 0.05). AORIF median survival was 27.7 months (6.0 months PathFx3.0 predicted; p < 0.05). At 12 months, patients with >10% increase in wbHU demonstrated superior median survival of 36.5 months (vs. 26.4 months, p < 0.05). CONCLUSION: Percutaneous stabilization leads to improvements in bone mass and may allow for delays in extensive open reconstruction procedures.

Comparison of Percutaneous Interventional Ablation-Osteoplasty-Reinforcement-Internal Fixation (AORIF), Long Intramedullary Nailing, and Hemiarthroplasty for the Treatment of Focal Metastatic Osteolytic Lesions in the Femoral Head and Neck.

PURPOSE: Osteolytic metastatic lesions in the femoral head and neck are traditionally treated with intramedullary long nailing (IM) or hemiarthroplasty (HA). Recovery, surgical complications, and medical co-morbidities delay oncologic care. This study sought to elucidate the comparative efficacy of percutaneous ablation-osteoplasty-reinforcement-internal fixation (AORIF), IM, and HA in stabilizing osteolytic lesions in the femoral head and neck. METHODS: A retrospective study of 67 patients who underwent IM, AORIF, or HA for osteolytic femoral head and neck lesions was performed. Primary outcome was assessed using a combined pain and ambulatory score (Range 1-10: 1 = bedbound, 10 = normal ambulation) at first follow-up (~ 2 weeks). Surgical complications associated with each treatment were compared. RESULTS: Sixty-seven patients (mean age, 65 ± 13, 36 men and 31 women) underwent IM (40), AORIF (19), and HA (8) with a mean follow-up of 9 ± 11 months. Two patients in the IM group (5%), three in the AORIF group (16%), and none in the HA (0%) group required revision procedures. AORIF demonstrated superior early improvement in combined pain and ambulatory function scores by 3.0 points [IQR = 2.0] (IM p = 0.0008, HA p = 0.0190). Odds of post-operative complications was 10.3 times higher in HA than IM (95% confidence interval 1.8 to 60.3). Future revision procedures were not found to be statistically significant between AORIF and IM (p = 0.234). CONCLUSIONS: A minimally invasive interventional skeletal procedure for focal femoral head and neck osteolytic lesions may serve as an effective alternative treatment to traditional surgical approaches, conferring a shorter recovery time and fewer medical complications.

Percutaneous Ablation, Osteoplasty, Reinforcement, and Internal Fixation for Pain and Ambulatory Function in Periacetabular Osteolytic Malignancies.

Background Osteolytic neoplasms to periacetabular bone frequently cause pain and fractures. Immediate recovery is integral to lifesaving ambulatory oncologic care and maintaining quality of life. Yet, open acetabular reconstructive surgeries are associated with numerous complications that delay cancer treatments. Purpose To determine the effectiveness for short- and long-term pain and ambulatory function following percutaneous ablation, osteoplasty, reinforcement, and internal fixation (AORIF) for periacetabular osteolytic neoplasm. Materials and Methods This retrospective observational study evaluated clinical data from 50 patients (mean age, 65 years ± 14 [SD]; 25 men, 25 women) with osteolytic periacetabular metastases or myeloma. The primary outcome of combined pain and ambulatory function index score (range, 1 [bedbound] through 10 [normal ambulation]) was assessed before and after AORIF at 2 weeks and then every 3 months up to 40 months (overall median follow-up, 11 months [IQR, 4-14 months]). Secondary outcomes included Eastern Cooperative Oncology Group (ECOG) score, infection, transfusion, 30-day readmission, mortality, and conversion hip arthroplasty. Serial radiographs and CT images were obtained to assess the hip joint integrity. The paired t test or Wilcoxon signed-rank test and Kaplan-Meier analysis were used to analyze data. Results Mean combined pain and ambulatory function index scores improved from 4.5 ± 2.4 to 7.8 ± 2.1 (P < .001) and median ECOG scores from 3 (IQR, 2-4) to 1 (IQR, 1-2) (P < .001) at the first 2 weeks after AORIF. Of 22 nonambulatory patients, 19 became ambulatory on their first post-AORIF visit. Pain and functional improvement were retained beyond 1 year, up to 40 months after AORIF in surviving patients. No hardware failures, surgical site infections, readmissions, or delays in care were identified following AORIF. Of 12 patients with protrusio acetabuli, one patient required a conversion hemiarthroplasty at 24 months. Conclusion The ablation, osteoplasty, reinforcement, and internal fixation, or AORIF, technique was effective for short- and long-term improvement of pain and ambulatory function in patients with periacetabular osteolytic neoplasm. © RSNA, 2023.

