Multicentre randomized clinical trial of the effect of chewing gum after abdominal surgery.

BACKGROUND: Postoperative ileus is a common complication of abdominal surgery, leading to patient discomfort, morbidity and prolonged postoperative length of hospital stay (LOS). Previous studies suggested that chewing gum stimulates bowel function after abdominal surgery, but were underpowered to evaluate its effect on LOS and did not include enhanced recovery after surgery (ERAS)-based perioperative care. This study evaluated whether chewing gum after elective abdominal surgery reduces LOS and time to bowel recovery in the setting of ERAS-based perioperative care. METHODS: A multicentre RCT was performed of patients over 18 years of age undergoing abdominal surgery in 12 hospitals. Standard postoperative care (control group) was compared with chewing gum three times a day for 30 min in addition to standard postoperative care. Randomization was computer-generated; allocation was concealed. The primary outcome was postoperative LOS. Secondary outcomes were time to bowel recovery and 30-day complications. RESULTS: Between 2011 to 2015, 1000 patients were assigned to chewing gum and 1000 to the control arm. Median LOS did not differ: 7 days in both arms (P = 0·364). Neither was any difference found in time to flatus (24 h in control group versus 23 h with chewing gum; P = 0·873) or time to defaecation (60 versus 52 h respectively; P = 0·562). The rate of 30-day complications was not significantly different either. CONCLUSION: The addition of chewing gum to an ERAS postoperative care pathway after elective abdominal surgery does not reduce the LOS, time to bowel recovery or the rate of postoperative complications. Registration number: NTR2594 (Netherlands Trial Register).

Long-term global quality of life in patients treated for colorectal liver metastases.

BACKGROUND: Surgical treatment of colorectal liver metastases has become increasingly aggressive. The influence of this more active surgical approach on patients' health-related quality of life (HRQoL) has hardly been evaluated. This study investigated the impact of surgical and systemic treatment on HRQoL in patients undergoing hepatic resection for colorectal metastases. METHODS: A total of 145 patients with colorectal liver metastases were entered prospectively into the study. Based on HRQoL values derived from the EuroQol-5D, health summary measures were calculated to express the overall impact on four distinct clinical states. The HRQoL instrument was used at baseline, 3 and 6 weeks after surgery, and every 3 months thereafter for up to 3 years. RESULTS: Patients showed a clear deterioration in HRQoL in the first weeks after surgery, followed by a recovery to baseline levels at 3 months after potentially curative surgery. In contrast, a sustained decline was noted when initial surgery for colorectal liver metastases was considered futile and palliative chemotherapy was started immediately. Three years after initial surgery, there were distinct differences in HRQoL between patients with or without recurrence. The latter group still had HRQoL scores at baseline levels, whereas patients with tumour recurrence showed a significant deterioration in HRQoL. Remarkably, there was no decline in HRQoL in patients with recurrent disease who could be treated by secondary surgical intervention. CONCLUSION: Superior overall HRQoL in the first 3 years after initial successful surgical intervention merits an aggressive surgical approach and intensive follow-up to detect recurrence early.

Sentinel node staging in colon carcinoma: value of sentinel lymph node biopsy with radiocolloid and blue staining.

BACKGROUND: Nodal staging accuracy is important in the prognosis and selection of patients for chemotherapy. This prospective study aims to assess the feasibility and accuracy of the sentinel lymph node procedure (SNP) using radiocolloid and blue dye in colon carcinoma. METHODS: In 56 patients, lymphatic mapping was accomplished by means of intraoperatively injecting patent blue and nanocoll subserosally around the tumour. Sentinel nodes (SNs) were harvested ex-vivo. Nodes were stained with H&E. If lymph nodes were interpreted as negative for metastatic tumour, serial sectioning and immunohistochemical staining were performed. RESULTS: At least one SN was detected in 49 of 53 patients (92.5%). Three patients were excluded because of preoperatively detected metastases. Overall, 121 SN were harvested with a mean of 2.2 SN/patients. Eighteen patients had tumour positive nodes. In four patients, pathological nodes were palpable during operation and were excluded. The SN was histologically negative in 2 of 14 patients with positive nodes (false-negative rate 14.3%). In 5 of 14 patients with positive nodes, the SN was the exclusive site of regional nodal metastasis. Four patients were upstaged by immunohistochemical staining (28.6%). The negative predictive value was 93.9% and the overall accuracy 95.6%. Scintigraphy was done in 17 patients. In three patients the SN was detected only by this modality. DISCUSSION: The SN biopsy with the combined technique proved a feasible technique with a steep learning curve. It can change the initial staging from stage II to stage III colon carcinoma. Scintigraphy can improve the success rate of the technique.

