Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.

BACKGROUND: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. PATIENTS AND METHODS: Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). RESULTS: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0). CONCLUSIONS: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).

Striving to cure adult T-cell leukaemia/lymphoma: a role for allogeneic stem cell transplant?

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive HTLV-1-related malignancy, rare outside of regions where the retrovirus is endemic. Although the use of antiviral therapy has improved outcomes, particularly for indolent forms of ATL, response to combination chemotherapy is poor and outcomes for aggressive subtypes remains dismal. Consolidation with allogeneic stem cell transplant (alloSCT) has an increasing role in the management of ATL in eligible patients, offering favourable long-term remission rates. However, relatively high-transplant-related mortality and issues with donor recruitment for certain ethnicities remain problematic. In this review, we discuss the rationale for and issues surrounding alloSCT in ATL in the context of conventional and emerging therapies.

The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies.

UNLABELLED: ESSENTIALS: Molecular diagnostics has improved the differentiation of acute thrombotic microangiopathys (TMAs). Atypical hemolytic uremic syndrome may have features mimicking thrombotic thrombocytopenic purpura. We identified novel complement mutations and a high incidence of CD46, with favorable long term outcomes. Complement mutation analysis in TMA where the diagnosis is unclear and ADAMTS-13 activity is >10%. BACKGROUND: Differentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS-13 activity. The identification of alternative complement pathway abnormalities in atypical hemolytic uremic syndrome (aHUS), along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS. OBJECTIVES: We describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs. PATIENTS/METHODS: Fourteen consecutive aHUS patients were screened for mutations in C3, CD46, CFH, CFI, and CFB, as well as factor H (FH) antibodies. All aHUS patients had ADAMTS-13 activity > 10%. RESULTS: Of 14 aHUS patients, 11 (79%) had platelet counts < 30 × 10(9) /L during the acute phase. Median presenting creatinine level was 295 µmol L(-1) , while five (36%) of 14 presented with a serum creatinine level < 200 µmol L(-1) . Alternative complement pathway mutations were detected in 9 (64%) of 14 patients, including CD46 mutations in five (36%) of 14 patients. Patients were identified with novel mutations in CFB and C3 that have not been previously reported. CONCLUSIONS: We demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations which may mimic TTP. ADAMTS-13 activity > 10% in a patient with a TMA should necessitate genetic screening for complement abnormalities.

Performance differences in laparoscopic surgical skills between true high-definition and three-chip CCD video systems.

BACKGROUND: Laparoscopic surgery requires surgeons to rely on visual clues for discrimination among differing tissues and for depth of field on a two-dimensional screen. High definition (HD) provides a superior image. If there is a measurable advantage with HD television (TV), the increase in the cost of the technology would be justified. METHODS: A digital three-chip CCD camera with a standard monitor (SD system) and a true HD camera (1,080 pixels) with a 16:9-ratio HD monitor (HD system) were compared in clinical and laboratory settings. Three experiments were performed: (1) subjective visual evaluation of the HD and SD systems during actual surgical cases, (2) subjective visual evaluation in a controlled laboratory surgical setting with simultaneous parallel recording, and (3) three laparoscopic surgical task evaluations in a laboratory setting, namely, task A (metric analysis of participants on the surgical simulator), task B (simple eye-hand coordination performance), and task C (knot tying). RESULTS: All 53 participants subjectively evaluated HD as superior to SD in the laboratory setting and during actual surgery. In task B, there was no significant difference between SD and HD (dominant hand: p = 0.19; nondominant hand: p = 0.07). In task C, the knot-tying time was significantly less when performed with HD (mean, 173 +/- 84 s vs 214 +/- 107 s; p = 0.003). Most importantly, subjects with less skill (more documented time required in the basic module on a surgical simulator) improved significantly in the knot-tying task with the HD system (R = 0.631; p = 0.005). CONCLUSION: All the participants preferred HD to SD. High definition significantly improved laparoscopic knot tying, which requires precise depth perception, proving that HD is more than just a pretty picture.

Laparoscopic transcystic duct common bile duct exploration.

