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Innovation in technology is crucial for improving healthcare. Robotic technology in surgical practice [1] and nextgeneration sequencing (NGS) platforms in genomics research [2] represent the most promising technological advances for improving clinical outcomes of patients with complex diseases such as cancer. However, technological innovation in healthcare is an important driver of cost growth. Very often, physicians and patients seeking the best treatment embrace new modes of treatment before there is evidence-based clinical utility of new medical devices. It is obvious that comparative-effectiveness research (CER) is required before new medical devices, diagnostics or novel drugs are incorporated into clinical practice [3]. Robotic surgical devices allow a surgeon at a console to operate remote-controlled robotic arms, which may facilitate the performance of laparoscopic procedures. Laparoscopic surgery, in turn, is associated with shorter hospital stays than open surgery, as well as with less postoperative pain and scarring, lower risks of infection and need for blood transfusion, and better aesthetic result. All these advantages can be termed as better short-term quality of life (QOL). Evidence for the superiority of laparoscopic versus open surgery has already been documented for colon cancer, and there is also a trend for similar benefits in patients with rectal cancer and gastric cancer [4–9]. However, there is still no evidence that robotic-assisted surgery significantly improves outcomes and reduces adverse effects as compared with laparoscopic-assisted surgery, while by contrast it appears that it is associated with higher costs. The hypothesis that more appropriate and precise total mesorectal excision (TME) can lead to higher complete cancer resection (R0), lower rates of local and locoregional recurrence, and improved survival with robot-assisted surgery compared with laparoscopic resection [10] requires data from CER, which remain scarce. In the November issue of Surgical Endoscopy, Bianchi and colleagues [11] address the question of potential shortterm benefits of robotic versus laparoscopic surgery in the treatment of patients with middle or lower rectal adenocarcinoma. The authors analysed the data of 50 patients with proven middle/lower rectal adenocarcinoma who all underwent minimally invasive TME either with a four-arm Da Vinci S robot (Intuitive Surgical, Sunnyvale, CA, USA) (n = 25) or with laparoscopic technique (n = 25). The groups were well balanced. Most patients underwent anterior resections (74%) and the remaining underwent abdominoperineal resections (26%), while about half of patients received preoperative (neoadjuvant) chemotherapy. There was no significant difference in median operating time, first bowel movement, median hospital stay or complications between the two groups. Extent of lymphadenectomy as measured by the median number of lymph nodes examined was similar (18 vs. 17). Distal resection margins were disease free in both groups, but circumferential margin was involved in one patient (4%) of the laparoscopic group. There was only one conversion to laparotomy. The authors conclude that robotic TME for rectal cancer is feasible with similar short-term oncologic and QOL outcomes compared with laparoscopic TME. They note that whether the greater manoeuvrability and visibility afforded by the robotic approach can result in better outcomes than those of laparoscopic surgery can be answered by future, more systematic studies considering also the costs of robotic-assisted surgery. C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Surg Endosc

Although no survival benefit can be expected, laparoscopic gastrectomy for patients with early gastric cancer has become popular during the last decade. Laparoscopic gastrectomy, compared with open gastrectomy, provides a series of strengths during the early postoperative period

