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Our study compares deglutition between a group who had undergone total esophagopharyngolaryngectomy and a group who had esophagectomy and partial pharyngectomy with preserved larynx, after reconstruction of the upper digestive tract with pedicled colon interposition. In four patients the laryngeal structures could be preserved (three caustic burns and one proximal esophageal tumor). Six patients underwent a total laryngopharyngectomy for large pharyngeal tumors. Swallowing was assessed by a questionnaire, clinical examination, and videofluoroscopy. All patients had normal intake of semisolid foods and fluids. All patients but three experienced some feeling of "narrowing" of the tract: four at the level of the hypopharynx, two at the oropharyngeal level, one at the oral level. In the laryngectomy group, solid food caused some degree of delayed swallowing in three patients. Dumping occurred in one case out of the nonlaryngectomy group. On clinical examination a tense motility in all laryngectomy patients appeared, food remnants in five and repeated swallowing movements in four. The videofluoroscopy confirmed repeated swallowing movements and presence of residual food in the oral cavity. Temporal stagnation occurred at the anastomosis site in all patients and in two patients at a place of colon redundancy. Colon interposition is a reliable reconstruction and gives the possibility of a good functional outcome. Although preservation of the larynx facilitates swallowing even in this reconstructive procedure, it may be better to perform a total laryngopharyngectomy and colon interposition in oncological cases where the pharyngeal remnant is borderline for primary closure.

Little is known on functional outcome after Ivor Lewis esophagectomy (ILE) with intrathoracic anastomosis.Patients who underwent ILE were identified from a prospective database. Clinicopathological data were retrieved and compared with functional outcome data based on patient self-assessment by a standard questionnaire. Predictive factors for selected functional complaints were identified with logistic regression analyses.Three hundred and twenty-two patients (80.4% male, mean age 62 years) were studied. Indications for surgery were adenocarcinoma (62.4%), squamous cell carcinoma (28%), and HG Barrett dysplasia (7%). Preoperative chemoradiation (CRT) was administered to 42.5% of patients. Anastomotic leakage occurred in 5.6% and was associated with higher age and diabetes mellitus. Functional symptoms identified were reflux (39%), delayed gastric emptying (37%), dumping (21.4%), and anastomotic stenosis (16%). In the multivariate models, anastomotic stenosis was associated with smaller stapler diameter and presence of esophagitis. Postoperative reflux was associated with higher BMI, whereas dumping was predicted by female gender and age. The quality of life questionnaires revealed a good general health status in 82% of the patients.Functional complaints after ILE consist of reflux, delayed gastric emptying, dumping, and dysphagia, and are affected by age, gender, BMI, diabetes mellitus, and stapler diameter.

Retroperitoneal liposarcoma (RLS) are rare, biologically heterogeneous tumors that present considerable challenges due to their size and deep location. As a consequence, the majority of patients with high grade RLS will develop locally recurrent disease following surgery, and this constitutes the cause of death in most patients. Here, we review current insights and controversies regarding histology, molecular biology, extent of surgery, (neo)adjuvant treatment, and systemic treatment including novel targeted agents in RLS.

Since the introduction of total mesorectal excision as the standard approach in mid and low rectal cancer, the incidence of local recurrence has sharply declined. Similar attention to surgical technique in colon cancer (CC) has resulted in the concept of complete mesocolic excision (CME), which consists of complete removal of the intact mesentery and high ligation of the vascular supply at its origin. Although renewed attention to meticulous surgical technique certainly has its merits, routine implementation of CME is currently unfounded. Firstly, in contrast to rectal cancer, local recurrence originating from an incompletely removed mesentery is rare in CC and usually a manifestation of systemic disease. Secondly, although CME may increase nodal counts and therefore staging accuracy, this is unlikely to affect survival since the observed relationship between nodal counts and outcome in CC is most probably not causal but confounded by a range of clinical variables. Thirdly, several lines of evidence suggest that metastasis to locoregional nodes occurs early and is a stochastic rather than a stepwise phenomenon in CC, in essence reflecting the tumor-host-metastasis relationship. Unsurprisingly, therefore, comparative studies in CC as well as in other digestive cancers have failed to demonstrate any survival benefit associated with extensive, additional or extra-mesenteric lymphadenectomy. Finally, routine implementation of CME may cause patient harm by longer operating times, major vascular damage and autonomic nerve injury. Therefore, data from randomized trials reporting relevant endpoints are required before CME can be recommended as a standard approach in CC surgery.

Background: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine. Methods: Circular smooth muscle strips were prepared from human large intestine; after incubation with [H-3]-choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied. Key Results: The non-selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX. Conclusions & Inferences: In human large intestinal circular muscle, the intracellular pathway of 5-HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT4 receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5-HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT4 receptor agonist in the large intestine.

Purpose Neoadjuvant chemoradiotherapy is used prior to surgery in curative treatment of esophageal cancer (EC). We evaluated the in-field control of this multimodal treatment by extraction of radiation dose parameters and determination of the spatial relation between tumor recurrence location(s) and radiation target volume (RTV). Methods and materials Treatment consisted of neoadjuvant chemotherapy (5-FU and cisplatin) and radiotherapy (36 Gy) followed by Ivor–Lewis esophagectomy. For patients with locoregional recurrence(s), image fusion was performed between radiotherapy planning CT and follow-up CT(s). A region-of-interest was contoured on the planning CT around each locoregional recurrence. Mean and maximum radiation doses were then extracted to classify recurrences as out-of-field, marginal or in-field. Results Eighty patients were included. The median follow-up duration was 19 months. Fifteen of 95 locoregional recurrences were detected in the RTV. These in-field relapses occurred in only 6 patients (7.8%) on 12 different anatomical locations. None of the patients with in-field failure had a pCR and all had concurrent distant failure on multiple anatomical sites. Conclusion Neoadjuvant chemoradiotherapy followed by Ivor–Lewis esophagectomy yields excellent in-field control, as only a clear minority (7.8%) of patients developed a relapse in the RTV. In-field recurrence is associated with widespread tumor dissemination and poor pathological response to neoadjuvant treatment.

