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Purpose We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D–mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment. Methods Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. Results Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D–mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. Conclusion The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D–mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.

The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests.In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p0.001) and ORR (odds ratio 2.16; p0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting.Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798.KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16).The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed.Merck KGaA.

Background: The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC). Patients and methods: The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented. Results: Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed. Conclusions: These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Background We aimed to improve the postoperative outcome of high-risk patients (American Society of Anesthesiologists class 3 and 4) recovering from colorectal cancer surgery by using recombinant human G-CSF (filgrastim) as perioperative prophylaxis. Methods In a double-blinded, placebo-controlled trial, 80 patients undergoing left-sided colorectal resection were randomized to filgrastim or placebo. Filgrastim (5 μg/kg) or placebo was administered in the afternoon on day –1, 0, and +1 relative to the operation. Primary endpoints were in a hierarchic order: quality of life (QoL) over time (determined at discharge, 2 and 6 months after operation with the European Organization for Research and Treatment of Cancer questionnaire) and the McPeek recovery score, which measures death and duration of stays in the intensive care unit and hospital. Predefined secondary endpoints were global QoL, subdomains of QoL, postoperative recovery, duration of stay, 6-month overall survival, complication rates, and cellular and immunologic parameters. Results There were no significant differences in both primary endpoints between the treatment groups. A significant improvement (P < .05) was obtained by filgrastim prophylaxis in the QoL subdomain family life /- social functioning,; thus, more patients recovered to their preoperative state (14 vs 4 with placebo) as determined by structured interviews. Duration of hospital stay (14 vs 12 days) and noninfectious complications were decreased from 8% to 3%. Conclusions High-risk patients undergoing major operation for colorectal cancer profited from filgrastim prophylaxis with regard to duration of hospital stay, noninfectious complications, social QoL, and subjective recovery from operation. These endpoints, however, were secondary, and the primary endpoints (overall QoL and the McPeek index) did not show comparable benefits. A new confirmatory trial with the successful endpoints of this trial, as well as a cost analysis, will be needed to confirm the results before a general recommendation for the prophylactic use of G-CSF in high-risk cancer patients can be given.

To evaluate the outcome of reoperations in patients with duodenopancreatic neuroendocrine tumors (PETs) in a tertiary referral center.The management of reoperations in PETs is still controversial.A total of 125 patients with PETs that underwent surgery between 1987 and 2004 at our institution were retrospectively evaluated. The diagnosis of PETs was based on clinical symptoms, biochemical tests, and histopathology. Patients with at least one reoperation were analyzed regarding clinical characteristics, pathology, operations, and long-term follow-up.A total of 33 patients with a median age of 42 years were identified for this study: 13 patients had gastrinomas, 12 patients had nonfunctional islet cell tumors, 6 patients had insulinomas, and 2 patients had vipomas; 24 patients had sporadic NETs, 9 patients had a MEN-1-syndrome; 27 patients had histologically verified malignant tumors; 33 initial operations and 50 reoperations were performed. The initial procedures comprised 27 resections of the primary tumor and 6 explorative laparotomies; 28 of all reoperations were resections of distant metastases, including 15 liver resections; 19 resections of the pancreas or duodenum were performed during reoperations. The overall morbidity and mortality was 45% and 4.8%, respectively. After a median follow-up of 124 months (range, 16-384 months), 27 of 33 patients are still alive, 12 without evidence of disease. All 6 patients with benign tumors are still alive. The 5-, 10-, and actuarial 25-year survival rate for patients with malignant tumors were 81%, 72%, and 36%, respectively. The survival rate was significantly related to the patients age at time of initial operation and better in patients younger than 50 years compared with patients older than 50 years (P = 0.0007), and the presence or development of metastases (none or lymph node metastases versus distant metastases: P = 0.01).We show that an aggressive surgical approach leads to long-term survival in patients with malignant PETs. Although long-term cure can only be achieved in a proportion of patients with malignant PETs, significant long-term palliation can be achieved.

