Dimosthenis Ziogas

Genetics and Personal Genomics for Personalized Breast Cancer Surgery: Progress and Challenges in Research and Clinical Practice

BackgroundThe age of personal genomics is here. A flood of translational research discoveries may influence also surgeon oncologist. Breast-conserving surgery (BCS) is standard care in early breast cancer. Classic clinicopathologic factors are suboptimal to predict risk of ipsilateral breast cancer (IBC) recurrence and/or contralateral breast cancer (CBC). Human genetic variation may be involved in local failures.ObjectiveTo describe the potential clinical utility of genetics, personal genomics, and epigenetics to identify IBC/CBC high-risk patients who might benefit from aggressive surgery (bilateral mastectomy).Data sources and synthesisPubMed (MEDLINE) was searched (January 1990 to November 2008).ResultsEven following current guidelines, IBC/CBC as isolated first event in a long-term aspect after treatment suggests a serious problem. Preclinical and clinical data reveal that at highest risk of IBC/CBC are patients with inherited BRCA1/2 mutations who benefited from bilateral mastectomy. Local failure risk prediction is currently unfeasible among familial non-BRCA1/2 (BRCA-test negative) and sporadic (no family history) breast cancer. Genome-wide association studies have already identified novel risk alleles with a series of tumor-initiating single-nucleotide polymorphisms (SNPs). Some of these variants and other novel SNPs and copy-number variants (CNVs) may also be relevant for local failures (IBC/CBC).ConclusionsBeyond established risk factors, genetic testing allows identification of high-risk patients (BRCA mutation carriers) who may benefit from bilateral mastectomy rather than BCS. Human genetic variation (SNPs/CNVs) and DNA methylation may be relevant for local failures assessment. Technological revolution has opened a new avenue but multiple challenges should be overcome to integrate SNPs/CNVs as markers for IBC/CBC risk-stratification-based personalized surgery.

CDH1 testing: can it predict the prophylactic or therapeutic nature of total gastrectomy in hereditary diffuse gastric cancer?

Gastric cancer has a poor prognosis. Primary prevention is a major goal to reduce incidence and mortality, but it is still an illusion. There is an exception: the rare hereditary diffuse gastric cancer (HDGC). This syndrome can be both accurately predicted and successfully prevented. How? If we could identify high-risk individuals in the general population and subsequently tailor an effective preventive intervention, then we could protect them by saving their lives. This achievement is now realistic, although it concerns a small only fraction of cases. Genetic testing in individuals with a family history of diffuse gastric cancer allows for identification of family members with inherited mutations at CDH1 gene. These mutation carriers have a very high risk of developing diffuse gastric cancer 1 and women have an additional lobular breast cancer risk. 2 This HDGC syndrome is characterized by early onset and requires primary prevention at a young age. 1,2

From tumor size and HER2 status to systems oncology for very early breast cancer treatment

Small breast cancers with node-negative status are associated with an excellent prognosis. This is widely accepted by phy-sicians, patients and society. Based on clin-ical follow-up data and the adverse effects of adjuvant systemic treatment, current guidelines do not recommend such treat-ment for most patients with pT1a,bN0M0 tumors

Robotic surgery for rectal cancer: may it improve also survival?

