What to do When Decompressive Gastrostomies and Jejunostomies are not Options? A Scoping Review of Transesophageal Gastrostomy Tubes for Advanced Malignancies.

BACKGROUND: In advanced malignant bowel obstruction, decompressive gastrostomy tubes (GTs) may not be feasible due to ascites, peritoneal carcinomatosis, and altered gastric anatomy. Whereas nasogastric tubes (NGTs) allow temporary decompression, percutaneous transesophageal gastrostomy tubes (PTEGs) are an alternative method for long-term palliative decompression. This study performed a scoping review to determine outcomes with PTEG in advanced malignancies. METHODS: A systematic literature search was performed to include all studies that reported the clinical results of PTEGs for malignancy. No language, national, or publication status restrictions were used. RESULTS: The analysis included 14 relevant studies with a total of 340 patients. In 11 studies, standard PTEGs were inserted with a rupture-free balloon's placement into the mouth or nose and esophageal puncture under fluoroscopy or ultrasound, followed by a guidewire into the stomach with placement of a single-lumen tube. Of 340 patients, 65 (19.1%) had minor complications, and 5 (2.1%) had significant complications, including bleeding and severe aspiration pneumonia. Of 171 patients, 169 with PTEGs (98.8%) reported relief of nasal discomfort from NGT and alleviation of obstructive symptoms. The one randomized controlled trial reported a significantly higher quality of life with PTEGs than with NGTs. CONCLUSIONS: When decompression for advanced malignancy is technically not feasible with a gastrostomy tube, the PTEG is a viable, safe option for palliation. The PTEG is associated with lower significant complication rates than the gastrostomy tube and significantly higher patient-derived outcomes than the NGT.

Locally Transplanted Adipose Stem Cells Reduce Anastomotic Leaks in Ischemic Colorectal Anastomoses: A Rat Model.