Recent evidence in western countries has confirmed the improvement in survival of open gastrectomy with D2 lymphadenectomy for resectable gastric cancer [1], which has been the standard approach over decades in Japan [2]. Laparoscopic or robotic surgery can improve short-term outcome and quality of life [3], but is laparoscopic D2 gastrectomy safe and effective when performed outside of elite surgeons and hospitals? Targeting gastric adenocarcinoma with human epidermal growth factor 2 (HER2) gene amplification with trastuzumab prolongs survival, but most patients with advanced disease develop recurrence as a consequence of therapeutic resistance and die from the disease. Mutational landscape heterogeneity [4] and highly complex transcriptional regulatory network diversity drive gene expression. This new evidence from sequencing studies and the ENCODE project now shape a much more complex and sophisticated research concept [5]. These latest advances raise for the first time rational hope for the next generation of biomarkers and drugs to improve cancer cure rates. But can enormous challenges be overcome? Using the propensity score matching method, Zhao et al. [6] reported in the August 2013 issue of Surgical Endoscopy the comparative results of D2 gastrectomy between laparoscopic (133 patients) and open (133) distal gastrectomy. There was no significant difference in the number of resected and examined lymph nodes and the postoperative short-term and long-term morbidity and mortality between the two groups. It appears that the only disadvantage of laparoscopic gastrectomy is the longer operating time. However, this report comes from a highly specialized institution with high-volume surgeons and skill in laparoscopic D2 gastrectomy. Laparoscopic D2 lymphadenectomy and laparoscopic total gastrectomy are highly demanding operations and the lack of data from nonspecialized institutions is cause for concern about the safety and efficacy of this approach by low-volume surgeons for whom such an approach cannot be recommended. In contrast to the wide clinical use of minimally invasive surgery such as laparoscopic or robotic resection for other common tumors, e.g., colorectal cancer [7–9], safe and effective laparoscopic D2 gastrectomy for advanced gastric cancer still remains an experimental approach outside of highvolume hospitals [10–13]. Progress in the successful treatment of patients with advanced gastric cancer is very slow. Genomic structural and functional heterogeneity and the complexity of the cancer genome explain the high rate of treatment resistance and the low survival rate for patients with advanced solid tumors, including gastric cancer [4]. Based on this genomic complexity with multiple and still unrecognized genomic subtypes, the disappointing results from current randomized trials using single-gene targeting drugs are not surprising. Trastuzumab for HER2-positive gastric cancer significantly prolongs survival but long-term mortality rates are high among patients with HER2-negative (80 % of all patients) or even HER2-positive disease [14]. Trastuzumab emtansine conjugate is improved treatment for breast cancer and can be similarly effective in HER2overexpressing gastric tumors, but we are still far from achieving high cure rates. We are now shifting from the ‘‘central dogma’’ of the single-gene/protein-phenotype (trait/disease) relationship established by Crick a half century ago to systems biology and genomic medicine. All currently available diagnostics and drugs have been developed based on this reductionist C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Based on previous phase 3 randomized clinical trials suggesting patient’s benefits, preoperative chemoradiotherapy has become popular for selected patients with advanced (T3, T4 tumors or node-positive) rectal cancer. However, meta-analyses published this year reporting data from recent phase 3 trials raise concerns on the clinical utility of this neoadjuvant chemoradiotherapy [1, 2]. Preoperative tumor responsiveness to this treatment was approximately 40–50 %, and the overall resistance and complications rates balanced with the benefits. These latest clinical results reveal the urgent need of biomedical research for developing robust biomarkers for tailoring neoadjuvant treatment to sensitive tumors only and explain the recent focus of next-generation sequencing (NGS)-based biomarkers [3, 4]. Although ideally laparoscopic rectal surgery should follow neoadjuvant treatment in selected patients with predictable tumor responsiveness, it is important to obtain data evaluating the impact of this preoperative multimodal treatment in the safety and efficacy of subsequent laparoscopic surgery. Therefore, either using conventional or novel genome-based selection criteria this information is important for laparoscopic surgeons. This clinically crucial question is highlighted by Denost et al. [5] in the July issue of Surgical Endoscopy. Of 422 patients treated by laparoscopic rectal excision with sphincter preservation, 292 received preoperative radiotherapy, and 130 had primary surgery. There was no significant difference in mortality rate between radiotherapy group (0.3 %) and surgical group (0.8 %). No significant difference was observed with respect to the rates of conversion (19 vs. 15 %), overall morbidity (37 vs. 29 %), surgical morbidity (20 vs. 18 %), or anastomotic leakage (13 vs. 11 %). Preoperative radiotherapy had no impact on conversion or surgical morbidity. The authors conclude that long-course radiochemotherapy (45 Gy during 5 weeks) does not influence the feasibility or short-term outcome of laparoscopic sphincter-saving rectal excision for rectal cancer. This study by Denost et al. [5] is limited by its retrospective nature. But despite that that there were more advanced and lower tumors with lower anastomosis in the neoadjuvant group, there was no significant difference between the groups suggesting the safety of laparoscopic surgery after preoperative adjuvant chemoradiotherapy. Anastomotic leakage and morbidity rates reported in this study are within the ranges of current papers suggesting the task to reduce anastomotic leakage rate substantially lower than 10 %. Despite advances with minimally invasive surgery for gastrointestinal cancer [6–13], cancer biology still remains a scientific mystery explaining the failure of biomedical research to discover robust biomarkers to accurately predict responsiveness or resistance to currently used adjuvant multimodal treatment. Resistance is even today a major problem and despite initial enthusiasm with anti-EGFR antibodies, such as cetuximab or panitumumab, more recent well-designed and conducted phase 3 randomized clinical found no survival benefit for selected, wild-type KRAS metastatic, or adjuvant colorectal cancer [14, 15]. Patient-to-patient and intratumor heterogeneity has been confirmed by using NGS and represent a step forward to understand the complexity of cancer genome and the slow progress to discover robust biomarkers for driving a combination of drugs effective to individual responder patients. Indeed, whole-exome sequencing (WES), whole-genome C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Survival rates after esophageal cancer diagnosis still remain poor despite standardization of surgery and adjuvant treatment for resectable tumors. Currently, the US cancer statistics for patients with regional or stage II/III TNM stage cancer show high mortality rates. Many patients relapse and die after complete tumor resection (R0) and multimodal adjuvant treatment with chemotherapy or chemoradiotherapy, which is associated with toxic side effects. Preoperative or neoadjuvant chemotherapy (NAC) for some cancer types, including esophageal tumor, has been associated with high response rates resulting in wider clinical use of this systemic treatment. However, how can the high relapse and death rates despite the high NAC response rates for esophageal cancer be explained? Currently, a whole-genome sequencing study provides scientific evidence that although most primary tumor cells are sensitive and are killed by initial chemotherapy, a subclone of the founding clone survives, gains additional mutations, and is expanded at relapse. DNA-damaging chemotherapy itself contributes to this treatment failure [1]. Therefore, despite tumor mass reduction in the conventional imaging technology, relapse and death occur, indicating the need for the development of robust prognostic and predictive markers [2, 3]. Considering this latest data on cancer genome and epigenome [4], can endoscopic ultrasound (EUS) be useful in the clinic for monitoring and predicting response to NAC for patients with esophageal cancer? In the February issue of Surgical Endoscopy, Misra et al. [5] evaluated whether EUS is a useful tool for assessing tumor response and staging esophageal cancers after NAC. The authors analyzed 110 patients with esophageal cancer by performing EUS before and after NAC and compared the data with the postsurgical pathologic stage (pTNM). Misra et al. [5] reported an 87 % response rate (n = 96), and among these patients, 39 % had a significant response and 61 % a partial response to NAC. In more than 50 % of the 110 patients there was an overstaging or understaging for T and N status which led the authors to conclude that EUS is an unreliable tool for staging esophageal cancer after NAC. Misra et al. [5] performed a careful study despite its retrospective nature. The data reported suggest caution in using EUS for surgical decision-making after NAC. Surgeons should critically consider the role of EUS or computerized tomography in deciding on tumor resectability and predicting R0 resection, relapse rate, and prognosis. In particular, T stage tumor that is substantially overstaged by EUS after NAC should not lead the surgeon to avoid surgery because T tumors are nonresectable or resection would be incomplete (R1/R2) because T overstaging may have resulted from a NAC-induced inflammatory effect or fibrosis. The clinical data provided by Misra et al. are in accordance with recent whole-genome, exome, transcriptome, epigenome, and functional genomic data for the heterogeneity and high complexity of esophageal and other major cancer types. Surgeons and oncologists need more effective tools than the currently used conventional clinicopathologic and imaging markers for accurately predicting therapeutic response, recurrence, and prognosis. Revolutionary technologies such as next-generation sequencing, living cells imaging using biosensors, and three-dimensional genome resolution now allow for the first time reliable systems computational biology, synthetic genomic biology, C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Predictive medicine is crucial for improving medical quality and health. Traditionally, epidemiological studies are used for patient’s outcome with a disease in the pretreatment setting to predict outcomes before therapeutic intervention with surgery, drugs, or both. Given the heterogeneity and complexity of chronic multifactorial disorders, such as cancer, emerging biomedical research is based on genomics, epigenomics, and microRNAs along with systems computational biology and mathematical models for the development of novel biomarkers and more accurate predictions [1, 2]. Based on the establishment and success of laparoscopic resection for colorectal cancer to improve quality of life by equal oncological outcomes compared with open surgery, laparoscopic gastrectomy has rapidly evolved during the past decade [3–10]. Pretreatment identification of gastric patients at risk for developing early postoperative complications or recurrence after laparoscopic gastrectomy has crucial clinical implications. In general for cancer, such markers can guide a tailored treatment for improving patient’s outcomes and this is a major goal of personalized medicine [11]. In the December issue of Surgical Endoscopy, Yoshikawa et al. [12] evaluated several markers that might be clinical useful for patients who are going to undergo laparoscopic gastrectomy for gastric cancer. The authors have classified 66 patients who underwent laparoscopy assisted gastrectomy (LAG) into two groups: body mass index (BMI) [\25 BMI-L group: n = 53; C25 BMI-H group: n = 13] and visceral fat areas (VFAs) [\100 cm AF-L group: n = 35; C100 cm AF-H group: n = 31]. Yoshikawa et al. [12] report that the BMI did not impact postoperative complications (p = 0.18) or blood loss (p = 0.21), whereas by contrast VFA significantly influenced complications, blood loss, and number of lymph nodes retrieved. The authors conclude that the area of visceral fat tissue assessed by CT and software was useful to predict risks of LAG and postoperative complications with higher precision compared with BMI. This study evaluated the area of visceral fat tissue and provides a new aspect for identifying predictive and prognostic markers for LAG for gastric cancer. However, it is limited not only by its retrospective nature but also by the very small number of patients in subgroups evaluated. Therefore, it could be considered an underpowered study for assessing valid significant differences. However, the data provided are promising and the authors may perform a study with large and accurate samples of patients to validate the potential impact of the area of visceral fat tissue in patients undergoing laparoscopic gastrectomy. Development of robust biomarkers for personalized cancer treatment has been proven to be much more difficult and complicated than we have supposed. Personalized medicine can improve dramatically the outcome in public health, but much more research work is needed. In the era of next-generation sequencing for whole-genome sequencing, functional genomics, transcriptomics, and epigenomics, new directions are being shaped. Assembling large-scale omics data together with clinical data and integrating all of this genome and clinical information into computational and mathematical models could result in the development of systems biology and systems medicinebased biomarkers [13–32]. C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

