Neoplastic conversion of human colon smooth muscle cells: No requirement for telomerase.

The role of telomerase as an essential requirement for the neoplastic conversion of human cells has been controversial. In the model of conversion of normal human cells to cancer cells by the combination of simian virus 40 (SV40) early region genes and oncogenic Ras (H-Ras(G12V)), telomerase (hTERT) was originally described as essential in conjunction with these other genes. Here we used primary cultures of colon smooth muscle cells isolated from surgical specimens. SV40 large T antigen (TAg) and oncogenic Ras(G12V) were introduced into the cells by retroviral transduction and cells were rapidly transplanted into the subrenal capsule space in immunodeficient mice, without selection in culture. Malignant tumors were formed from transduced cells. Extensive invasion into the kidney occurred even when tumors were small; in contrast, at the same tumor size, oncogene-expressing fibroblasts did not show much invasion. Increased invasiveness was also observed in vitro. However, cells in these cancers showed morphological evidence of crisis, consistent with their lack of telomerase. These experiments on human colon smooth muscle cells support the concept that Ras(G12V) and SV40 TAg form a minimal set of genes that can convert normal human cells to cancer cells without a requirement for hTERT.

Accuracy of lymphatic mapping and sentinel lymph node biopsy after previous wide local excision in patients with primary melanoma.

BACKGROUND: Sentinel lymph node (SLN) status is the most important prognostic factor with respect to the survival of patients with primary cutaneous melanoma. However, lymphatic mapping and SLN biopsies (LM/SLNBs) performed in patients who have had a wide local excision (WLE) may not accurately reflect the pathologic status of the draining lymph node basins. The purpose of this study was to assess the feasibility and accuracy of LM/SLNB in patients who have had a previous WLE. METHODS: A single-institution database was examined to identify patients who had a WLE before LM/SLNB and patients who had a concomitant LM/SLNB. Primary clinicopathologic features (age, tumor thickness, and ulceration), SLN identification rate, SLN pathologic status, and the incidence and sites of recurrences were compared between patients with and without prior WLE. RESULTS: Of the 1395 patients identified, 104 had WLE before LM/SLNB. The mean preoperative WLE radial margin was 1.4 cm (median, 1.0 cm). LM/SLNB was successful in 103 of 104 (99%) patients. Age, tumor thickness, incidence of ulceration, and incidence of SLN positivity in the group with prior WLE were similar to those of the cohort of patients who had concomitant LM/SLNB and WLE (n = 1291). In 97 (93%) of the 104 prior-WLE patients, the surgical defects were closed by either primary closure or skin graft; 7 patients (7%) had rotational flaps. The median follow-up of these 104 patients was 51 months. Among the prior-WLE group, 19 patients (18%) had a positive SLNB; of these 19 patients, 4 (21%) had recurrences (3 distant failures and 1 local and distant failure). There were no lymph node recurrences-in a mapped or unmapped basin-in these 104 patients with a negative or positive SLNB. CONCLUSIONS: SLNs can be successfully identified and accurately reflect the status of the regional lymph node basin in carefully selected melanoma patients with a previous WLE. Prior WLE does not appear to adversely impact the ability to detect lymphatic metastases, although the utility of LM/SLNB in patients who have undergone extensive reconstruction of the primary excision site remains to be defined. Because more extensive surgery may be required to accomplish accurate lymph node staging in patients who have undergone prior WLE-including the possible removal of SLNs from additional lymph node basins and an additional surgical procedure-to minimize morbidity and cost, concomitant WLE and LM/SLNB is strongly preferred whenever possible.

Colorectal cancer in Hispanics: a population at risk for earlier onset, advanced disease, and decreased survival.

BACKGROUND: While colorectal cancer (CRC) incidence and mortality rates have declined slightly over the past decade, there remain marked differences by ethnicity. Our aim was to investigate ethnic differences in occurrence, clinical presentation and outcome of CRC at a tertiary university center that serves a predominantly Hispanic population. METHODS: Prospectively collected data from the tumor registry on patients diagnosed with colorectal cancer from 1985 through 2001 was examined. Age at diagnosis, mode of presentation, sex, tumor location, ethnicity, TNM stage, and survivals were assessed and ethnic differences were sought. RESULTS: Records from 453 patients with CRC were reviewed. There were 296 (65%) patients that were Hispanics, 112 (25%) non-Hispanic Whites, 37 (8%) African Americans, and 8 (2%) of other or unknown ethnicity. Compared with non-Hispanic Whites, Hispanics presented at a younger age (58.5 +/- 14 versus 53.6 +/- 12.73, respectively; P < 0.01), with a significantly greater incidence of stage IV disease (19% versus 32%, respectively; P = 0.02). They had significantly poorer age-adjusted survival (median survival of 92 months for <55 years and 77 months for >55 years versus 48 months for <55 years and 48 months for >55 years, respectively; adjusted log rank P = 0.045). There were no differences in tumor location, mode of presentation or adjuvant treatment received. CONCLUSIONS: Hispanic patients with CRC in our catchment area present at a younger age with more metastatic disease and have a poorer survival than non-Hispanic Whites. Modification of screening criteria and treatment paradigms may be required for Hispanics.