Isolated lung perfusion with melphalan: pharmacokinetics and toxicity in a pig model.

BACKGROUND: In patients with unresectable lung cancer or pulmonary metastases, isolated lung perfusion (ILP) has been described as an alternative method to deliver high-dose chemotherapy to the lungs, thereby minimizing systemic toxicity. Pharmacokinetics of ILP have not been extensively investigated. Therefore, we studied the feasibility of ILP with melphalan in a pig model with emphasis on pharmacokinetics and acute lung damage. METHODS: Five pigs underwent ILP with melphalan. Blood and tissue samples were obtained for determination of melphalan levels. Tissue biopsies were taken for microscopic evaluation of lung damage. RESULTS: During ILP, no hemodynamic effects of importance were noted. No systemic leakage of melphalan was observed in any of the animals. Compared with normal lung tissue, microscopic examination of lung tissue after perfusion without melphalan showed pulmonary edema. Directly after melphalan perfusion additional hemorrhagic areas were seen; however, electron microscopy displayed no irreversible endothelial damage. CONCLUSION: This study on pigs proved to be a well reproducible model for ILP with melphalan. Pharmacokinetics show a safety profile with no systemic toxicity, which could justify further patient studies, necessary to determine its effect on pulmonary metastases in humans, especially in case of adjuvant therapy after surgical resection or in unresectable disease.

Insufficient ability of omental milky spots to prevent peritoneal tumor outgrowth supports omentectomy in minimal residual disease.

BACKGROUND: The greater omentum is frequently involved in the course of gastrointestinal and ovarian tumors. Therefore, common practice in surgical treatment for especially gastric and ovarian cancer includes removal of the greater omentum. Paradoxically, many immune cells, such as macrophages that accumulate in so-called milky spots, reside within the omentum and are cytotoxic against tumor cells ex vivo. Consequently, omental macrophages might play an important role in killing tumor cells, and may hereby prevent development into local peritoneal recurrences. In the present study, we therefore evaluated the role of the omentum and the clinical relevance of omentectomy in minimal residual disease (MRD). METHODS: Tumor cell dissemination patterns on the omentum in a rat model were examined using DiI-labelled CC531s tumor cells. Additionally, intra peritoneal (i.p.) tumor load was investigated in rats that underwent omentectomy or sham laparotomy followed by i.p. injection of CC531s cells on day 21, which represented MRD. RESULTS: At 4 h post injection, tumor cells predominantly adhered on milky spots. Number of cells thereafter declined rapidly suggesting initial tumor killing functions in these specific immune aggregates. Despite initial reduction observed in milky spots, numbers of tumor cells however increased at fatty tissue stripes that border the omentum. This indicated proliferation at these locations, which corresponded to macroscopic observations of the omenta on day 21 after tumor cell injection. Omentectomy resulted in reduced intra-abdominal tumor load, which was completely attributable to the absence of the omentum, as tumor development did not differ on other sites. Even in the MRD group microscopic clusters of tumor cells located in the omentum eventually developed into macroscopic nodules. CONCLUSION: Since the ability of omental milky spots is, even in MRD, insufficient to prevent intra abdominal tumor outgrowth, omentectomy, which reduces tumor load, is recommended in surgical treatment of intra abdominal tumors that are prone to disseminate intraperitoneally.

Surgery promotes implantation of disseminated tumor cells, but does not increase growth of tumor cell clusters.