The most pressing and daunting challenge of treating patients with advanced but potentially curable stage II and III gastric cancer is how to reduce the risk of recurrence after complete tumor resection (R0). Most efforts of biomedical research and the pharmaceutical industry to improve recurrence-free and overall survival are focused on the development of effective adjuvant therapies, but could laparoscopic R0 resections have an influence on the risk of relapse? To highlight this crucial question, Jeong et al. [1] performed a retrospective study and reported the results in the March issue of Surgical Endoscopy. The authors evaluated the clinicopathologic, treatment, and survival follow-up data of 398 patients with gastric cancer who underwent an R0 resection. Based on comparative-effectiveness research (CER), Jeong et al. compared the recurrence rates after laparoscopic and open gastrectomy. Laparoscopic gastrectomy (LAG) was performed in 261 patients (65.4%) and open gastrectomy (OG) in 138 patients (34.6%). After a mean follow-up of 37 months, recurrence was observed in 58 patients (14.6%). In univariate analysis, the recurrence rate was higher in the OG group but in multivariate analysis the laparoscopic approach (LAG) was not an independent predictor of recurrence. The authors conclude that LAG appears to be a safe and feasible procedure, even for advanced gastric cancer. Recurrence after an R0 resection is the most common cause of death of patients with gastric cancer or other solid cancers. The ultimate goal of biomedical research is to understand the molecular and genomics mechanisms underlying recurrence and to develop new more effective drugs to control locoregional and distant relapses [2, 3]. Despite standardization of R0 resections, including extended D2 lymph node dissection and adjuvant chemotherapy, radiotherapy, and targeted therapy [4–9], recurrence rates in patients with stage II/III solid cancer still remain high, suggesting the complexity of cancer and the problems in improving oncological outcomes [10]. Evidence suggests that laparoscopic surgery improves postoperative short-term outcomes and quality of life (QOL) without any negative effects on the oncological outcome of patients with colon cancer. However, no solid evidence exists for a potential recurrence risk reduction due laparoscopic surgery for gastric, rectal, or any other type of solid-organ cancer [11–18]. Large retrospective studies and small randomized controlled trials have demonstrated that laparoscopy-assisted distal gastrectomy for early gastric cancer (T1) is a safe and feasible procedure [12]. Based on the paradigm of advanced colon cancer with evidence that laparoscopic colectomy in stage II/III has no negative effect on disease-free survival, the trend is to evaluate the safety and efficacy of laparoscopic gastrectomy in advanced stages. The study by Jeong et al. [1] supports the safety of laparoscopic surgery for advanced gastric cancer. However, this study is limited by its retrospective nature and relatively small number of patients in each TNM stage. Further work is needed with CER either with randomized trials or large-scale retrospective studies with quality control. Although laparoscopic D2 gastrectomy can be performed safely even in advanced stages, in the West this minimally invasive approach still suggests a challenge. For stage IV tumors in particular, an R0 resection is difficult to achieve even with open surgery in Europe or the U.S., and most of these patients are currently treated with neoadjuvant chemotherapy or chemoradiotherapy. In the study by Jeong et al. [1], 41 patients with stage III/IV cancer were treated C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt am Main, Germany e-mail: info@gastricbreastcancer.com

We now see a great increase in the use of minimally invasive surgery for the treatment of solid tumors [1]. Patients and their physicians are increasingly seeking cancer-specialized institutions to benefit from cancer management by a multidisciplinary team. This fact has increased the competition among hospitals and surgeons. As a result, laparoscopic surgery has rapidly become involved given that it is associated with a shorter hospital stay, less postoperative pain and scarring, and lower risk of infection and for the need for blood transfusion than open surgery. For the treatment of gastrointestinal cancers, the use of laparoscopic surgery has progressed very fast [2–7]. A paradigm of rapid evolution in the treatment of colorectal cancer with laparoscopic surgery is presented in the study by Ramos-Valadez et al. [8], published in the October issue of Surgical Endoscopy. Using a rapidly emerging technique—the single-incision laparoscopic colectomy (SILC)—the authors evaluated the safety and feasibility of performing SILC for a right hemicolectomy using the SILS Port Multiple Instrument Access Port (Covidien, Mansfield, MA). Within 4 months, a SILC right hemicolectomy was performed in 13 consecutive, unselected patients with a benign or malignant tumor. Demographic data, intraoperative parameters, and postoperative outcomes were assessed. Two cases required conversion to a hand-assisted procedure. In 11 patients, the SILC procedure was performed with a mean incision length of 3.1 cm and a mean operative time of 131 min. Operative time was related to the body mass index. Among the five patients with malignant tumor, the mean number of lymph nodes resected and evaluated by pathologists was 26. There were no intraoperative complications and only one postoperative complication. The safety of SILC is reflected in the overall mean hospital stay of only 2.5 days. Based on these results, the authors concluded that the SILC procedure is a safe and feasible procedure for treating benign and malignant diseases requiring a right hemicolectomy. Indeed, although this was a small retrospective study, it provides evidence that SILC can be performed with a low complication rate and a short postoperative hospital stay. It should be noted, however, that these excellent results are from a study conducted at a highly specialized institution by surgeons who have performed a high volume of minimally invasive surgeries. Therefore, reports that include a larger number of patients treated with this technique, particularly in low-volume hospitals, should be awaited to assess the safety of single-incision laparoscopic surgery in the treatment of colorectal cancer. Recently, complete laparoscopic colorectal cancer resection (R0), including resection of a sufficient number of examined lymph nodes, has been reported. Despite this procedure and adjuvant systemic chemotherapy and radiotherapy, recurrence and death rates from cancer still remain high. With respect to adjuvants, there is still no evidence that the anti-EGFR agents cetuximab and panitumumab can improve overall survival and cure rates. However, there is evidence for progression-free survival benefit without any overall survival benefit and this effect is limited to genotype-based selection of patients with wild-type KRAS status in the metastatic setting [9, 10]. Similarly, caution is suggested for use of the anti-VEGF drug bevacizumab, for which the latest evidence indicates lower expectations for overall survival benefit without biomarker-based selection of patients with solid tumors [11]. These results with modest efficacy and true response C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