BACKGROUND: Anastomotic leakage remains a dreaded complication after colorectal surgery. Stem-cell-based therapies have been shown to increase angiogenesis and cell proliferation. OBJECTIVE: The purpose of this research was to investigate the use of adipose-derived stem cells on the healing of ischemic colonic anastomoses in a rat model. DESIGN: This is an animal research study using xenotransplantation. SETTINGS: Male Wistar rats (300-400 g, n = 48) were purchased from a licensed breeder. PATIENTS: Adipose stem cells were isolated from the subcutaneous fat of healthy human donors. INTERVENTIONS: The rats underwent laparotomy with creation of an ischemic colorectal anastomosis created by ligation of mesenteric vessels. The animals were divided into 3 groups: control group with an ischemic anastomosis, vehicle-only group in which the ischemic anastomosis was treated with an absorbable gelatin sponge, and a treatment group in which the ischemic anastomosis was treated with an absorbable gelatin sponge plus adipose stem cells. Animals were killed at postoperative days 3 and 7. MAIN OUTCOME MEASURES: Anastomotic leakage was defined as the finding of feculent peritonitis or perianastomotic abscess on necropsy. Rat mRNA expression was measured using real-time polymerase chain reaction. RESULTS: Adipose-derived stem cells significantly decreased anastomotic leakage when compared with control at both postoperative days 3 (25.0% vs 87.5%; p = 0.02) and 7 (25.0% vs 87.5%; p = 0.02). The use of an absorbable gelatin sponge alone had no effect on anastomotic leakage when compared with control and postoperative days 3 or 7. We found that stem cell-treated animals had a 5.9-fold and 7.4-fold increase in the expression of vascular endothelial growth factor when compared with control at 3 and 7 days; however, this difference was not statistically significant when compared with the absorbable gelatin sponge group. LIMITATIONS: This is a preclinical animal research study using xenotransplantation of cultured stem cells. CONCLUSIONS: Locally transplanted adipose stem cells enhance the healing of ischemic colorectal anastomoses and may be a novel strategy for reducing the risk of anastomotic leakage in colorectal surgery. See Video Abstract at http://links.lww.com/DCR/B203. EL TRANSPLANTE LOCAL DE CÉLULAS MADRE ADIPOSAS REDUCE LA FUGA ANASTOMÓTICA EN LAS SUTURAS COLORRECTALES ISQUÉMICAS: MODELO EN RATAS: Las fugas anastomóticas son una complicación pusilánime después de toda cirugía colorrectal. Se ha demostrado que el tratamiento con células madre aumenta la angiogénesis y la proliferación celular.Investigar el uso de células madre derivadas de tejido adiposo en la cicatrización de una anastomosis colónica isquémica basada en ratas como modelo.Estudio de investigación en animales utilizando xenotrasplantes.Adquisición de típicas ratas de laboratorio raza Wistar, todas machos (300-400 g, n = 48) de un criadero autorizado.Aislamiento de células madre de tipo adiposo del tejido celular subcutáneo en donantes humanos sanos.Las ratas se sometieron a laparotomía con la creación de una anastomosis colorrectal isquémica obtenida mediante ligadura controlada de los vasos mesentéricos correspondientes. Los animales se dividieron en tres grupos: grupo de control con anastomosis isquémica, grupo de vehículo único en el que la anastomosis isquémica se trató con una esponja de gelatina absorbible, y un grupo de tratamiento en el que la anastomosis isquémica se trató con una esponja de gelatina absorbible asociada a un vástago adiposo de células madre. Los animales fueron sacrificados el POD3 y el POD7.La fuga anastomótica fué definida como el hallazgo de peritonitis fecaloidea o absceso perianastomótico a la necropsia. La expresión de RNAm de las ratas se midió usando PCR en tiempo real.Las células madre derivadas de tejido adiposo disminuyeron significativamente la fuga anastomótica en comparación con el grupo control tanto en el POD3 (25% frente a 87.5%, p = 0.02) como en el POD7 (25% frente a 87.5%, p = 0.02). El uso de una esponja de gelatina absorbible sola, no tuvo efecto sobre la fuga anastomótica en comparación con los controles el POD3 o el POD7. Descubrimos que los animales tratados con células madre adiposas tenían un aumento de 5,9 y 7,4 veces en la expresión de VEGF en comparación con el control a los 3 y 7 días, respectivamente; sin embargo, esta diferencia no fue estadísticamente significativa en comparación con el grupo de esponja de gelatina absorbible.Este es un estudio preclínico de investigación en animales que utiliza xenotrasplantes de células madre adiposas cultivadas.Las células madre de tipo adiposo trasplantadas localmente mejoran la cicatrisación en casos de anastomosis colorrectales isquémicas, y podrían convertirse en una nueva estrategia para reducir el riesgo de fugas anastomóticas en casos de cirugía colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B203. (Traducción-Dr Xavier Delgadillo).

Features of mixed medullary thyroid tumors: An NCDB analysis of clinicopathologic characteristics and survival.

BACKGROUND: Mixed medullary-papillary thyroid carcinoma (MMPTC) and mixed medullary-follicular thyroid carcinoma (MMFTC) are rare variants with little known regarding behavior and prognosis. METHODS: Using the National Cancer Database (NCDB), demographics, clinicopathologic features, treatment, and overall survival (OS) from patients with MMPTC and MMFTC were compared to more prevalent subtypes. RESULTS: There were 296,101 patients: 421 MMPTC (0.14%), 133 MMFTC (0.04%), 263,140 PTC (88.87%), 24,208 FTC (8.18%) and 8,199 MTC (2.77%). Compared to PTC, MMPTC and MMFTC patients were older (p < 0.001) with a higher Charlson-Deyo comorbidity index (p < 0.001). Mixed tumors exhibited lower rates of nodal disease but more distant metastases compared to PTC (p < 0.001). MMPTC demonstrated lower estimated 10-year OS than PTC and FTC (76.04%vs 89.04% and 81.95%,p < 0.001), yet higher than MTC (70.29%,p < 0.001). MMFTC had a worse OS compared to all groups (63.32%,p < 0.001). CONCLUSION: Patients with MMFTC had significantly worse OS compared to DTC, portending a worse prognosis.

