A. Scott Pearson

Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies.

BACKGROUND The majority of patients with primary or metastatic malignancies confined to the liver are not candidates for resection because of tumor size, location, multifocality, or inadequate functional hepatic reserve. Cryoablation has become a common treatment in select groups of these patients with unresectable liver tumors. However, hepatic cryoablation is associated with significant morbidity. Radiofrequency ablation (RFA) is a technique that destroys liver tumors in situ by localized application of heat to produce coagulative necrosis. In this study, we compared the complication and early local recurrence rates in patients with unresectable malignant liver tumors treated with either cryoablation or RFA. PATIENTS AND METHODS Patients with hepatic malignancies were entered into two consecutive prospective, nonrandomized trials. The liver tumors were treated intraoperatively with cryoablation or RFA; intraoperative ultrasonography was used to guide placement of cryoprobes or RFA needles. All patients were followed up postoperatively to assess complications, treatment response, and local recurrence of malignant disease. RESULTS Cryoablation was performed on 88 tumors in 54 patients, and RFA was used to treat 138 tumors in 92 patients. Treatment-related complications, including 1 postoperative death, occurred in 22 of the 54 patients treated with cryoablation (40.7% complication rate). In contrast, there were no treatment-related deaths and only 3 complications after RFA (3.3% complication rate, P<0.001). With a median follow-up of 15 months in both patient groups, tumor has recurred in 3 of 138 lesions treated with RFA (2.2%), versus 12 of 88 tumors treated with cryoablation (13.6%, P<0.01). CONCLUSIONS RFA is a safe, well-tolerated treatment for patients with unresectable hepatic malignancies. This study indicates that (1) complications occur much less frequently following RFA of liver tumors compared with cryoablation of liver tumors, and (2) early local tumor recurrence is infrequent following RFA.

Prognostic Factors in Resectable Pancreatic Cancer: p53 and Bcl-2

The p53 tumor suppressor gene and the Bcl-2 proto-oncogene regulate cell cycle progression and apoptosis. We evaluated the expression of these molecular markers with standard pathologic prognostic variables in patients who received multimodality therapy for resectable adenocarcinoma of the pancreas to study the effect of p53 and Bcl-2 on survival duration. Immunohistochemical staining of archival material was performed to determine levels of expression of p53 and Bcl-2 proteins in 70 patients with adenocarcinoma of pancreatic origin. All patients underwent a potentially curative pancreaticoduodenectomy and standardized pathologic analysis of resected specimens. Potential pathologic and molecular prognostic variables were assessed for their effect on survival duration. Nuclear staining for p53 was observed in 33 (47%) of 70 specimens. Immunostaining for Bcl-2 was observed in 23 specimens (33%). A trend toward improved survival duration was seen in patients whose tumors stained positive for either p53 or Bcl-2. Negative staining for both markers predicted short survival (P = 0.01). By univariate and multivariate analyses, no single pathologic factor was associated with survival duration. Immunohistochemical staging using both p53 and Bcl-2 significantly predicted survival duration by univariate and multivariate analysis; patients whose tumors stained positively for p53 and/or overexpressed Bcl-2 had a significantly longer survival than those whose tumors stained negative for both proteins.

Identification and optimization of small molecules that restore E-cadherin expression and reduce invasion in colorectal carcinoma cells.

E-cadherin is a transmembrane protein that maintains intercellular contacts and cell polarity in epithelial tissue. The down-regulation of E-cadherin contributes to the induction of the epithelial-to-mesenchymal transition (EMT), resulting in an increased potential for cellular invasion of surrounding tissues and entry into the bloodstream. Loss of E-cadherin has been observed in a variety of human tumors as a result of somatic mutations, chromosomal deletions, silencing of the CDH1 gene promoter, and proteolytic cleavage. To date, no compounds directly targeting E-cadherin restoration have been developed. Here, we report the development and use of a novel high-throughput immunofluorescent screen to discover lead compounds that restore E-cadherin expression in the SW620 colon adenocarcinoma cell line. We confirmed restoration of E-cadherin using immunofluorescent microscopy and were able to determine the EC(50) for selected compounds using an optimized In-Cell Western assay. The profiled compounds were also shown to have a minimal effect on cell proliferation but did decrease cellular invasion. We have also conducted preliminary investigations to elucidate a discrete molecular target to account for the phenotypic behavior of these small molecules and have noted a modest increase in E-cadherin mRNA transcripts, and RNA-Seq analysis demonstrated that potent analogues elicited a 10-fold increase in CDH1 (E-cadherin) gene expression.

Detection of telomerase activity in breast masses by fine-needle aspiration

AbstractBackground: Telomerase is an RNA-dependent DNA polymerase that compensates for the telomere shortening that occurs in its absence. Reactivation of telomerase is thought to be an important step in cellular immortalization, and recent studies have indicated that telomerase activity is often detected in primary human malignancies. The clinical implications of telomerase activity in human tumors are currently under investigation. Methods: Eighty-nine samples (46 FNAs and 43 gross tissue biopsies) from 44 patients with breast masses were analyzed prospectively for the presence of telomerase activity by a modification of the telomere repeat amplification protocol (TRAP). All samples were obtained directly from the excised mass at the time of specimen removal in the operating room. Results: Telomerase activity was detected in 17 of 19 (90%) FNA samples and 15 of 18 (83%) invasive breast cancer tissue biopsies. Telomerase was also detected in 9 of 16 (56%) FNAs and 8 of 15 (53%) tissue biopsies from 16 fibroadenomas. Other benign proliferative lesions (n=5) did not have detectable telomerase activity in either FNA or tissue specimens. FNA-TRAP results correlated with the gross tissue specimen TRAP results in 95% of all cases. Conclusion: The FNA-TRAP assay for telomerase detection is a highly sensitive and accurate method for the detection of telomerase activity in breast masses. Future application of these techniques should facilitate evaluation of telomerase as a tumor marker in the clinical management of breast and other solid malignancies.

