Jon A. Tsai

Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers

The long‐term survival benefits of neoadjuvant chemotherapy (NAC) and chemoradiotherapy (NACR) for oesophageal carcinoma are well established. Both are burdened, however, by toxicity that could contribute to perioperative morbidity and mortality.

A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction

BACKGROUND Neoadjuvant therapy improves long-term survival after oesophagectomy, treating oesophageal cancer, but the evidence to date is insufficient to determine which of the two main neoadjuvant therapy types, chemotherapy (nCT) or chemoradiotherapy (nCRT), is more beneficial. We aimed to compare the effects of nCT with those of nCRT. PATIENTS AND METHODS This multicentre trial, which was conducted in Sweden and Norway, recruited 181 patients with carcinoma of the oesophagus or the gastro-oesophageal junction who were candidates for curative-intended treatment. The primary end point was histological complete response after neoadjuvant treatment, which has been shown to be correlated with increased long-term survival. Study participants were randomized to nCT or nCRT, followed by surgery with two-field lymphadenectomy. Three cycles of platin/5-fluorouracil were administered in both arms, whereas 40 Gy of concomitant radiotherapy was added in the nCRT arm. RESULTS The trial met the primary end point, histological complete response being achieved in 28% after nCRT versus 9% after nCT (P = 0.002). Lymph-node metastases were observed in 62% in the nCT group versus 35% in the nCRT group (P = 0.001). The R0 resection rate was 87% after nCRT and 74% after nCT (P = 0.04). There was no difference in overall survival between the treatment arms. CONCLUSION The addition of radiotherapy to neoadjuvant chemotherapy results in higher histological complete response rate, higher R0 resection rate, and a lower frequency of lymph-node metastases, without significantly affecting survival. CLINICALTRIALSGOV NCT01362127 (https://clinicaltrials.gov; The full study protocol was registered in the Clinical Trials Database).

Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation

OBJECTIVE To compare the incidence and severity of postoperative complications after oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction (GOJ) after randomized accrual to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). BACKGROUND Neoadjuvant therapy improves long-term survival after oesophagectomy. To date, evidence is insufficient to determine whether combined nCT, or nCRT alone, is the most beneficial. METHODS Patients with carcinoma of the oesophagus or GOJ, resectable with a curative intention, were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway. Study participants were randomized to nCT or nCRT followed by surgery with two-field lymphadenectomy. Three cycles of cisplatin/5-fluorouracil was administered in all patients, while 40 Gy of concomitant radiotherapy was administered in the nCRT group. RESULTS Of the randomized 181 patients, 91 were assigned to nCT and 90 to nCRT. One-hundred-and-fifty-five patients, 78 nCT and 77 nCRT, underwent resection. There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications (P-value = 0.69 and 0.13, respectively). There was no 30-day mortality, while the 90-day mortality was 3% (2/78) in the nCT group and 6% (5/77) in the nCRT group (P = 0.24). The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group (P = 0.001). CONCLUSION There was no significant difference in the incidence of complications between patients randomized to nCT and nCRT. However, complications were significantly more severe after nCRT. REGISTRATION TRIAL DATABASE The trial was registered in the Clinical Trials Database (registration number NCT01362127).

Obesity alters cytokine gene expression and promotes liver injury in rats with acute pancreatitis.

Objective: Obesity is a negative prognostic factor in patients with critical illnesses such as acute pancreatitis (AP). The outcome of AP is determined by the severity of systemic inflammation and organ dysfunction. In a previous study, we found that AP caused more deaths in obese rats than in lean rats. In the present study, we examined whether the effect of obesity on rats with AP is associated with distinct alterations in inflammatory cytokine expression in organs involved in AP.

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: A direct and adjusted indirect comparison meta-analysis

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

Predictors for failure of stent treatment for benign esophageal perforations - a single center 10-year experience.