It is thought that laparoscopic low anterior resection (LLAR) for lower rectal cancer improves quality of life (QOL) of these patients. However, it is a highly demanding surgical procedure. Despite an increasing surgical experience in high-volume hospitals, anastomotic leakage still remains a challenge [1, 2]. To reduce this leak rate, Fujii and colleagues [3] have developed and propose in the February issue of Surgical Endoscopy a new technique. The authors have tested the safety and efficiency of this method in 28 patients with low-lying rectal cancer and compared the results with those of 107 patients with similar tumor location treated by using multiple stapling for rectal transaction. Total mesorectal excision (TME) has been standard in the surgical treatment of rectal cancer. For the vast majority of patients, a sphincter-preserving treatment strategy is a primary desire. As a result of intensive research, low anterior resection (LAR) has been developed, and many patients benefit from this surgical approach. However, in many cases, decision-making between LAR and total rectal excision is currently too hard. Criteria for surgical decisions have not been standardized, and there is debate among surgeons about which is the optimal surgery for patients with low-lying rectal cancer. Standardized surgical quality is fundamental for improving outcomes of patients with gastrointestinal cancer [4–6], and the oncological principles of open surgery regarding R0 resection should also be met in laparoscopic surgery [7, 8]. Laparoscopic rectal resection has not been included in guidelines, even though evidence for the superiority of laparoscopic over open colectomy for colon cancer, and positive results from retrospective studies and small randomized controlled trials [9] suggest the safety and efficacy of laparoscopic approach. Moreover, a better view of the pelvis allows precision in performing safer and more effective TME by LLAR rather than by open surgery [1, 2]. There are expectations that not only will the underway randomized controlled trials provide positive results in favor of LLAR but also that the precision of laparoscopic or robotic surgery in TME may also improve local control and overall survival [10, 11]. Anastomotic leakage after laparoscopic TME (LTME), with a rate of approximately 10% despite rapid advances, still remains a substantial problem [1, 2]. Risk factors related to anastomotic failure have been reported to be TME and multiple anastomotic stapling, which may decrease blood supply to the remaining rectum stump and increase the risk of colorectal anastomosis leakage [1]. To reduce the clinical consequences of this anastomosis failure a protective temporal ileostoma is used, but there is still debate on its clinical utility [12]. Fujii and colleagues [3] looked at whether their technique, called the Y-Hood method, was safe and more effective in reducing anastomotic leak as compared with the double-stapling technique. The authors developed clamp forceps for intestinal lavage and a Y-shaped vinyl hood that can be operated under pneumoperitoneum for airproof surgery. According to authors, these devices enabled secure clamping and cleansing of the area and use of automatic suture instruments for open laparotomy through a minilaparotomy wound. Anastomotic leakage rates were 11.2% (12 patients) in the groups treated by using multiple stapling for rectal transaction and 7% (2 patients) in the group in which the authors used the Y-Hood technique. The number of times stapling for rectal C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

SocieteInternationale de Chirurgie 2010 Several clinicopathologic features have been found to influence survival of patients with gastric cancer. Of these, tumor depth (T), nodal status (N), tumor location (cardia, noncardia), histological type according to the Lauren classification (intestinal, diffuse type), age, type of resec- tion (R0, R1/2), and extent of lymphadenectomy (D2) have been recognized as standard prognostic factors in poten- tially curable gastric cancer. All these factors are consid- ered in the decision for or against recommending adjuvant chemotherapy. But this decision is suboptimal, particularly in patients with early-stage disease because some of them could avoid adjuvant chemotherapy, whereas others who do not receive such a treatment might benefit from the systemic therapy. Research efforts are underway to identify either additional traditional risk factors or new prognostic and predictive biomarkers based on cancer genetics, genomics, and epigenetics.

