Gary Bass

Targeting therapy for esophageal cancer in patients aged 70 and over

BACKGROUND While cancer is a disease of the elderly, these patients are under-represented in randomized trials. Esophageal cancer-management in the elderly is challenging because of the morbidity and mortality associated with surgery. OBJECTIVES We examined a strategy of neo-adjuvant chemo-radiotherapy (naCRT), followed by surgery or surveillance, in selected patients with cancer aged 70 and older. METHODS A prospectively-accrued database identified 56 consecutive patients over a 90-month period, who were aged 70years and over, presented with esophageal carcinoma and were treated with neo-adjuvant CRT (naCRT)±surgery. RESULTS Of 129 eligible patients, 66 (51%) received palliative measures, while 63 (49%) had curative intervention, namely 7 had surgery and 56 had naCRT±surgery. Of these 56 patients, 33 (59%) had adenocarcinoma (AC) and 23 (41%) had squamous cell carcinoma (SCC). Twenty-five (45%) had a complete clinical response (cCR), of which 6 had immediate resection; 4 (67%) had a complete pathological response (pCR); 19 patients with a cCR declined or were unfit for surgery and underwent surveillance; of these, 3 had interval esophagectomy; 16 were not offered or declined resection. Eight (50%) have survived ≥3years. Mean overall survival was 28months for the entire cohort; 47months for cCRs; 61months for patients undergoing primary resection, 46months for cCRs who did not undergo resection and 29months for those undergoing interval resection for recurrent disease. In cCRs, surgery did not provide a survival advantage (p=0.861). CONCLUSION cCR yields an overall 3-year survival of 50% without operation. As 45% of patients have a cCR to naCRT, obligatory resection in high-risk cCR patients makes little sense. With the option for salvage esophagectomy in re-emergent disease, this selective strategy is an attractive alternative for elderly patients with cancer.

Chemoradiotherapy, with adjuvant surgery for local control, confers a durable survival advantage in adenocarcinoma and squamous cell carcinoma of the oesophagus

INTRODUCTION Oesophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. AIMS Long-term results of two simultaneous randomised controlled trials (RCTs) comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of adenocarcinoma (AC) and squamous cell carcinoma (SCC) to identical regimens compared. METHODS Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately-randomised to identical protocols of MMT or surgical monotherapy. RESULTS 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0.004), SCC (P=0.01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery (64% versus 29%, P<0.001). MMT produced a pathologic complete response (pCR) in 25% and 31% of AC and SCC, respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR versus surgical monotherapy (P=0.001); residual disease following MMT versus surgical monotherapy (P=0.008); SCC pCR versus surgical monotherapy (P=0.033). CONCLUSIONS A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumour down-staging to extinction in 25-31% of patients, potentially permitting personalised treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localised disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease.

Validating the 5Fs mnemonic for cholelithiasis: time to include family history

Background The time-honoured mnemonic of ‘5Fs’ is a reminder to students that patients with upper abdominal pain and who conform to a profile of ‘fair, fat, female, fertile and forty’ are likely to have cholelithiasis. We feel, however, that a most important ‘F’—that for ‘family history’—is overlooked and should be introduced to enhance the value of a useful aide memoire. Methods To assess the usefulness of each of the existing factors of a popular mnemonic, 398 patients admitted with upper abdominal pain between March 2009 and April 2010 were studied. The clinical features expressed in the cholelithiasis mnemonic in patients with sonographic evidence of cholelithiasis were compared with those of patients without. Findings In the cholelithiasis group, significantly more patients were women (150/198 (75.8%) vs 111/200 (55.5%), p<0.001), fair (144/198 (62.9%) vs 54/200 (32.1%), (p<0.001)), fertile (135/198 (68.2%) vs 50/200 (25%) (p<0.001)) and had a body mass index >30 (56/198 (28.3%) vs 19/200 (9.5%) (p<0.001)) compared with controls; but age over 40 years did not predict cholelithiasis (82/198 (41.4%) vs 79/200 (39.5%) (p=0.697)). In the cholelithiasis group, 78/198 (39.4%) had a family history in at least one first-degree relative, compared with 27/200 (13.5%) of controls, (p<0.001). Where the phenotypic elements of the history existed in combination, that patient was found to be at an increased risk of cholelithiasis. Interpretation Our study found that the validated ‘students’ 5Fs’ mnemonic retains a role in clinical diagnosis of patients suspected of cholelithiasis but the factor ‘familial’ should be substituted for ‘forty’ in recognition of the role of inheritance and the changing demographics of gallstone incidence.

Nimesulide Alters Cell Recruitment into Mitosis in Murine Intestinal Crypts Without Influencing the Cell Production Rate

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) that exhibit COX-2 selectivity is associated with fewer gastrointestinal side effects than seen with more traditional NSAIDs. To determine whether the early effects on cell kinetics in the intestinal mucosal epithelium described after COX-2 selective inhibition are sustained following continuous therapy with these inhibitors, assessments of morphometry and cryptal cell proliferation in the murine small intestinal mucosa were made at 24 hr after treatment with indomethacin, a dual COX inhibitor (10 mg/kg body weight intraperitoneally), nimesulide, a selective COX-2 inhibitor (15 mg/kg body weight intraperitoneally), or vehicle. Nimesulide-treated intestine was elongated beyond control values, in contrast to the shorter indomethacin-treated intestine, but anomalous villous forms were present in both treated groups. Both treatments induced expansion and contraction of proliferating compartments in the crypts in different regions of the intestine but nimesulide did not alter crypt cell production rates, in contrast to the down-regulation induced by indomethacin. These findings may provide some of the fundamental basis for the gut-sparing properties seen in patients treated with COX-2 selective inhibitors.