Postoperative outcome of patients is determined by recovery characteristics and self-reported quality of life. The first can be assessed with the McPeek score which values three aspects of recovery: mortality, postoperative critical care and duration of hospitalization. We calculated the McPeek score of 669 patients in three trials: (1) colorectal cancer surgery, (2) antihistamine/volume loading in various operations, and (3) cholecystectomy. Beforehand, the average of intensive care unit treatment and duration of hospitalization were determined for the different operations to define McPeek score points. The score was tested on reliability, validity, and sensitivity. In addition, clinical applicability was assessed in a survey. The score was reliable with similarly distributed score points in the three trials at different institutions. Inter-rater reliability was high (97% overlap). Validity was proven by moderate high correlation to convergent criteria such as complications (trial I to III r=0.43, r=0.38, r=0.60), preoperative American Society of Anesthesiologists class (ASA) (r=0.24, r=0.28, r=0.57), and age (r=0.23, r=0.32, r=0.31). The score was different between patients with and without neoplasms (P

To evaluate the outcome of an aggressive surgical approach for duodenopancreatic neuroendocrine tumors (PETs) associated with multiple endocrine neoplasia type 1 (MEN1).The management of PETs is still controversial in the setting of the autosomal dominant inherited MEN1 syndrome.MEN1 patients that had either biochemical evidence of functioning PETs or visualized nonfunctioning PETs larger than 1 cm in size on imaging were operated. Since 1997, patients were followed annually by biochemical testing and imaging studies.Twenty-six genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 17) or nonfunctioning (n = 9) PETs. Ten (38%) patients had malignant PETs as characterized by the presence of lymph node (10 patients) and/or distant metastases (2 patients). The surgical approach was selected based on the type, location, and size of PETs. Four Zollinger-Ellison syndrome (ZES) patients required pylorus preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure, 20 patients underwent other duodenopancreatic resections, and 2 patients had simple enucleations of PETs. After median 83 months (range, 5-241 months), 24 patients were alive and 2 patients died of an unrelated cause. All patients with insulinoma or vipoma and 7 of 11 patients with ZES were biochemically cured, including the ZES patients who underwent PPPD. However, 19 of 26 (73%) patients developed new small PETs (1 cm) in the pancreatic remnant, but no patient had yet detectable metastases on imaging.Early and aggressive surgery of PETs in MEN1 patients prevents the development of liver metastases, which are the most life-threatening determinant. PPPD might be the procedure of choice for MEN1-ZES, which has to be proven in large scale studies.

Background The appropriate treatment for a sporadic endocrine tumour may be different from those that present as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. As primary hyperparathyroidism (pHPT) and pancreaticoduodenal endocrine tumours (PETs) are the most common organ manifestations of MEN1, the prevalence of germline mutations in the MEN1 gene was determined in young patients with apparently sporadic pHPT or PETs. Methods Eighteen of 705 patients with pHPT and 11 of 93 patients with PETs operated on between 1987 and 2001 had no family history of MEN1, only one organ manifestation and were aged 40 years or less at the time of diagnosis. Fifteen patients with pHPT and eight with PETs agreed to MEN1 gene mutation analysis, which was performed by single-strand conformational variant analysis and direct DNA sequencing. Results Two of 15 patients (13·3 (95 per cent confidence interval (c.i.) 1·6 to 40·4) per cent) with apparently sporadic pHPT had a MEN1 germline mutation. Both mutations were found in patients with pHPT due to multiglandular disease, whereas the remaining 13 patients had a solitary adenoma. None of the eight patients with PETs carried a MEN1 germline mutation. Conclusion Sporadic pHPT due to multiglandular disease in patients younger than 40 years may represent the first organ manifestation of MEN1 despite a negative family history.

