Theodore Liakakos

More Controversy than Ever – Challenges and Promises Towards Personalized Treatment of Gastric Cancer

Clinical decisions for the treatment of localized gastric cancer have become much more sophisticated and complicated than ever. Two recent large-scale trials published in NEJM for East Asian 1 and Western patients 2 strongly support the routine use of adjuvant chemotherapy. However, differences in design, extent of surgery, kind of chemotherapy timing of administration, and survival results in the two trials as well as potential differences in genetic background of Asian and Western gastric caner patients raise critical questions and grow confusion and uncertainty. Which is the optimum update treatment for Western patients? Is the Japanese model with standardized D2 surgery followed by one year S-1 chemotherapy applicable in the West and can it produce similar excellent results or should treatment decisions be based on Western patients data from the UK MAGIC trial 2 and the USA INT-0116 trial? 3 This editorial approaches this critical question towards a live-saving decision. Emphasis is given to current advances in network biology, 4 cancer genome and functional studies 5–10 as well as a current comprehensive benchto-bedside genomic-based protocol for biomarkersbased personalized treatment of gastric cancer. 11 The landmark ACTS-GC Japanese study demonstrated excellent survival results with primary standardized D2 surgery followed by S-1 chemotherapy for advanced stages II and III. 1 Most patients (89%) had node-positive disease; these advanced tumor stages are associated with poor prognosis in the West. 12 Despite this advanced disease, the overall 3year survival rate was 70% after D2 surgery alone and 80% in the S-1 chemotherapy group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% CI, 0.52–0.87; p = 0.003). Because of this significant survival difference the trial was stopped. Local control is now increasingly recognized to have a crucial role in the treatment strategy not only of gastric cancer 13–15 but also for many other solid tumor including breast cancer despite the use of adjuvant treatment. 16,17 Appropriate surgery alone

Genotype-phenotype map and molecular networks: a promising solution in overcoming colorectal cancer resistance to targeted treatment

Despite traditional molecular research advances being translated into approved targeted agents, including cetuximab, panitumumab and bevacizumab, the overall survival benefit of patients with colorectal cancer (CRC) is small. At the end of the first postgenomic decade, emerging genomics data revealed a high complexity and heterogeneity of the disease, which explains the clinical limitations of classic single-gene research. Here we discuss whether and how ‘big’ biology and science for completing the cancer mutations catalog and advances in systems biology and molecular networks modeling may lead to a genotype–phenotype map. This relationship prediction can lead to the next-generation of biomarkers and biologic agents to change poor outcomes of advanced CRC.

Selecting a specific pre- or postoperative adjuvant therapy for individual patients with operable gastric cancer.

Although the very high locoregional recurrence rates reported with limited D0/D1 surgery can be reduced with extended D2 gastrectomy for operable gastric cancer, overall relapse and survival rates remain poor and can only be improved with adequate perioperative adjuvant treatment. However, despite intensive research, no regimen has been established as standard. Meta-analyses have demonstrated a marginal survival benefit with adjuvant chemotherapy. Two recent large randomized trials for operable gastric cancer, the MAGIC trial and the INT-0116 trial, provide evidence that some patients may benefit from perioperative chemotherapy and chemoradiation, respectively. However, while both trials suggest an overall survival benefit with adjuvant treatment, they don’t provide the harm–benefit ratio for specific subsets of patients wih different extent of surgery (D1 or D2) and tumor stage (early [T1,2]/advanced [T3,4]). This lack of evidence complicates current therapeutic adjuvant decisions. Estimating the risk of local and distant recurrence (high, moderate or low) after D1 or D2 surgery in various tumor stages and the expected harm–benefit ratio, the authors provide useful information for decisions on adjuvant chemotherapy with or withour radiotherapy in individual patients. Research on newer cytotoxic and targeted agents may improve treatment efficacy. Simultaneously, advances with microarray-based gene-expression profiling signatures may improve individualized treatment decisions. However, the validation and translation of these genomic classifiers as biomarkers into a completed ‘bench-to-bedside’ cycle for tailoring treatment to individuals is a major challenge and limits inflated expectations.

Laparoscopic gastrectomy: advances enable wide clinical application.