Safety and feasibility of single use cholecystoscopy for guiding laser or mechanical cholelithotripsy, and mechanical cholelithotomy.

PURPOSE Patients with acute calculus cholecystitis and contraindications to cholecystectomy receive cholecystostomy drainage catheters, many of which remain in place until end of life. This study aims to assess safety, feasibility, and early clinical outcomes of percutaneous cholecystoscopy using the LithoVue endoscope, laser/mechanical cholelithotripsy, and mechanical cholelithotomy for management of symptomatic cholelithiasis. METHODS This was a single-institute retrospective analysis of 17 patients with acute calculus cholecystitis who had contraindications to cholecystectomy, underwent cholecystostomy catheter placement between 2015 and 2017, and stone removal between 2017 and 2018. The LithoVue 7.7- 9.5 F endoscope was used in combination with laser/mechanical cholelithotripsy, mechanical retrograde, and balloon-assisted anterograde cholelithotomy to remove gallstones and common bile duct stones. Surgical contraindications ranged from cardiopulmonary disease to morbid obesity to neoplastic processes. Timing and number of interventions, as well as technical and clinical successes, were assessed. RESULTS The median time interval from cholecystostomy catheter placement to cholelithotripsy was 58 days, after an average of 2 tube exchange procedures. Technical and clinical success were achieved in all patients (stone-free gallbladder and cholecystostomy tube removal). On average, three sessions of cholecystoscopy and laser and mechanical cholelithotripsy were required for complete gallstone extraction. The mean interval time between the first cholelithotripsy session and removal of cholecystostomy was 71.8±60.8 days. There were neither major nor minor procedure-related complications. CONCLUSION Percutaneous cholecystoscopy using the LithoVue endoscope, in combination with laser/ mechanical cholelithotripsy and mechanical cholelithotomy, is feasible, safe, well-tolerated, and was able to remove the cholecystostomy tube in the patients with contraindication to cholecystectomy.

Ablation, Osteoplasty, Reinforcement, and Internal Fixation for Percutaneous Endoskeletal Reconstruction of Periacetabular and Other Periarticular Osteolytic Metastases.

For osteolytic metastatic disease in the pelvis and acetabulum of patients with unpredictable and limited lifespans, first-line treatment focuses on targeting the primary cancer with anticancer drugs, osteoclastogenesis inhibitors, analgesics, and radiation therapy. Uncontrolled pain and progressive bone destruction refractory to these interventions often warrant surgical stabilization. Conventional open surgical procedures using metal implants or prostheses may provide immediate biomechanical stability but are associated with various complications without local cancer control. Outcomes of conventional open surgical reconstructive procedures depend on local cancer progression and progressive bone loss. Percutaneous cancer ablation and bone augmentation with polymethyl methacrylate cement alone often lack optimal internal fixation and integration with surrounding bone. The current literature demands a multipurpose minimally invasive surgical intervention that provides local cancer control, bone protection, and stabilization. An overview of new, alternative percutaneous procedure consisting of image-guided ablation, balloon osteoplasty, cement reinforcement, and internal fixation, which offers a minimally invasive percutaneous treatment option for patients with osteolytic metastatic cancers with the advantages of concurrent thermal necrotization of cancers, zoledronate-loaded bone cementoplasty, and surgical stabilization in an ambulatory surgery setting, is warranted. Early clinical results have shown that the ablation, balloon osteoplasty, cement reinforcement, and internal fixation is a safe and effective alternative solution for stabilizing and palliating osteolytic lesions in patients seeking new effective therapies in the era of rapidly evolving oncologic care.

Safety and Efficacy of Percutaneous Cholecystostomy for Emphysematous Cholecystitis.