Safety and efficacy of metallic stents in the management of colorectal obstruction.

BACKGROUND: The use of self-expandable metallic stents in the management of obstructing colorectal cancer has been described with increasing frequency in the literature. Our goal was to evaluate the efficacy and associated morbidity of the use of self-expandable metallic stents to relieve colorectal obstruction at our institution. METHODS: A retrospective chart review of patients who underwent colorectal stent placement between December 2001 and December 2003 in a tertiary referral center was performed. RESULTS: Stents were placed successfully in 17 of 21 patients (81%) with colorectal obstruction. Placement was achieved endoscopically in 13 patients and radiologically in 4. Ten self-expandable metallic stents were used as a bridge to surgery, and 7 were used for palliation. The obstructions were located in the sigmoid colon (11 patients), the rectosigmoid (3), the splenic flexure, the hepatic flexure, and the rectum. Malignant obstruction was noted in 14 patients. One patient with malignancy experienced a sigmoid perforation, and 2 patients with benign disease had complications (1 stent migration and 1 re-obstruction). Stent patency in obstruction secondary to colonic adenocarcinoma was 100% in our follow-up period (range, 5 to 15 months). CONCLUSIONS: The use of stents as a bridge to surgery is associated with low morbidity, allows for bowel preparation, and thus avoids the need for a temporary colostomy. Long-term patency suggests that stents may allow for the avoidance of an operation in patients with metastatic disease and further defines their role in the palliation of malignant obstruction. Further prospective randomized studies are necessary to fully elucidate the use of stents in the management of colorectal cancer.

Squamous cell carcinoma of the anal canal.

Squamous cell carcinoma (SCC) of the anal canal is a rare condition with increasing incidence rates in the United States population in the past several decades. This review article provides a complete overview of the etiology, anatomy and the approach to the multidisciplinary management of the patient with anal SCC. Chemoradiation therapy for the treatment of SCC of the anal canal provides excellent disease control and survival while preserving anal sphincter function in the majority of patients. The surgeon plays a key role in the diagnosis and follow-up of this disease. Surgical salvage with APR for disease persistence or recurrence in carefully selected patients can result in reasonable 5-year survivals.

Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal.

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter, and GABA receptors have been recently detected on epithelial colon cancer cells. Nembutal (pentobarbital) is a barbiturate with GABA-agonistic effects. We demonstrate that GABA receptors are present on colon cancer cell lines (KM12SM, HT29, RKO). Nembutal (0.1-500 microg/ml) continuous exposure resulted in an IC50 level of 58 microg/ml for the KM12SM cells and 120 microg/ml for the HT29 cells. Nembutal reduced cellular cAMP concentration in colon cancer cells and resulted in a dose and time dependent decrease in MMP-2 and MMP-9 levels. In the KM12SM intracecal injected mice, 9 of 10 mice in the metaphane group developed a primary tumor (mean weight = 2.16 g +/- 0.76) compared to 7 of 10 mice in the nembutal group (mean weight = 0.41 g +/- 0.21, p = 0.03). In the KM12SM intrasplenic injected mice, the tumor weight in the spleen was 85% smaller in the nembutal group compared to the metaphane group (p = 0.008). In the HT29 injected mice, the metaphane group and nembutal group had similar tumor incidence, but combined tumor weight (primary tumor and liver metastases) was significantly higher in the metaphane group (1.61+/- 0.45 g) versus 0.07 +/- 0.05 g; p = 0.008. The incidence of liver metastases in the nembutal group was zero compared to eight out of nine in the metaphane group. To the best of our knowledge, this is the first evidence that nembutal is a potent inhibitor of primary colon cancer and metastasis. These findings may have therapeutic implications for the treatment of colon and other cancers.

HER-2/neu expression as a predictor of response to neoadjuvant docetaxel in patients with operable breast carcinoma.