The modern era of common bile duct (CBD) surgery started with Mirizzi, who introduced intraoperative cholangiography in 1932. Intraoperative choledoscopy had been developed as an adjunctive to intraoperative cholangiography, which helped to detect CBD stones in an additional 10% to 15% of instances that otherwise would have been missed. Findings have shown choledochoscopy to be an important technique for efficient and effective management of CBD stones. Efforts to treat patients with common duct stones in one session and to avoid the potential complications of endoscopic sphincterotomy resulted in several laparoscopic transcystic CBD (LTCBDE) techniques. The techniques of transcystic stone extraction include lavage, trolling with wire baskets or biliary balloon catheters, cystic duct dilation, biliary endoscopy, and stone retrieval with wire baskets under direct vision and antegrade sphincterotomy, lithotripsy, and catheter techniques. The indications for LTCBDE are filling or equivocal defects at cholangiography, stones smaller than 10 mm, fewer than 9 stones, and possible tumor. The contraindications are stones larger than 1 cm, stones proximal to the cystic duct entrance into the CBD, small friable cystic duct, and 10 or more stones. Experience with LTCBDE shows that the approach is applicable in more than 85% of cases, with a success rate of 85% to 95%. It also is shown to be more cost effective than postoperative endoscopic retrograde cholangiopancreatography. Recent developments in LTCBDE have focused mainly on implementation of robotically assisted surgery and new imaging methods such as magnetic resonance cholangiopancreatography with three-dimensional virtual cholangioscopy and three-dimensional ultrasound. Further technological advances will facilitate the application of laparoscopic approaches to the common duct, which should become the primary strategy for the great majority of patients.

Leveling the learning curve for laparoscopic bariatric surgery.

BACKGROUND: The learning curve for laparoscopic bariatric surgery is associated with increased morbidity and mortality. METHODS: The study included the first 100 patients undergoing laparoscopic Roux-en-Y gastric bypass (LGB) by a designated surgical team. Surgeon A operated as primary surgeon, with surgeon B assisting (Stage 1). Surgeon B learned LGB in stages: exposure and jejunojejunostomy (stage 2), gastric pouch (stage 3), gastrojejunostomy (stage 4), and sequence all steps (stage 5). RESULTS: Surgeon A achieved confidence with LGB after 20 cases and surgeon B after 25 cases (stage 2), 18 cases (stage 3), 21 cases (stage 4), and 16 cases (stage 5). Complications (8%) included small bowel obstruction (three); pulmonary embolus (two), and leak, stomal stenosis, and gastrogastric fistula (one each). There was a decreasing trend for operative duration, length of stay, and complications across the five stages (p < 0.05). CONCLUSIONS: By transferring skills in stages, a laparoscopic bariatric program can be established with minimal morbidity and mortality.

Consider the diagnosis of splenosis for soft tissue masses long after any splenic injury.

Splenosis represents the autotransplantation of splenic tissue after splenic trauma or surgery. Disruption of the splenic capsule causes fragments of splenic tissue to be seeded mainly throughout the peritoneal cavity, where they are characterized by diffusely scattered bluish implants. Extraperitoneal locations are very rare and mainly include the thoracic cavity after thoracoabdominal trauma with simultaneous splenic rupture and diaphragmatic laceration. We retrospectively identified all patients in the pathology registry with the diagnosis of splenosis between December 1974 and July 2003 at our urban teaching hospital. Data collected included presenting signs and symptoms, history, imaging studies, treatment, pathology, and outcome. Five cases of splenosis were identified and described. Location of the splenosis was intraperitoneal in two and intrahepatic, intrathoracic, and subcutaneous in one each. In these cases, there was an average interval of 29 years between splenic injury and diagnosis, and most were found incidentally. One of the cases was managed entirely laparoscopically and another thoracoscopically.

Current status of laparoscopic ventral hernia repair.

Ventral abdominal wall hernias are a common problem for the general surgeon. Historically, the best results have been obtained with the open Rives-Stoppa approach. This is done by fixing a large piece of prosthetic mesh behind the rectus muscle. Extensive dissection is required and can lead to postoperative pain and wound complications. A laparoscopic approach allows similar mesh placement with minimal dissection. Several small comparative studies have found laparoscopic ventral hernia repair to have fewer complications, a shorter length of stay, and possibly a lower recurrence rate when compared to open mesh repair. Large prospective studies have now confirmed these findings, with recurrence rates below 4%. This is significantly lower than the best reported rates of open mesh repair. Additionally, the morbidity appears to be significantly less. This technique is easily mastered by anyone with basic laparoscopic skills and is briefly presented.

