Differential Expression of PEG10 Contributes to Aggressive Disease in Early Versus Late-Onset Colorectal Cancer.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death. Early onset colorectal cancer (age ≤45 y) is increasing and associated with advanced disease. Although distinct molecular subtypes of colorectal cancer have been characterized, it is unclear whether age-related molecular differences exist. OBJECTIVE: We sought to identify differences in gene expression between early and late-onset (age ≥65 y) colorectal cancer. DESIGN: We performed a review of our institution's colorectal cancer registry and identified patients with colorectal cancer with tissue specimens available for analysis. We used the Cancer Genome Atlas to initially identify differences in gene expression between early and late-onset colorectal cancer. In vitro experiments were performed on 2 colorectal cancer cell lines. SETTINGS: The study was conducted at a tertiary medical center. PATIENTS: Patients with early onset (n = 28) or late onset (age ≥65 y; n = 38) at time of diagnosis were included. MAIN OUTCOME MEASURES: The primary outcome was differential gene expression in patients with early versus late-onset colorectal cancer. The secondary outcome was patient mortality. RESULTS: Seven genes had increased expression in younger patients using The Cancer Genome Atlas. Only PEG10 was sufficiently expressed with quantitative polymerase chain reaction and had increased expression in our early onset group. Multivariable linear regression analysis identified age as a significant independent predictor of increased PEG10 expression. Outcomes data from The Cancer Genome Atlas suggests that PEG10 is associated with poor overall survival. In vitro studies in HCT-116 and HT-29 cell lines showed that PEG10 contributes to cellular proliferation and invasion in colorectal cancer. LIMITATIONS: Tissue samples were from formalin-fixed, paraffin-embedded sections. Many patients did not have mutational status for review. CONCLUSIONS: PEG10 is differentially expressed in early onset colorectal cancer and may functionally contribute to tumor cell proliferation and invasion. An increase in PEG10 expression correlates with decreased overall survival. See Video Abstract at http://links.lww.com/DCR/B343. LA EXPRESIÓN DIFERENCIAL DE PEG10 CONTRIBUYE A LA ENFERMEDAD AGRESIVA EN EL CÁNCER COLORRECTAL DE INICIO TEMPRANO VERSUS INICIO TARDÍO: El cáncer colorrectal es una de las principales causas de muerte relacionada con el cáncer. El cáncer colorrectal de inicio temprano (edad ≤45 años) está en aumento y asociado con enfermedad avanzada. Aunque se han caracterizado distintos subtipos moleculares del cáncer colorrectal, no está claro si existen diferencias moleculares relacionadas con la edad.Se buscó identificar diferencias en la expresión génica entre el cáncer colorrectal de inicio temprano y tardío (edad ≥ 65 años).Realizamos una revisión del registro de cáncer colorrectal de nuestra institución e identificamos pacientes con cáncer colorrectal con muestras de tejido disponibles para su análisis. Utilizamos el Atlas del Genoma del Cáncer para identificar inicialmente las diferencias en la expresión génica entre el cáncer colorrectal de inicio temprano y de inicio tardío. Se realizaron experimentos in vitro en dos líneas celulares de cáncer colorrectal.El estudio se realizó en un centro médico de tercer nivel.Se incluyeron pacientes con inicio temprano (n = 28) e inicio tardío (edad ≥65 años, n = 38) al momento del diagnóstico.El resultado primario fue la expresión diferencial de genes en pacientes con cáncer colorrectal de inicio temprano versus tardío. El resultado secundario fue la mortalidad de los pacientes.Siete genes aumentaron su expresión en pacientes más jóvenes usando el Atlas del Genoma del Cáncer. Solo PEG10 se expresó suficientemente con la reacción en cadena de la polimerasa cuantitativa y tuvo una mayor expresión en nuestro grupo de inicio temprano. El análisis de regresión lineal multivariable identificó la edad como un predictor independiente significativo del aumento de la expresión de PEG10. Los datos de resultados de el Atlas del Genoma del Cáncer sugieren que PEG10 está asociado con una pobre supervivencia general. Los estudios in vitro en líneas celulares HCT-116 y HT-29 mostraron que PEG10 contribuye a la proliferación e invasión celular en el cáncer colorrectal.Las muestras de tejido fueron de portaobjetos embebidos en parafina fijados con formalina. Muchos pacientes no tenían el estado de mutación para su revisión.El PEG10 se expresa diferencialmente en el cáncer colorrectal de inicio temprano y puede contribuir funcionalmente a la proliferación e invasión de células tumorales. El aumento en la expresión de PEG10 se correlaciona con la disminución de la supervivencia general. Consulte Video Resumen en http://links.lww.com/DCR/B343.

Assessing the Value of Endoscopy Simulator Modules Designed to Prepare Residents for the Fundamentals of Endoscopic Surgery Examination.