INTRODUCTION: Local recurrence and peritoneal dissemination is common after intentionally curative resection of colorectal carcinoma. It is not yet clear which mechanisms stimulate post-operative intra-abdominal tumor development. Enhanced adhesion or growth of tumor cells and/or post-operative immuno suppression may influence tumor recurrence. AIMS OF THE STUDY: In the present study, we evaluated effects of local and remote surgery on intra-abdominal tumor development. MATERIALS AND METHODS: A standardized intra-abdominal trauma was inflicted by rubbing both uterus horns in laparotomy groups, while a dorsolateral thoracotomy was performed in thoracotomy groups (on day -1, 0, or +3). To induce tumor development rats were injected intra-peritoneally with the coloncarcinoma cell line CC531s on day 0 and evaluated after 21 days. RESULTS: Rats undergoing laparotomy and injection on day 0 showed significantly higher tumorload than control rats (195 +/- 20 vs. 47 +/- 29, P < 0.001). When a laparotomy was performed, the day before tumor inoculation even higher tumorload was seen (245 +/- 37 vs. 195 +/- 20, P < 0.01). Strikingly, performing a thoracotomy on the day before or on the same day as tumor inoculation resulted in enhanced tumorload compared to controls as well (135 +/- 84 vs. 47 +/- 29; P < 0.001 and 88 +/- 38 vs. 47 +/- 29; P < 0.02, respectively). Either laparotomy or thoracotomy 3 days after tumor cell inoculation did not affect growth of pre-existing tumor cell clusters. CONCLUSIONS: The (post) surgical intra-peritoneal microenvironment enhances successful implantation of spilled tumor cells, whereas growth of adhered tumor cell clusters is not affected. The inflammatory response as a result of remote surgery promotes successful tumor development as well.

Cosmetic outcome of breast conserving therapy after sentinel node biopsy versus axillary lymph node dissection.

INTRODUCTION: Next to locoregional control, good cosmetic outcome is one of the main goals of breast conserving treatment (BCT) for breast cancer surgery. Factors affecting cosmetic outcome are well known. The sentinel node (SN) procedure avoids lymphedema in the breast, which might influence cosmetic outcome. The aim of this study was to evaluate the cosmetic outcome of BCT after the SN procedure compared to that after axillary lymph node dissection (ALND). METHODS: The subjects were 20 patients who underwent ALND and 20 patients who underwent the SN procedure. After a minimum follow-up period of 43 months, we photographed each patient. Fifteen healthy women served as control subjects. We used the percentage breast retraction assessment index (pBRA=BRA/reference length x 100) to compare cosmetic outcome. RESULTS: The median pBRAs of the ALND group and SN group (14.3 and 6.71, respectively) significantly differed ( p=0.001). The pBRA of the SN group was comparable to the pBRA (6.1) of the control group ( p=0.317). CONCLUSION: Cosmetic outcome of BCT after the SN procedure was superior compared to the cosmetic outcome after ALND. This is an important additional reason to implement the SN procedure in routine daily practice.

DNA copy number changes at 8q11-24 in metastasized colorectal cancer.

BACKGROUND: C-Myc, a well-known oncogene located on 8q24.12-q24.23, is often amplified and over-expressed in both primary and metastasizing colorectal cancer. In addition, PRL-3 (also known as PTP4A3), a tyrosine phosphatase located on 8q24.3, is amplified in colorectal cancer metastasis. Beside PRL-3 and c-myc, other oncogenes located on the 8q23-24 region might be involved in this process. Therefore, the present study aims to correlate DNA copy number status of a series of genes at 8q23-24 in colorectal cancer at high resolution in correlation to metastatic disease. MATERIALS AND METHODS: Thirty-two cases of colorectal cancer, 10 stage B1, 10 B2 and 12 D (Astler-Coller) with their corresponding liver metastasis and one colorectal cell line (colo205, previously analyzed by array-CGH), were included in this study. A chromosome 8 specific MLPA probe mixture was used to analyze the presence of DNA copy number changes. The probe mixture contained 29 probes covering 25 genes on chromosome 8, as well as 6 control probes on other chromosomes. RESULTS AND DISCUSSION: MLPA results obtained of the colo205 colorectal cell line were comparable with previous array-CGH results, thus validating the MLPA probe mixture. Astler-Coller B1 and B2 colorectal cancers differed significantly in DNA copy number of the genes, MOS (p=0.04), MYC (p=0.007), DDEF1 (p=0.004), PTK2 (p=0.02) and PTP4A3 (p=0.04). When comparing these with Astler-Coller D primary tumors, significant differences were seen for several genes as well (MYC (p<0.000), DDEF1 (p<0.000), SLA (p<0.000), PTK2 (p<0.000), PTP4A3 (p=0.002), and RECQL4 (p=0.01)). When comparing primary Astler-Coller D tumors and their corresponding liver metastases, a similar pattern of gains and losses was observed. Most of the liver metastases showed higher DNA copy number ratios than the corresponding primary tumors, but this difference was only significant for TPD52 (p=0.02) and EIF3S6 (p=0.007). CONCLUSION: In addition to c-myc, multiple genes on chromosome 8 differed significantly between primary colorectal cancers with and without liver metastases. This observation is consistent with the concept that clinical behaviour, like risk of liver metastasis, is determined by the genomic profile that is already present in the primary tumor.