Cost-Benefit Analysis of Robotic vs. Laparoscopic Hepatectomy: A Propensity-Matched Retrospective Cohort Study of American College of Surgeons National Surgical Quality Improvement Program Database.

BACKGROUND: Robotic and laparoscopic hepatectomies having increased utilization as minimally invasive techniques are explored for hepatobiliary malignancies. Although the data on outcomes from these 2 approaches are emerging, the cost-benefit analysis of these approaches remains sparse. This study compares the costs associated with robotic vs. laparoscopic liver resections, taking into account 30-day complications. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, a propensity-matched cohort of patients with laparoscopic or robotic liver resections between 2014 and 2017 was identified. Costs were assigned to perioperative variables, including operating room (OR) time, length of stay, blood transfusions, and 30-day complications. Cost estimates were obtained from the Centers for Medicare and Medicaid Services billing data (2017), American Hospital Association data (2017), relevant literature, and local institutional cost data. RESULTS: In our matched cohort of 454 patients (227 per group), total costs associated with laparoscopic liver resections were estimated at $5.5 M ($24 K per patient) vs. $6.8 M ($29.8 K per patient) for robotic liver resections (21.3% difference, P < .001). The higher cost associated with robotic hepatectomies was related to blood transfusions ($22.0 K vs. $12.1 K, P = .02), length of stay ($2.05 M vs. $1.76 M, P = .046), and OR time ($4.01 M vs. $3.24 M, P < .0001). DISCUSSION: Robotic hepatectomies were associated with higher costs compared to laparoscopic hepatectomies. The 2 major contributors to the cost disparity were increased OR time and increased length of stay. Future studies are warranted to analyze high-volume Minimally Invasive Surgery surgeons' impact in specialty centers on potentially mitigating this current cost disparity.

Simple Versus Radical Resection for Duodenal Adenocarcinoma: A Propensity Score Matched Analysis of National Cancer Database.

BACKGROUND: Duodenal adenocarcinoma treatment consists of either simple or radical surgical resection. Existing evidence suggests similar survival outcomes between the two but is limited by small numbers and single-institution analysis. We aim to compare survival after partial versus radical resection for duodenal adenocarcinoma using the National Cancer Database (NCDB). METHODS: Using NCDB results from 2004 to 2014, we compared patients with duodenal adenocarcinoma undergoing partial resection (n = 1247) and radical resection (n = 1240) by age, sex, facility type, facility location, cancer stage, cancer grade, lymph node sampling, node status, tumor size, margin status, neoadjuvant therapy, and adjuvant therapy using chi-square analysis. Survival was compared using propensity matching. RESULTS: Patients undergoing partial resection had overall earlier cancer stage, more favorable tumor grade, and were less likely to undergo lymph node sampling and neoadjuvant therapy. When overall survival was compared between the 2 propensity-matched groups, the median survival was 46.7 months after partial resection and 43.2 months after radical resection (P = .329), and overall survival was similar between the 2 groups (P = .894). The use of adjuvant therapy demonstrated improved survival over either surgery alone (P < .0001, P = .0037). CONCLUSION: Partial resection did not demonstrate worse survival outcomes than radical resection for duodenal adenocarcinoma. The use of adjuvant therapy in addition to surgery demonstrated improved survival regardless of surgery type and played a larger role in survival than the type of surgery. Our findings provide evidence to support the continued use of both partial and radical surgical resections to treat duodenal malignancy.

Role of metastasectomy for liver metastasis in stage IV anal cancer.