Laparoscopic diaphragmatic hernia repair.

BACKGROUND: Adult-congenital diaphragmatic hernias and chronic traumatic diaphragmatic hernias are uncommon entities that are often technically challenging to repair. There is growing experience with a minimal access approach to these defects. METHODS: We reviewed the English-language literature using a MEDLINE search for "diaphragmatic hernia" and "laparoscopy." RESULTS: We found 19 case reports of laparoscopic adult-congenital diaphragmatic hernia repair. Reported complications included two enterotomies, one of which required conversion to laparotomy. We also found 11 case reports of laparoscopic chronic traumatic diaphragmatic hernia repair, with no reported complications or recurrences. Average operative time was 98 min, and average length of stay was 4.5 days. All reports claimed that there was less postoperative pain and an earlier return to full activity with the laparoscopic approach. Herein we discuss anatomy, pathophysiology, diagnosis, method of repair, and recurrence. CONCLUSION: Adult-congenital diaphragmatic hernia and chronic traumatic diaphragmatic hernia are amenable to laparoscopic repair. Although experience is still limited, laparoscopic repair appears safe and is associated with a shorter hospital stay.

Mesh crural repair of large paraesophageal hiatal hernias.

Surgical repair is indicated in patients with paraesophageal hernias but is associated with a high recurrence rate. Our objective was to assess the safety and efficacy of mesh reinforcement of the crural closure in laparoscopic paraesophageal hernia repair. We conducted a 7-year retrospective review of all patients undergoing laparoscopic paraesophageal hernia repair with or without use of mesh. The main outcome measures were use of mesh, reason for use, age, sex, preoperative symptoms, length of operation, length of hospital stay, postoperative complications, and long-term follow-up conducted by physician interview. Twelve patients were repaired with mesh (Group A) and 12 without (Group B). Age, sex, operating time, length of hospital stay, and postoperative complications were similar in both groups. In Group A two patients required an interposition graft and ten required mesh reinforcement of the crural closure. One Group A patient developed an early recurrence requiring a reoperation, and one Group B patient developed a gastric leak where the fundus was sutured to the crura. The remainder of the patients experienced resolution of their symptoms at 2 weeks follow-up. Long-term follow-up (average 37 months) showed one Group B patient with a recurrence of reflux symptoms, but an upper gastrointestinal study showed no recurrence of hernia. All others remained asymptomatic. We conclude that the use of mesh in laparoscopic repair of large paraesophageal hernias appears safe and may reduce recurrence.

Splenectomy for splenic metastases: a changing clinical spectrum.

Splenic metastases from solid tumors are unusual with only scattered case reports of patients treated with splenectomy before 1987. We conducted a retrospective chart review at our large tertiary-care private teaching hospital between January 1990 and September 1999 and found splenic metastases in 31 patients. In eight patients (26%), the spleen was the only site of metastatic disease. Of the 31 splenectomies for metastases, 23 were performed for ovarian neoplasms, five during primary operative procedures, and 18 during secondary cytoreductive procedures or explorations for late recurrences at an average of 3.9 years after the original operation. Nearly half of the metastases (15 of 31) appeared entirely within the splenic parenchyma, representing probable hematogenous spread, whereas seven involved both the splenic parenchyma and capsule and nine involved the capsule only. Between 1990 and 1999 we identified a statistically significant increase in use of splenectomy for treatment of metastatic tumor with a Spearman rank correlation value of 0.86 (P < 0.05). Most of this increase was attributable to ovarian cancer cases and may be due to expansion of treatment options or improved imaging methods. We report the largest series of splenectomy for splenic metastases and the ninth case report in the world literature of splenectomy for isolated splenic metastasis due to colorectal cancer.

Safety of laparoscopic splenectomy in elderly patients with idiopathic thrombocytopenic purpura.

