Christos Katsios

Individual genomes and personalized medicine: life diversity and complexity

Patients and tumors are unique. The conceptual design is great. Identifying the genetic variants underlying phenotype can lead to personalized medicine. Tailoring the best medical intervention to the right individual or patient can dramatically improve health. A decade after the first draft of human genome sequence [1,2] and the promises of a health revolution, what progress has been made in both genomics and personalized medical practice and what are the challenges and perspectives to deal with for the next decade? The use of personalized medicine to improve both the prevention and cure of disease is potentially achievable through: predicting both the disease risk among healthly individuals in the general population and the therapeutic response among patients. Genomic information from individuals or patients can substantially contribute to biomarker-based guided personalized prevention and treatment. The first strategy to use personalized medicine, in the prevention setting, involves identifying high-risk individuals that may develop major common diseases, such as cardiovascular disorder, diabetes and cancer, and then selecting the most appropriate preventive intervention to protect them from these diseases. This strategy can substantially reduce disease incidence and it is particularly important for hard-to-treat disorders, such as cancer. However, despite current research efforts, the development of robust biomarkers based on primary prevention has only modestly improved. In the second strategy, in the treatment setting, efforts by academia and industry have been focused on how to improve diagnostics and prognosis of diseases and how, through the development of predictors of drug response and adverse effects, to improve the safety and efficacy of drugs. Indeed, not only is the therapeutic response rate for several complex diseases low, but general toxicity rates of currently used agents are also still alarmingly high. Several research strategies and scientific fields have been developed towards personalized medicine. Pharmacogenetics, studying the genetic associations with drug efficacy and toxicity has led to the identification of several dugmetabolizing enzymes, with the most important belonging to the cytochrome P450 family [3]. The aim is to predict adverse effects to guide individualized treatment. Despite overlap with pharmacogenetics, the term pharmacogenomics is distinct because it evaluates the application of genomics to drug discovery. Pharmacogenomics involves the mechanism of the action of drugs on cells as revealed by gene-expression patterns. Pharmacoproteomics provides a more functional representation of patient-to-patient variation than that which is provided by genotyping, and therfore also contributes to personalized medicine. A ‘pharmacometabonomic’ approach involves the study of metabolites and how these can contribute to personalizing drug treatment.

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.

Multigene assays and isolated tumor cells for early breast cancer treatment: time for bionetworks

Despite advances with adjuvant endocrine treatment for hormone receptor-positive tumors and with trastuzumab for HER2-positive disease, overall, over 50% of women with early-stage breast cancer experience recurrence and die of the disease. Biomarkers for tailoring systemic adjuvant treatment to responder patients are needed. The multigene assays, 21-gene recurrence score (Oncotype DX® [Genomic Health, CA, USA]) and 70-gene signature (MammaPrint™ [Agendia, CA, USA]), and the isolated tumor cells in sentinel lymph node(s) represent the latest advances for improving adjuvant chemotherapy decisions. This article evaluates how these new markers, added to current standard factors (age, tumor size, grade, hormone receptor status and HER2 status), could improve early breast cancer treatment decisions. Moreover, emerging evidence from the latest large-scale studies using next-generation DNA-sequencing technology reveals a high heterogeneity and complexity of breast cancer. This assessment now shapes a new research strategy towards completion of a breast cancer causal (driver) mutations catalog and understanding complex genetic interactions and signaling pathway networks. Despite multiple challenges, advances in cancer genomes and systems biology approaches promise the future development of robust biomarkers.

Small bowel adenocarcinoma presenting as a first manifestation of Crohn's disease: report of a case, and a literature review.

Small bowel Crohns disease has been related to an increased incidence of small bowel adenocarcinoma, but the total number of reported cases is small. We present an interesting case of a young male patient with nephrolithiasis in childhood, an atypical intermittent history of diarrhoea also since his childhood, who developed obstructive ileus and underwent an urgent operation. The operation revealed a stenosis of the ileum owing to a mass, which proved to be a small bowel adenocarcinoma. One month later, the patient underwent a curative surgical resection of the tumour with additional lymphadenectomy, followed by chemotherapy for 6 months. Since then, the patient had mild diarrhoea but enteroclysis was normal. Approximately 2 years after the resection of the tumour, a new ileocolonoscopy demonstrated deep ulcerations of the terminal ileum and the adjacent area of the colon as well as anal ulcerations. The new biopsy specimens were convincing for Crohns disease. There were no signs of residual or relapsing cancer. There is growing evidence that Crohns disease is one of the triggering factors for the development of small bowel adenocarcinoma. Underlying Crohns disease should be suspected in a young patient with an atypical history of diarrhoea and small bowel adenocarcinoma.

Potential of antibody–drug conjugates and novel therapeutics in breast cancer management

Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of “central dogma” of simplified reductionist transcription and single gene–phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.

From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers

Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

Surgical management of hydatid liver disease

BACKGROUND large retrospective clinical study describing the long-term experience of a single center in the surgical management of liver echinococcosis in an endemic area. METHODS 232 patients were operated for liver hydatid disease between 1978 and 2012. Seventy-three patients (Group A) underwent a radical procedure (total pericystectomy or hepatectomy), while 145 (Group B) were treated with a more conservative method (partial cystectomy, with external drainage, omentoplasty or capitonnage) and 14 (Group C) received a combination of total and partial cystectomies. Morbidity, mortality, post-operative complications and recurrence rates in the long-term setting were retrospectively evaluated. RESULTS Group A patients were treated with zero mortality and a morbidity rate of 10.95%. No recurrence was documented. In Group B, mortality reached 2.76%, (p = 0.153 compared to Group A) morbidity 24.13% (p = 0.021) and there were 10 cases of relapse (6.9%) at three-year complete follow-up (p = 0.989). Extrahepatic sites of disease were not uncommon. DISCUSSION radical surgical procedures were better tolerated by patients and yielded better results in terms of recurrence rates.

