Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial.

BACKGROUND: Transanal local excision has been suggested as an attractive approach for patients with rectal cancer who show a major clinical response after preoperative chemoradiotherapy. OBJECTIVE: To evaluate the impact of transanal local excision on the local recurrence of rectal cancer in patients who had a major clinical response after preoperative chemoradiotherapy. DESIGN: Sequential 2-stage phase II study for early efficacy. SETTING: Multicenter study. PATIENTS: Patients with clinical T3 or low-lying T2 rectal adenocarcinoma that showed a major clinical response after a preoperative chemoradiotherapy. Eligible patients underwent a full-thickness transanal local excision. According to their histopathology, the patients staged as ypT0-1 were observed, while the remaining patients were recommended to undergo a subsequent total mesorectal excision. MAIN OUTCOME MEASURES: A local recurrence rate of ≤5% was set as a successful rate for stopping the trial early after the first stage. RESULTS: The study group included 63 patients. Before chemoradiotherapy, patients were staged as clinical T3 (n = 42) and T2 (n = 21). After the local excision, 43 patients fulfilled the criteria to be observed with no further treatment. Nine of the remaining 20 patients for whom a subsequent total mesorectal excision was recommended refused surgery. Two of these patients who refused surgery had intraluminal local recurrence; both had a ypT2 tumor and underwent salvage surgery. The estimated cumulative 3-year overall survival, disease-free survival and local disease-free survival were 91.5% (95% CI: 75.9-97.2), 91.0% (95% CI: 77.0-96.6) and 96.9% (95% CI: 80.3-99.5), respectively. LIMITATIONS: The time of follow-up is still short and the sample size is limited. CONCLUSIONS: Our data suggest that local excision is a good option for patients with a major clinical response after chemoradiotherapy. A longer period of follow-up is required to confirm these findings.

Long-term outcome of patients with complete pathologic response after neoadjuvant chemoradiation for cT3 rectal cancer: implications for local excision surgical strategies.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by radical surgery including total mesorectal excision (TME) is standard treatment in patients with locally advanced rectal cancer. Emerging data indicate that patients with complete pathologic response (ypCR) after CRT have favorable outcome, suggesting the possibility of less invasive surgical treatment. We analyzed long-term outcome of cT3 rectal cancer treated by neoadjuvant CRT in relation to ypCR and type of surgery. METHODS: The study population comprised 139 patients (93 men, 46 women; median age 62 years) with cT3N0-1M0 mid and distal rectal adenocarcinoma treated by CRT and surgery (110 TME and 29 local excision) at our institution between 1996 and 2008. At pathology, ypCR was defined as no residual cancer cells in the primary tumor. RESULTS: Tumors of 42 patients (30.2%) were classified as ypCR. After a median follow-up of 55.4 months, comparing patients with ypCR to patients with no ypCR, 5-year disease-specific survival was 95.8% versus 78.0% (P = 0.004), and 5-year disease-free survival was 90.1% vs. 64.0% (P = 0.004). In patients with ypCR, no statistically significant outcome difference was observed between TME and local excision. In patients treated by local excision, comparing patients with ypCR to patients with no ypCR, 5-year disease-free survival was 100% vs. 65.5% (P = 0.024), and 5-year local recurrence-free survival was 92.9% vs. 66.7% (P = 0.047). CONCLUSIONS: With retrospective analysis limitations, our data confirm favorable long-term outcome of cT3 rectal cancer with ypCR after CRT and warrant clinical trials exploring local excision surgical strategies.

Protein pathway biomarker analysis of human cancer reveals requirement for upfront cellular-enrichment processing.

Tissues are complex structures composed of different cell types, each of which present specific functions and characteristics. To better understand and measure the effect of tumor cell enrichment on protein pathway profiling and drug target activation measurements, the signaling activation portraits of laser capture microdissected (LCM) cancer epithelium and tumor stroma were compared with patient-matched whole-tissue specimens from 53 primary colorectal cancer samples. Microdissected material and whole-tissue lysate from contiguous cryostat sections were subjected to reverse-phase protein microarray analysis to determine the level of phopshorylation and expression of 75 different proteins known to be involved in cancer progression. The results revealed distinct differences in the protein activation portraits of cancer epithelium and stroma. Moreover, we found that the signaling activation profiles of the undissected whole-tissue specimens are profoundly different from the matched LCM material. Attempts to rescale the undissected pathway information based on percent endogenous tumor epithelium content were unsuccessful in recapitulating the LCM tumor epithelial signatures. Analysis of epidermal growth factor receptor phosphorylation and COX2 expression in these same sample sets revealed wholesale differences in the rank ordering of patient determination when LCM was compared with undissected samples. On the basis of these data, we conclude that accurate protein pathway activation status, which is under evaluation as a basis for patient selection and stratification for personalized therapy, must include upfront cellular-enrichment techniques such as LCM to generate accurate drug target activation status.