Treatment and survival of patients with solid cancers havebeen improved over the last years. Two of the major goalsand challenges for various cancers including colorectal,stomach, breast and other tumors are: local control byappropriate surgery alone or plus chemoradiotherapy [1–4]and personalized adjuvant systemic treatment throughmolecular and genetic biomarkers [5–8].Laparoscopic surgery has been increasingly adopted intoclinical practice, mostly to improve the quality of life(QOL) of patients with gastrointestinal cancer. However,there is no evidence that it improves also survival rates.Perhaps, low anterior rectal resection with total mesorectalexcision (TME) represents a field in which the laparoscopicapproach might lead to better local control, disease-freesurvival, and overall survival than the open procedure.In a recent issue of the Journal Baik et al. report on theuse of the da Vinci system in rectal cancer surgery [9].Why should this technique, beyond QOL improvement,also provide survival benefit? Why can this benefit not beobtained for other cancer sites in the gastrointestinal tract?Total mesorectal excision (TME) has become the stan-dard surgical procedure for localized rectal cancer [1]. Theprinciple underlying TME is secure dissection of an avas-cular plane between the presacral fascia and the fasciapropria of the rectum without injuring the proper fascia ofthe rectum [1]. This principle can better be ensured withthe laparoscopic than the open approach. The da Vincisystem, beyond this, provides the surgeon with a three-dimensional surgical view that permits a steadier dissectionwith tremor elimination and motion scaling.Baik et al. report on safety, feasibility, and efficiency innine patients who underwent robotic TME using fourrobotic arms for the treatment of mid or low rectal cancer.The facts that this technique allows a perfect TME thatmight also result in sparing radiation if pathologicalexamination reveals tumor-free proper fascia of the rectum,and perhaps most importantly local recurrence reductionand improved survival, suggests that a prospective vali-dation of this robotic technique is warranted.Personalization in health care maximizes the benefits forsociety and individual patients. At the present time, thisgoal appears more realistic in the prevention and treatmentof the inherited cancer syndromes than of the sporadiccommon cancers. Indeed, prophylactic surgery in carriersof mutations in mismatch-repair genes (hereditary nonpo-lyposis colorectal cancer or Lynch syndrome), in BRCA1/2(hereditary breast ovarian cancer syndrome) and in CDH1(hereditary diffuse gastric cancer syndrome) seems to bemore effective than close surveillance [10–17]. Given that,with the exception of early-stage cancer [18–21], cure ratesof patients with colorectal, gastric, breast, and other com-mon solid tumors are moderate or low [22–31], appropriatepreventive intervention may save the lives of many indi-vidual patients.Although longer follow-up data after laparoscopic sur-gery over open traditional resection demonstrates that thebenefits in QOL for colorectal cancer are limited to theearly postoperative course of months or a few years,robotic surgery for rectal cancer through an excellent TMEmay improve local control without the addition of radiationin some selected patients. A prospective evaluation toassess whether robotic surgery may improve local recur-rence and survival is warranted.

Radiation burden of patients undergoing endovascular abdominal aortic aneurysm repair

INTRODUCTION Endovascular repair of abdominal aortic aneurysm (EVAR) requires the patients extended exposure to x-rays, before, during, and after the intervention. The aim of this study was to determine the radiation exposure of patients undergoing EVAR and to assess the probability for the induction of both late and early radiation-related effects. METHODS During the period of May 2006 to December 2007 EVAR was carried out in 62 patients using a mobile C-arm unit. The following dosimetric quantities were assessed: fluoroscopy time, cumulative dose in air, dose-area product, field area, and peak skin dose. RESULTS The duration of fluoroscopy and the body mass index were found to be the main factors that influence the radiation burden in our hospital. The mean effective dose per procedure, 6.2 mSv, was between that from a planar coronary angiography and a coronary angioplasty. Taking into account the computed tomography (CT) procedure-related angiographies carried out during the first year, patients receive a total effective dose of about 62 mSv within the first year. In vivo dosimetry showed that the peak skin dose was linearly correlated with cumulative dose in air and did not exceed 1.0 Gy, ie, it was less than the threshold for any acute skin reaction. CONCLUSION Repair of abdominal aortic aneurysm results in substantial radiation burden. Radiation-related risks for carcinogenesis and skin injuries are factors that have to be taken into account in the selection of the strategy of each facility.

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.

Highly elevated serum levels of CA 19-9 in choledocholithiasis: a case report

We present a case of a 79-year-old woman admitted to our hospital with pain in the right upper abdominal quadrate radiated to the back, jaundice, fever and chills. The laboratory tests showed serum carbohydrate antigen 19-9 levels of 99.070 U/ml (normal values: 0-37 U/ml). The rest of the biochemistry showed alkaline phosphatase of 550 IU/l, direct bilirubin: 17.5 mg/dl, total bilirubin: 28.4 mg/dl. Abdominal sonography demonstrated dilated common bile duct. Two weeks postoperatively, the carbohydrate antigen 19-9 fell to 970 U/ml and returned within normal range (31 U/ml) two months later. Furthermore, the magnetic resonance cholangiopancreatography performed postoperatively demonstrated normal configuration of the biliary tree and the common bile duct.