Surgery is a discipline which profoundly affects human integrity. Therefore, there is an ethical and scientific imperative that surgical practice depends on the best possible trial-based evidence. Traditionally, the quality and quantity of clinical research have been lagging behind other disciplines in clinical medicine. However, recent collaborative initiatives, such as the IDEAL framework which tests surgical innovation, international registries, and quality assurance platforms, the development of modified randomized controlled trials and alternative trial designs as well as the impending reforms of the regulatory framework surrounding nonpharmaceutical interventions and devices offer significant and timely opportunities to enhance the relevance of clinical research in surgery. Here, we provide an overview of the current state of clinical research in surgery, identify possible obstacles, and discuss realistic and emerging solutions that have the potential to change the way surgical research is organized, funded, and translated to the patient's benefit.

To study the effects of preoperative radiochemotherapy (RCT) on the healing of colonic anastomosis, the rectosigmoid colon in male Wistar rats was irradiated up to an end dose of 41.6 Gy (RT) or sham-irradiated (SR). During the last 5 days of the irradiation schedule, 5-fluorouracil (5-FU) was administered intraperitoneally in either a high dose (20 mg/kg, chemotherapy-high dose [CH]) or a low dose (10 mg/kg, chemotherapy-low dose [CL]). Animals were randomly arranged into six groups: group I, control (SR + saline intraperitoneally); group II, RT only; group III, SR + CL; group IV, RT + CL; group V, SR + CH; group VI, RT + CH. Four days after RCT, a side-to-side anastomosis was constructed between the irradiated rectosigmoid and the nonirradiated caecum. Animals were killed 10 days postoperatively. No significant differences were found in the anastomotic bursting pressure or the bursting wall tension. In group VI, mitoses were less (P < 0.01) and mucosal ulceration was more (P = 0.03) pronounced compared to group I. Sclerotic arteries were seen in all irradiated groups and in animals that received high-dose 5-FU alone. 5-FU administration in high or low dose, with or without RT, induced more inflammation in the submucosa compared to controls (P < 0.05). Conclusively, RCT has no detrimental effect on the mechanical strength of colonic anastomosis in this rat model. However, RCT with high-dose 5-FU induces more histological alterations at the anastomotic site.

Einleitung: Zwei verschiedene Bander zur laparoskopischen Anlage am Magen wurden an 2 Patientenkollektiven im Hinblick auf peri- und postoperative Komplikationen und den Erfolg der Gewichtsreduktion untersucht. Patienten und Methoden: 120 Patienten wurden behandelt und prospektiv dokumentiert. In der Lernphase (LP) handelte es sich um 50 Falle des anpassbaren Silicon Gastric Bandings (ASGB, Bioenterics®). Das Band wurde nach der Technik von Belachew im Bereich der distalen Magenkardia angelegt. In Gruppe I (n = 29) wurde das gleiche Band in der Technik von Forsell angelegt. In Gruppe II (n = 41) wurde das Schwedische anpassbare Gastric Banding (SAGB, Obtech®) nach der Methode von Forsell angelegt. Als Indikation zur Operation wurde ein Body Mass Index (BMI) uber 35 sowie sekundare Komplikationen der Obesitas und gescheiterte konservative Gewichtsreduktionstherapien angesehen. 30 Patienten waren mannlich, 90 weiblich mit einem gemittelten Alter von 37 Jahren (18–60). Resultate: In der LP mussten 8 Patienten wegen eines Bandslipping und/oder Pouchdilatation reoperiert werden (16 %), in Gruppe I 6 (19 %) und in Gruppe II 1 (3 %) (p = 0,02, II vs I). Der gemittelte Krankenhausaufenthalt betrug 3,7 ± 0,5, 3,4 ± 0,8 und 3,3 ± 0,4 Tage in der LP, I und II respektive. Langzeitresultate: Nach einer Beobachtungszeit von gemittelt 24 Monaten (19–42) betrug der Gewichtsverlust 8,4 kg nach 3, 13,9 kg nach 6, 22,1 kg nach 12 Monaten und 27,8 kg nach 18 Monaten in der LP. In Gruppe I nach gemittelt 14 Monaten (12–19) 10,3 kg nach 3, 18,7 kg nach 6, 24,8 kg nach 12 Monaten. In Gruppe II nach gemittelt 10 Monaten (6–16) betrug die Gewichtsreduktion 7,9 kg nach 3 und 19,4 kg nach 6 Monaten. Schlussfolgerung: In unserer Erfahrung erscheint die Anlage des SAGB leicht durchzufuhren und weniger komplikationsanfallig zu sein im Hinblick auf Dysphagie und Slipping des Bandes vermutlich wegen der guten Fixation des Bandes auf Grund seiner Breite. Eine prospektiv randomisierte Studie ist erforderlich.

Background: Laproscopic single-site surgery is the natural evolution of minimally invasive surgery. Methods: A 70-year-old male was planned for a resection of a gastric GIST (gastrointestinal stromal tumor). A Triport® trocar (Olympus, Aartselaar, Belgium) was placed through a 2-cm periumbilical incision. Besides the placement of a Nathanson liver retractor in the subxiphoidal position, no additional trocars had to be added. The partial gastrectomy was carried out by using clinical prototypes of double-bended intruments and of a “goose neck” videolaparoscope, all specially designed for single-port surgery. Results: Total operative time was 140 minutes, and estimated blood loss was 10 mL. No intra- or postoperative complications occurred. Hospital stay was 4 days. Final pathology revealed the complete resection of a GIST tumor of gastric origin. Conclusions: We have demonstrated the technical feasibility and described the detailed surgical technique of laparoendoscopic single-site surgery gastric ...