INTRODUCTION: There is a paucity of data on the role of metastasectomy for metastatic anal cancer on survival outcomes. We aim to define the role of metastasectomy in stage IV anal cancer. METHODS: National Cancer Database (NCDB) from 2004 to 2014 was accessed to include patients with metastatic anal cancer, excluding adenocarcinoma, neuroendocrine, and 'other' histologies. We compared patients undergoing metastasectomy (n = 165) to those who did not have metastasectomy (n = 2093) by age, sex, cancer grade, and site of metastasis, including metastasis to bone, liver, and lung, using chi-square analysis. The primary outcome was overall survival. RESULTS: Patients had equal distribution of metastatic sites between those who underwent metastasectomy versus no metastasectomy: bone (7.64% vs 4.85%, p = 0.22), brain (0.24% vs 0%, p = 1.0), liver (23.22% vs 29.70%, p = 0.07), and lung (11.85% vs 9.09%, p = 0.38). Survival following metastasectomy was increased at one year (71% vs. 61%, p = 0.016), two years (50% vs. 38%, p = 0.014), and five years (30% vs. 19%, p = 0.025). Median overall survival was increased (23 months vs. 16 months; p = 0.015) for patients with metastasectomy. Survival increases were demonstrated only in the group with liver metastasis undergoing metastasectomy. When stratifying for liver metastases only, median overall survival time was further increased (34 months vs. 16 months; p < 0.0001) following metastasectomy. CONCLUSION: These results demonstrate a survival benefit for hepatic metastasectomy in stage IV anal cancer. Our findings demonstrate a potential survival benefit in highly select patients with metastatic anal cancer to the liver. These findings support further investigation in a randomized clinical trial to delineate these findings.

Omental patch versus gastric resection for perforated gastric ulcer: Systematic review and meta-analysis for an unresolved debate.

BACKGROUND: Perforated gastric ulcers are surgical emergencies with paucity of data on the preferred treatment modality of resection versus omental patch. We aim to compare outcomes with ulcer repair and gastric resection surgeries in perforated gastric ulcers after systematic review of literature. METHODS: A systematic literature search was performed for publications in PubMed Medline, Embase, and Cochrane Central Register of Controlled Trials. We included all studies which compared ulcer repair vesus gastric resection surgeries for perforated gastric ulcers. We excluded studies which did not separate outcomes gastric and duodenal ulcer perforations. RESULTS: The search included nine single-institution retrospective reviews comparing ulcer repair (449 patients) versus gastric resection surgeries (212 patients). Meta-analysis was restricted to perforated gastric ulcers and excluded perforated duodenal ulcers. The majority of these studies did not control for baseline characteristics, and surgical strategies were often chosen in a non-randomized manner. All of the studies included were at high risk of bias. The overall odds ratio of mortality in ulcer repair surgery compared to gastric resection surgery was 1.79, with 95% CI 0.72 to 4.43 and p-value 0.209. CONCLUSION: In this meta-analysis, there was no difference in mortality between the two surgical groups. The overall equivalence of clinical outcomes suggests that gastric resection is a potentially viable alternative to ulcer repair surgery and should not be considered a secondary strategy. We would recommend a multicenter randomized control trial to evaluate the surgical approach that yields superior outcomes. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level III.

HIV protease inhibitor nelfinavir inhibits growth of human melanoma cells by induction of cell cycle arrest.

HIV protease inhibitors (HIV PI) are a class of antiretroviral drugs that are designed to target the viral protease. Unexpectedly, this class of drugs is also reported to have antitumor activity. In this study, we have evaluated the in vitro activity of nelfinavir, a HIV PI, against human melanoma cells. Nelfinavir inhibits the growth of melanoma cell lines at low micromolar concentrations that are clinically attainable. Nelfinavir promotes apoptosis and arrests cell cycle at G(1) phase. Cell cycle arrest is attributed to inhibition of cyclin-dependent kinase 2 (CDK2) and concomitant dephosphorylation of retinoblastoma tumor suppressor. We further show that nelfinavir inhibits CDK2 through proteasome-dependent degradation of Cdc25A phosphatase. Our results suggest that nelfinavir is a promising candidate chemotherapeutic agent for advanced melanoma, for which novel and effective therapies are urgently needed.

Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.