Laparoscopic splenectomy (LS) for immune thrombocytopenic purpura (ITP) is very successful. However, the safety of LS in older patients who have less cardiac and pulmonary reserve has not been studied. Our objective was to compare results of LS in elderly and younger patients with ITP. LS performed for ITP between 1992 and 1999 were studied. Perioperative data were collected concurrently. Follow-up was obtained by chart review and phone interview. Groups were arbitrarily divided: Group A, age > or =70; group B, age <70. Main outcome measures were platelet response, duration of operation, hospitalization, blood loss, and complications were compared using t test and Chi-square analyses. Group A had more comorbid conditions (80% vs 28%, P = 0.04). Operative time (80 vs 119 minutes, P = 0.23), estimated blood loss (156 vs 189 cm3, P = 0.62), and hospitalization (3.6 vs 2.8 days, P = 0.23) were similar for both groups. Although group B had significantly more patients with an early platelet response (70% vs 97%, P = 0.02), there was no difference in platelet response at long-term follow-up (70% vs 84%, P = 0.22). Long-term follow-up was completed on 87 per cent of patients at an average of 43 months postoperatively. We conclude that LS is safe and effective in elderly patients with ITP.

Gastroesophageal disease and nausea: does fundoplication help or hurt?

HYPOTHESIS: Nausea associated with gastroesophageal reflux disease is cured by laparoscopic Nissen fundoplication (LNF). DESIGN: Prospective cohort study of unselected patients who underwent LNF from January 1, 1995, through March 31, 1999. Patients were followed up by a physician for 6 to 36 months. SETTING: A large community teaching hospital. PATIENTS: One hundred consecutive patients with gastroesophageal reflux disease who underwent LNF; all patients were followed up. Patients were grouped according to the presence (group A, n = 33) or absence (group B, n = 67) of preoperative nausea. Interventions were LNF, esophageal manometry, 24-hour pH monitoring, and nuclear gastric emptying studies. MAIN OUTCOME MEASURES: Resolution of symptoms after LNF. RESULTS: Nausea was the most common atypical symptom of gastroesophageal reflux disease, occurring in 33 patients (33%). There were no differences in esophageal manometry or 24-hour pH results between groups. There was a female preponderance in group A (55% vs 33%; P = .003). Patients in group A had a higher prevalence of preoperative dysphagia (P = .02). Patients with persistent postoperative nausea had a higher prevalence of cough (P = .003) and dysphagia (P = .009). The LNF was more effective in reducing heartburn (95% reduction) and regurgitation (95% reduction) than cough and dysphagia (60% reduction). There was a 79% reduction in the number of patients with nausea (33 to 7; P<.001). CONCLUSION: Laparoscopic Nissen fundoplication is effective in eliminating nausea associated with gastroesophageal reflux disease and is not contraindicated in these patients.

Iatrogenic gallbladder perforation during laparoscopic cholecystectomy: etiology and sequelae.

Iatrogenic perforation of the gallbladder (PGB) during laparoscopic cholecystectomy (LC) leads to spillage of bile and gallstones into the peritoneal cavity, which can result in serious postoperative infection. The objective of this study is to prospectively evaluate with long-term follow-up the risk factors, mechanisms, and complications associated with PGB in patients undergoing LC. Data from 1412 patients undergoing LC were collected prospectively between 1989 and 1995. Patients with and without iatrogenic gallbladder perforation were compared. Long-term follow-up was obtained using mailed questionnaires and telephone interviews, when needed. Of the 1412 patients, 512 (36%) sustained a PGB. Male sex, weight, gallbladder inflammation, thickening of the gallbladder, presence of adhesions, and a difficult hilar dissection were all associated with an increased incidence of PGB. The most common mechanisms of PGB were laceration due to grasper traction (55%) and electrocautery dissection (40%). Both the operating time and length of hospital stay were significantly longer in the PGB group. No difference was observed in the rate of wound infections between PGB and non-PGB patients (1.6% versus 1.8%). Only one patient (with an inflamed and perforated gallbladder) developed an early postoperative intra-abdominal abscess. Long-term follow-up averaging 48 months was achieved with a response rate of 44 per cent. No late intra-abdominal abscesses or complications attributable to retained gallstones were discovered.