BACKGROUND: The Fundamentals of Endoscopic Surgery examination is required for all general surgery residents. The test modules are not available for practice before the examination; however, similar modules are commercially available. OBJECTIVE: This study aims to determine which modules are most valuable for resident training and preparation for the examination by evaluating which correlates best with experience level. DESIGN: This was a single-institution study. SETTING: A virtual reality endoscopy simulator was utilized. PARTICIPANTS: General surgery residents and faculty endoscopists performed endoscopy simulator modules (Endobasket 2, Endobubble 1 and 2, Mucosal Evaluation 2, and Basic Navigation) designed to prepare residents for the Fundamentals of Endoscopic Surgery examination. Residents were assigned into junior and senior groups based on the completion of a dedicated endoscopy rotation. MAIN OUTCOME MEASURES: The primary outcomes measured were the mean time to completion, mean number of balloons popped, and mean number of wall hits for the 3 groups. RESULTS: A total of 21 junior residents, 11 senior residents, and 3 faculty participated. There were significant differences among groups in the mean time to completion for the Endobasket, Endobubble, and Mucosal Evaluation modules. The modules that correlated best with experience level were Endobubble 2 and Mucosal Evaluation 2. For Endobubble 2, juniors were slower than seniors, who were in turn slower than faculty (junior 118.8 ± 20.55 seconds, senior 100.3 ± 11.78 seconds, faculty 87.67 ± 2.848 seconds; p < 0.01). Juniors popped fewer balloons than seniors, who popped fewer balloons than faculty (junior 9.441 ± 3.838, senior 15.62 ± 4.133, faculty 28.78 ± 1.712; p < 0.001). For Mucosal Evaluation 2, juniors were slower than seniors, who were in turn slower than faculty (junior 468.8 ± 123.5 seconds, senior 368.6 ± 63.42 seconds, faculty 233.1 ± 70.45 seconds; p < 0.01). LIMITATIONS: Study residents have not completed the Fundamentals of Endoscopic Surgery examinations, so correlation with examination performance is not yet possible. CONCLUSIONS: Performance on Endobasket, Endobubble, and Mucosal Evaluation correlated well with experience level, providing benchmarks for each level to attain in preparation for the Fundamentals of Endoscopic Surgery examination. See Video Abstract at http://links.lww.com/DCR/A823.

Who Undergoes Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Appendiceal Cancer? An Analysis of the National Cancer Database.

BACKGROUND: We sought to identify patterns of care for patients with appendiceal cancer and identify clinical factors associated with patient selection for multimodality treatment, including cytoreductive surgery and perioperative intraperitoneal chemotherapy (CRS/PIC). MATERIALS AND METHODS: National Cancer Database (NCDB) data from 2004 to 2014 of all diagnoses of appendiceal cancers were examined. We examined treatment modalities, as well as demographic, tumor-specific, and survival data. A multivariate logistic regression analysis was performed to determine the patient cohort most likely to receive CRS/PIC. Kaplan-Meier was used to estimate survival for all treatment groups. Significance was evaluated at P ≤ 0.05. RESULTS: We analyzed data on 18,055 patients. Nine thousand nine hundred ninety-two (55.3%) were treated with surgery only, 5848 (32.4%) received surgery and systemic chemotherapy, 1393 (7.71%) received CRS/PIC, 520 (2.88%) received chemotherapy alone, and 302 (1.67%) received neither surgery nor chemotherapy. Significant predictors of receiving CRS/PIC included male sex (OR 1.33, 95% CI: 1.11-1.59), white race (OR 2.00, 95% CI 1.40-2.86), non-Hispanic ethnicity (OR 1.92, 95% CI 1.21-3.05), private insurance (OR 1.52, 95% CI 1.26-1.84), and well-differentiated tumors (OR 4.25, CI: 3.39-5.32) (P < 0.05). Treatment with CRS/PIC was associated with a higher 5-year survival for mucinous malignancies, when compared to surgery alone (65.6% versus 62.4%, P < 0.01). Treatment with CRS/PIC was also associated with higher 5-year survival for well-differentiated malignancies, when compared to all other treatment modalities (74.9% versus 65.4%, P < 0.01). CONCLUSIONS: Patients were more likely to undergo CRS/PIC if they were male, white, privately insured, and with well-differentiated tumors. CRS/PIC was associated with improved survival in patients with mucinous and low-grade tumors.

Appendiceal cancer masked as inflammatory appendicitis in the elderly, not an uncommon presentation (Surveillance Epidemiology and End Results (SEER)-Medicare Analysis).