Multiplexed cell signaling analysis of metastatic and nonmetastatic colorectal cancer reveals COX2-EGFR signaling activation as a potential prognostic pathway biomarker.

The identification of prognostic determinants of colorectal cancer (CRC), including prediction of occult metastasis, is of urgent consideration, based on the tremendous differences in outcome and survival between patients who present with metastasis or develop metastasis versus those patients with organ-confined or nonrecurrent disease. Currently, a great deal of attention has been focused on using gene expression profiles of tumor specimens as a launch point for prognostic biomarker discovery. In our study, we chose to focus on functional protein-based pathway biomarkers as a new information archive because it is these proteins that form the functional signaling networks that control cell growth, motility, apoptosis, survival, and differentiation. We used reverse-phase protein microarray analysis of laser capture microdissected CRC tumor specimens to profile broad cell signaling pathways from patients who presented with liver metastasis versus patients who remained recurrence free after follow-up. Our results indicate that members of the EGFR and COX2 signaling pathways appear differentially activated in the primary tumors of patients with synchronous metastatic disease. If validated in larger study sets, this pathway defect might be useful as a prognostic clinical tool as well as a guide to potential therapeutic intervention strategies that target occult disease and/or preventative measure.

Huge renal cyst with parietal renal cell carcinoma, osseous metaplasia and a papillary adenoma: a case report with unique clinicopathological features and literature review.

The unique clinicopathological features of a giant solitary renal cyst with a parietal clear cell carcinoma in contiguity with a focus of osseous metaplasia and a papillary adenoma are reported. Ultrasonography and computed tomography showed a single cyst with a focal wall irregularity. During surgery, a frozen section revealed the presence of a renal cell carcinoma of clear cell type, so a nephrectomy was performed. After extensive pathological sampling of the cyst's wall, a focus of osseous metaplasia in contiguity with the main tumour and a microscopic papillary adenoma were found. Diagnostic implications for the present case are discussed within a pertinent literature review.

Laparoendoscopic Percutaneous Endoscopic Gastrostomy in Adults.

BACKGROUND: Since its introduction, the placement of percutaneous endoscopic gastrostomy (PEG) has been increasing in the Western countries. Nevertheless, it is not always possible to perform this operation. Laparoscopic-assisted endoscopic gastrostomy (LAPEG) is an effective alternative solution. MATERIALS AND METHODS: Indication to PEG placement was established only for people who required a nutritional support of >4 weeks and without metastatic carcinoma. Sixteen patients underwent LAPEG after the failure of the original PEG operation. Two trocars of 5 mm and one of 12 mm were used, and a fourth trocar of 5 mm was placed when necessary to lift the liver. In four cases a gastrotomy was performed, in seven patients it was not necessary. When PEG was placed, the stomach was not fixed with stitches to the abdominal wall. RESULTS: Sixteen patients were selected for LAPEG and were all successful; in one case it was necessary to replace the PEG, and the same procedure was performed again. Median age was 73 years. Placement of laparoscopic PEG was not associated with other surgical procedures. Nutritional feeding started the day after for patients with sutureless technique and 2 days after in patients with gastrotomy. CONCLUSION: LAPEG is a safe technique with a low complication rate. It should be considered a minimal alternative in all cases where the placement of PEG is not possible.

Late gastric pouch necrosis after Lap-Band, treated by an individualized conservative approach.