Large incidental gastrointestinal stromal tumors in a patient presenting with acutely symptomatic nephrolithiasis: A case report.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms, representing approximately 1%-2% of all primary gastrointestinal malignancies. Incidental GISTs are often less than 1 cm when discovered and have been reported predominantly in obese patients undergoing surgery for other medical indications. We present the rare case of a large incidental GIST in a nonobese patient with acutely symptomatic nephrolithiasis. Large GISTs may be treated with neoadjuvant imatinib mesylate to reduce tumor size prior to surgery, though some tumors may experience little change in size despite effective treatment. Treatment response for GISTs can be monitored via imaging studies, such as computed tomography or magnetic resonance imaging, but computed tomography is generally preferred over magnetic resonance imaging.

Phase I study of preoperative radiation therapy with concurrent infusional 5-fluorouracil and oxaliplatin followed by surgery and postoperative 5-fluorouracil plus leucovorin for T3/T4 rectal adenocarcinoma: ECOG E1297.

PURPOSE: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. METHODS AND MATERIALS: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. RESULTS: Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). CONCLUSIONS: Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.

Postoperative mortality after esophagectomy for cancer: development of a preoperative risk prediction model.

BACKGROUND: Surgical resection for the treatment of esophageal cancer remains a high-risk procedure. To develop a model to predict risk of postoperative death, we sought to identify factors associated with postoperative mortality for Medicare patients undergoing esophagectomy for cancer. METHODS: We evaluated patients in the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare database who underwent esophagectomy for esophageal cancer from 1997 to 2003. Variables evaluated were patient age, race, marital status, sex, tumor stage, Charlson score, and hospital volume. Hospital volume was evaluated in tertiles of even volume groups (low, < .67 cases a year; medium, .68 to 2.33 cases a year; high, > 2.33 cases a year). The primary outcome measure was postoperative mortality, defined as death within 30 days of esophagectomy or death during the hospitalization in which the primary surgical procedure was performed. In-hospital deaths more than 30 days after esophagectomy were included in the outcomes to more accurately estimate the true mortality of this procedure. Multivariable logistic regression analyses were performed to evaluate the relationship between patient and provider characteristics and postoperative mortality. Finally, characteristics identified by the regression analysis were used to generate a simplified, clinically applicable model predicting risk of postoperative mortality in the Medicare population. RESULTS: A total of 1172 patients underwent esophageal cancer surgery during this study period. Overall postoperative mortality was 14%. Multivariable logistic regression demonstrated that age, Charlson score, and hospital volume were statistically significant predictors of postoperative mortality. The other variables such as race, martial status, sex, and disease stage were not found to be significant. The odds of postoperative mortality at low-volume hospitals were almost twice those at a high-volume hospital. Age greater than 80 increased odds of mortality almost twofold. Similarly, Charlson scores of > or = 2 resulted in more than a 1.5-fold risk of postoperative mortality. Our prediction model using these variables accurately stratified postoperative mortality for this population. CONCLUSIONS: Postoperative mortality (30-day and in-hospital) remains high after esophagectomy. Age, Charlson score, and hospital volume were identified as independent predictors of postoperative mortality. A simple risk prediction model that uses preoperative clinical data accurately predicted patient postoperative mortality for this SEER-Medicare population.

Primary Malignancy Is an Independent Determinant of Morbidity and Mortality after Liver Resection.