AIM To investigate possible predictors for failed self-expandable metallic stent (SEMS) therapy in consecutive patients with benign esophageal perforation-rupture (EPR). METHODS All patients between 2003-2013 treated for EPR at the Karolinska University Hospital, a tertiary referral center, were studied with regard to initial management with SEMS. Patients with malignancy as an underlying cause and those with anastomotic leakages were excluded. Sealing of the perforation with a covered SEMS was the primary strategy whenever feasible. Stent therapy failure was defined as a radical change of treatment strategy due to uncontrolled mediastinitis, which in this setting consisted of emergency esophagectomy with end-esophagostomy or death as a consequence of the perforation and subsequent uncontrolled sepsis. Patient and lesion characteristics were analyzed and are presented as median and interquartile range. Possible predictors for failed stent therapy were analyzed with uni-variate logistic regression, while variables with P < 0.2 were further analyzed with multi-variate logistic regression. RESULTS Of the total number of 48 patients presenting with EPR, 40 patients (83.3%) were treated with SEMS at the time of admission, with an intention to heal the perforation. Twenty-three patients had Boerhaaves syndrome (58%), 16 had an iatrogenic perforation (40%) and 1 had external trauma to the esophagus (3%). The total in-hospital mortality, including the cases that had other initial treatments (n = 8), was 10.4% and 7.5% among those who were subjected to the SEMS-based strategy. In 33 of the 40 patients (82.5%) who were treated with stent, the EPR healed without further change in treatment strategy. Patients classified as treatment success received a SEMS at a median time of 1 (1-1) d after the actual EPR, compared to 3 (1-10) d among those where the initial treatment failed, P = 0.039 in uni-variate analysis and P = 0.052 in multi-variate analysis. No other significant factors emerged, indicating an increased risk for failure. Six of 7 patients, where stent treatment of the defect failed, underwent an emergency esophagectomy with end esophagostomy and one patient died. CONCLUSION SEMS as an upfront therapeutic strategy seems to be a successful concept, when applied to an unselected group of patients with EPR.

Toupet versus Dor as a procedure to prevent reflux after cardiomyotomy for achalasia: Results of a randomised clinical trial

BACKGROUND The optimal anti-reflux procedure after Heller cardiomyotomy for oesophageal achalasia remains unclear. The most commonly used procedure is the anterior partial fundoplication according to Dor, although during recent years the posterior counterpart (Toupet) has become popular. METHODS Patients with newly diagnosed achalasia and referred for cardiomyotomy were randomised to receive either an anterior or partial posterior fundoplication following a classical cardiomyotomy. The effect of surgery was assessed during the first postoperative year by Eckardt scores, EORTC QLQ-OES18 scores and HRQL questionnaires. Timed barium oesophagogram (TBO) and ambulatory 24-h pH monitoring were performed to determine oesophageal emptying and the degree of reflux control, respectively. RESULTS Forty-two patients were randomised into Dor (n = 20) and Toupet (n = 22) groups. Eckardt scores improved dramatically with both procedures, but the EORTC QLQ-OES18 (functional scales) scores revealed significantly better relative improvements in the Toupet group compared to the Dor repair (P = 0.044). Corresponding advantages in favour of Toupet were observed postoperatively in the percentage of oesophageal emptying at TBO (P = 0.011 in height and P = 0.018 in area), an effect not observed in the Dor group. There were no other significant differences recorded between the study groups concerning HRQL evaluations and objective assessment of gastro-oesophageal acid reflux. CONCLUSIONS A partial posterior fundoplication after cardiomyotomy seems to achieve more improvement in oesophageal emptying and EORTC QLQ-OES18 functional scale scores than the anterior fundoplication. Otherwise no differences between the two anti-reflux repairs were noted. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT01933373.

Per-oral endoscopic myotomy for achalasia. Are results comparable to laparoscopic Heller myotomy?