There is now debate about how many lymph nodes should be dissected during colorectal cancer (CRC) by surgery and subsequently retrieved from the specimen and examined by pathologists. Appropriate lymphadenectomy is crucial for the patient’s oncological outcome for two reasons. First, it reduces the risk of residual nodal disease, and second, examination of only a large number of lymph nodes allows for accurate nodal staging. The pathological tumor-nodemetastasis (pTNM) staging by examining a sufficient number of lymph nodes allows an accurate estimation of the ratio between positive and total number of lymph nodes evaluated. This global nodal status information is necessary for making a decision about adjuvant systemic chemotherapy. Recent guidelines from scientific associations and organizations, including the American College of Surgeons (ACS), the National Quality Forum (NQF), the National Comprehensive Cancer Network (NCCN), and the American Society for Clinical Oncology (ASCO), recommend that a minimum of 12 lymph nodes should be removed and histopathologically examined for appropriate treatment of patients with CRC [1]. However, two large retrospective studies question this strategy. Based on a retrospective analysis of the national Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database (19952005) of patients in the U.S. (n = 30625) who underwent colectomy for nonmetastatic colon cancer, Wong et al. [2] came to the provocative conclusion that ‘‘Efforts by payers and professional organizations to increase node examination rates may have limited value as a public health intervention.’’ In another more recent retrospective analysis of 24,477 stage III colon cancer patients identified from the SEER cancer registry, Wang et al. [3] found that the total number of lymph nodes examined is not a reliable prognostic factor for stage III colon cancer. How many lymph nodes should be removed in laparoscopic CRC surgery? This question is relevant because laparoscopic resection has been increasingly used in dayto-day clinical practice not only for CRC but also other gastrointestinal cancers [4–8]. In a current review [9] and an international survey of surgeons about laparoscopic rectal surgery [10] it was found that there was more emphasis on the optimal extent of surgery rather than the number of lymph nodes retrieved. Indeed, most surgeons in the European Association for Endoscopic Surgery (EAES), the Indian Association of Gastrointestinal Endo-Surgeons (IAGES), and the Society of Laparoscopic Surgeons (SLS) and renowned surgeons who perform laparoscopic total mesorectal excision (LTME) agreed on the necessity and utility of standardized laparoscopic surgery. For example, standardization of the highly demanding laparoscopic low anterior resection with high ligation of the inferior mesenteric artery at its origin, splenic flexure mobilization, and TME with safety distal resection margins of at least 2 cm provides the greatest possibility for the good oncological and quality-of-life outcomes [9, 10]. In the January 2010 issue of this journal, El-Gazzaz et al. [11] added important information on laparoscopic CRC surgery. The authors emphasized assessing the number of lymph nodes dissected during surgery and examined by the pathologists after laparoscopic or open surgery. The authors compared 243 patients who underwent laparoscopic surgery C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Gastrointestinal stromal tumors (GIST) represent a model for targeted cancer therapy and also a prime paradigm of how laparoscopic GIST surgical resection and adjuvant treatment with tyrosine kinase inhibitors (TKIs) can result in excellent short-term and long-term outcomes of these patients. The relatively simple concept of GIST development and progress by activating mutations in only two genes, either the KIT or platelet-derived growth factor A (PDGFRA) gene, and the high pathological and clinical response to tyrosine kinase inhibitors (TKIs) [1]. By contrast, multiple genes are involved in highly complex biological processes underlying tumorigenesis and metastasis for major cancer types [2]. The potential for long-term survival or even cure of GIST patients with resectable tumors treated with surgery and adjuvant targeted treatment raises the question for improving quality-of-life (QOL) of these patients through laparoscopic surgery. This question of feasibility, safety, and efficacy of laparoscopic surgery for GIST treatment is highlighted by De Vogelaere et al. [3] in the August issue of Surgical Endoscopy. The authors report on 31 consecutive patients presenting with a primary gastric GIST without metastases. The most common symptoms were melena, anemia, and abdominal pain, and in one patient a laparoscopic approach for a GIST with acute bleeding was performed. In all 31 patients, a successful laparoscopic resection was performed. Most patients (n = 26) had a tumor larger than 2 cm in size. The duration of operation (60 vs. 103 min) and duration of hospital stay (6 vs. 8 days) were lower when tumor size was less than 2 cm compared with larger tumors. Postoperative hemorrhage was occurred in only one patient. After a median follow-up of 52 months, there were no recurrences or metastases. The authors conclude that laparoscopic resection is safe and effective in treating gastric GISTs, even for tumors larger than 2 cm. Given that GIST is uncommon, this is a large series with excellent short-term and oncological outcomes associated with laparoscopic surgical resection. The size of the tumor appears to have a modest impact in clinical treatment and outcomes, although the small number of patients (n = 5) with tumors less than 2 cm in size in this study does not allow for valid comparisons. Laparoscopic and robotic surgery for tumors located at different sites of gastrointestinal tract has evolved rapidly and become popular for the surgical treatment of resectable colon rectal and gastric cancer improving QOL of these patients [4–11]. The high responsiveness of GIST to small-molecules selective TKIs, such as imatinib [1], raises the question of laparoscopic surgery also in the treatment of locally advanced or metastatic GIST. In addition, advances in biomedical research exploring the molecular mechanisms responsible for imatinib resistance have led to the development of second generation inhibitors of mutated KIT/ PDGFRA tyrosine kinase, such as nilotinib [12]. The power of whole-exome sequencing (WES) to identify not only primary causal (driver) mutations in KIT and PDGFRA genes but also acquired (secondary) mutations in these genes involved in resistance to TKI reveals a new class of biomarkers to predict responsiveness or resistance for tailoring the best drug to individual patient with GIST. Taking lessons from this simplified two-gene model of GIST, we may improve the design of future cancer genome-based studies to evaluate much more complex molecular mechanisms of resistance to targeted drugs for common cancer types, such as colorectal cancer, C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