The current trend is toward laparoscopic gastrectomy. Although no level 1 randomized evidence or cost-effective analysis exists to show the superiority of laparoscopic gastrectomy over open gastrectomy, the indications and use of laparoscopic gastrectomy in clinical practice have been expanded beyond the carefully selected older patients described in the report by Singh et al. [1] in a recent issue of this journal. A current published report shows the clinical use of laparoscopic gastrectomy for early-stage gastric cancer with a trend also toward locally advanced carcinoma [2] and for carriers of CDH1 mutations to prevent hereditary diffuse gastric cancer (HDGC) syndrome [3, 4]. As laparoscopic gastrectomy currently is being applied in an environment of strong competition within various countries and among specialized institutions worldwide to attract patients, what are the benefits and risks of the laparoscopic approach? Laparoscopic gastrectomy is unlikely to improve survival or cure rates for gastric cancer patients, but evidence supports its superiority over open gastrectomy in improving quality of life (QOL). Singh et al. [1] report on a series of 20 elderly patients who underwent laparoscopic gastrectomy procedures. These patients were at risk for high morbidity and mortality with the use of conventional gastric surgery. There were no perioperative deaths. Four patients experienced significant complications, with two patients requiring reoperation. Extended D2 lymphadenectomy should be considered for patients with gastric cancer. Lee et al. [2] recently reported on laparoscopically assisted distal gastrectomy (LADG) with extended D2 lymphadenectomy for patients with early-stages gastric cancer. Two surgeons performed the procedure for 64 patients over an 8-month period, with a postoperative complication rate of only 3% and no deaths. The high-volume surgeons who performed the procedures are the key for these excellent results. The D2 lymphadenectomy compliance rate for the LADG was similar to that for open gastrectomy. Should D2 gastrectomy be the standard procedure for localized gastric cancer? Despite a long-term debate in the West [5–8], D2 surgery is a standard approach in Eastern countries [9, 10]. High cure rates have been reported with D2 surgery for early-stage gastric malignant tumors [9, 11, 12], but there still is no level 1 evidence in favor of D2 surgery [13]. The current status of the treatment for localized gastric cancer [14] includes either D2 surgery performed by experienced surgeons [15, 16] or, if this criterion is not met, limited D1 surgery plus chemoradiotherapy [17, 18]. With the randomized evidence for the safety and efficacy of the laparoscopic approach for colorectal cancer, laparoscopic gastrectomy has been growing rapidly. The advantages of laparoscopic over open gastrectomy include quicker return of gastrointestinal function, faster ambulation, and earlier discharge from the hospital, although the operating time is longer than for open gastrectomy [19]. Another important field of laparoscopic approach is the primary prevention of gastric cancer for individuals with familial susceptibility to the disease. This patient-friendly technique may increase the number of health individuals who are carriers of germ-line mutations in the CDH1 (Ecadherin) gene. For these carriers, who face a very high T. Liakakos (&) Third Surgical Department, University of Athens, Athens, Greece e-mail: theodlia@otenet.gr

Short bowel syndrome: current medical and surgical trends.

Short bowel syndrome is a chronic malabsorptive state usually resulting from extensive small bowel resections. A combination of diarrhea, nutrient malabsorption, dysmotility, and bowel dilatation may constitute the clinical symptomatology of this syndrome. The remaining bowel undergoes a process called adaptation, which may replace lost intestinal function. Chronic complications include nutrient, electrolyte, and vitamin deficiencies. Therapy depends largely on the administration of various factors stimulating intestinal adaptation of the remaining bowel. If the patient despite medical therapy fails to return to oral diet alone, then long-term parenteral nutrition is required. However, long-term parenteral nutrition may gradually induce cholestatic liver disease. Surgical methods may be required for treatment including intestinal transplantation, as a last resort for the treatment of end-stage intestinal failure. The goal of this review is to analyze the clinical spectrum and pathophysiologic aspects of the syndrome, the process of intestinal adaptation, and to outline the medical and surgical methods currently used to treat this complicated group of patients.

Is there any long-term benefit in quality of life after laparoscopy-assisted distal gastrectomy for gastric cancer?