Cholecystogastric fistula: a brief report and review of the literature

Abstract Cholecystogastric fistula is a rare, life-threatening complication of cholelithiasis that presents a difficult challenge to the surgeon when it occurs in elderly and co-morbid patients. Following a case of a 68-year-old female who presented with a short history of epigastric pain and vomiting, and in whom a cholecystogastric fistula was identified on abdominal computed tomography and confirmed on upper gastrointestinal endoscopy, we performed a systematic review of the literature on the management of cholecystogastric fistula. Our patient underwent laparotomy without excision of the fistula nor cholecystectomy and had an uncomplicated post-operative course. Surgical management using an open approach remains the mainstay of treatment of cholecystogastric fistula although laparoscopic techniques are used with increasing success. Surgical closure of the fistula is not always necessary. Improved surgical techniques including the use of laparoscopic surgery have led to improved outcomes in the management of cholecystogastric fistula.

The timing of antibiotic therapy must be controlled for when assessing appendectomy outcomes.

W e would like to commend Teixeira and colleagues for their large retrospective observational study,1 which reexplored predictors of surgical site infective (SSI) complications appearing after appendectomy. Their conclusions, in part, contradict similar prior work2,3 and thus are worthy of considered scrutiny. In particular, the authors demonstrated that after adjustment for age, leukocytosis, sex, and surgical technique (open vs laparoscopic), early operation (within 6 hours of admission) was associated with a decreased incidence of SSI in patients with a nonperforated appendicitis compared with operation within 6 to 12 hours of admission (1.9% vs 3.3%; P = 0.03). The data fail to demonstrate a correlation, however, between any further delay to operation beyond 12 hours and a further significant increase in SSI, with a ceiling incidence of SSI of 3.9% seen in cases of perforated appendicitis (P = 0.475). A criticism of similar earlier studies has been heterogenous reporting of antibiotic administration practices. This is also a potential weakness of the current study, which does not analyze the initiation of effective antibiotic therapy or its timing with relation to time elapsed since admission.

Effect of chemoradiotherapy, with adjuvant surgery for local control, on survival in AC and SCC of the esophagus.

81 Background: Esophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. Aims:Long-term results of 2 simultaneous RCTs comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of AC (AC) and SCC (SCC) to identical regimens compared. Methods: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately randomised to identical protocols of MMT or surgical monotherapy. Results: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0·004), SCC (P=0·01). There was a 54% relative risk-reduction in lymph-nod...

Video thoracoscopic assistance in open en bloc 2-stage esophagectomy facilitates both R0 dissection and thoracostomy tube placement.

Dear Editor, The incidence of adenocarcinoma of the esophagus has risen greatly in the Western world—by more than 2% per annum in the United States over a 5-year period from 1998 to 2003. Although surgical therapy with curative intent has changed radically over the past 20 years, leading to a significantly more favorable long-term prognosis, the outlook is still poor. Adjuvant esophagectomy following primary chemotherapy and external-beam radiation therapy can be successfully performed for patients with adenocarcinoma with an acceptable perioperative morbidity and mortality; this is the therapeutic approach in our institution. In the majority of our 2-stage oncologic esophagectomies, laparoscopic mobilization and tubularization of the stomach is followed by en bloc resection of the tumor and surrounding lymphatics via open thoracotomy. Esophagogastric anastomosis is then performed in the chest. This approach, based on sound oncologic principles, allows R0 resection and adequate lymphadenectomy. One technical difficulty of this approach, however, has been the provision of adequate illumination, particularly to the posteromedial mediastinum close to the diaphragm. Peridiaphragmatic dissection “in twilight” has led many surgeons to innovate, and an array of different lamps, head-mounted and otherwise, has been tried. We have found in our practice that the use of a 0° thoracoscope, inserted via a 10-mm bladeless trocar port (such as VersaSTEP, Autosuture Inc, MA; numerous alternatives exist), provides an excellent directional light source that greatly improves visualization of the mediastinum for the operating surgeon and assistants. Intraoperative video obtained by this method provides better teaching and sharper clinical photography. A further benefit of this approach is that a thoracostomy drainage tube may be safely placed, in a controlled manner, through the 10-mm port. The port can then be removed over the drain and the chest tube secured in situ with a standard Roman sandal drain-stitch. This avoids blind insertion of a trocar, which may lead to iatrogenic damage to intercostal nerves or arteries or to the lung parenchyma, with consequent pneumothorax, hemothorax, or empyema. The snug fit of the thoracostomy tube in the precisely machined thoracoscopy port site also minimizes any air leak around the chest drain, which could complicate drain placement. Having benefited from this approach in 20 consecutive esophagectomies, we commend this technique to your readers for their consideration.