OBJECTIVE: The objective of the study was to evaluate the safety and efficacy of percutaneous cholecystostomy (PC) in treating critically ill patients with emphysematous cholecystitis who were deemed poor surgical candidates. MATERIALS AND METHODS: The Institutional Review Board exemption was obtained for this retrospective study. Patients with emphysematous cholecystitis who were deemed to be poor operative candidates by the treating surgeon and underwent PC placement between May 2008 and April 2017 at a single institution were identified through a medical records search. Demographics, laboratory values, imaging data, procedural technique, complications, hospitalization course, clinical outcome, and survival data were obtained. RESULTS: Ten consecutive patients were included, with a mean age of 75.0 ± 12.2 years, including six men and four women. The most common comorbidity was diabetes (60%, 6/10) followed by hypertension (40%, 4/10). Intraluminal or intramural gas as well as gallbladder wall thickening were noted in all patients. Procedure technical success rate was 100%. There was a complete resolution of symptoms in 90% (9/10) of patients at a mean of 2.9 ± 1.4 days post-procedure. Thirty-day survival rate was 90% (9/10); one patient died on the 6th post- procedure day from sepsis. Two more deaths occurred within a year after PC from unrelated causes. About 50% (5/10) of patients underwent elective cholecystectomy at a median interval of 69 days post-procedure. In 40% (4/10) of patients, cholecystostomy was the definitive treatment, with tube removal at a median of 140 days post- procedure. CONCLUSION: PC appears to be a safe and generally effective alternative management option in patients with emphysematous cholecystitis that is considered very high risk for surgery.

Simultaneous proximal embolic protection and inferior vena cava mechanical thrombectomy using the FlowTriever system.

Interventional radiologists have the unique ability to apply their imaging knowledge, wide scope of technical skills, and use of innovative technologies to comprehensively address the percutaneous management of the thromboembolic disease processes. This report illustrates successful management of a thrombosed IVC, while protecting against possible pulmonary embolism. Here, we present a 49-year-old female with stage IIIB ovarian cancer who presented with severe bilateral lower extremity edema and anasarca in setting of occlusive thrombus of IVC. The thrombus was the result of compressionfrom a large hepatic hematoma which gradually developed after radical hysterectomy. A new mechanical thrombectomy device approved for use in pulmonary embolism, Inari FlowTriever catheter, was used off-label to remove the clot. The self-expanding mesh discs in the Inari FlowTriever catheter were utilized to protect against pulmonary embolism while percutaneously draining the hepatic hematoma and alleviating the IVC compression. The IVC was largely patent at the end of the procedure, and the patient experienced complete resolution of her symptoms. This case report demonstrates the successful and safe off-label use of a new mechanical thrombectomy device approved for pulmonary embolism thrombectomy in the IVC and illustrates a novel application of the nitinol mesh discs in the device as proximal embolic protection.

Minimally Invasive Image-Guided Ablation, Osteoplasty, Reinforcement, and Internal Fixation (AORIF) for Osteolytic Lesions in the Pelvis and Periarticular Regions of Weight-Bearing Bones.

PURPOSE: To assess early outcome, safety, and complications of an alternative to open surgical treatments of osteolytic lesions in periarticular load-bearing bones. MATERIALS AND METHODS: A single-center, prospective clinical cohort study of 26 lesions in 23 consecutive patients with painful osteolytic skeletal lesions was performed. Patients were followed for an average of 7 mo (1-18 mo). Lesions were targeted from the most intact bone via minimally invasive percutaneous approach for stable anchorage of internal fixation screws using fluoroscopic guidance. Cannulated screws served as universal portals for ablation, balloon osteoplasty, and delivery of bone cement in addition to internal fixation for cement anchoring and prophylactic stabilization of uninvolved bone. RESULTS: There were 19 osteolytic lesions in the pelvis, 4 in the proximal femur, 2 in the proximal tibia, and 1 in the calcaneus. All defects were associated with severe pain or fractures. There were no conversions to open surgery and no infection or bleeding requiring transfusion, embolization, or additional procedures. There was significant improvement in visual analogue scale (VAS) pain score from 8.32 ± 1.70 to 2.36 ± 2.23, combined pain and functional ambulation score from 4.48 ± 2.84 to 7.28 ± 2.76, and Musculoskeletal Tumor Society score from 45% to 68% (P < .05). CONCLUSIONS: Ablation, osteoplasty, reinforcement, and internal fixation is a safe and effective minimally invasive percutaneous image-guided treatment option for functional improvement or palliation of painful osteolytic lesions in the pelvis and periarticular loadbearing bones.

Vertebroplasty-associated cement leak leading to iatrogenic venous compression and thrombosis.

A 91-year-old woman presented with left lower extremity swelling and pain diagnosed as phlegmasia cerulea dolens. Doppler ultrasound and venography revealed extensive left lower extremity deep venous thrombosis. Review of prior images revealed cement leakage causing compression of the left common iliac vein. She underwent successful mechanical thrombectomy using the ClotTriever device (Inari Medical, Irvine, Calif) and subsequent stent placement. Phlegmasia cerulea dolens resolved on the following day, and the stent remained patent at the 1-month follow-up appointment. Cement leakage from L5 vertebroplasty can cause extrinsic compression on the left common iliac vein, resulting in iatrogenic venous compression syndrome and the development of deep venous thrombosis in the affected lower extremity.