Late band slippage has occurred in nearly 3-10% of patients after laparoscopic adjustable gastric banding (LAGB) with an average delay of 13 months. Band slippage can rarely lead to necrosis of the enlarged pouch, a potentially life-threatening condition. We report a female (BMI 39.92 with co-morbidities) who developed acute outlet obstruction 2 years after LAGB placement. After prompt band deflation, an urgent Gastrografin swallow showed stomach slippage without emptying. At re-operation pouch strangulation was discovered. The pouch appeared to be ill-fated, but as no tear was evident on intra-operative assessment, we decided to simply remove the band and drain. The patient was successfully discharged after 8 days, and the last upper endoscopy showed only a large ulcer in the fundus that was healing. Proper and prompt management of symptomatic patients with stomach slippage, with early operation when acute obstruction is evident, can enable a successful stomach-sparing approach.

Weight loss and postoperative complications in morbidly obese patients with binge eating disorder treated by laparoscopic adjustable gastric banding.

BACKGROUND: The authors investigated the outcome of morbidly obese patients with binge eating disorder (BED) treated surgically with laparoscopic adjustable gastric banding. METHODS: The 5-year outcomes of 130 patients with BED and 249 patients without BED are described. The diagnosis of BED was made preoperatively and all patients with BED were supported with psychological therapy. RESULTS: Patients with and without BED had similar BMI levels before surgery. More patients with than without BED had depressive symptoms and associated minor disturbances of eating behavior (night eating and grazing). Percent excess weight loss (%EWL) in the first 5 years after surgery was similar in patients with and without BED. The percentage of BED patients showing %EWL >50% at the 5-year evaluation was 23.1, and 25.7% in non-BED patients. The percentage of patients showing weight regain in the last 4 years of follow-up was similar in binge eaters (20.8%) and in non-binge eaters (22.5%). The 5-year frequency of gastric pouch and esophageal dilatation was significantly higher in binge eaters than in non-binge eaters (25.4 vs 17.7 %, P<0.05 and 10.0 vs 4.8%, P<0.05, respectively). Binge eaters underwent a higher number of postoperative band adjustments than non-binge eaters (3.0+/-2.1 vs 2.6+/-1.9, P<0.05) and the maximum band fill after surgery was higher in the BED patients than in non-BED patients (3.2+/-1.2 vs 2.8+/-1.3 ml, P<0.01). CONCLUSION: Morbidly obese patients with BED supported by adequate psychological treatment can have good outcomes after gastric banding.

HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment.

An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host's immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3'UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3'UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3'UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3'UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3'UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38-0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26-0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19-5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16-6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3'UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G.

Postoperative management of laparoscopic gastric banding.

BACKGROUND: The authors investigated the postoperative management of morbidly obese patients treated by laparoscopic adjustable gastric banding (LAGB) with the Lap-Band System. METHODS: The 3-year postoperative band management is presented in 379 morbidly obese patients, divided according to intra-operative band filling and quartiles of maximum postoperative band filling. RESULTS: LAGB resulted in a 40.8 +/- 24.5 percent excess weight loss (%EWL). Stoma stenosis occurred in 87 patients (23.0%), pouch dilatation in 52 (13.7%) and esophageal dilatation in 22 (5.8%). Most band-related complications were controlled by simple band deflation. The mean number of postoperative band adjustments was 2.3 +/- 1.7, and mean maximum band filling after surgery was 2.8 +/- 1.2 ml. Weight loss at 3 years was identical in 205 patients who had the band completely unfilled at surgery and in 174 patients who had the band filled with 1 to 3 ml of sterile saline. The rate of band-related complications was significantly lower in the first group. No differences in %EWL were observed between quartiles of maximum band filling after surgery. The rate of band-related complications increased with increasing levels of postoperative maximum band filling. In patients with the band filled with < 3.0 ml of sterile saline at 6 months, the inflation of further saline produced a dose-related increase in the rate of weight loss. In patients with the band filled with > 3.0 ml of sterile saline at 6 months, the inflation of further saline was associated with a reduced %EWL. CONCLUSION: Postoperative adjustability of the Lap-Band was useful in the treatment of band-related complications and was able to significantly influence the rate of weight loss. On the other hand, aggressive postoperative band filling was associated with an increased rate of complications.

Radiology for laparoscopic adjustable gastric banding: a simplified follow-up examination method.