BACKGROUND: The use of biologic markers to predict response to neoadjuvant chemotherapy may permit tailoring regimens to achieve maximal tumor response. Taxanes have demonstrated excellent activity in breast carcinoma; however, tumor-specific factors that predict clinical response have not been characterized thoroughly. METHODS: The authors performed a historic review evaluating the association of tumor prognostic factors and response to neoadjuvant cyclophosphamide and doxorubicin (AC) with or without docetaxel (D) (AC vs. AC+D) in 121 women who previously were enrolled in a Phase III, randomized, clinical trial. Using pretreatment biopsy materials, immunohistochemical studies were performed for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, p53, and Ki-67. Outcome variables were pathologic complete response (pCR) and positive clinical response (cPOS), which was defined as a >/= 50% regression in clinical tumor size prior to surgery. RESULTS: In a multivariate analysis that controlled for tumor size and lymph node status, improved cPOS rates were observed with the addition of docetaxel in women with HER-2/neu-negative tumors (81% vs. 51%; P < 0.05), yielding an adjusted odds ratio of 3.5 (95% confidence interval, 1.2-13.0) in favor of docetaxel. Women who had HER-2/neu-negative tumors appeared to have a lower response rate with AC alone compared with women who had HER-2/neu-positive tumors (51% vs. 75%; P = 0.06), but response rates were matched when docetaxel was added (81% vs. 78%; P = 0.99). ER, PR, p53, and Ki-67 results were not associated significantly with response rates. CONCLUSIONS: HER-2/neu status may predict improved clinical response rates from the addition of docetaxel to anthracycline-based neoadjuvant chemotherapy. Docetaxel may "rescue" the response in women who have HER-2/neu-negative tumors to match that observed in women who have HER-2/neu-positive tumors treated with AC alone.

The new staging system for cutaneous melanoma in the era of lymphatic mapping.

In 2002, the American Joint Committee on Cancer (AJCC) revised the staging system for cutaneous melanoma on the basis of a survival analysis of important melanoma prognostic factors. Features of the revised system include new strata for primary tumor thickness, incorporation of primary tumor ulceration as an important staging criterion in both the tumor (T) and node (N) classifications, revision of the N classification to reflect the prognostic significance of regional nodal tumor burden, and new categories for distant metastatic disease. These changes reflect evolving insight into melanoma arising from the results of numerous clinical investigations and database analyses. One of the most important recent changes in melanoma care is the establishment of lymphatic mapping and sentinel lymph node (SLN) biopsy as a highly accurate and minimally morbid technique for pathologic regional nodal staging. In this article, the salient features of the revised melanoma staging system are examined, with specific attention paid to its use in this era of lymphatic mapping and SLN biopsy.

Overview of anal cancer for the surgeon.

Cancers of the anal canal represent a diverse group of pathology and require a multidisciplinary approach for treatment. For the most common anal canal cancer, anal SCC, the primary therapy is CMT with systemic chemotherapy and radiation. The surgeon plays a key role in the diagnosis and follow-up after treatment, with surgical intervention reserved for residual or recurrent disease. The overall prognosis for this disease is favorable. For anal adenocarcinoma, aggressive surgical resection remains the mainstay of therapy, with radiation therapy and chemotherapy used to aid in local disease control and for treatment of metastatic disease. A high rate of distant failure in this disease is responsible for the poor long-term prognosis. Anorectal melanoma has a high rate of distant failure and a poor overall survival rate. Surgical intervention is focused on local disease control with preservation of sphincter function. The biggest improvements in survival for this disease will come with more effective systemic therapy.

Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients.

BACKGROUND: The American Joint Committee on Cancer (AJCC) has recently modified staging criteria for primary melanoma patients and recommends sentinel lymph node (SLN) biopsy in many because microscopic nodal metastasis represents the most important factor predicting survival. The purpose of this study was to correlate the incidence of SLN metastasis with revised AJCC staging. METHODS: The records of 1375 melanoma patients undergoing SLN biopsy were reviewed. Univariate and multivariate analyses were performed to identify predictors of a positive SLN. Patients were stratified by using revised AJCC criteria to determine whether such groups also predicted positive SLNs. RESULTS: A positive SLN was found in 16.9% of patients. By multivariate analysis, tumor thickness (relative risk [RR], 3.4) and ulceration (RR, 2.2) were dominant independent predictors of SLN metastases; age < or =50 years (RR, 1.8) and axial tumor location (RR, 1.5) were also significant. When patients were stratified by AJCC staging criteria, a significant increase in SLN metastases between successive stages was demonstrated. CONCLUSIONS: Stratification of patients by using AJCC classification reveals an increasing risk of SLN metastases with successive stage groups. Given the significant association of SLN status and survival, the ability of the revised AJCC staging system to predict survival is likely due to its ability to predict the risk of occult nodal disease.

Liver imaging. A surgeon's perspective.

Advances in the diagnosis and treatment of liver lesions have improved therapy for a broad range of clinical conditions, many of which could not be effectively treated in the recent past. These advances are the result of better surgical techniques as well as diagnostic imaging. This article discusses the anatomy of the liver and the clinical evaluation of patients with liver lesions. Common benign and malignant liver lesions are presented with radiologic characteristics and treatment options.