The safety and efficacy of laparoscopic gastrectomy has been demonstrated in phase II studies [1] and remain to be confirmed in large-scale phase III clinical trials. There are two potential advantages for performing laparoscopic gastrectomy rather than open gastrectomy: first, it improves quality of life (QOL) and, second, an increase in survival rates. Based on data from laparoscopic colorectal surgery, it is unlikely that laparoscopic gastrectomy may improve survival or cure rates for gastric cancer patients. What is the impact of laparoscopic approach on QOL? Evidence indicates that laparoscopic provides better QOL over open gastrectomy. The advantages over open gastrectomy include quicker return of gastrointestinal function, faster ambulation, and earlier discharge from hospital, although the operating time is longer than in open gastrectomy [2]. But what is the impact of laparoscopic gastrectomy in the long-term postoperative course? Yasuda et al. [3] report on the important issue of longterm QOL after laparoscopic distal-assisted gastrectomy (LAG) over open distal gastrectomy (ODG) for early gastric cancer. With a long-term follow-up of 99 months QOL was similar between LAG and ODG groups. The incidence of postoperative intestinal obstruction was higher in the ODG than LAG but this finding requires prospective evaluation. This study for laparoscopic surgery in gastric cancer confirms the results from large-scale trials for colorectal laparoscopic surgery that the QOL benefit in the early postoperative course is lost in the long-term course. Despite this limited benefit of LAG in the early postoperative period, patients’ desire for minimally invasive approach will increase the number of patients who will choose laparoscopic approach in the future. It is expected that indications for laparoscopic surgery will be expanded to include not only early-stage cancer but also more-advanced tumor stages. The efficacy of the approach beyond safety is important. D2 lymphadenectomy now appears to be essential. Indeed, the landmark Japanese, large-scale, the adjuvant chemotherapy trial of TS-1 for gastric cancer (ACTS-GC) [4] has established D2 gastrectomy followed by adjuvant S1 chemotherapy for East Asian stage II and III gastric cancer patients. Therefore, laparoscopic approach, at least in East Asian patients, is warranted only when laparoscopic gastrectomy is associated with extended (D2) lymphadenectomy. In the Western world the efficiency of D2 surgery in improving survival of gastric cancer patients is controversial [5–12]. The current status in the treatment of localized gastric cancer [13] includes either D2 surgery if it is performed by experienced surgeons [14–18] or, if this criterion is not met, limited D1 surgery plus chemoradiotherapy [19, 20] or perioperative adjuvant chemotherapy [5, 21, 22]. Another important field of increasing trend for application of laparoscopic surgery is the prevention of hereditary diffuse gastric cancer (HDGC) syndrome. This patient-friendly technique may increase the number of health individuals who are carriers of germ-line mutations in the CDH1 (E-cadherin) gene. For these carriers, who face a very high lifetime risk of gastric cancer (60–80%), a T. Liakakos (&) 3rd Surgical Department, University of Athens, Athens, Greece e-mail: theodlia@otenet.gr

Protective effect of remote ischemic preconditioning in renal ischemia/reperfusion injury, in a model of thoracoabdominal aorta approach.

BACKGROUND Thoracoabdominal aortic aneurysm open surgery is accompanied by a significant incidence of renal failure due to renal ischemia. The effect of remote ischemic preconditioning (RIPC) in renal ischemia/reperfusion (IR) injury during a thoracoabdominal aortic aneurysm open repair approach was examined on an animal model. MATERIALS AND METHODS Three groups of rats underwent the following operations respectively: (a) Sham operation in control group; (b) Renal IR injury produced by subphrenic aortic cross-clamping (45/45 min IR), in IR group; (c) The same renal IR injury following RIPC produced by a brief occlusion of the infrarenal aorta (15/15 min IR) in RIPC group. Levels of lactate, base excess, and malondialdehyde (MDA) were measured in selective blood samples from the left renal vein, while levels of MDA were measured in samples of kidney tissues. RESULTS Renal blood base excess was significantly reduced in IR and RIPC groups as compared to sham group, but it was significantly higher in RIPC compared to the IR group (-7.69 +/- 0.62 versus -15.15 +/- 0.86, P < 0.001). Renal blood lactate was significantly increased in both IR and RIPC groups as compared to the sham group, but it was significantly lower in RIPC group compared to IR group (6.76 +/- 0.19 versus 11.99 +/- 0.33, P < 0.001). Renal blood MDA was increased in both IR and RIPC groups compared to the sham group, but it was significantly less compared in the RIPC group compared to IR group (1.55 +/- 0.38 versus 2.94 +/- 0.16, P = 0.002). Finally, kidney tissue MDA was increased in both IR and RIPC groups versus sham group, but it was significantly lower in RIPC group compared to the IR group (5.92 +/- 0.82 versus 13.98 +/- 2.41, P = 0.005). CONCLUSIONS RIPC induced by a temporary infrarenal aortic occlusion decreased the IR renal injury caused by subphrenic aortic cross-clamping.