During the past four decades, open gastrectomy with D2 lymphadenectomy has been the standard approach for resectable gastric cancer in Japan. But only recently with evidence from western phase 3 randomized controlled trials for the safety and survival benefit of D2 versus D1 surgery [1], D2 surgery can be recommended for wide practical implementation when it results in a complete tumor resection (R0). During the past decade, large retrospective studies and small randomized trials, mostly from Korea and Japan, have reported positive results with laparoscopic surgery mainly for early gastric cancer [2]. However, totally laparoscopic D2 gastrectomy particularly for advanced gastric cancer, is a highly demanded, timeconsuming procedure that requires evaluation in clinical trials for its safety and efficacy considering also cost-benefit analysis compared with standard open D2 surgery [3]. The recent report for laparoscopic D2 gastrectomy for gastric cancer by Moisan and colleagues [4] in the March issue of Surgical Endoscopy comes not from Korea, Japan, or specialized hospitals in the United States or European Union but from Chile. In this country, along with Asia and east European countries, incidence of gastric cancer continues to be high, which may explain advances with laparoscopic surgical treatment. Moisan and colleagues [4] compared early and longterm outcomes of 31 gastric cancer patients who underwent totally laparoscopic D2 gastrectomy (LG) with intracorporeal handsewn esophagojejunostomy between 2003 and 2010 with those of 31 patients who received an open D2 gastrectomy (OG) as the standard group. There were major complications with two vs. no duodenal stump leakages in LG and OG respectively and two esophagojejunostomy anastomotic leakages in each group. After a median followup of 3 years, there was no significant difference in recurrence-free survival or overall survival between the two groups. The authors conclude that laparoscopic D2 surgery is feasible, safe, and as effective as open D2 surgery regarding oncological outcomes. This study provides many positive aspects. Totally laparoscopic gastrectomy with total gastrectomy and D2 lymphadenectomy is a highly demanding procedure that is feasible, safe, and effective with respect to long-term survival only when it is performed by high-volume surgeons with expertise and skill in this technique. The 35 retrieved lymph nodes in the laparoscopic group reveals the standardized and completeness of D2 lymphadenectomy that is essential for locoregional tumor control in advanced lymph node-positive disease. However, some questions raise the relatively high rates of leakages in duodenal stump and esophagojejunostomy. Laparoscopic surgery has evolved rapidly and provides evidence for its superiority for the treatment of colon cancer and positive data for rectal cancer treatment [5–7]. However, at present, totally laparoscopic D2 gastrectomy for advanced potentially curable gastric cancer, despite sporadic reports with enhanced results, requires evaluation within clinical trials and cannot be recommended outside highly specialized hospitals [3]. Although laparoscopic surgery can improve quality of life [8–11], the grand challenge remains of how the cancer genome heterogeneity and complexity of cancer cells in individual patient’s tumors can be overcome. Recently, the addition of trastuzumab to chemotherapy in HER2-positive metastatic or advanced gastric cancer has become the new standard, and new phase 3 trials also may establish its use C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Laparoscopic surgery for the treatment of gastrointestinal cancer has rapidly evolved over the last decade. Although critical analysis of the short-term outcomes of laparoscopic gastrectomy has provided evidence for the safety of this minimally invasive approach, little long-term survival data, particularly for patients with advanced stage II and III gastric cancer, are available [1]. This lack of evidence increases the skepticism about the ability of laparoscopic gastrectomy for advanced gastric cancer to control cancer cell dissemination and prevent recurrence. This gap between expectations of and concerns about the long-term impact of laparoscopic gastrectomy on gastric cancer patients has been bridged by the study of Pak et al. [2] reported in the January issue of Surgical Endoscopy. The authors have analyzed the results of 714 consecutive patients with gastric cancer who underwent laparoscopic gastrectomy in their institution between May 2003 and December 2009. After a median follow-up of 46 months, recurrence was observed in 26 patients (3.7 %), with the secondary tumor located in the peritoneum in seven patients), locoregional in six patients, in distant organs with hematogenous spread in five patients, and other less frequent failures. The 5-year recurrence-free survival rates according to the TNM staging system categories were 95.8 % in stage I patients, 83.4 % in stage II patients, and 46.4 % in stage III patients. This study provides excellent results, similar to those reported by the randomized controlled trials (RCTs) with open D2 gastrectomy for stage II–III disease by Sasako et al. [3]. However, what is the reality from a Western point of view? In contrast to the excellent expertise in laparoscopic gastrectomy of Korean surgeons, a sample size as large as 714 patients treated within 7 years is unrealistic in Western countries, even in specialized hospitals. This lack of high-volume surgeons, which is a predictive factor for safe and effective laparoscopic surgery, raises attention. Indeed, although laparoscopic resection tends to be routinely performed for colorectal cancer, laparoscopic D2 gastrectomy for advanced tumors still remains a grand challenge for Western surgeons [4–11]. Such an approach is less familiar to Western surgeons and can be associated with the reports of increased postoperative complications and mortality. While awaiting the results of confirmatory RCTs for laparoscopic D2 gastrectomy for advanced resectable gastric cancer, biomedical research is focused on novel drugs developed based on the concept of signaling transduction interaction networks. In the era of systems science and biological circuits, there is emerging research based on the latest genome sequencing technology and living-cells networks-based imaging technologies. These advances together with substantial progress in computational systems biology, synthetic biology engineered-based reconstruction of signaling circuits, and mathematical models now shape new horizons in the discovery of innovative biomarkertargeted drug complexes for personalized treatment of cancer patients [12–32].

A decade after the approval of the Da Vinci Surgical System (DVSS) by the US Food and Drug Administration (FDA), evidence of its superiority with respect to safety and efficacy for selected types of surgery compared with conventional laparoscopic surgery (CLS) has been accumulated. The potential advantages of the DVSS over CLS include its greater precision, lower error rates, reduced bleeding, shorter hospital stays, more rapid patient recovery, and reduced pain. As a result many surgeons have begun to use the DVSS in daily practice for a wide variety of surgeries, including general, oncological, urological, gynecological, and cardiothoracic [1]. However, because robotic surgery is still in its early stages, comparativeeffectiveness research (CER) evidence is scarce, and costs must be considered in an economical crisis [2], a more critical approach is required [2]. Robotic surgery may not be suitable for specific types of surgical procedures. A paradigm of potential limitations of robotic surgery was published by Scozzari et al. [3] in the February issue of Surgical Endoscopy. Given the difficulties with traditional laparoscopic surgery for morbidly obese patients, the authors thought to use the DVSS to improve the outcomes of these patients. Data from 110 morbidly obese patients who underwent laparoscopic Roux-en-Y gastric bypass with robot-assisted hand-sewn gastrojejunal anastomosis using the DVSS (DVSS group) were compared with data of 423 patients who underwent standardized CLS group. The patients had a mean weight of 127.5 kg and a mean body mass index (BMI) of 46.7 kg/ m. There were statistically significant differences in favor of the CLS over the DVSS group with respect to the operative time (P \ 0.001) and the cost per patient (P \ 0.001), whereas no differences were found in terms of the intraor postoperative complication rates, revision surgery, or hospital length of stay. The authors concluded that although robot-assisted surgery was safe and intuitive, it did not seem to provide a real advantage over standard laparoscopy in terms of hospital length of stay and complications rates. This study suggests that the use of the DVSS may be indicated for some specific organs and anatomical areas, while it may not be superior to CLS for other disorders and locations. Minimally invasive surgery such as laparoscopyor robot-assisted surgery also has important implications in surgical oncology for a variety of solid tumors. For example, laparoscopic surgery has been the standard approach for colon cancer and promising data have been available for its use in other gastrointestinal cancers, whereas evidence is increasing for the superiority of robotassisted surgery for rectal cancer [4–10]. The age of robotic surgery has dawned and there is still a lot of improvement to be made in the near future. For example, robotic surgery for prostate cancer or rectal cancer is new and has its own learning curve to be overcome. If we remind ourselves of all the debates brought by each new innovative technology, such as laparoscopic surgery, on its first appearance, we believe that further intensive and largescaled studies will answer the upcoming questions about the safety and efficacy of robotic surgery. Translating innovative ideas and concepts into medical practice suggests a key driver to improve health care. However, costs should be considered. A prime paradigm of how costs can drastically be reduced is the competition between biotechnology and pharmaceutical companies and academia regarding next-generation sequencing technology. C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt am Main, Germany e-mail: info@gastricbreastcancer.com