Although outcomes after liver resection have improved, there remains considerable perioperative morbidity and mortality with these procedures. Studies suggest a primary liver cancer diagnosis is associated with poorer outcomes, but the extent to which this is attributable to a higher degree of hepatic dysfunction is unclear. To better delineate this, we performed a matched pair analysis of primary versus metastatic malignancies using a national database. The American College of Surgeons National Surgical Quality Improvement Program (2005-2013) was analyzed to select elective liver resections. Diagnoses were sorted as follows: 1) primary liver cancers and 2) metastatic neoplasms. A literature review identified factors known to impact hepatectomy outcomes; these variables were evaluated by a univariate analysis. The most predictive factors were used to create similar groups from each diagnosis category via propensity matching. Multivariate regression was used to validate results in the wider study population. Outcomes were compared using chi-squared test and Fisher exact test. Matched groups of 4838 patients were similar by all variables, including indicators of liver function. A number of major complications were significantly more prevalent with a primary diagnosis; overall major morbidity rates in the metastatic and primary groups were 29.3 versus 41.6 per cent, respectively. The mortality rate for primary neoplasms was 4.6 per cent (vs 1.6%); this represents a risk of death nearly three-times greater (95% confidence interval = 2.20-3.81, P < 0.0001) in cancers of hepatic origin. Hepatectomy carries substantially higher perioperative risk when performed for primary liver cancers, independent of hepatic function and resection extent. This knowledge will help to improve treatment planning, patient education, and resource allocation in oncologic liver resection.

Preferential involvement of CX chemokine receptor 4 and CX chemokine ligand 12 in T-cell migration toward melanoma cells.

Our previous analysis of the role of chemokines in T lymphocyte trafficking toward human tumor cells revealed the migration of a melanoma patient's cytotoxic T lymphocytes (CTL) toward autologous tumor cells, resulting in tumor cell apoptosis, in an organotypic melanoma culture. CTL migration was mediated by CX chemokine receptor (CXCR) 4 expressed by the CTL and CX chemokine ligand (CXCL) 12 secreted by the tumor cells, as evidenced by blockage of CTL migration by antibodies to CXCL12 or CXCR4, high concentrations of CXCL12 or small molecule CXCR4 antagonist. Here, we present the results of T cell migration in one additional melanoma patient and T cell and tumor cell analyses for CXCR4 and CXCL12 expression, respectively, in 12 additional melanoma patients, indicating the preferential role of CXCR4 and CXCL12 in CTL migration toward melanoma cells. These studies add to the increasing body of evidence suggesting that CXCL12 is a potent chemoattractant for T cells.

Use of radiotracer for sentinel lymph node mapping in breast cancer optimizes staging independent of site of administration.

PURPOSE: In an effort to optimize sentinel lymph node (SLN) mapping for breast cancer, sites of mapping agent administration and types of mapping agents used continue to be evaluated. This study compares SLN mapping using peritumoral (PT) or subareolar (SA) injection of radiolabeled colloid and examines the relative contributions of radiotracer and blue dye to SLN identification. MATERIALS AND METHODS: A retrospective review was performed of 456 patients with breast cancer and clinically negative axillae who underwent SLN mapping. Sequential groups of patients were injected with filtered Tc-99m SC, 326 peritumorally (group 1) and 130 subareolarly (group 2). All patients had intraoperative SA injection of 1% isosulfan blue dye. RESULTS: The SLN identification and isotope success rates were 97% and 96% in group 1 and 98% and 98% in group 2, respectively. Eighty-one patients (25%) in group 1 and 44 patients (34%) in group 2 had positive SLNs. Of these patients, 15% from group 1 and 14% from group 2 had only positive nodes detected by radiotracer, and 9 of these patients (6 from group 1 and 3 from group 2) had other nodes identified by both radiotracer and blue dye that were negative for metastases. Six percent of patients with positive SLNs were upstaged because of use of radiotracer. CONCLUSIONS: PT and SA injection of radiotracer have comparable success rates for axillary SLN identification. Given that 15% of patients in group 1 and 14% in group 2 had only positive SLNs detected by radiotracer, independent of site of administration, radiotracer remains essential for optimizing breast SLN mapping.

Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells.