Cholangiolithiasis postliver transplantation: Successful treatment utilizing percutaneous transhepatic cholangioscopy and laser lithotripsy.

Liver transplant is a risk factor for the development of cholangiolithiasis and choledocholithiasis. While usually addressed by endoscopic techniques, percutaneous transhepatic cholangioscopy combined with laser lithotripsy can be considered a suitable alternative option in select patients. A 29-year-old male with a 27-year history of liver transplant presented with new onset of persistent pain localized to the lower abdomen 9 days after a liver biopsy. Abdominal CT scan and MRCP showed large calculi expanding intra- and extrahepatic bile ducts. All intrahepatic ductal calculi were removed after 2 sessions of laser lithotripsy and basket retrieval, while common hepatic duct calculi were anterogradely swept into the jejunum after balloon cholangioplasty of the hepaticojejunal anastomosis. No major procedure-related complications were seen. Percutaneous transhepatic cholangioscopy and choledochoscopy with laser lithotripsy is a minimally invasive and efficient technique for removal of intra- and extrahepatic bile duct stones postliver transplantation.

Risk Factors of Infection and Role of Antibiotic Prophylaxis in Totally Implantable Venous Access Port Placement: Propensity Score Matching.

BACKGROUND: To evaluate risk factors of infection and effectiveness of preprocedural single-dose intravenous prophylactic antibiotic (PABX) during totally implantable venous access port (TIVAP) placement in preventing procedure-related infections. METHODS: This was a retrospective single-institution multicenter study evaluating short-term (30-day) infection outcomes after TIVAP placement. Correlation between infection rates and clinical factors, including hematologic versus non-hematologic malignancy, inpatient versus outpatient status, single versus double lumen and PABX, was investigated using univariate and multivariable analysis in the overall study population as well as the propensity-score-matched cohort. RESULTS: Overall, 5967 patients underwent TIVAP placement from 2005 to 2016, of which 3978 (67%) patients received PABX. On propensity score matching, 1952 patients with PABX were matched to the same number of patients without PABX. TIVAP was removed due to infection concern in 48 patients in unmatched and 30 patients in matched population. There was no difference in the rate of infection between those who received PABX and those who did not in both unmatched and matched population (p = 0.5387 and 0.9999). Although infection rate was significantly higher in patients who had TIVAP placement in inpatient setting (p < 0.0001), who received a double-lumen TIVAP (p < 0.0001), or who had hematologic malignancy (p = 0.0004) on univariate analysis, inpatient status was the sole factor associated with higher rate of TIVAP infection on multivariable analysis of both overall (odds ratio 2.31, p < 0.0001) and matched populations (odds ratio 4.36, p = 0.0004). CONCLUSION: Placement of TIVAP in inpatient setting increases the risk of TIVAP infection. PABX before TIVAP placement does not prevent short-term procedure-related infections.

Selective Trans-Catheter Coil Embolization of Cystic Duct Stump in Post-Cholecystectomy Bile Leak.

BACKGROUND: Percutaneous drainage is a first-line treatment for bilomas developed post-cholecystectomy in the setting of bile leak from the cystic duct stump. Percutaneous drainage is usually followed by surgical or endoscopic treatment to address the leak. AIMS: This study aimed to evaluate outcome of selective coil embolization of the cystic duct stump via the percutaneously placed drainage catheters in patients with post-cholecystectomy bile leak. METHODS: Seven patients with persistent bile leak after laparoscopic cholecystectomy who underwent percutaneous catheter placement for biloma/abscess formation in the region of the gallbladder fossa were followed. These patients underwent selective trans-catheter cystic duct stump coil embolization from Feb 2013 to Feb 2019. Procedural management, complications, and success rates were analyzed. RESULTS: All patients underwent placement of a percutaneous catheter for drainage of biloma formation in the gallbladder fossa post-cholecystectomy. Selective coil embolization of the cystic duct was performed through the existing percutaneous tract on average 3.5 weeks after percutaneous catheter placement, resulting in resolution of the biloma. All bile leaks were immediately closed. None of the patients showed recurrent bile leak or further clinical symptoms. Coil migration to the common bile duct was diagnosed in a single case, after 2.5 years, with no bile leak reported. CONCLUSIONS: Selective trans-catheter coil embolization of the cystic stump is a feasible and safe procedure, which successfully seals leaking cystic duct stumps and can circumvent the need for repeat surgical or endoscopic intervention in selected patient populations.

