B. M. Smithers

Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma

BACKGROUND Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. METHODS We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. CONCLUSIONS Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

Comparison of the outcomes between open and minimally invasive esophagectomy.

Objective:We report patient outcomes from esophageal resection with respect to morbidity and cancer survival comparing open thoracotomy and laparotomy (Open), with a thoracoscopic/laparotomy approach (Thoracoscopic-Assisted) and a total thoracoscopic/laparoscopic approach (Total MIE). Methods:From a prospective database of all patients managed with cancer of the esophagus or esophagogastric junction, patients who had a resection using one of three techniques were analyzed to assess postoperative variables, adequacy of cancer clearance, and survival. Results:The number of patients for each procedure was as follows: Open, 114; Thoracoscopic-Assisted, 309; and Total MIE, 23. The groups were comparable with respect to preoperative variables. The differences in the postoperative variables were: less median blood loss in the Thoracoscopic-Assisted (400 mL) and Total MIE (300 mL) groups versus Open (600 mL); longer time for Total MIE (330 minutes) versus Thoracoscopic-Assisted (285 minutes) and Open (300 minutes); longer median time in hospital for Open (14 days) versus Thoracoscopic-Assisted (13 days), Total MIE (11 days) and less stricture formation in the Open (6.1%) versus Thoracoscopic-Assisted (21.6%), Total MIE (36%). There were no differences in lymph node retrieval for each of the approaches. Open had more stage III patients (65.8%) versus Thoracoscopic-Assisted (34.4%), Total MIE (52.1%). There was no difference in survival when the groups were compared stage for stage for overall median or 3-year survival. Conclusion:Minimally invasive techniques to resect the esophagus in patients with cancer were confirmed to be safe and comparable to an open approach with respect to postoperative recovery and cancer survival.

Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus

Objective: To measure the relative risks of adenocarcinomas of the oesophagus and gastro-oesophageal junction associated with measures of obesity, and their interactions with age, sex, gastro-oesophageal reflux symptoms and smoking. Design and setting: Population-based case–control study in Australia. Patients: Patients with adenocarcinomas of the oesophagus (n = 367) or gastro-oesophageal junction (n = 426) were compared with control participants (n = 1580) sampled from a population register. Main outcome measure: Relative risk of adenocarcinoma of the oesophagus or gastro-oesophageal junction. Results: Risks of oesophageal adenocarcinoma increased monotonically with body mass index (BMI) (ptrend <0.001). Highest risks were seen for BMI ⩾40 kg/m2 (odds ratio (OR) = 6.1, 95% CI 2.7 to 13.6) compared with “healthy” BMI (18.5–24.9 kg/m2). Adjustment for gastro-oesophageal reflux and other factors modestly attenuated risks. Risks associated with obesity were substantially higher among men (OR = 2.6, 95% CI 1.8 to 3.9) than women (OR = 1.4, 95% CI 0.5 to 3.5), and among those aged <50 years (OR = 7.5, 95% CI 1.7 to 33.0) than those aged ⩾50 years (OR = 2.2, 95% CI 1.5 to 3.1). Obese people with frequent symptoms of gastro-oesophageal reflux had significantly higher risks (OR = 16.5, 95% CI 8.9 to 30.6) than people with obesity but no reflux (OR = 2.2, 95% CI 1.1 to 4.3) or reflux but no obesity (OR = 5.6, 95% 2.8 to 11.3), consistent with a synergistic interaction between these factors. Similar associations, but of smaller magnitude, were seen for gastro-oesophageal junction adenocarcinomas. Conclusions: Obesity increases the risk of oesophageal adenocarcinoma independently of other factors, particularly among men. From a clinical perspective, these data suggest that patients with obesity and frequent symptoms of gastro-oesophageal reflux are at especially increased risk of adenocarcinoma.

Laparoscopic versus Open Appendectomy: Prospective Randomized Trial

Abstract. A prospective randomized trial comparing laparoscopic appendectomy with open appendectomy in patients with a diagnosis of acute appendicitis was conducted between October 1992 and April 1994. Of the 158 patients randomized, 7 patients were excluded because of protocol violations (conversion to laparotomy in 4, appendix not removed in 3). The 151 patients randomized to either a laparoscopic (n = 79) or an open appendectomy (n = 72) showed no difference in sex, age, American Society of Anesthesiology (ASA) rating, or previous abdominal surgery. The histologic classification of normal, catarrhal, inflamed, suppurative, and gangrenous appendicitis was not different between the two groups. Conversion from laparoscopic to open appendectomy was necessary in seven patients (9%) who had advanced forms of appendiceal inflammation. When compared to open appendectomy the laparoscopic group had a longer median operating time (63 minutes versus 40 minutes), fewer wound infections (2% versus 11%), less requirement for narcotic analgesia, and an earlier return to normal activity (median 7 days versus 14 days). There was no difference in morbidity, and both groups had a median time to discharge of 3 days. Laparoscopic appendectomy is as safe as open appendectomy; and despite the longer operating time, the advantages such as fewer wound infections and earlier return to normal activity make it a worthwhile alternative for patients with a clinical diagnosis of acute appendicitis.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma

BACKGROUND Sentinel‐lymph‐node biopsy is associated with increased melanoma‐specific survival (i.e., survival until death from melanoma) among patients with node‐positive intermediate‐thickness melanomas (1.2 to 3.5 mm). The value of completion lymph‐node dissection for patients with sentinel‐node metastases is not clear. METHODS In an international trial, we randomly assigned patients with sentinel‐node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph‐node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma‐specific survival. Secondary end points included disease‐free survival and the cumulative rate of nonsentinel‐node metastasis. RESULTS Immediate completion lymph‐node dissection was not associated with increased melanoma‐specific survival among 1934 patients with data that could be evaluated in an intention‐to‐treat analysis or among 1755 patients in the per‐protocol analysis. In the per‐protocol analysis, the mean (±SE) 3‐year rate of melanoma‐specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log‐rank test) at a median follow‐up of 43 months. The rate of disease‐free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log‐rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log‐rank test); these results must be interpreted with caution. Nonsentinel‐node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS Immediate completion lymph‐node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma‐specific survival among patients with melanoma and sentinel‐node metastases. (Funded by the National Cancer Institute and others; MSLT‐II ClinicalTrials.gov number, NCT00297895.)

Laparoscopic Nissen fundoplication--200 consecutive cases.

PATIENTS--Laparoscopic Nissen fundoplication was undertaken in 200 patients between 1991 and 1994. METHODS--Pre-operative assessment included symptom score, endoscopy, manometry, and 24 hour pH monitoring of the oesophagus. Patients were evaluated at three and 12 months after surgery with symptom scoring and 96 patients also underwent 24 hour pH studies at three to six months postoperatively. RESULTS--In the first 100 patients median duration of operation was 155 minutes (range: 70-330), conversion rate to laparotomy was 7%, median hospital stay was three days (range: 2-57), and total morbidity was 16%. This compared with a median operation time of 120 minutes (60-240) (p = 0.0003, 95% CI 10, 40), a conversion rate of 2% (p = 0.2), a hospital stay of three days (1-18) (p = 0.0016, 95% CI 0, 1), and total morbidity of 7% (p = 0.15) in the second 100 patients. Median total symptom scores fell from 5/9 to 0/9 after fundoplication (< 0.0001) while median 24 hour oesophageal acid exposure in 96 patients was reduced from 10% to 1% (p < 0.001). CONCLUSIONS--Laparoscopic Nissen fundoplication is a safe and effective procedure for gastro-oesophageal reflux disease. With experience, the duration of operation falls and the hospital stay is shorter. Shortterm symptomatic and pH results are consistently improved by surgery.

Thoracoscopic mobilization of the esophagus: A 6 year experience

BackgroundTraditionally, esophageal resection has been performed using a thoracotomy to access the intrathoracic esophagus. With the aim to avoid the potential morbidity of the open thoracic approach, mobilization of the esophagus under direct vision recently has been described. We report our experience at attempting thoracoscopic mobilization of the esophagus in 162 patients during a 6-year period.MethodsPatients with malignancy or end-stage benign disease of the esophagus considered suitable for a three-stage esophagectomy underwent a thoracoscopy with a view to endoscopic mobilization of the esophagus. Of the 162 patients in whom the procedure was attempted, it was abandoned in 9 patients (6%), and the procedure was converted to open surgery in 11 patients (7%).ResultsIn the patients whose esophagus was mobilized, the average blood loss was 165 ml, and the average time for the thoracoscopic segment of the surgery was 104 min. In the 133 patients who underwent a resection for invasive malignancy, a limited mediastinal nodal dissection retrieved an average of 11 nodes, and the median survival was 29 months. The 30-day mortality was 3.3% and the in-hospital mortality 5.3%.ConclusionsThoracoscopic mobilization can be performed safely with satisfactory outcomes in a center performing a large volume of esophageal surgery and possessing advanced endoscopic surgery skills. Further assessment of this technique and comparisons with traditional open procedures are needed to assess this approach further as an appropriate oncologic procedure.

Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7-57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0-11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development.

Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus

Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was -56.8% (SD 29) and in the non-responders -27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was -49.1% (SD 44.8) in the responders and in the non-responders -27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3-6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.

Minimally invasive esophagectomy : Short- and long-term outcomes

BackgroundWe aimed to assess the outcomes including the effect on quality of life (QoL) of a group of patients having a minimally invasive esophagectomy (MIE).MethodsPatients with esophageal cancer were offered MIE over a 22-month period. Data on outcomes were collected prospectively, including formal quality-of-assessments.ResultsThere were 25 patients offered MIE. Two patients were converted to a laparotomy to improve the lymphadenectomy. There were no deaths. Respiratory problems (pneumonia, 28%) were the most common in the 64% of patients who had a complication. The median blood loss was 300 ml, time of surgery 330 min, and time to discharge 11 days. There was a decrease in the measured QoL both in general and specifically for the esophageal patients, taking 18–24 months to return to baseline.ConclusionsMIE was performed with morbidity similar to other approaches. There were no clear benefits shown in this group of patients with respect to postoperative recovery or short- to medium-term QoL.