EGFR as a Prognostic Marker for Gastric Cancer

To the Editor Current treatment decisions on gastric cancer are based on the TNM staging system. But because of well-recognized limitations [1], there is urgent need for prognostic biomarkers and novel targeted therapy. Overall, prognosis of gastric cancer is poor, with a 5-year survival rate in the USA of only 23% [2]. At present, cure can practically be achieved primarily in localized disease when appropriate local treatment, as adequate D2 surgery, is applied [3–6]. Most patients with stages I and II gastric adenocarcinona [7] or lymphoma [8] have local disease and can be cured with adequate D2 surgery [9, 10] or, alternatively, limited D1 surgery plus chemoradiation [11, 12]. The addition of systematic adjuvant chemotheraphy can increase the 5– year survival rate but only moderately, by 13% [13]. All these data suggest the need for prognostic and predictive biomarkers to identify the patients who would most benefit from systemic adjuvant treatment [14]. Therefore, the report by Galizia et al. [15] in the July issue of the World Journal of Surgery on the potential use of EGFR as a prognostic tool is very useful. EGFR could potentially be used for making decisions about adjuvant chemotherapy and/or anti-EGFR targeted therapy for gastric cancer. This is an excellent but very complex topic. In the era of network biology [16], high-throughput technologies now enable the identification of new genes, mutations, and multiple oncogenic pathways, which are involved in various cancers including gastric cancer [17]. It is likely therefore, that in gastric carcinogenesis, progression, and metastasis, several other signaling pathways are activated beyond EGFR [18]. This aspect is also supported by the lack of association between EGFR expression levels and anti-EGFR agents for gastric cancer and other solid tumors [19]. Molecular and genetic tools hold great promise for personalized cancer treatment [18, 20–22]. For example, genetic testing has already been incorporated into the prevention and treatment of hereditary diffuse gastric cancer and hereditary breast ovarian cancer syndromes [23–28]. However, much more basic and clinical research work is needed to reach clinical treatment decisions for tailoring the best combinatorial treatment for individual patients with gastric cancer [29].

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

Laparoscopic gastrectomy for organ-confined cancer: a reality in the west?

Open gastrectomy with extended (D2) lymphadenectomy for the treatment of resectable gastric cancer has become the de facto standard of care in Japan and Korea. Excellent outcomes for advanced stages of this disease have reported recently from a high-quality, multicenter, phase III, randomized, controlled trial at 24 hospitals in Japan [1]. Sasako et al. reported a 5-year survival rate of 70% with extended lymphadenectomy for Japanese stages II and III disease without adjuvant treatment [1]. Yet, these results represent a dream for the real western world [2]. Even in specialized institutions in the west, 5-year survival rate for these advanced stages is reported to be less than 40%, and notably these data are derived from nonrandomized studies [3–7]. Laparoscopic gastrectomy may dramatically improve postoperative quality of life (QOL) outcomes. Rapidly mounting evidence in the last years from Korea and Japan suggests excellent outcomes. Nevertheless, these reports come from highly specialized centers in which a few only experienced surgeons with skill in laparoscopic approaches perform the laparoscopic gastrectomy. A very large retrospective study of approximately 1,500 patients and a randomized, controlled trial on QOL and a recent report on long-term oncological outcomes provide evidence for the similar safety and efficiency and superiority of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG) for early gastric cancer [8– 10]. In the western world, data on laparoscopic gastrectomy are scarce. To determine whether laparoscopic gastrectomy is safe and effective in countries outsides East Asian, Sarela [11] reported his personal experience with laparoscopic gastrectomy for gastric cancer in the United Kingdom in a recent issue of Surgical Endoscopy. Within 2 years (2005– 2007), the author performed gastrectomy in 29 patients: 18 patients were treated with laparoscopic gastrectomy (6 with total gastrectomy), and 11 patients with open gastrectomy. In five patients, laparoscopic gastrectomy was converted to open procedures. Not surprisingly, laparoscopic resection had a longer operation time than open gastrectomy, and mortality was similar between laparoscopic and open gastrectomy. This study has strengths and weaknesses. Laparoscopic total gastrectomy, which requires a high level of experience and skill and there are a few reports with a small number of cases even from Japan and Korea, was performed in one-third of the cases. The number of lymph nodes retrieved was in most cases appropriate and similar to recent reports from the west for open D2 gastrectomy. Serious concern and caution suggests the inclusion of patients with serosa-positive cancer (pT3) for laparoscopic gastrectomy in the present study [11]. The microscopically positive resection (R1 resection) was 4 of 18 (22.22%). This rate is considered too high for open D2 gastrectomy in patients with pT3 disease [3]. Moreover, the peritoneal dissemination risk of cancer cells through laparoscopic gastrectomy in patients with pT3 tumor may be high. This is the reason for limited data for laparoscopic gastrectomy from Korea or Japan in pT3 disease, particularly when for this tumor stage excellent survival rates are reported from Japan [1]. Although strong evidence for advanced stage E. Hanisch (&) Asklepios Klinik Langen, Akademisches, Lehrkrankenhaus der JWG-Universität, Klinik für Allgemein-, Viszeralund Endokrine Chirurgie, Frankfurt am Main, Germany e-mail: E.Hanisch@Asklepios.com