Background Surgical treatment of intra-abdominal cancer is often followed by local recurrence. In a subgroup of patients, local recurrence is the sole site of disease, reflecting biologically low-grade malignancy. These patients might, therefore, benefit from local treatment. Recently, debulking surgery followed by hyperthermic chemoperfusion has been proposed in the treatment of locally advanced or recurrent intra-abdominal cancer. This paper reviews the rationale and assesses the currently accepted indications for and results of this novel treatment. Methods A systematic web-based literature review was performed. Information was also retrieved from handbooks, congress abstracts and ongoing clinical trials. Results A growing body of experimental evidence supports the use of hyperthermia combined with chemotherapy as an adjunct to cytoreductive surgery. Randomized clinical trials are available to support its use in the treatment and prevention of peritoneal carcinomatosis following resection of pathological tumour stage pT3 or pT4 gastric cancer; several other phase III trials are ongoing. Numerous phase I and II trials have reported good results for various other indications, with acceptable morbidity and mortality rates. Case mix, limited patient numbers and absence of a standardized technique are, however, a drawback in many of these series. Conclusion For a subgroup of patients with peritoneal cancer without distant disease, debulking surgery followed by hyperthermic chemoperfusion may offer a chance of cure or palliation in this otherwise untreatable condition. This novel therapy should, however, be considered experimental until further results from ongoing phase III trials become available.

Despite the improvements in preoperative staging, surgical technique and adjuvant therapy, local recurrence remains a significant problem in rectal cancer surgery. Several patient- and tumour-related risk factors for the development of local recurrence have been identified and are being addressed by regimens of pre- or postoperative adjuvant therapy. Total mesorectal excision (TME) recently has been shown to result in a low recurrence rate even without the use of adjuvant therapy. Nevertheless, conclusive evidence in the form of a prospective randomized trial is to date not available. This paper describes the technique of TME and reviews the clinical and pathological data supporting its use in rectal cancer surgery.

Mucinous colorectal carcinoma represents a subtype of colorectal carcinoma (CRC), which is characterized by abundant amount of extracellular mucin. We reviewed the molecular, histological and clinical aspects of mucinous CRC as compared to the non-mucinous type.A systematic web-based research was performed using Web of Knowledge. The combination of the Boolean search terms "COLO" AND "MUC" was used. The literature was searched until July 2013.Patients with mucinous CRC have distinct clinical and pathological features. Mucinous CRC tends to occur in younger patients, are often seen in the proximal colon, are more diagnosed at an advanced stage and are more frequently associated with hereditary non-polyposis colorectal cancer (HNPCC) and young-age sporadic colorectal cancer. The prognostic significance of mucinous differentiation remains uncertain; some studies have shown a poor response to oxaliplatin and/or irinotecan based chemotherapy. Mucinous CRC is associated with a higher expression of MUC2 and MUC5AC, but a lower expression of MUC1. The differential expression of mucins has been related to altered risk of metastasis and death. Recently, mucins have been used as targets for molecular therapy and as a source of immune therapy. Mucinous differentiation is associated with other specific genetic and molecular features such as increased BRAF mutation rate and microsatellite instability.Mucinous CRC is a distinct clinical, pathological, and molecular entity. The implications of mucinous differentiation for treatment response and outcome are not fully elucidated, but the available data suggest an adverse effect. The use of mucins as immunotargets may show therapeutic promise for mucinous CRC.

A strong pharmacokinetic rational exists for the use of (Hyperthermic) Intraperitoneal Perioperative Chemotherapy in peritoneal carcinomatosis. However, controversy remains regarding the optimal treatment strategies. Paclitaxel is believed to be a good compound for IPEC treatment because of its favourable pharmacokinetic properties.Rat experiments were set up to gain insight in PTX's pharmacokinetics and pharmacodynamics after IPEC treatment with Taxol®. Afterwards a Pharmacokinetic-Pharmacodynamic model was developed, that concurrently describes plasma and tumour exposure post IPEC dosing. Moreover, the developed model adequately describes the time-course of tumour apoptosis as well as the treatment effect on tumour volume.We show that the complex absorption processes underlying PTX absorption from the peritoneal cavity post IPEC dosing, give rise to a markedly non-linear dose response relationship. Furthermore, we show that, in order to optimize treatment efficiency whilst concurrently minimizing the possibility of systemic toxicities, lowering the dose and extending exposure to the cytotoxic solution is the way forward.Based on the close resemblance between tumour exposure in our animal model and tumour exposure in patients treated under similar conditions, we hypothesise that, according to our findings in the rat, in the treatment of PC using IPEC administration of PTX, less is truly more.

Background The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. Methods Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. Results Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6–66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78–284) and 96 (86–284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. Conclusion The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10–15 million inhabitants would be ideal.

The recent introduction of biological anticancer therapy has renewed the interest in functional imaging of tumor-associated angiogenesis (TAA) as a tool to monitor early therapy response. The present study evaluated imaging of TAA using P1227, a novel, small molecular magnetic resonance imaging (MRI) probe targeting alpha(v)beta(3) integrin. HT29 human colorectal cancers were grown in athymic mice. Dynamic MRI was performed using a three-dimensional VIBE sequence up to 110 min after injection of P1227 or gadolinium-tetraazacyclododecane tetraacetic acid (Gd-DOTA). Specificity was assessed by using P1227 1 h after intravenous administration of the alpha(v)beta(3) inhibitor cilengitide. Regions of interest were drawn encompassing the tumor rim and normal muscle. Imaging data were compared with microvessel density and alpha(v)beta(3) expression. Using P1227, specific enhancement of the angiogenic tumor rim, but not of normal muscle, was observed, whereas Gd-DOTA enhanced tumor and normal muscle. After administering cilengitide, enhancement with P1227, but not with DOTA, was significantly suppressed during the first 20 min. When using P1227, a significant correlation was observed between normalized enhancement of the tumor rim and immunohistochemical alpha(v)beta(3) integrin expression. Molecular MRI using a small monogadolinated tracer targeting alpha(v)beta(3) integrin and moderate magnetic field strength holds promise in assessing colorectal TAA.