BackgroundThe value of peritoneal lavage for intra-abdominal contamination and infection has never been proven scientifically. In contrast, the stimulation of host defence mechanisms with cytokines such as granulocyte colony-stimulating factor (G-CSF) has appeared promising in recent clinical trials.MethodsClinic modelling randomized trials (CMRTs), which model the complexity of the clinical reality, were used in rats in which peritoneal contamination and infection (PCI) was produced with human stool bacteria. The following groups were compared: trial 1, intraoperative peritoneal lavage with saline versus taurolin (18 rats per group); trial 2, no lavage versus saline lavage versus saline lavage plus subcutaneous administration of G-CSF (18 rats per group); trial 3, lavage with saline versus no lavage (30 rats per group). The primary endpoint was mortality at 120 h. Secondary endpoints were the phagocytic activity of granulocytes, and systemic and peritoneal cytokine levels.ResultsIn trial 1 lavage with taurolin was not superior to that with saline (five of 18 versus eight of 18 animals survived; P = 0·32). In trial 2, six of 18 animals having no lavage and three of 18 receiving saline lavage survived. The combination of lavage and G-CSF increased the number of animals surviving to 11 of 18 (P < 0·05). Lavage combined with G-CSF stimulated granulocyte phagocytic activity (P < 0·01) and reduced the levels of interleukin (IL) 6 (P < 0·01) and tumour necrosis factor α (P < 0·05) in peritoneal fluid, as well as plasma levels of IL-6 (P < 0·05) and IL-10 (P < 0·01). In trial 3, survival was not significantly different in animals having lavage (14 of 30) and no lavage (19 of 30) (P = 0·14).ConclusionIn these CMRTs of intra-abdominal contamination and infection, peritoneal lavage was not beneficial, but when lavage was combined with subcutaneous administration of G-CSF mortality was reduced and the local and systemic cytokine response was downgraded. Results from these CMRTs were used directly to define the trial conditions of a randomized clinical trial with G-CSF. Peritoneal lavage is not recommended.

Objective and design: Mesenteric traction syndrome is described as sudden tachycardia, hypotension and flush. Among other etiological factors eventeration or mesenteric traction of the small intestine may cause histamine release from mesenteric mast cells. We hypothesized that mesenteric traction syndrome may be positively influenced by prophylactic antihistamine administration.¶Methods: Male patients (n = 17, ASA groups III-IV, 48–78 years old) were investigated in a randomised double blind study during elective abdominal aortic aneurysm (AAA) repair. Eight patients had pre-anaesthetic prophylaxis with dimetindene (H1-receptor antagonist) plus cimetidine (H2-receptor antagonist), 9 patients received placebo. Anaesthesia and invasive haemodynamic monitoring were standardised in all patients. Haemodynamic parameters, plasma histamine concentrations and clinical symptoms were determined 1 min after skin incision, as well as 5 and 20 min after mesenteric traction. Statistical analyses were performed using the Student's t-test, Chi2-test for incidences and Mann-Whitney-U-test for continuous data.¶Results: The incidence of histamine release was 55.5 % (5/9) in the placebo group vs. 37.5 % (3/8) in the antihistamine group (p > 0.05, Chi2-test). Plasma histamine levels (mean ± SD) were higher in the placebo group than in the antihistamine group at 5 and 20 min after mesenteric traction but the difference did not reach statistical significance. Arrhythmias were significantly more frequent in the placebo group (6 times) than in the antihistamine group (none) (p = 0.005 Chi2-test). Systolic blood pressure was not statistically different between groups (e.g. 5 min after mesenteric traction, mean ± SD; placebo 111 ± 20 mm Hg vs. antihistamines 119 ± 35 mm Hg). However, in the placebo group the haemodynamics only stabilised 5 min after mesenteric traction when anaesthetic gas concentration was repeatedly reduced and vasopressor/volume administration was increased (placebo-group = 20 times/ antihistamine-group = 8 times, p = 0.001, t-test).¶Conclusion: Prophylactic administration of antihistamines reduced the incidence of histamine release as well as the incidence of arrhythmias and the amount of stabilising measures during mesenteric traction. Prophylaxis with H1 and H2 antihistamines may be of perioperative benefit and should therefore be considered in AAA-surgery.