Abdominal aortic aneurysms and malignant neoplasia : Double jeopardy

BACKGROUND This study was performed to determine whether there is a significant association between abdominal aortic aneurysms (AAAs) and malignancy and to determine the impact of malignancy on late survival in patients with AAA. METHODS We studied 126 men undergoing AAA repair and compared them with 99 men undergoing aortofemoral bypass (AFB) for occlusive disease and with 100 men undergoing herniorrhaphy during the same period. RESULTS Fifty-one (40%) patients with AAA, 23 (23%) patients undergoing AFB, and 21 (21%) patients undergoing herniorrhaphy were diagnosed with cancer (p = 0.002). By life table analysis the proportion of subjects remaining cancer free at 5 years was 0.60 +/- 0.05 for AAA, 0.83 +/- 0.04 for AFB, and 0.81 +/- 0.04 for herniorrhaphy (p = 0.004). Multivariate analysis selected four independent risk factors for cancer: presence of AAA (p = 0.003, odds ratio 1.4, confidence interval [CI] 1.2 to 1.7), age (p = 0.001, odds ratio per year 1.1, CI 1.0 to 1.1), smoking (p = 0.04, odds ratio 1.5, CI 1.0 to 2.2), and hypertension (p = 0.04, odds ratio 0.73, CI 0.5 to 1.0). Cancer deaths accounted for 32% of late deaths in patients with AAA, which was not different compared with 26% of late deaths in patients undergoing AFB and 36% of late deaths in patients undergoing herniorrhaphy. Five-year cancer-free survival was 0.44 +/- 0.05 for patients with AAA, 0.64 +/- 0.05 for patients undergoing AFB, and 0.70 +/- 0.05 for patients undergoing herniorrhaphy (p < 0.001, AAA versus herniorrhaphy only). CONCLUSIONS Cancer is more prevalent in men with AAA than in men undergoing AFB or herniorrhaphy. The presence of AAA appears to be an independent risk factor for cancer. Despite the higher cancer prevalence in patients with AAA, cardiovascular disease accounted for the largest number of late deaths in this series, minimizing differences in cancer-free survival between patients with AAA and patients undergoing AFB.

Veterans Affairs general surgery service: the last bastion of integrated specialty care

BACKGROUND In a time of increasing specialization, academic training institutions provide a compartmentalized learning environment that often does not reflect the broad clinical experience of general surgery practice. This study aimed to evaluate the contribution of the Veterans Affairs (VA) general surgery surgical experience to both index Accreditation Council for Graduate Medical Education (ACGME) requirements and as a unique integrated model in which residents provide concurrent care of multiple specialty patients. METHODS Institutional review board approval was obtained for retrospective analysis of electronic medical records involving all surgical cases performed by the general surgery service from 2005 to 2009 at the Nashville VA. Over a 5-year span general surgery residents spent an average of 5 months on the VA general surgery service, which includes a postgraduate year (PGY)-5, PGY-3, and 2 PGY-1 residents. Surgeries involved the following specialties: surgical oncology, endocrine, colorectal, hepatobiliary, transplant, gastrointestinal laparoscopy, and elective and emergency general surgery. The surgeries were categorized according to ACGME index requirements. RESULTS A total of 2,956 surgeries were performed during the 5-year period from 2005 through 2009. Residents participated in an average of 246 surgeries during their experience at the VA; approximately 50 cases are completed during the chief year. On the VA surgery service alone, 100% of the ACGME requirement was met for the following categories: endocrine (8 cases); skin, soft tissue, and breast (33 cases); alimentary tract (78 cases); and abdominal (88 cases). Approximately 50% of the ACGME requirement was met for liver, pancreas, and basic laparoscopic categories. CONCLUSIONS The VA hospital provides an authentic, broad-based, general surgery training experience that integrates complex surgical patients simultaneously. Opportunities for this level of comprehensive care are decreasing or absent in many general surgery training programs. The increasing level of responsibility and simultaneous care of multiple specialty patients through the VA hospital systems offers a crucial experience for those pursuing a career in general surgery.

Significance and management of local recurrences and limited metastatic disease in the abdomen

The management of patients with synchronous or metachronous metastatic carcinoma, sarcoma, or melanoma in the abdomen requires a knowledge of the natural history of the disease and of the available treatment options. Patients with advanced malignant disease may be of marginal performance status yet may require large surgical procedures or combined modality therapy; the most challenging therapeutic decisions involve such patients. The authors highlight the role of surgery in selected patients with metastatic or recurrent malignancy as it is practiced at The University of Texas M. D. Anderson Cancer Center.