Gastrodoudenal Embolization: Indications, Technical Pearls, and Outcomes.

The gastroduodenal artery (GDA) is frequently embolized in cases of upper GI bleed that has failed endoscopic therapy. Additionally, it may be done for GDA pseudoaneurysms or as an adjunctive procedure prior to Yttrim-90 (Y90) treatment of hepatic tumors. This clinical review will summarize anatomy and embryology of the GDA, indications, outcomes and complications of GDA embolization.

Gastrointestinal carcinoids: the evolution of diagnostic strategies.

Carcinoid tumors are rare, often insidious neoplasms arising from neuroendocrine cells. The majority arise in the gastrointestinal system, and are often incidentally found during investigation, although some may present as an emergency bleed or perforation. The prosaic symptoms of flushing, diarrhea, and sweating are often overlooked; thus, the diagnosis is usually much delayed and the tumor is advanced at presentation. This diagnostic delay renders effective management difficult and adversely affects outcome. This overview provides a current assessment of the evolution of the diagnostic techniques available to establish an accurate biochemical (5-hydroxyindole-3-acetic acid and chromogranin A) and topographic diagnosis (octreoscan, radio-labeled metaidobenzylguanidine, computerized tomography, magnetic resonance imaging, positron emission tomography, enteroclysis, endoscopic ultrasound, enteroscopy, capsule endoscopy, and angiography) of carcinoid tumors. The utility and shortcomings of the respective modalities available are evaluated. Although considerable advances have been made in establishing the diagnosis of carcinoid tumors and in defining the topography of metastatic disease, the major limitation is the inability to establish an early and timely diagnosis before the advent of metastatic disease.

Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed.

OBJECTIVE: To use differential gene expression of candidate markers to discriminate benign appendiceal carcinoids (APCs) from malignant and mixed cell APCs. SUMMARY BACKGROUND DATA: Controversy exists in regard to the appropriate surgical management of APCs since it is sometimes difficult to predict tumor behavior using traditional pathologic criteria. We have identified 5 differentially expressed genes (a mitosis-regulatory gene NAP1L1, an adhesin MAGE-D2, an estrogen-antagonist, the metastasis marker MTA1, the apoptotic marker NALP, and chromogranin A) that define gut neuroendocrine cell behavior. METHODS: Total RNA was isolated using TRIzol reagent from 42 appendiceal samples, including appendiceal carcinoids identified at exploration for appendicitis (no evidence of metastasis; n = 16), appendicitis specimens (n = 11), malignant appendiceal tumors (> 1.5 cm, evidence of metastatic invasion; n = 7), and mixed (goblet) cell appendiceal adenocarcinoids (n = 3), normal appendiceal tissue (n = 5), and 5 colorectal cancers. Gene expression (CgA, NAP1L1, MAGE-D2, MTA1, and NALP1) was examined by Q-RT PCR (Applied Biosystems) and quantified against GAPDH. RESULTS: CgA message was elevated (> 1000-fold, P < 0.05) in all tumor types. NAP1L1 was elevated (> 10-fold, P < 0.03) in both malignant and goblet cell adenocarcinoids compared with normal and incidental lesions (P < 0.006). MAGE-D2 and MTA1 message were significantly elevated (> 10-fold, P < 0.01) in the malignant and goblet cell adenocarcinoid tumors but not in the appendicitis-associated carcinoids or normal mucosa. The apoptotic marker, NALP1, was overexpressed (> 50-fold, P < 0.05) in the appendicitis-associated and malignant appendiceal carcinoids but was significantly decreased (> 10-fold, P < 0.05) in the goblet cell adenocarcinoids. Elevated CgA transcript and protein levels indicative of a carcinoid tumor were identified in one acute appendicitis sample with no histologic evidence of a tumor. CONCLUSIONS: These data demonstrate that malignant APCs and goblet cell adenocarcinoids have elevated expression of NAP1L1, MAGE-D2, and MTA1 compared with appendiceal carcinoids identified at surgery for appendicitis. This and the differences in NALP1 gene expression (decreased in goblet cell adenocarcinoids) provide a series of molecular signatures that differentiate carcinoids of the appendix. CgA identified all appendiceal tumors as well as covert lesions, which may be more prevalent than previously recognized. The molecular delineation of malignant appendiceal tumor potential provides a scientific basis to define the appropriate surgical management as opposed to morphologic assessment alone.