Intraperitoneal (IP) administration of nano-sized delivery vehicles containing small interfering RNA (siRNA) has recently gained attention as an alternative route for the efficient treatment of peritoneal carcinomatosis. The colloidal stability of nanomatter following IP administration has, however, not been thoroughly investigated yet. Here, enabled by advanced microscopy methods such as single particle tracking and fluorescence correlation spectroscopy, we follow the aggregation and cargo release of nano-scaled systems directly in peritoneal fluids from healthy mice and ascites fluid from a patient diagnosed with peritoneal carcinomatosis. The colloidal stability in the peritoneal fluids was systematically studied as a function of the charge (positive or negative) and poly(ethylene glycol) (PEG) degree of liposomes and polystyrene nanoparticles, and compared to human serum. Our data demonstrate strong aggregation of cationic and anionic nanoparticles in the peritoneal fluids, while only slight aggregation was observed for the PEGylated ones. PEGylated liposomes, however, lead to a fast and premature release of siRNA cargo in the peritoneal fluids. Based on our observations, we reflect on how to tailor improved delivery systems for IP therapy.

Background: Gastric banding for the treatment of morbid obesity is one of the means to treat the disease effectively. Based on the experience of more than 1,000 vertical gastroplasties and gastric bypass operations and more than 1,000 gastric banding operations at two different institutions, this study aims to evaluate a cohort of 625 patients receiving a low-pressure Swedish adjustable gastric band with major emphasis on secondary complications within the 1- to 3-year follow-up period. Patients and Methods: Between January 1998 and October 2001, 126 men and 499 women received Swedish gastric banding via a laparoscopic approach. The mean age of the patients was 36.6 years and their mean body mass index 41 kg/m2. 61.8% had degenerative osteoarticular disease, 25.8% hypertension, and 7.2% diabetes. Results: After a mean follow-up of 19.5 months the incidence of hypertension was reduced from 26 to 18.6% (p

In selected patients with colorectal peritoneal carcinomatosis (PC), cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) may improve survival. We aimed to assess whether neoadjuvant chemotherapy with or without bevacizumab is indicated in this patient population. Colorectal PC patients were treated with CRS and HIPEC using oxaliplatin (200–460 mg/m2) or mitomycin C (35 mg/m2). Postoperative outcome and long-term survival were prospectively recorded. The impact of clinical variables on overall survival (OS) was assessed using univariate and Cox multivariate analysis. Between October 2002 and May 2012, 166 patients were treated with CRS and HIPEC. Neoadjuvant chemotherapy alone was administered to 21 % and neoadjuvant chemotherapy with bevacizumab to 16 % of patients. Postoperative mortality and major morbidity were 2.4 and 35 %, respectively. Half of the patients received adjuvant chemotherapy. After a median follow-up of 18 months, OS was 27 months (95 % confidence interval 20.8–33.2). On univariate analysis, OS was associated with extent of disease (P

The development of suitable animal models is essential to experimental research on intraperitoneal chemotherapy (IPC). This review of the English literature (MEDLINE) presents a detailed analysis of current animal models and gives recommendations for future experimental research. Special consideration should be given to cytotoxic drug dose and concentration, tumor models, and outcome parameters.

Purpose: The objective of this experiment is to establish a continuous postmortem circulation in the vascular system of porcine lungs and to evaluate the pulmonary distribution of the perfusate. This research is performed in the bigger scope of a revascularization project of Thiel embalmed specimens. This technique enables teaching anatomy, practicing surgical procedures and doing research under lifelike circumstances. Methods: After cannulation of the pulmonary trunk and the left atrium, the vascular system was flushed with paraffinum perliquidum (PP) through a heart-lung machine. A continuous circulation was then established using red PP, during which perfusion parameters were measured. The distribution of contrast-containing PP in the pulmonary circulation was visualized on computed tomography. Finally, the amount of leak from the vascular system was calculated. Results: A reperfusion of the vascular system was initiated for 37 min. The flow rate ranged between 80 and 130 ml/min throughout the experiment with acceptable perfusion pressures (range: 37-78 mm Hg). Computed tomography imaging and 3D reconstruction revealed a diffuse vascular distribution of PP and a decreasing vascularization ratio in cranial direction. A self-limiting leak (i.e. 66.8% of the circulating volume) towards the tracheobronchial tree due to vessel rupture was also measured. Conclusions: PP enables circulation in an isolated porcine lung model with an acceptable pressure-flow relationship resulting in an excellent recruitment of the vascular system. Despite these promising results, rupture of vessel walls may cause leaks. Further exploration of the perfusion capacities of PP in other organs is necessary. Eventually, this could lead to the development of reperfused Thiel embalmed human bodies, which have several applications.

Background Surgery-induced acceleration of tumour growth has been observed since several centuries. Methods We reviewed recent insights from in vitro data, animal experimentation, and clinical studies on how surgery-induced wound healing or resection of a primary cancer influences the tumour–host ecosystem in patients harbouring minimal residual or metastatic disease. Results Most of the growth factors, chemokines, and cytokines orchestrating surgical wound healing promote tumour growth, invasion, or angiogenesis. In addition, resection of a primary tumour may accelerate synchronous metastatic growth. In the clinical setting, indirect evidence supports the relevance of the above findings. Randomized clinical trials are underway comparing resection versus observation in metastatic breast and colon cancer with asymptomatic primary tumours. Conclusions In depth knowledge of how surgical intervention alters the tumour–host-metastasis communicating ecosystems could have important implications for clinical decision making in patients with synchronous metastatic disease and for the design and timing of multimodality treatment strategies.