Surgical trauma and peritoneal recurrence of colorectal carcinoma.

BACKGROUND: Local peritoneal recurrence is a relatively common complication after intentionally curative surgery for colorectal cancer and has unfavourable prognosis. METHODS: This manuscript reviews the relevant experimental and clinical literature on surgical trauma and development of local recurrences, which was obtained by extensive search in the PubMed database. RESULTS AND CONCLUSION: Although surgery is required as the only option for treatment, operative trauma and subsequent wound healing promote development of local recurrences. Minimizing peritoneal trauma reduces local tumour outgrowth in animal models, but clinical trials have not been conclusive so far. Recognition of the increased susceptibility to tumour establishment in the early post-operative phase challenges the aim for further research, targeting at strategies that obstruct local tumour implantation or outgrowth and/or improve (local) anti-tumour response.

Sentinel lymph node investigation in melanoma: detailed analysis of the yield from step sectioning and immunohistochemistry.

AIMS: To evaluate in detail the extent to which step sectioning and immunohistochemical examination of sentinel lymph nodes (SLNs) in patients with melanoma reveal additional node positive patients, to arrive at a sensitive yet workable protocol for histopathological SLN examination. METHODS: The study comprised 29 patients with one or more positive SLN after a successful SLN procedure for clinical stage I/II melanoma. SLNs were lamellated into pieces of approximately 0.5 cm in size. One initial haematoxylin and eosin (H&E) stained central cross section was made for each block. When negative, four step ribbons were cut at intervals of 250 microm. One section from each ribbon was stained with H&E, and one was used for immunohistochemistry (IHC). RESULTS: When taking the cumulative total of detected metastases at level 5 as 100%, the percentage of SLN positive patients increased from 79%, 83%, 83%, 90% to 93% in the H&E sections through levels 1-5, and with IHC these values were 83%, 86%, 90%, 97%, and 100%, respectively. One of six patients in whom metastases were detected at levels 2-5 only had metastases in the subsequent additional lymph node dissection. CONCLUSIONS: Multiple level sectioning of SLNs (five levels at 250 microm intervals) and the use of IHC detects additional metastases up to the last level in melanoma SLNs. Although more levels of sectioning might increase the yield even further, this protocol ensures a reasonable workload for the pathologist with an acceptable sensitivity when compared with the published literature.

Results of radio frequency ablation of primary and secondary liver tumors: long-term follow-up with computed tomography and positron emission tomography-18F-deoxyfluoroglucose scanning.