BACKGROUND: The misdiagnosis of appendiceal cancer as inflammatory appendicitis is becoming of greater clinical concern because of the rise of nonoperative management especially in the elder population. To quantify this rate of misdiagnosis, we retrospectively reviewed SEER-Medicare data. METHODS: The SEER-Medicare database was reviewed from 2000 to 2014. We identified patients older than 65 years old who were diagnosed with appendiceal cancer and then cross-referenced them for a diagnosis of inflammatory appendicitis. Demographic data and oncologic stage were collected. RESULTS: Our results showed that 28.6% of appendiceal cancer patients received an incorrect initial diagnosis of inflammatory appendicitis. Patients older than 75 years of age were more likely to be misdiagnosed than those between ages 65 and 75 (risk ratio [RR]: 0.81; 95% confidence interval: 0.70-0.93; P = .003). We found that 42% of patients within the misdiagnosis group presented with an earlier stage of disease (stage 1 or 2) compared to 26% of those primarily diagnosed with appendiceal cancer (P < .001). CONCLUSION: A significant proportion of patients older than 65 years old with appendiceal cancer were initially misdiagnosed with acute appendicitis. We suggest caution when considering a nonoperative approach for appendicitis in the elderly and follow-up imaging or an interval appendectomy should be part of the treatment plan.

Small Bowel and Colorectal Carcinoids.

Neuroendocrine tumors, or carcinoid tumors, of both the midgut and hindgut are quite rare, but their incidence is increasing. Surgery is the treatment of choice in patients who can tolerate an operation and have operable disease. Options for the treatment of metastatic disease include cytoreductive surgery, somatostatin analogues, interferon α, local liver therapies (hepatic arterial embolization, ablation), chemotherapy, Peptide-Receptor Radionucleotide Radiotherapy, angiogenesis inhibitors, and mammalian target of rapamycin inhibitors.

Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia.

OBJECTIVE: Thrombolysis and open surgical revascularization are current options for the treatment of acute limb ischemia (ALI). Despite the several randomized controlled trials comparing the two options, no single treatment can yet be recommended as a universal initial management of ALI. The purpose of this study was to evaluate contemporary endovascular and surgical revascularization for ALI. METHODS: Consecutive patients with ALI treated with endovascular revascularization (ER) or open revascularization (OR) between 2005 and 2011 were identified and reviewed. Procedural success and outcomes were compared between the two groups. Limb salvage and survival were assessed by time-to-event methods, including Kaplan-Meier estimation and competing-risks regression models. RESULTS: A total of 154 limbs were treated in 147 patients in the ER group, compared with 326 limbs in 296 patients in the OR group. The mean follow-up was 14 ± 18.5 months. The majority of patients presented with Rutherford II ischemia (83% for OR, 90% for ER). In Rutherford II patients, technical success was achieved in 90.7% of the OR group vs 79.9% of the ER group (P = .002), with amputation rates of 10.0% vs 7.2% (P = .35) at 30 days and 16.3% vs 13.0% (P = .37) at 1 year, respectively. In Rutherford II patients with failed bypass graft, technical success rate was 95.0% (OR) vs 75.0% (ER) (P = .001), whereas the amputation rate was 6.3% vs 15.38% (P = .13) at 30 days and 24.1% vs 23.1% (P = .90) at 1 year, respectively. The overall 30-day mortality rate was 13.2% (OR) and 5.4% (ER) (P = .012). Overall amputation rates were 13.5% (OR) vs 6.5% (ER) at 30 days (P = .023) and 19.6% (OR) vs 13.0% (ER) at 1 year (P = .074). The primary patency rate was 57% (OR) and 51% (ER) at 1 year (P = .74). Predictors of limb loss by life-table analysis included coronary artery disease (hazard ratio [HR], 2.0; P = .007) and Rutherford category III (HR, 19.0; P < .001). Predictors of death by life-table analysis included age (HR, 1.03; P < .001), end-stage renal disease (HR, 7.28; P < .001), cancer (HR, 1.65; P = .005), and chronic obstructive pulmonary disease (HR, 1.61; P = .005). CONCLUSIONS: In patients presenting with class II ALI, ER or surgical OR resulted in comparable limb salvage rates. Although technical success is higher with OR for patients presenting with failed bypass grafts, the amputation rates are comparable. Overall mortality rates are significantly higher at 30 days and 1 year in the OR group.

Contemporary outcomes of endovascular interventions for acute limb ischemia.