Laparoscopic total gastrectomy: further progress in gastric cancer

Gastrectomy with extended D2 lymphadenectomy preserving the spleen and pancreas has been the standard approach for distal gastric cancer. However, for proximal advanced ([T2) tumors, splenectomy usually is performed to dissect the splenic hilum (no. 10) and lymph nodes along the splenic artery (no. 11). The risk of residual positive lymph nodes at these nodal stations (nos. 10 and 11) is calculated to be approximately 15 and 25%, respectively. The pancreas should be preserved except when achievement of a complete tumor resection (R0) requires distal pancreatectomy [1–9]. This surgical strategy has become the preferred procedure for open surgery. What about laparoscopic surgery for tumors located in the proximal or middle third of the stomach? Laparoscopically assisted distal gastrectomy has been performed widely in Asian countries [10], and more currently, totally laparoscopic distal gastrectomy without minilaparotomy is performed even in the West [11] for distal gastric cancers. But is laparoscopic total gastrectomy technically feasible and safe? Should the spleen be preserved or resected with the laparoscopic approach? Sakuramoto et al. [12] have provided useful data for approaching these questions. Between 2004 and 2007, these authors performed pancreasand spleen-preserving total gastrectomy with D1?beta or D2 lymph node dissection and Roux-en-Y reconstruction for 74 patients with cancer located in the upper or middle third of the stomach. Of these 74 patients, 30 underwent laparoscopically assisted total gastrectomy (LATG), and 44 underwent open total gastrectomy (OTG). Although the operating time was longer by 95 min for LATG than for OTG (p \ 0.001), blood loss less (p \ 0.001) and the hospital stay was significantly shorter, by 5 days (p\0.05), in the LATG group than in the OTG group. The number of lymph nodes harvested was high not only in the OTG group (n = 51) but also in the LATG group (n = 43). Given that anastomotic leakage, abdominal abscess, and pancreatic leakage occurred for 6 patients (13.6%) in the OTG group but for none of the 30 patients in the LATG group, the authors conclude that LATG is superior to OTG for proximal or middle-third tumors because it provides better quality of life (QOL) and fewer complications. This study [12] supports the conclusion that not only laparoscopic distal gastrectomy but also laparoscopic total gastrectomy is technically feasible, safe, and effective. The results of laparoscopic spleen-preserving total gastrectomy are excellent. Minimal postoperative morbidity and a high number of lymph nodes dissected and examined certainly reflect surgeons and hospitals performing a high volume of laparoscopic gastrectomies. We discuss only some oncologic principles. The authors carefully selected the patients for laparoscopic surgery, including mostly those with early-stage disease. Nevertheless, spleen preservation for patients with advanced serosa-positive (T3) and node-positive disease is associated with a substantial risk of splenic hilum-positive lymph nodes. Thus, preservation of the spleen may be with increased risk of residual disease in these nodes (station no. 10), nodal recurrence, and death. Despite efforts, it E. Hanisch Klinik fur Allgemein, Viszeral, und Endokrine Chirurgie, Asklepios Klinik in Langen, Langen, Germany

BMI and lymph node ratio may predict clinical outcomes of gastric cancer.

AIM BMI and the lymph node (LN) ratio can affect short- and long-term outcomes of patients with gastric cancer. PATIENTS & METHODS This study includes 104 consecutive patients with gastric adenocarcinoma who underwent curative gastrectomy divided in two groups: overweight group (group A) and normal weight group (group B). RESULTS We found that 53.4% of our patients were overweight (group A). The overall rate of postoperative complications was 16.3%, while mortality was 1%. Statistical analyses revealed that postoperative morbidity was significantly higher in group A (p < 0.05). Long-term survival was significantly higher in group B. Cox regression showed a statistically significant correlation between higher BMI and poor long-term survival after curative gastrectomy. Multivariate analysis has identified age and the LN ratios as independent prognostic factors of survival. CONCLUSION In this retrospective analysis, BMI and LN ratio were independently associated with survival in patients with gastric cancer. Further studies are needed to confirm our findings.

Progress, challenges and new genome-based concepts in the multidisciplinary treatment of gastric cancer

Despite declining incidence, stomach cancer remains the second most common cause of death from cancer worldwide. Aiming at complete tumor resection (R0), gastrectomy with extended (D2) lymphadenectomy for resectable tumor has been standardized and is widely used. Chemotherapy improves overall survival but there is debate between Western and East Asian countries on timing (preoperative, postoperative or peri operative) and a standard regimen, as well as on the clinical utility of chemoradiotherapy outside the USA. Particularly controversial is the treatment of an increasing incidence of cancers located at the gastroesophageal junction (GEJ). Evidence from a recent, large-scale Phase III trial indicates that targeting HER2-positive gastric or GEJ cancer with trastuzumab added to cytotoxic drugs improves overall survival. Despite these advances, survival of patients with advanced disease remains poor. In the postgenomic era, an impressive amount of research is moving from the cancer genome to regulatory networks, and here we discuss how advances in epigenetic modifications and miRNAs could lead to novel biomarkers and targeted drugs for improving the outcomes of patients with gastric cancer. With over 700,000 deaths occurring each year from gastric cancer worldwide, stomach cancer still remains a major health problem, despite declining incidence [1]. In contrast to the decreasing incidence of noncardia cancer, particularly in the USA and Northwest Europe, the incidence of cardia or GEJ cancer has increased [2,3]. Various genetic and environmental factors including Helicobacter pylori infection and diet have been evaluated to understand the complex gene–environment inter actions, but the elucidation of mechanisms underlying long-term carcinogenesis thus far remains unclear.