Type I IFNs are known to inhibit tumor cell growth and stimulate the immune system. However, little is known of the mechanism of type I IFN-induced apoptosis in human cancer cells. In this study, we have IFN-beta treatment of a human colorectal cell line (KM12L4) and a resistant clone of this cell line, L4RIFN. We demonstrate the induction of apoptosis in the parent cell line. This process was associated with the induction of the Jak-Stat signaling pathway, induction of the proapoptotic mediator tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and activation of procaspase-3, -8, -9, and -10. Additionally, we evaluated the role of Stat1 in mediating IFN-beta induction of these proapoptotic signals in a fibrosarcoma cell line (2ftgh) and a Stat1-deficient clone (U3A). Our results demonstrate that IFN-beta induction of apoptosis and the induction of proapoptotic mediator TRAIL is Stat1 dependent. Evaluation of a stable transfectant of the KM12L4 cell line expressing c-FLIP supports the role of TRAIL and the cell-surface death signaling pathways in IFN-beta induction of apoptosis. Studies evaluating the TRAIL promoter indicate induction of TRAIL promoter activity by IFN-beta. These results may represent a novel pathway by which IFN-beta may induce therapeutic effects.

Bullous pemphigoid associated with a lymphoepithelial cyst of the pancreas.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disorder. A possible paraneoplastic association has been suggested; however, debate remains regarding the precise relationship of these neoplasms with BP. We present a case of recalcitrant BP in a 67-year-old man with a pancreatic neoplasm that was found to be a lymphoepithelial cyst. Immunoperoxidase staining of the cyst demonstrated C3d along the basement membrane of the stratified squamous epithelium, suggesting that the BP may have involved the lymphoepithelial cyst itself. Shortly after excision of the cyst, BP rapidly resolved without any immunosuppressive treatment, raising the possibility that the immunologic process involving the lymphoepithelial cyst of the pancreas was the inciting factor for the patient's cutaneous disease. Although rare, some cases of BP may be a paraneoplastic process. A thorough screening via patient history and directed laboratory studies may be warranted in recalcitrant cases.

AKT activation and response to interferon-beta in human cancer cells.

Significant growth inhibition and induction of apoptosis by IFN-beta in cancer cells including colorectal cancer cells have been observed. We and others have previously reported the Stat 1 induction of TRAIL is a crucial step in the IFN-beta induced apoptosis pathway. However, when evaluating the sensitivity of a panel of colorectal cancer cell lines, we found no clear correlation between activation of the Jak/Stat signaling pathway and response to interferon. In the present study, we have evaluated the interaction of the PI3k/Akt pathway and IFN-beta induced apoptosis in human colorectal cancer cells. The results demonstrate a correlation between Akt activity, phosphorylation of Bad and resistance to interferon-induced apoptosis in these cells. The association of activation of Akt, phosphorylation of Bad and resistance to IFN-beta-induced apoptosis was further supported by the observation that disruption of the pathway in a more resistant cell line led to sensitization, and expression of an activated Akt in a more sensitive cell line led to increased resistance. Taken together, this data indicates that the PI3/Akt kinase pathway may be an important contributor to IFN-beta sensitivity and resistance in colorectal cancer cells. This data demonstrates a potential pathway by which cells may develop resistance to IFN, and further elucidation of this process may allow us to better target IFN therapy.

Combined 5-fluorouracil/systemic interferon-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Preclinical in vitro and in vivo studies have demonstrated synergistic interactions between 5-fluorouracil (5-FU) and type I and II IFNs against human colorectal cancer cells. Despite these activities, randomized human trials have failed to identify a clinical benefit for this combination treatment. These limited clinical results may be secondary to the short half-life of recombinant IFN protein and the increased systemic toxicities of 5-FU/IFN combinations. We have previously reported an adenoviral-mediated IFN-beta gene therapy strategy, which may circumvent the pitfalls of recombinant IFN therapy. However, a dose-dependent toxicity and acute inflammatory response to systemically administered adenovirus vectors may limit the clinical application of this therapy. The combination of adenoviral-mediated IFN-beta gene therapy and 5-FU resulted in tumor regression, apoptosis, and improved survival in an established liver metastases model. These therapeutic effects were observed at a significantly lower vector dose than we had previously reported and with limited toxicity. This approach may allow for an effective clinical application of this therapy and warrants additional investigation.