Laparoscopic common bile duct exploration: long-term outcome.

HYPOTHESIS: Transcystic laparoscopic common bile duct exploration (LCBDE) with biliary endoscopy results in excellent long-term clinical outcome and patient satisfaction. DESIGN: Prospective cohort study of unselected patients found to have common bile duct stones during laparoscopic cholecystectomy between October 1989 and April 1998. A mailed survey assessed symptoms, outcome, and satisfaction. SETTING: A large community teaching hospital. PATIENTS: Two hundred seventeen patients with common bile duct stones. INTERVENTION: Transcystic LCBDE with choledochoscopy. MAIN OUTCOME MEASURES: Success of LCBDE, morbidity, postoperative symptoms, and satisfaction. RESULTS: One hundred sixteen surveys (54%) were returned. Mean follow-up was 60 months. The LCBDE procedure failed in 6 patients and endoscopic retrograde cholangiopancreatography was performed in 4 patients (3%). One patient had unsuspected retained stones. No patient had late recognition of retained stones or a bile duct stricture. Abdominal pain was present in 90 patients (89%) preoperatively and in 29 patients (26%) postoperatively (P = .001). The LCBDE procedure reduced 3 specific pain profiles: epigastric, from 47% (n = 54) to 7% (n = 8); back, from 31% (n = 36) to 6% (n = 7); and shoulder, from 18% (n = 21) to 2% (n = 2). When pain persisted, it was different in character in 15%. All nonpain symptoms (such as nausea, bloating, indigestion, and gas) were reduced from 78% (n = 91) to 34% (n = 39) (P = .001) except diarrhea. Diarrhea was present in 24 patients (22%) preoperatively and postoperatively, though it was a new postoperative symptom in 11 patients (11%). One hundred two patients (95%) were satisfied or mostly satisfied with LCBDE. CONCLUSIONS: Pain and nonpain symptoms, while reduced significantly after LCBDE, may persist. The LCBDE procedure does not result in common bile duct strictures or a significant rate of retained stones. This relatively new treatment for common bile duct stones is safe and effective.

Laparoscopic common bile duct exploration.

Laparoscopic cholecystectomy has become the procedure of choice for laparoscopically skilled surgeons when dealing with both chronic and acute cholecystitis. When choledocholithiasis is encountered in the treatment of these patients the skilled laparoscopist has several treatment options available to treat the patient in one stage and avoid the morbidity of endoscopic sphincterotomy. Although still controversial, laparoscopic common bile duct exploration has been shown to be safe, applicable, and cost-effective in the treatment of choledocholithiasis. This report details several laparoscopic treatment alternatives for choledocholithiasis.

Laparoscopy identifies unexpected groin hernias.

Diagnostic laparoscopy performed before laparoscopic repair of groin hernias offers an opportunity to examine all hernial orifices. This study was undertaken to evaluate the accuracy of the preoperative clinical diagnoses and to determine the frequency of unexpected groin hernias. Between December 1990 and November 1997, 253 patients (243 male) underwent laparoscopic repair of 560 hernias. The total extraperitoneal technique was used in 93 per cent of the cases. Diagnostic laparoscopy was performed before and after the preperitoneal dissection and repair. Preoperatively, hernias were thought to be unilateral in 73 patients (Group A) and bilateral in 180 patients (Group B). Incorrect diagnoses in 50 of 73 patients (68%) thought to have unilateral hernias included bilateral hernias in 37 patients (50%), a different type of ipsilateral inguinal hernia in 7 patients (10%), or a femoral hernia in 6 patients (8%). Incorrect diagnoses in 91 of 180 patients (50%) thought to have bilateral hernias included a different and/or additional type of ipsilateral inguinal hernia on either side in 63 patients (35%), a femoral hernia in 21 patients (12%), or a unilateral hernia in 7 patients (4%). Unexpected hernias that would not have been treated with an anterior approach were found in 64 patients (25%; 27 were femoral and 37 were contralateral). The laparoscopic technique allows for identification and repair of previously undiagnosed contralateral and femoral hernias at the first operation.