Background : Preoperative radiotherapy (RT) decreases local recurrence rate and improves survival in stage II and III rectal cancer patients. The combination of chemotherapy with RT has a sound radiobiological rationale, and phase II trials of combined chemoradiation (CRT) have shown promising activity in rectal cancer. Objectives : To compare preoperative RT with preoperative CRT in patients with resectable stage II and III rectal cancer. Search methods : We searched the Cochrane Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until June 2012. A manual search was performed of Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys and the proceedings of ASTRO, ECCO and ASCO from 1990 until June 2012. Selection criteria : Relevant studies randomized resectable stage II or III rectal cancer patients to at least one arm of preoperative RT alone or at least one arm of preoperative CRT. Data collection and analysis : Primary outcome parameters included overall survival (OS) at 5 years and local recurrence (LR) rate at 5 years. Secondary outcome parameters included disease free survival (DFS) at 5 years, metastasis rate, pathological complete response rate, clinical response rate, sphincter preservation rate, acute toxicity, postoperative mortality and morbidity, and anastomotic leak rate. Outcome parameters were summarized using the Odds Ratio (OR) and associated 95% confidence interval (CI) using the fixed effects model. Main results : Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years. Authors' conclusions : Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials.

Intraperitoneal (IP) chemotherapy is an effective way of treating peritoneal carcinomatosis of colorectal origin after complete cytoreduction. Although IP therapy has been already performed for many years, no standardized treatment design has been developed in terms of schedule, residence time, drug, or carrier solution. Because of the fast clearance of the conventional intravenous (IV) drug delivery systems used for IP therapy, a lot of research is performed to optimize IP drug delivery and extend the residence time of the cytotoxic agent in the peritoneal cavity. This paper reviews the recent advances made in drug delivery systems for IP chemotherapy, discussing the use of microparticles, nanoparticles, liposomes, micelles, implants, and injectable depots for IP delivery.

The literature dealing with abdominal wall surgery is often flawed due to lack of adherence to accepted reporting standards and statistical methodology.The EuraHS Working Group (European Registry of Abdominal Wall Hernias) organised a consensus meeting of surgical experts and researchers with an interest in abdominal wall surgery, including a statistician, the editors of the journal Hernia and scientists experienced in meta-analysis. Detailed discussions took place to identify the basic ground rules necessary to improve the quality of research reports related to abdominal wall reconstruction.A list of recommendations was formulated including more general issues on the scientific methodology and statistical approach. Standards and statements are available, each depending on the type of study that is being reported: the CONSORT statement for the Randomised Controlled Trials, the TREND statement for non randomised interventional studies, the STROBE statement for observational studies, the STARLITE statement for literature searches, the MOOSE statement for metaanalyses of observational studies and the PRISMA statement for systematic reviews and meta-analyses. A number of recommendations were made, including the use of previously published standard definitions and classifications relating to hernia variables and treatment; the use of the validated Clavien-Dindo classification to report complications in hernia surgery; the use of "time-to-event analysis" to report data on "freedom-of-recurrence" rather than the use of recurrence rates, because it is more sensitive and accounts for the patients that are lost to follow-up compared with other reporting methods.A set of recommendations for reporting outcome results of abdominal wall surgery was formulated as guidance for researchers. It is anticipated that the use of these recommendations will increase the quality and meaning of abdominal wall surgery research.

Background mRNA levels of members of the Vascular Endothelial Growth Factor family (VEGF-A, -B, -C, -D, Placental Growth Factor/PlGF) have been investigated as tissue-based markers of colon cancer. These studies, which used specimens obtained by surgical resection or colonoscopic biopsy, yielded contradictory results. We studied the effect of the sampling method on the marker accuracy of VEGF family members. Methods Comparative RT-qPCR analysis was performed on healthy colon and colon carcinoma samples obtained by biopsy (n = 38) or resection (n = 39) to measure mRNA expression levels of individual VEGF family members. mRNA levels of genes encoding the eicosanoid enzymes cyclooxygenase 2 (COX2) and 5-lipoxygenase (5-LOX) and of genes encoding the hypoxia markers glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX) were included as markers for cellular stress and hypoxia. Results Expression levels of COX2, 5-LOX, GLUT-1 and CAIX revealed the occurrence in healthy colon resection samples of hypoxic cellular stress and a concurrent increment of basal expression levels of VEGF family members. This increment abolished differential expression of VEGF-B and VEGF-C in matched carcinoma resection samples and created a surgery-induced underexpression of VEGF-D. VEGF-A and PlGF showed strong overexpression in carcinoma samples regardless of the sampling method. Conclusions Sampling-induced hypoxia in resection samples but not in biopsy samples affects the marker-reliability of VEGF family members. Therefore, biopsy samples provide a more accurate report on VEGF family mRNA levels. Furthermore, this limited expression analysis proposes VEGF-A and PlGF as reliable, sampling procedure insensitive mRNA-markers for molecular diagnosis of colon cancer.

The dramatic improvement in local control of rectal cancer observed during the last decades is to be attributed to attention to surgical technique and to the introduction of neoadjuvant therapy regimens. Nevertheless, systemic relapse remains frequent and is currently insufficiently addressed. Intensification of neoadjuvant therapy by incorporating chemotherapy with or without targeted agents before the start of (chemo)radiation or during the waiting period to surgery may present an opportunity to improve overall survival. An increasing number of patients can nowadays undergo sphincter preserving surgery. In selected patients, local excision or even a “wait and see” approach may be feasible following active neoadjuvant therapy. Molecular and genetic biomarkers as well as innovative imaging techniques may in the future allow better selection of patients for this treatment option. Controversy persists concerning the selection of patients for adjuvant chemotherapy and/or targeted therapy after neoadjuvant regimens. The currently available evidence suggests that in complete pathological responders long-term outcome is excellent and adjuvant therapy may be omitted. The results of ongoing trials will help to establish the ideal tailored approach in resectable rectal cancer.