BACKGROUND: The aim of this study was to identify factors which allow a reliable, standardized and simplified approach for the radiologic follow-up of obese patients who have undergone surgery for laparoscopic adjustable gastric banding (LAGB) placement. METHODS: A study was made of 370 consecutive single-contrast upper gastrointestinal series in 159 consecutive patients (122 women, 31 men; mean age 40.6 years; mean body weight 135.8 kg) who had undergone LAGB for morbid obesity and were symptomatic or had inadequate weight loss. The control group consisted of 38 subjects who had undergone LAGB, had satisfactory weight loss and were asymptomatic at follow-up. RESULTS: Each gastric portion above the band was satisfactorily evaluated by measuring its vertical diameter. The optimal projection for measurement of stoma size was predicted before administration of the contrast agent and was achieved when the band was visualized in profile. The clinical pictures were not always related to stoma size. Surgical complications were gastric herniation (8 patients, twice in 1 patient, 5.7%), malpositioned band (1 patient, 1.6%), port twisting (13 patients, 8.2%), and disconnection or leakage of the device (8 patients, 5.0%). CONCLUSION: Essential criteria for the radiologic evaluation of LAGB are: position of port and tubing; stoma size; and volume of each upper gastric portion.

Outcome predictors in morbidly obese recipients of an adjustable gastric band.

BACKGROUND: The authors investigated the outcome predictors in obese patients who underwent laparoscopic adjustable banding with the Lap-Band. METHODS: The 3-year excess weight loss (EWL) and rate of band-related complications (pouch dilatation and port leakage) were analyzed in 260 morbidly obese patients, according to several possible predictive characteristics. Success rate (EWL > 50%), failure rate (EWL < 20%) and weight regain rate (regain of > 10% EWL between 1 and 3 yrs) were considered. RESULTS: The Lap-Band produced a 43.0 +/- 22.3% EWL, corresponding to a BMI reduction from 46.6 +/- 7.0 to 36.8 +/- 6.6 kg/m2. Success rate was 35.7%, failure rate was 14.1% and weight regain rate was 20.7%. Pouch dilatation occurred in 32 patients (12.3%), band erosion in 2 (0.8%), port leakage in 74 (28.5%), and port twisting in 2 (0.8%). Major band-related surgery was requested in 11 patients (4.2%) and minor port-related surgery in 62 patients (23.9%). Significant success predictors were found to be age < 40 years and BMI < 50 kg/m2. Significant failure predictors were found to be male sex and non-sweet eating behavior. Significant weight regain predictors were found to be BMI < 50 kg/m2 and the occurrence of a port leakage. Port leakage was significantly more frequent in women and in patients with BMI < 50 kg/m2. The prevalence of pouch dilatation was threefold higher in women than in men. CONCLUSIONS: Lap-Band was associated with a good outcome and with a low rate of severe complications. The outcome was more influenced by physiological and technical reasons than by psychological or behavioural factors.

An adjustable silicone gastric band for laparoscopic treatment of morbid obesity--technique and results.

The laparoscopic application of an adjustable silicone gastric band (Lap-Band System, Bioenterics, Carpinteria, CA) (Fig. 1), based on a similar device introduced by Kuzmak in 1986, is gaining widespread acceptance as a gastric restrictive procedure in treatment of morbid obesity. The advantage of an operation that does not open the gastrointestinal tract and can be performed laparoscopically is obvious. This procedure, using the laparoscopic approach , has been performed in our institutions since 1992. The goals of this article are to describe both our standardized surgical technique that minimized the morbidity rate and its results.

Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations.

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.

Multiplexed protein signal pathway mapping identifies patients with rectal cancer that responds to neoadjuvant treatment.

BACKGROUND: Currently there is no reliable technique for predicting clinical or pathologic complete tumor response after radiochemotherapy (RCT) in patients with rectal cancer. We applied reverse phase protein microarray (RPMA) technology to find a signal pathway that may predict the response to preoperative treatment. PATIENTS AND METHODS: Fifteen rectal cancer samples were collected during preoperative RCT. Seven patients had a good response to preoperative therapy (Mandard grade I-II) and 8 patients had a poor response (Mandard grade III-V). Using laser capture microdissection (LCM) and RPMA analysis, we measured the phosphorylation level of nearly 80 end points and analyzed the signaling pathways. RESULTS: We identified 4 signaling proteins whose phosphorylation levels were significantly different (P < .05) between the good vs. poor responders; CHK2 and ß-catenin were more highly phosphorylated in poor responders, whereas PDK1 and glycogen synthase kinase (GSK)-3α/ß had lower phosphorylation levels in poor responders. Interestingly GSK-3α/ß, ß-catenin, and PDK1 are all present in the phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway. CONCLUSIONS: Based on our results, we hypothesize that the activating state of the PI3K-AKT pathway can stratify patients who could benefit most from neoadjuvant treatment. Moreover, identification of theranostic targets has the potential to pinpoint new therapeutic strategies for the nonresponsive population.