Therapeutic options for gastrointestinal carcinoids.

Although wide surgical resection is the optimal curative therapy for carcinoid tumors, in most patients the presence of metastatic disease at diagnosis usually renders excision a palliative procedure. This nevertheless decreases tumor burden, facilitates symptom control, and prevents complications caused by bleeding, perforation, or bowel obstruction resulting from fibrosis. In the stomach (types I and II) and rectum endoscopic excision may be adequate provided the lesion(s) are local. Long-term therapy is focused on symptom alleviation and improvement of quality of life using somatostatin analogues, particularly in a subcutaneous depot formulation. In some instances interferons may have a role but their usage often is associated with substantial adverse events. Conventional chemotherapy and external radiotherapy either alone or in a variety of permutations are of minimal efficacy and should be balanced against the decrease in quality of life often engendered by such agents. Hepatic metastases may be amenable to surgery, radiofrequency ablation, or embolization either alone or in combination with chemotherapeutic agents or isotopically loaded microspheres. Rarely hepatic transplantation may be of benefit although controversy exists as to its actual use. Peptide-receptor-targeted radiotherapy for advanced disease using radiolabeled octapeptide analogs (111In/90Yt/177Lu-octreotide) appear promising but data are limited and its status remains investigational. A variety of antiangiogenesis and growth factor-targeted agents have been evaluated, but as yet have shown little promise. The keystone of current therapy remains the long-acting somatostatin analogues that alleviate symptomatology and substantially improve quality of life with minimal adverse effects.

Utility of molecular genetic signatures in the delineation of gastric neoplasia.

BACKGROUND: Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors. METHODS: Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray. RESULTS: CgA was elevated in Type I/II (10-fold; P < .01) and Type III/IV (100-fold, P < .005), decreased in GISTs (100-fold, P < .03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P < .05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (> 5-fold, P < .01) was elevated in GCs (Type III/IV>I/II, P < .05), in GISTs (> 4-fold, P < .05), and GCAs. CgA protein levels were elevated in GCs (P < .005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P < .02) compared with normal, and especially with tumor invasion (P < .05). CONCLUSION: CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.

The role of genetic markers--NAP1L1, MAGE-D2, and MTA1--in defining small-intestinal carcinoid neoplasia.

BACKGROUND: Standard clinical and immunohistochemical methods cannot reliably determine whether a small intestinal carcinoid (SIC) is indolent or aggressive. We hypothesized that carcinoid malignancy could be defined by using quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemical approaches that evaluate potential marker genes. METHODS: Candidate marker gene expression (nucleosome assembly protein 1-like 1 [NAP1L1], melanoma antigen D2 [MAGE-D2], and metastasis-associated protein 1 [MTA1]) identified by Affymetrix transcriptional profiling was examined by QRT-PCR in SIC, liver, and lymph node (LN) metastases, colorectal carcinomas, and healthy tissues. Immunohistochemical expression levels of MTA1 were analyzed quantitatively by a novel automated quantitative analysis in a tissue microarray of 102 gastrointestinal carcinoids and in a breast/prostate carcinoma array. RESULTS: Affymetrix transcriptional profiling identified three potentially useful malignancy-marker genes (out of 1709 significantly altered genes). By QRT-PCR, NAP1L1 was significantly (P < .03) overexpressed in SIC compared with colorectal carcinomas and healthy tissue. Increased levels (P < .05) were identified in both liver and LN metastases. Levels in colorectal carcinomas were the same as in healthy mucosa. MAGE-D2 and MTA1 were increased (P < .05) in primary tumors and metastases and overexpressed in carcinomas. Automated quantitative analysis demonstrated the highest levels of MTA1 immunostaining in malignant primary SICs and in metastases to the liver and LN. These were significantly increased (P < .02) compared with nonmetastatic primary tumors. MTA1 was overexpressed in breast and prostate carcinomas (P < .05). CONCLUSIONS: SICs overexpress the neoplasia-related genes NAP1L1 (mitotic regulation), MAGE-D2 (adhesion), and MTA1 (estrogen antagonism). The ability to determine the malignant potential of these tumors and their propensity to metastasize provides a biological rationale for the management of carcinoids and may have prognostic utility.