Purpose Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. Patients and Methods A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Results Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. Conclusion The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.

Hyperthermic intraperitoneal chemoperfusion (HIPEC) with oxaliplatin is increasingly used in patients with carcinomatosis from colorectal cancer. For reasons of chemical stability, oxaliplatin can only be administered in a dextrose (D5%) solution, and this causes peroperative glucose and electrolyte shifts. Here, we examined the influence of perfusion temperature on glucose and electrolyte transport, metabolic shifts, and surgical morbidity.Patients with carcinomatosis underwent cytoreduction and HIPEC using oxaliplatin (460 mg/m(2) in D5%, open abdomen) during 30 min at 39°-41 °C. Intraperitoneal (IP) temperature was measured at three locations using thermocouple probes. The area under the temperature versus time curve (AUCt) was calculated using the trapezoid rule. The influence of perfusion temperature on surgical outcome was assessed using linear regression models and the Mann Whitney U test where appropriate.From July 2005 until March 2011, 145 procedures were performed in 139 patients with a diagnosis of CRC (70%), pseudomyxoma peritonei (11%), ovarian cancer (10%), or miscellaneous peritoneal malignancies (9%). Postoperative mortality and major morbidity were 1.4% and 26%, respectively. Higher perfusion temperature was related to more pronounced changes in serum glucose (P = 0.058), sodium (P = 0.017), and lactate (P0.001). The median duration of nasogastric drainage was 5 days, and this was unrelated to perfusion temperature (P = 0.76). The GI fistula rate and reoperation rate were 12.4% and 16.5% respectively; neither was related to perfusion temperature.In patients undergoing HIPEC with oxaliplatin, perfusion temperature exacerbates peroperative metabolic shifts but does not affect surgical outcome.

Cancer is rapidly becoming the worldwide leading cause of premature death. Iconographic techniques have traditionally provided information on tumor anatomy. The recent introduction of functional and molecular imaging techniques allows probing tumor physiology and biology in addition to mere anatomical description. In addition to the research implications, these novel imaging techniques offer early response assessment and target visualization which, in the era of personalized medicine, may offer significant advances in cancer therapy. Here, we provide an overview of the most important developments in cancer imaging, with a focus on the clinical applications.

BACKGROUND: The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and F-18-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions. METHODS: A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUVmax) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (K-trans) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index. RESULTS: Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P = 0.002) and 40% (P = 0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in K-trans (P = 0.019). In the group of radiological responders, the median baseline SUVmax was 3.77 (IQR: 2.88-5.60) compared with 7.20 (IQR: 4.67-8.73) in nonresponders (P = 0.021). A higher follow-up SUVmax was correlated with worse PFS (P = 0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P = 0.016). CONCLUSION: High relative decrease in K-trans, low follow-up SUVmax and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery. British Journal of Cancer (2012) 106, 1926-1933. doi:10.1038/bjc.2012.184 www.bjcancer.com Published online 17 May 2012 (C) 2012 Cancer Research UK

Up to 25% of patients with metastatic colorectal cancer (CRC) present with peritoneal carcinomatosis (PC) as the only site of metastases. Complete cytoreductive surgery (CCRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) aims for locoregional disease control and long-term survival. Oxaliplatin is effective for treating advanced CRC. This study assesses the safety and efficacy of CCRS with HIPEC with oxaliplatin for patients with PC of CRC. A Belgian prospective multicenter registry was performed to monitor perioperative morbidity and assess mortality, disease-free survival (DFS), and overall survival (OS). Forty-eight consecutive patients underwent CCRS (R0/1) with HIPEC (male/female ratio 17/31, median age 60 years, range 24–76 years). Median PC index was 11 (range 1–22). Median operation time was 460 (range 125–840) min, with a median blood loss of 475 (range 2–6,000) ml. Thirty-day mortality was 0%. Complication rate (any grade) was 52.1%. Anastomotic leakage occurred in 10.4% of patients, bleeding in 6.3%, and bowel perforation in 2.1%. Median hospital stay was 20 (range 5–65) days. At median follow-up of 22.7 (range 3.2–55.7) months, OS was 97.9% [95% confidence interval (CI) 86.1–99.7] at 1 year and 88.7% (95% CI 73.6–95.4) at 2 years. DFS at 1 year was 65.8% (95% CI 52.3–76.2) and 45.5% (95% CI 34.3–55.9) at 2 years. Median time until recurrence was 19.8 months (95% CI 12–upper limit not defined). Only after dichotomizing PC index was a significant difference in OS found between low and high PC index. CCRS followed by HIPEC with oxaliplatin for PC from CRC can be implemented with acceptable morbidity. Long-term DFS and OS can be achieved in selected patients.

Spoiled gradient echo pulse (SPGRE) sequences are commonly used in dynamic contrast-enhanced MRI (DCE-MRI) studies to measure the contrast agent concentration in a tissue of interest over time. However, due to improper tuning of the SPGRE parameters, concentration uncertainty can be very high, even at high signal-to-noise ratio in the MR measurement. In this work, an optimization procedure is proposed for selecting the optimal value of the SPGRE-flip angle FA(opt), given the expected concentration range. The optimization condition ensures that every concentration in the assumed range has the lowest possible uncertainty. By decoupling the R(1)- and R*(2)-effects caused by the presence of the contrast agent, a contour plot has been generated from which FA(opt) can be read off for any study design. Investigation of ten recent DCE-MRI studies showed that improper flip angle selection unnecessarily increases the concentration uncertainty, up to 742% and 72% on average for the typical physiological concentration ranges of 0-2 mM in tumour tissue and 0-10 mM in blood, respectively. Simulations show that the reduced noise levels on the concentration curves, observed at the optimal flip angle, effectively increase the precision of the kinetic parameters estimates (up to 82% for K(trans), 82% for ν(e) and 92% for ν(p) in the case of an individually measured arterial input function (AIF), up to 53% for K(trans), 59% for ν(e) and 67% for ν(p) in the case of a standard AIF). In vivo experiments confirm the potential of flip angle optimization to increase the reproducibility of the kinetic parameter estimates.