Liver volume and visceral obesity in women with hepatic steatosis undergoing gastric banding.

OBJECTIVE: To investigate the relationships between visceral obesity and hepatic steatosis in obese patients undergoing adjustable silicone gastric banding with the LAP-BAND. RESEARCH METHODS AND PROCEDURES: Six premenopausal, morbidly obese women with an ultrasonographic diagnosis of liver steatosis were evaluated before surgery and 8 and 24 weeks after surgery. Liver volume and body fat distribution were simultaneously analyzed by total-body multislices magnetic resonance imaging. RESULTS: Before surgery, the only variable found to be correlated with liver volume was visceral adipose tissue volume (r = 0.91; p < 0.01). Weight loss was 9.9 +/- 3.8 kg in the period from 0 to 8 weeks (p < 0.01) and 7.1 +/- 4.9 kg in the the period from 8 to 24 weeks (p < 0.05). Total fat showed a statistically significant reduction of 6.2 +/- 4.0 liters in the 0- to 8-week period and a further significant reduction of 7.7 +/- 3.9 liters in the 8- to 24-week period. Visceral adipose tissue showed a statistically significant reduction of 1.0 +/- 0.9 liters in the 0- to 8-week period (p < 0.05) but only a further, not significant reduction of 0.6 +/- 0.7 liters in the 8- to 24-week period. The relative reduction of visceral fat in the 0-to 8-week period was higher than the relative reduction of total fat. Liver volume also showed a statistically significant reduction of 0.24 +/- 0.26 liters in the first phase of weight loss (p < 0.05), corresponding to a relative reduction of 12.3 +/- 10.6%. During the 8- to 24-week period, liver volume was substantially stable. DISCUSSION: Hepatomegaly was associated with visceral obesity in morbidly obese women with liver steatosis. In the phase of rapid weight loss after gastric surgery, a preferential mobilization of visceral fat, compared with total adipose tissue, occurred. This preferential visceral fat loss was associated with a significant reduction in liver volume.

Short-term effects of weight loss on the cardiovascular risk factors in morbidly obese patients.

OBJECTIVE: To analyze the short-term effects of weight loss on the cardiovascular risk factors in morbidly obese patients. RESEARCH METHODS AND PROCEDURES: Five metabolic cardiovascular risk factors (blood glucose, blood pressure, total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides) were determined before and 15.3 +/- 2.1 months after laparoscopic gastric banding in 650 morbidly obese patients. Global cardiovascular risk was calculated according to the Prospective Cardiovascular Münster (PROCAM) scoring system. RESULTS: Mean weight loss was 22.7 +/- 20.4 kg. Normalization of the metabolic alteration was observed in 67.3% of patients with diabetes, 38.3% of patients with hypercholesterolemia, 72.5% of patients with low HDL-cholesterol, 72.3% of patients with hypertriglyceridemia, and 46.7% of patients with hypertension. PROCAM score fell from 31.4 +/- 11.6 to 28.0 +/- 12.0 points (p < 0.001). The modifications of total cholesterol and blood pressure were unrelated to percentage weight loss. Percentage weight loss was significantly related to the reductions of fasting blood glucose, triglyceride level, and the PROCAM score and to the increase of HDL-cholesterol concentrations observed after surgery. However, the strength of these four relationships was generally low. The variations of HDL-cholesterol concentrations and blood pressure levels were more influenced by actual energy balance than by the extent of weight loss. DISCUSSION: Weight loss observed in the first 12 to 18 months after gastric banding was associated with a significant improvement of single cardiovascular risk factors and global risk. On the other hand, the extent of weight loss was poorly related to the magnitude of improvement in cardiovascular risk.