BACKGROUND: In the literature, promising results have been obtained with radiofrequency ablation (RFA) of primary liver malignancies (e.g. hepatocellular carcinoma, HCC) and secondary liver malignancies (e.g. metastases of colorectal tumors). In our center, positron emission tomography with FDG (FDG-PET) and computed tomography (CT) were used for follow-up. Patient outcome was compared with that in the literature, and PET and CT were analyzed regarding positive and negative predictive values for early detection of tumor recurrence. METHODS: The data were analyzed of patients who were treated with RFA for primary or secondary liver tumors between January 1999 and December 2002. Indications for treatment with RFA were liver tumors that could not be resected owing to size, number, or tumor location. In all patients, a CT scan was performed before RFA, and follow-up was performed with a CT scan in all patients and with an additional PET scan at various intervals in 11 patients. At evaluation with PET, tumor recurrence was defined as positive uptake of tracer either at the previous RFA lesion or at a new site in the liver. RESULTS: In total, 15 patients (8 M, 7 F) were treated in 21 sessions with RFA. The mean follow-up period was 16.8 months (range: 7-42). Average age of the patients was 63 years (range: 40-74). One patient had a primary liver tumor; all other patients had metastases of the breast (1), ovary (1), renal cells (1), and colorectal carcinoma (11 patients). The mean number of tumors per patient was 2.7 (range: 1-5). No treatment-related morbidity or mortality occurred. In 4 of 11 patients evaluated with PET at a mean period of 6.8 months, positive uptake of tracer was noted. At CT evaluation, tumor recurrence was observed in 4 of these patients, at a mean time of 9.8 months. Two patients (13.3%) died of cancer recurrence during follow-up. CONCLUSIONS: Tumor recurrence is comparable with that in other studies. Centrally located tumors showed more recurrence than peripheral tumors. The use of PET in combination with CT scan at follow-up may lead to earlier detection of tumor recurrence than contrast-enhanced CT alone.

[Negative sentinel node in breast cancer patients a good indicator for continued absence of axillary metastases]. / Negatieve schildwachtklier bij borstkankerpatiënten goede indicator voor het uitblijven van okselmetastasen.

OBJECTIVE: To determine the prevalence of axillary recurrences in sentinel-node-negative patients with breast cancer who had no axillary dissection. DESIGN: Follow-up study. METHOD: The first one hundred consecutive sentinel-node-negative patients with a minimal follow-up of 36 months (median 47) were included in this study. All patients underwent sentinel-node biopsy using the triple technique. During the first year after the operation patients were seen on a 3-monthly basis and thereafter every 6 months. RESULTS: Intensive pathological examination of the harvested sentinel nodes revealed no (micro)metastases in any patient. One patient developed an axillary recurrence after 24 months. Three out of the 100 patients developed distant metastases during follow-up; 2 of them died as a result of these metastases. One patient was treated for a local mammary recurrence. In terms of survival the sentinel-node procedure did not appear to be disadvantageous: the 3-year survival rate in our study was 98% for node-negative patients, compared to 88-94% quoted in the literature for node-negative patients after axillary dissection. This apparent improvement may be due to better staging of breast-cancer patients through the use of the sentinel-node procedure (stage migration). CONCLUSION: The triple technique was a reliable method for identifying the sentinel node in breast-cancer patients. Compared to the historical data on node-negative breast cancer, the sentinel-node procedure improved the prognosis of node-negative breast-cancer patients. This effect was probably due to the more accurate staging of breast-cancer patients using the sentinel-node procedure.

[The treatment of colorectal liver metastases: good 5 year survival chance after partial liver resection at the Rotterdam University Hospital, 1984/1999]. / De behandeling van colorectale levermetastasen: goede 5-jaarsoverlevingskans na partiële leverresectie in het Academisch Ziekenhuis Rotterdam, 1984/'99.

OBJECTIVE: To evaluate the results of partial liver resection in patients with liver metastases. DESIGN: Retrospective. METHOD: All of the patients who underwent a partial liver resection at the Rotterdam University Hospital during the period June 1984-August 1999 due to one or more metastases of a colorectal carcinoma were traced in the computerised hospital archive. Data concerning the primary tumour, the diagnostics carried out, the liver resection carried out and the clinical outcome after the operation were analysed using the statistical software SPSS. The actuarial survival was determined according to the Kaplan-Meier method. RESULTS: In total 163 patients underwent an operation: 108 men and 55 women, with a mean age of 58 years (range: 32-77). Postoperative morbidity occurred in 34 patients (21%), mostly infections and gall leakage. During the hospital admission 10 patients died (6%). In the follow-up period, mean 30.2 months (median: 23.8) there was a recurrence of colorectal carcinoma in 82 of the patients (50%). The actuarial 5-year survival chance was 37%. The only statistically significant unfavourable prognosis factor for survival, was a larger tumour volume in the liver at the time of the hepatectomy.