Prosthetic repair of incisional hernia combined with elective bowel operation.

BACKGROUND AND AIMS Incisional hernia repair with mesh is considered a clean operation and it is not recommended to be perfomed at the same time with a potentially contaminated operation. The aim of this study is to assess the short-term results of a group of patients who underwent a colon operation and simultaneous incisional hernia repair with an onlay polypropylene mesh technique. PATIENTS AND METHODS From Novemberto June 2006, 19 patients underwent incisional hernia repair with polypropylene mesh, with simultaneous colonic operation. In 13 patients reestablishment of bowel continuity after a Hartmann procedure was done, whereas in four patients a loop colostomy was closed. Two patients underwent colectomy for cancer. RESULTS Post-operatively one patient had a seroma and two others had wound infections which required mesh removal. The mean follow-up was 70.15 +/- 48.40 months (range 3 to 142 months). During this period five patients died, four from progression of malignancy and one from myocardial infarction. Three patients (15.78%) developed recurrence, two patients with previous Hartmanns operation for complicated diverticulitis and wound infection and the third patient due to inappropriate mesh fixation with buttonhole hernia development. CONCLUSION Prosthetic repair of incisional hernias can be safely performed simultaneously with a colonic operation, with an acceptable rate of infectious complications and recurrence. It is unjustifiable to avoid the use of mesh in a potentially contaminated field when an appropriate technique is used.

Gastroesophageal Reflux Disease: Medical or Surgical Treatment?

Background. Gastroesophageal reflux disease is a common condition with increasing prevalence worldwide. The disease encompasses a broad spectrum of clinical symptoms and disorders from simple heartburn without esophagitis to erosive esophagitis with severe complications, such as esophageal strictures and intestinal metaplasia. Diagnosis is based mainly on ambulatory esophageal pH testing and endoscopy. There has been a long-standing debate about the best treatment approach for this troublesome disease. Methods and Results. Medical treatment with PPIs has an excellent efficacy in reversing the symptoms of GERD, but they should be taken for life, and long-term side effects do exist. However, patients who desire a permanent cure and have severe complications or cannot tolerate long-term treatment with PPIs are candidates for surgical treatment. Laparoscopic antireflux surgery achieves a significant symptom control, increased patient satisfaction, and complete withdrawal of antireflux medications, in the majority of patients. Conclusion. Surgical treatment should be reserved mainly for young patients seeking permanent results. However, the choice of the treatment schedule should be individualized for every patient. It is up to the patient, the physician and the surgeon to decide the best treatment option for individual cases.

Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology

AIM To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). METHODS 120 cases of primary gastric carcinomas and 45 matched lymph node metastases from patients with full clinicopathological features were mounted onto multiple-punch and single-punch tissue microarrays, respectively, and examined for HER2 overexpression and gene amplification by IHC and CISH. RESULTS Twenty-four tumors (20%) expressed HER2 immunohistochemically. An IHC score of ≥ 2+ was observed in 20 tumors (16.6%). HER2 amplification was detected by CISH in 19 tumors (15.8%) and in their matched lymph node metastases. A high concordance rate was found between HER2 positivity (as detected by IHC) and HER2 gene amplification (as detected by CISH), since 19 of the 20 IHC positive cases were amplified (95%). All amplified cases had 2+ or 3+ IHC results. Amplification was associated with intestinal phenotype (P < 0.05). No association with grading, staging or survival was found. CONCLUSION In gastric cancer, HER2 amplification is the main mechanism for HER2 protein overexpression and is preserved in lymph node metastases.