SocieteInternationale de Chirurgie 2010 Every surgeon performing low anterior resection for rectal cancer thinks of ways to prevent anastomotic leakage. The mean rate of this serious complication is approxi- mately 10%, and in some cases the outcome may be fatal. Identifying factors associated with increased risk of this complication may—if feasible—lead to improved man- agement to reduce this serious postoperative morbidity

In a recent issue of Surgical Endoscopy, Ohnita and colleagues [1] reported the risk factors for incomplete tumor resection after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). This identification can result in preventing pathohistologically assessed residual microscopic disease (R1) at resection margins. In 2003, the Japanese Gastric Cancer Association published recommendations for the treatment of EGC by limited surgical resection [2]. In these guidelines, strict criteria were defined to ensure the safety and efficacy of endoscopic mucosal resection (EMR) for the treatment of EGC. These criteria were: tumor size \2 cm, confined to mucosal without ulcers, and differentiated histological type. Treating patients with EMR can dramatically improve their quality of life (QOL); however, a relatively small number of patients with EGC meet these criteria. ESD was developed to expand the indications, and many patients gained substantial benefit in their QOL. However, many questions remain regarding the safety of ESD when larger undifferentiated submucosal ulcerative cancers are included for ESD. This is a very large series of ESD within a relatively short time period (2003–2008). The experience provided by these authors is valuable for institutions planning ESD, and the lessons taken from this study are important. Complications related to ESD were perforations in 21 patients (4.2%) and bleeding in 7 patients (1.4%). This morbidity rate can be considered modest and within an acceptable level. The complete tumor resection (R0) rate was high: 96%. In 476 of 495 lesions, a R0 resection was achieved. The authors exclude undifferentiated, large, submucosal cancers, and this selection may explain the high R0 rate. In another recent study, the incomplete resection rate was high: 45% [3]. However, in this report undifferentiated, ulcerative, large submucosal cancer was included, confirming the limitations of ESD. The study by Ohnita et al. [1] is limited by the absence of follow-up, which is very important to define two major risks of ESD: local recurrence and nodal recurrence. It reconfirms how carefully the EGC patients should be selected. ESD achieves a better local control than EMR regarding deeper gastric wall resection margins. However, peripheral tumor margins and nodal residual disease should be considered for achieving oncological resection quality control. Prognosis of gastric cancer with adequate open or laparoscopic surgery is excellent for early gastric cancer [4, 5]. Quality control in surgery and multimodal adjuvant treatment can substantially improve survival rates even for patients with advanced resectable stage II or III disease [6–14]. Minimally invasive approaches represent substantial progress in improving the QOL of patients. The strict selection criteria are essential for safe oncological outcomes. If there is even a modest risk of incomplete resection by ES, then laparoscopic or open gastrectomy should be considered. Despite these developments, standardized open D2 surgery is the procedure of choice for advanced gastric cancer. An improvement in oncological outcomes of advanced gastric cancer should be the first priority of biomedical sciences, whereas QOL improvement remains a secondary goal when curability has been achieved. Recent advances C. Hottenrott (&) Chirurgische Klinik St. Elisabethenkrankenhaus Ginnheimer Strase 3, Frankfurt 60487, Germany e-mail: info@gastricbreastcancer.com

Complete tumor resection (R0) for stages I to III, if feasible, has been essential as the basis of multimodal treatment of solid cancer [1–5]. However, the adequate extent of lymph node dissection for solid tumors, including colorectal cancer (CRC), has not been established to date [6–14]. Over recent decades there have been two main treatment trends. The first trend considers an appropriate lymphadenectomy to be an important part of an R0 resection. The main argument is that local and nodal control is important not only for recurrence-free survival but also for overall survival. Such lymphadenectomy requires resection and examination of at least 12 lymph nodes CRC [6]. The National Quality Forum has endorsed the examination of at least 12 lymph nodes for patients undergoing colon cancer surgery as a means of improving staging and survival. Using data from the National Cancer Data Base, researchers have shown that patient survival increases when 12 or more nodes are examined [6]. The second trend contends that the number of lymph nodes harvested does not have an impact on survival. In a retrospective cohort study using the national Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database (1995–2005), the data for 30,625 U.S. patients undergoing colectomy for nonmetastatic colon cancer were analyzed. Emphasis was given to whether more or less than 12 lymph nodes were examined. Wong et al. [7] concluded that the number of lymph nodes hospitals examine after colectomy for colon cancer is not associated with staging, use of adjuvant chemotherapy, or patient survival. These too large retrospective contrasting studies reemphasize that well-designed, randomized, phase III, controlled trials are important in the approach to the truth. Until high-quality evidence becomes available, a R0 resection, including the resection of metastatic lymph nodes, via surgical endoscopy appears to be a rational approach to the prevention of nodal recurrence. Can laparoscopic surgery result in such a quality R0 surgery with adequate lymphadenectomy? To highlight this issue, El-Gazzaz et al. [15] report in a recent issue of Surgical Endoscopy the number of lymph nodes harvested after laparoscopic and open colorectal cancer resections. Of the 729 patients who underwent surgical resection with curative intent between 1996 and 2007, 243 patients had laparoscopic surgery, and 486 had open surgery. The number of nodes harvested did not differ significantly between laparoscopic and open surgery. In this retrospective study, the mean number of lymph nodes retrieved and examined was high: 24.8 ± 20.6 per patient. The lymph nodes obtained were twice the number recently recommended, reflecting the quality of laparoscopic surgery. Although no conclusion can be drawn from the study whether this appropriate lymphadenectomy may provide a survival benefit, it reflects a rational approach accepted by most surgeons. Laparoscopic colectomy has become the standard of care for colon cancer patients with potentially curable disease (stages I to III). To achieve optimal R0 resection, metastatic lymph nodes also should be removed. Given that preoperative or operative nodal staging is inaccurate in distinguishing node-positive from node-negative disease, a standardized lymphadenectomy determined by more than 12 lymph nodes harvested appears to be beneficial for patients with node-positive colon cancer. This surgical approach is adequate for local and nodal control C. Hottenrott (&) St. Elisabethenkrankenhaus, Chirurgische Klinik, Frankfurt, Germany e-mail: info@gastricbreastcancer.com