Objective: Computed tomography (CT) perfusion studies can provide valuable information regarding tumor vascularization. We report on a study assessing CT perfusion characteristics in the normal pancreas and in patients with pancreatic adenocarcinoma. Methods: Twenty healthy subjects and 20 patients with histologically confirmed pancreatic adenocarcinoma were included in the study after written informed consent and approval by our institutional review board. All subjects underwent perfusion CT imaging of the pancreas using 128-slice dual-source CT. The scanning sequence included 18 scans. Parametric maps of blood volume (BV), blood flow (BF), and permeability surface area product (PS) were generated and compared with density measurements. Results: In normal pancreas, no significant difference in perfusion values was observed between head, body, and tail of the pancreas. Mean organ values were 76.76 (SD, 15.6) mL/100 g/min, 15.80 (SD, 2.40) mL/100 g, and 27.74 (SD, 16.8) mL/100 g/min for BF, BV, and PS, respectively. Compared with the normal pancreas, a 60% reduction in BF and BV was observed in the tumor tissue. Perfusion values gradually increased toward the tumor rim. Necrotic tumor areas were identified in 25% of patients. No significant differences were observed when comparing normal pancreas and healthy pancreatic tissue in adenocarcinoma patients. Conclusions: The feasibility of whole-tumor perfusion imaging using 128-slice CT was demonstrated in patients with pancreatic adenocarcinoma. Perfusion CT provides additional information compared with image assessment based on density measurements (Hounsfield units) and allows noninvasive assessment of vascularization in the tumor tissue.

Background. The abdominal compartment syndrome (ACS) refers to organ dysfunction that may occur as a result of increased intra-abdominal pressure (IAP). Successful management may require abdominal decompression and temporary abdominal closure (TAC). The aim of this study was to analyze the characteristics of patients requiring abdominal decompression, to describe the methods used for TAC, and to study the outcome of these patients. Methods. A series of critically ill patients who required abdominal decompression for ACS between January 2000 and March 2007 were reviewed retrospectively. Age, gender, severity of organ dysfunction before decompression and the cause of ACS as well as the type of abdominal closure system and length of ICU-stay were recorded. Definitive abdominal closure and in-hospital mortality were the main outcome parameters. Results. Eighteen patients with primary ACS and 6 with secondary ACS required decompressive laparotomy. Patients ages ranged from 18 to 89 years (mean 50.7). The median preoperative IAP was 26mmHg, and IAP decreased to 13mmHg after decompressive laparotomy. Organ function, as quantified by the SOFA scoring system, improved significantly after the intervention. Eight patients had immediate primary fascial closure after the decompressive procedure and 16 patients required TAC. The majority of the survivors underwent planned ventral hernia repair at a later stage. The mean length of stay in the ICU was 23 (+/- 16) days. Overall, fifteen patients survived (63%). Conclusions. Decompressive laparotomy was effective in reducing IAP and was associated with an improvement in organ function. In most of the patients, the abdomen could not be closed after decompression, and fascial repair was delayed.

The objective of this study was to study the long-term outcome of adjustable gastric banding in the treatment of morbid obesity. In Europe, the preference for gastric band has declined in favor of Roux-Y-gastric bypass. This is a follow-up of a prospective study on a large cohort of patients after laparoscopic gastric banding (LAGB) for morbid obesity. Complete data were collected on 656 patients (88%) from a cohort of 745 patients. After a median follow-up of 95 months (range 60–155), the mean BMI dropped from 41.0 ± 7.3 to 33.2 ± 7.1 kg/m2, with a 46.2 ± 36.5% excess weight loss (EWL). A more than 50% EWL was achieved in 44% of patients. The band was still in place in 77.1% of patients; conversion to gastric bypass after band removal was carried out in 98 (14.9%) patients, while a simple removal was done in only 52 (7.9%) patients. Band removal was more likely in women and patients with a higher BMI. After LAGB, band removal was necessary for complications or insufficient weight loss in 24% of patients. Nearly half of the patients achieved a more than 50% EWL, but in 88%, a more than 10% EWL was observed. LAGB can achieve an acceptable weight loss in some patients, but the failure in one out of four patients does not allow proposing it as a first-line option for the treatment of obesity.

Morbidity after converting failed laparoscopic adjustable gastric banding (LAGB) to laparoscopic Roux-en-Y gastric bypass (LRYGB) is three- to fivefold higher than after primary LRYGB. Allowing a time interval between band removal and actual gastric bypass might reduce local inflammation and reduce morbidity. This study is a retrospective single-center study of patients who needed conversion to LRYGB because of failed LAGB. Outcomes after conversion of LAGB to LRYGB in one or two steps were compared. Between October 2008 and June 2010, 23 patients had a conversion in one step (group A) while, in 14 patients, the conversion was carried out at least 2 months after band removal (group B). The mean duration of surgery in group A was 150 ± 39 min while it took 181 ± 39 min to complete both steps in group B (p = 0.02). Length of stay in group A was 3 (3–8) days, but was 5 (4–8) days for the two steps in group B (p = 0.004). During a follow-up of 6–23 months, one pulmonary embolism, one epigastric artery bleeding, and three anastomotic strictures occurred in group A, while no complications were observed in group B. The BMI dropped from 41.4 ± 6.7 to 28.7 ± 10.8 kg/m2 in group A and from 43.8 ± 5.8 to 35.3 ± 7.55 kg/m2 in group B. Operating time and hospital stay are increased when conversion is performed in two steps, but, in this small series, this strategy decreased morbidity and more specifically the rate of anastomotic strictures.