Abstract Objective. Per-oral endoscopic myotomy (POEM) has recently been introduced as a minimal invasive alternative to conventional treatment for achalasia. This study aimed to clarify the feasibility and the short-term clinical efficacy of POEM as compared to laparoscopic Heller myotomy (LHM). Methods. Treatment outcomes were prospectively recorded and compared between the procedures in a nonrandomized fashion. Reduction rate (RR) in timed barium esophagogram (TBE) was calculated at 1, 2 and 5 min after barium ingestion as: RR = 1− postoperative barium height/preoperative barium height. Risk factors for treatment failure defined as the proportion of patients with RR <0.5 (1 min) and gastroesophageal reflux (GER) after POEM were analyzed. Results. Forty-two consecutive patients who underwent POEM were compared to 41 patients who had a LHM during the immediate time period prior to the introduction of POEM. Ninety percent of the cases reported complete symptom relief after POEM. The percentage of esophageal emptying and RR in TBE improved dramatically by both procedures without significant difference. A longer operation time (odds ratio [OR] 32.80, 95%CI 2.99–359.82, p = 0.004) and younger age (OR 26.81, 95%CI 2.09–344.03, p = 0.012) were the independent predictors of treatment failure after POEM. GER was observed in seven patients where previous dilatation (OR 8.59, 95%CI 1.16–63.45, p = 0.035) and higher body mass index (OR 8.69, 95%CI 1.13–66.63, p = 0.037) were the independent predictors for symptomatic GER after POEM. Conclusion. POEM seems to be a safe and effective treatment option for achalasia in the short-term perspective; an effect well comparable to LHM.

One-Lung Ventilation During Thoracoabdominal Esophagectomy Elicits Complement Activation

BACKGROUND One-lung ventilation (OLV) during thoracoabdominal esophagectomy may induce an inflammatory response that can contribute to the induction and propagation of frequently occurring postoperative respiratory distress. Markers of such a response might be detected in the pulmonary as well as in the systemic circulation. Inflammation and tissue damage may be key pathogenetic pathways and we hypothesized that 1-lung ventilation may induce an inflammatory cascade reflected by markers for such a response. MATERIALS AND METHODS Thirty patients with esophageal cancer were randomized to OLV (n = 16) or 2-lung ventilation (TLV; n = 14) during the thoracic part of the operation. Compounds involved in inflammation and coagulation were measured perioperatively and during the 1st, 2nd, 3rd, and 10th postoperative d. RESULTS During the perioperative phase, the proinflammatory cytokine interleukin-6 and thrombin, measured as thrombin-antithrombin complexes, started to increase. Thrombin, which can induce complement activation, peaked at the end of surgery and interleukin-6 at the 1st to 2nd postoperative d, but there were no differences between the OLV and TLV groups. C3a and terminal complement complex (TCC) started to increase on the 2nd postoperative d and continued to do so for the rest of the study period. The increase of TCC was significantly higher in the OLV group compared to the TLV group, whereas C3a attained similar levels in the 2 groups. CONCLUSIONS OLV is associated with an augmented inflammatory response as reflected by the activation of the TCC. This may induce pulmonary tissue damage and recruitment of inflammatory cells.

Increased central memory T cells in patients with chronic pancreatitis

Background/Aims: A dysregulated immune response has been suggested to be important for the pathogenesis of chronic pancreatitis (CP). Formation of immunological memory is based on the differentiation of naïve T lymphocytes to memory T lymphocytes after exposure to antigens and specific cytokines. The aim of this study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with CP for different T lymphocyte subsets including naïve and memory T cells. Methods: PBMCs from 9 patients who had undergone pancreatic resection due to CP, 9 CP patients who had not been resected and 9 healthy controls were analyzed by flow cytometry. Results: Patients with CP had a skewed distribution of T lymphocytes, with an increased level of CCR7+/CD45RA– central memory T lymphocytes compared to healthy controls. Nonresected CP patients and subjects who had undergone pancreatic resection due to CP had similar levels of central memory T lymphocytes. Conclusion: Our results indicate that the dysregulation of the immune system in chronic pancreatitis seems to persist even after removal of large parts of the local inflammatory site. We suggest that the increase of central memory T lymphocytes may be important for maintaining the inflammatory process in chronic pancreatitis.