OBJECTIVE: Thrombolysis as a treatment for acute limb ischemia (ALI) has become a first-line therapy based on studies published over 2 decades ago. The purpose of this study was to assess outcomes of patients treated for ALI using contemporary thrombolytic agents and endovascular techniques. METHODS: Consecutive patients with ALI of the lower extremities treated between 2005 and 2011 were identified, and their records were retrospectively reviewed. All patients were treated with tissue plasminogen activator delivered via catheter-directed thrombolysis (CDT) and/or pharmacomechanical thrombolysis (PMT), with other adjunctive endovascular or surgical interventions. Procedural success, thrombolysis duration, and 30-day and long-term outcomes were obtained for the whole series and were also compared between the CDT and PMT groups. Limb salvage and survival were assessed using time-to-event methods, including Kaplan-Meier estimation and Cox proportional hazards models. RESULTS: A total of 154 limbs were treated in 147 patients presenting with ALI (Rutherford class I, 9.7%; class IIa, 70.1%; class IIb, 20.1%). The mean follow-up was 15.20 months (range, 0.56-56.84 months). Indications for intervention included embolization (14.3%), thrombosed bypass (36.4%), thrombosed stent (26.6%), native artery thrombosis (24.0%), and thrombosed popliteal aneurysm (3.2%). Technical success was achieved in 83.8% of cases, with a 30-day mortality rate of 5.2%. Procedural complications included systemic bleeding (5.2%), access site hematoma (4.5%), acute renal failure (1.9%), and distal embolization (9.7%). The mean runoff score decreased from 13.42 preintervention to 7.43 postintervention. Adjuvant revascularization procedures were required in 89.0% of patients and were endovascular (68.8%), hybrid (9.1%), or open (11.0%). Only 3.2% of patients required a fasciotomy. The overall rate of major amputation was 15.0% (18.1% for CDT only, 11.3% for PMT; P = NS). Predictors of limb loss by Cox proportional hazards models included end-stage renal disease (hazard ratio [HR], 8.563; P < .001) and poor pedal outflow, with an incremental protective effect for improved pedal outflow (HR, 0.205; P < .001 for one pedal outflow vessel; HR, 0.074; P < .001 for ≥ two pedal outflow vessels). Gender, smoking, diabetes, Rutherford score, runoff score, thrombosed popliteal aneurysm, and PMT were not significant predictors of limb loss. The use of PMT was a significant predictor of technical success (odds ratio, 2.67; P = .046). CONCLUSIONS: Endovascular therapy with thrombolysis using tissue plasminogen activator remains an effective treatment option for patients presenting with mild or moderate lower extremity ALI, with equal benefit derived with CDT or PMT. Patients with end-stage renal disease or poor pedal outflow have an increased risk of limb loss and may benefit from alternative revascularization strategies.

Predictive factors for in-stent late loss and coronary lesion progression in patients with type 2 diabetes mellitus randomized to rosiglitazone or placebo.

BACKGROUND: Type 2 diabetics (DM2) are at increased risk for restenosis as well as nonculprit coronary artery lesion (NCCL) progression. Rosiglitazone (RSG) favorably modifies many of the altered biologic processes in DM2, although recent reports have questioned its safety. We conducted a double-blind randomized trial to assess the effects of RSG versus placebo on in-stent late lumen loss (LL) and angiographic progression of NCCL. METHODS: A total of 65 DM2 were randomized to RSG (4 mg/d) (n = 32) or placebo (n = 33) at the time of stenting and underwent clinical and laboratory analysis at 1 and 4 months and 8-month angiography (n = 46 patients). Rapid angiographic progression (RAP) was defined as > or =20% diameter reduction of preexisting NCCL by quantitative coronary angiography, or a new narrowing > or =30%. RESULTS: Mean LL in RSG (n = 33 lesions) was not different from that of placebo (0.62 +/- 0.59 vs 0.70 +/- 0.67, P = NS). Seven (13.5%) of 52 NCCLs have RAP in RSG versus 9 (16.1%) of 56 in placebo (P = NS). High-sensitivity C-reactive protein (hs-CRP) was the only predictor of RAP. Patients with a 120-day hs-CRP > or =75th percentile had an OR of 7.35 (95% CI 2.35-23) for RAP versus those below. Although RSG treatment also lowered log (hs-CRP) at 4 months (RSG 0.10 +/- 0.37 vs placebo 0.26 +/- 0.49, P = .06), it did not decrease the likelihood of plaque progression while also raising LDL and N-terminal brain naturetic peptide. CONCLUSIONS: Rosiglitazone appears not to lower LL or reduce angiographic progression of NCCL in DM2 and had complex effects on markers of cardiac risk.

Colorectal polyposis and inherited colorectal cancer syndromes.

The majority of colorectal cancer (CRC) cases are sporadic, with hereditary factors contributing to approximately 35% of CRC cases. Less than 5% of CRC is associated with a known genetic syndrome. Although adenomatous polyposis syndromes, hamartomatous polyposis syndromes, and those previously classified as non-polyposis CRC syndromes are quite rare, it is important for clinicians to know the characteristics of each syndrome and to understand the differences in cancer risks between the different conditions. This information is very important when treatment and surveillance plans are formulated for each individual patient.