Purpose: To investigate the accuracy of a method neglecting T*(2)-relaxation, for the conversion of spoiled gradient echo pulse sequence signal intensity to contrast agent (CA) concentration, in dynamic contrast enhanced MRI studies. In addition a new closed form conversion expression is proposed that accounts for a first order approximation of T*(2)-relaxation. Materials and Methods: The accuracy of both conversion methods is compared theoretically by means of simulations for four pulse sequences from literature. Both methods are tested in vivo against the numerical conversion method for measuring the arterial input function in mice. Results: Simulations show that the T*(2)-neglecting method underestimates typical tissue CA concentrations (0 mM to 2 mM) up to 6%, while the errors for arterial concentrations (0 mM to 10 mM) range up to 43%. The results from our first order method are numerically indistinguishable from the simulation input values in tumor tissue, while for arterial concentrations the error is reduced up to a factor 10. In vivo, peak Gd-DOTA concentration is underestimated up to 14% with the T*(2-)neglecting method and up to 0.9% with our first order method. Conclusion: Our conversion method reduces the underestimation of CA concentration severely in a broad physiological concentration range and is easy to perform in any clinical setting.

The aim of this study was to evaluate the usefulness of visual and semiquantitative [¹⁸F]fluorodeoxy-glucose (FDG) positron emission tomography-computed tomography (PET-CT) data for the diagnosis of peri-anastomotic colorectal cancer recurrence, taking into account the time period between surgery and [¹⁸F]FDG PET-CT scanning.The study population consisted of 70 patients who had prior preoperative radiochemotherapy and surgical resection of the primary tumor and who underwent whole body [¹⁸F]FDG PET-CT scanning for the detection of recurrent disease. Visual and semiquantitative (SUV(max)) analysis of [¹⁸F]FDG uptake at the peri-anastomosis was performed. The final diagnosis was based on pathological proof or clinical and/or imaging follow-up data.On visual reading, 27 patients exhibited increased [¹⁸F]FDG uptake at the peri-anastomosis. Of these, 11 (41%) patients had a local tumor recurrence and 16 (59%) had no recurrent tumor. Among the 43 patients without increased [¹⁸F]FDG uptake at the peri-anastomosis, none had local tumor recurrence. On semiquantitation, SUV(max) in patients with and without a local recurrence overlapped. However, when the time period between surgery and [¹⁸F]FDG PET-CT scanning was taken into account, overlap of SUV(max) was mainly observed within a postoperative period of ≤12 months; thereafter, a threshold SUV(max) of 3.2 discriminated between benign and malignant lesions in all but one patient.In our series, visually increased [¹⁸F]FDG uptake at the peri-anastomosis was 100% sensitive but non-specific (73% specificity) for the diagnosis of local tumor recurrence. On the other hand, normal [¹⁸F]FDG uptake at the peri-anastomosis precluded a local tumor recurrence (a negative predictive value of 100%). In addition, semiquantitative (SUV(max)) analysis of [¹⁸F]FDG uptake at the peri-anastomosis may increase specificity (up to 97%), while preserving maximum sensitivity, if the postoperative period is12 months.

Dynamic contrast enhanced MRI and pharmacokinetic modelling provide a powerful tool for tumour diagnosis and treatment evaluation. However, several studies show low reproducibility of the technique and poor precision of the transendothelial transfer constant K trans. This work proposes a theoretical framework describing how finite signal-noise-ratio (SNR) in the MR images is propagated throughout the measurement protocol to uncertainty on the kinetic parameter estimates. After deriving a distribution for the contrast agent concentration, a maximum likelihood estimator (MLM) is proposed that exhibits Cramer–Rao lower bounds (CRLB). An analytical expression is derived for the CRLB that can be used to determine confidence intervals for kinetic parameters and to investigate the influence of protocol parameters as scan time and temporal resolution on K trans-precision. Ktrans-uncertainty can be reduced up to 30% by using MLM in comparison with least square estimator. Ktrans-precision is proportional to the SNR and depends strongly on the kinetic parameter values themselves. Minimal scan time and temporal resolution were found to be 15 min and 15 s, respectively, for Gd-DTPA. Temporal resolution should be enhanced by decreasing the NEX parameter (NEX ≤ 1). CRLB provide a golden standard to construct 95% confidence intervals, which can be used to perform protocol optimization and to test the statistical significance of K trans-changes in treatment evaluation.

Erythropoietin (EPO) has been used to correct cancer-related anemia and to improve tumor hypoxia, which both adversely affect the clinical condition of cancer patients and response to radiotherapy. Data available on the effects of EPO treatment in cancer are, however, conflicting. Several clinical studies investigating the influence of EPO treatment have given contradictory results as to whether or not this treatment positively influences survival. In light of these conflicting results, we studied the effects of EPO treatment either alone or in combination with radiotherapy on tumor oxygenation and on the expression pattern of several proteins related to tumor metabolism, survival, and spread in a rat colorectal cancer model. We found a statistically significant upregulation of hexokinase I, N-cadherin, and glucose transporter 3 when EPO treatment was combined with radiotherapy. Because these three proteins have distinct functions in protecting the cell in compromised conditions, these results indicate a detrimental role for the combination of EPO treatment and radiotherapy through the stimulation of tumor-cell metabolism, inhibition of apoptosis, and stimulation of tumor spread and seem to indicate that recombinant human EPO treatment negatively modulates radiotherapy efficacy.