Despite experimental evidence that myocardial depression resulting from rapid transfusion of ACD blood (citrate binds ionic calcium) is avoidable by simultaneous calcium administration, most hypovolemic patients receive calcium either after transfusion or not at all. Similar iatrogenic hypocalcemic myocardial depression occurs in normovolemic patients with known myocardial damage who are dialyzed for acute uremia when ACD blood prime is used at high initial flow rates (350 c.c. per minute) and when dialysis is performed against low calcium dialysate (2.5 mEq. per liter or less). This study tests the hypotheses that (I) rapid transfusion of as little as one unit of CPD blood causes a significant reduction in ionized calcium, (2) the depressive effect of CPD blood is significant and similar to that of ACD blood, (3) rapid blood transfusion (ACD or CPD) is safe if calcium is given simultaneously, (4) addition of calcium to the extracorporeal heparinized blood prime used in dialysis prevents initial depression, and (5) hemodynamic instability during dialysis is prevented when the dialysate is normocalcemic. From the results of our study, we made the following conclusions: (1) Ionized calcium is reduced significantly by rapid transfusion of CPD blood; (2) acute myocardial depression noted with CPD blood is similar to that previously observed with ACD blood and is prevented during transfusion of either type of blood by simultaneous calcium administration; and (3) hemodialysis in patients who have had cardiac surgery is safe if calcium is added to blood prime and dialysate is made normocalcemic.

Subendocardial ischemia develops in hearts that are fibrillated during cardiopulmonary bypass when: (1) the normal ventricle is fibrillated with a sustained electrical stimulus, (2) the hypertrophied ventricle is allowed to fibrillate spontaneously, (3) the fibrillating heart becomes distended, or (4) the perfusion pressure is reduced to approximately 50 mm Hg. Myocardial hypothermia reduces cardiac oxygen requirements during fibrillation but does not prevent ischemia when perfusion pressure falls to levels frequently attained during clinical open-heart operations. The ischemia occurs because flow cannot rise sufficiently to meet the metabolic demands of ventricular fibrillation. The forces interacting to impede adequate flow to the subendocardium during ventricular fibrillation are: (1) the compressive forces exerted on subendocardial muscle by the strength of fibrillation, (2) the compressive forces resulting from raised intracavitary pressure due to occlusion or malfunction of the ventricular vent, and (3) the evolution of myocardial edema as ischemia is prolonged. We have abandoned the use of ventricular fibrillation in clinical open-heart operations and now allow the heart to beat continually with adequate perfusion pressure. We have not needed to use inotropic drugs postoperatively after aortic or mitral valve replacement since adopting this technique.

This study assesses the effects of ventricular distention during spontaneously and electrically maintained ventricular fibrillation on coronary blood flow distribution, myocardial metabolism, and ventricular performance. Distention of the spontaneously fibrillating, adequately perfused, heart causes a redistribution of left ventricular coronary flow away from the subendocardial region and results in biochemical evidence of ischemia and moderately impaired ventricular function. While electrical fibrillation alone causes these deleterious effects on coronary flow distribution, myocardial metabolism, and performance, distention of the electrically fibrillating heart accentuates the degree of subendocardial underperfusion and metabolic and functional impairment. We conclude that overstretching of muscle fibers by ventricular distention is not the only cause of impaired ventricular function following cardiopulmonary bypass.

This report analyzes the mechanisms of subendocardial ischemia during ventricular fibrillation in normal and hypertrophied hearts and focuses primarily upon (1) the role of the fibrillating stimulus, (2) how ventricular distention impedes flow, and (3) why coronary vascular resistance progressively rises as the duration of fibrillation is prolonged. The forces interacting to impede the adequacy of flow to the subendocardium during ventricular fibrillation are (1) the compressive forces exerted on subendocardial muscle by the strength of fibrillation, (2) the compressive forces resulting from raised intracavitary pressure due to occlusion or malfunction of the ventricular vent, and (3) the evolution of myocardial edema as the ischemia is prolonged. These compressive forces may become exaggerated in hypertrophied hearts where increased wall thickness may add to the distortion of subendocardial vessels.

This study shows that noncoronary collateral flow occurs in normal hearts after chronic coronary occlusion and with left ventricular hypertrophy in variable amounts (0.2 to 16 ml/100 gm/min). Luminal–left ventricular flow is negligible in the working heart. Nonluminal noncoronary collateral flow is greatest when the heart is arrested by aortic cross-clamping, falls significantly when perfusion pressure is lowered to 50 mm Hg, and increases slightly when blood viscosity is reduced (hemodilution). Our findings indicate that the heart which is arrested by aortic cross-clamping may not be anoxic.

Despite experimental evidence that myocardial depression resulting from rapid transfusion of ACD blood (citrate binds ionic calcium) is avoidable by simultaneous calcium administration, most hypovolemic patients receive calcium either after transfusion or not at all. Similar iatrogenic hypocalcemic myocardial depression occurs in normovolemic patients with known myocardial damage who are dialyzed for acute uremia when ACD blood prime is used at high initial flow rates (350 c.c. per minute) and when dialysis is performed against low calcium dialysate (2.5 mEq. per liter or less). This study tests the hypotheses that (I) rapid transfusion of as little as one unit of CPD blood causes a significant reduction in ionized calcium, (2) the depressive effect of CPD blood is significant and similar to that of ACD blood, (3) rapid blood transfusion (ACD or CPD) is safe if calcium is given simultaneously, (4) addition of calcium to the extracorporeal heparinized blood prime used in dialysis prevents initial depression, and (5) hemodynamic instability during dialysis is prevented when the dialysate is normocalcemic. From the results of our study, we made the following conclusions: (1) Ionized calcium is reduced significantly by rapid transfusion of CPD blood; (2) acute myocardial depression noted with CPD blood is similar to that previously observed with ACD blood and is prevented during transfusion of either type of blood by simultaneous calcium administration; and (3) hemodialysis in patients who have had cardiac surgery is safe if calcium is added to blood prime and dialysate is made normocalcemic.

Fifteen hypovolemic dogs and 16 hypovolemic patients (following cardiopulmonary bypass) were studied, while heparinized whole blood and citrated whole blood were administered alternately in equal volumes at equal rates. Heparinized blood quickly restored cardiac output and arterial pressure with physiologic elevations in left atrial pressure (LAP) and central venous pressure (CVP) while cardiac work showed a normal function curve. In contrast, citrated blood, administered at the same rate, often failed to restore and frequently depressed cardiac output and arterial pressure, caused pathologic elevations in LAP and resulted in abnormal (heart failure) function curves. The CVP was an unreliable and often misleading guide to volume therapy. When citrated blood was effective in raising cardiac output and arterial pressure, larger volumes were required than if noncitrated blood was employed. The administration of calcium chloride before or after transfusion did not always prevent citrate intoxication, although simultaneous administration was always effective.