Sepsis is still a major problem in human medicine with a high mortality rate. Nearly all attempts to improve the outcome of septic patients with immune modulators failed. In most of these trials only mechanistic endpoints such as mortality rate, complication rate, cytokine levels and physiological parameters were assessed. Only in a very few trials quality of life had been chosen as primary endpoint. In basic research and especially in animal experiments in the field of sepsis and oncology, only molecular investigations which explain drug and treatment interactions were in the focus of the scientific community. Animal models simulating clinical complexity and investigating outcomes like quality of life were very rare. The aim of this study was to demonstrate alterations in sickness behaviour – the animal equivalent to quality of life in man – in rats as a response to sepsis after prophylaxis with G-CSF and antibiotics. Sickness behaviour was assessed by measurement of core body temperature, food and water intake, locomotor activity and circadian rhythm of these parameters. Complex animal experiments in rats were performed including anaesthesia, antibiotic and cytokine (G-CSF) prophylaxis, volume substitution, laparotomy, contamination and infection with human faecal suspension and postoperative analgesia. In group A (sham) and D (antibiotic + G-CSF) the mortality rate was 0% , but in group B (no prophylaxis) 33% (3/9) and in group C (antibiotic prophylaxis) 11% (1/9) of the animals died. Before infection all rats showed clear circadian patterns of locomotor activity and body temperature with physiologically higher values during the night-time. Immediately after operation and infection temperature increased, water and food intake, locomotor activity decreased and circadian rhythms were lost. Body temperature and water consumption were already normalised at day 2 after infection in all groups. Normal food intake was re-established in group C and D at day 3 while one more day was needed for recovery in Group C. Restoration of locomotor activity occurred in group D at day 5, in group C at day 7. In group B locomotor activity remained suppressed during the whole observation period of 8 days postoperatively. In conclusion, in septic rats sickness behaviour, an equivalent to quality of life in humans, is improved rapidly by a prophylaxis with G-CSF in combination with antibiotics and can be used as a new outcome in preclinical surgical research.

Adding cetuximab to chemotherapy improved survival in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. Although HPV and p16 statuses have prognostic value, the observed survival benefit conferred by cetuximab is independent of both. This pattern remained in a combined analysis of both p16 and HPV and in patients with oropharyngeal cancer separately.Tumor human papillomavirus (HPV) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Prognostic value in recurrent and/or metastatic (R/M) disease remains to be confirmed. This retrospective analysis of the EXTREME trial, comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN, investigated efficacy and prognosis according to tumor p16 and HPV status. Paired tissue samples were used: p16INK4A expression was assessed by immunohistochemistry, and HPV status determined in extracted DNA samples using oligonucleotide hybridization assays. Altogether, 416 of 442 patients had tumor samples available for p16 and HPV: 10% of tumors were p16 positive and 5% were HPV positive. Adding cetuximab to chemotherapy improved survival, irrespective of tumor p16 or HPV status. This pattern remained in a combined analysis of p16 and HPV. p16 positivity and HPV positivity were associated with prolonged survival compared with p16 negativity and HPV negativity. Subgroup analysis of patients with oropharyngeal cancer demonstrated a similar pattern to all evaluable patients. The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status.

Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients.We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044).High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting.Merck KGaA.

Purpose The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. Patients and Methods Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. Results The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. Conclusion The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

Parathyroid surgery (PTX) in patients with tertiary hyperparathyroidism (tHPT) may endanger the long-term survival of transplanted renal grafts. The mechanism by which graft function deteriorates is unknown. We reviewed our experience in regard to the operative procedures and postoperative outcome. Sixty-nine patients were operated on for tHPT between 1987 and 2006 at our institution. Serum (s) calcium, s-creatinine, and levels of intact parathyroid hormone (PTH) were measured before and after PTX. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (GFR). The entire patient group developed a deterioration of kidney graft function after PTX. Nineteen of 69 patients developed a decrease in GFR of more than 20% during the hospital stay, persisting for more than one year after PTX. Ten of them had to restart dialysis during the first year after PTX. Mean preoperative s-creatinine was 4.4 ± 0.6 mg/dl in these patients. When divided according to the surgical procedure performed, only the subgroup who underwent total parathyroidectomy showed a significant worsening of graft function when compared to subtotal or reoperative PTX. PTX is an efficient way to treat tHPT but represents a risk for impairing graft function, especially for patients that already demonstrate poor kidney function at the time of surgery. In the aim to prevent transient hypoparathyroidism, which may provoke reduced graft perfusion, as one possible cause of kidney graft deterioration associated with PTX, one should consider subtotal instead of total parathyroidectomy.

We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.

OBJECTIVES Tissue inhibitor of metalloproteinase-3 (TIMP3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastases. In the present study, the involvement of TIMP3 in the tumorigenesis of 34 pancreatic adenocarcinomas was evaluated. METHODS Immunohistochemistry, methylation-specific PCR, and RNA expression analysis (RT-PCR) of TIMP3 were performed in 34 resected and microdissected primary pancreatic adenocarcinomas. RESULTS Immunohistochemistry showed loss or strongly reduced protein expression in 17 of 34 pancreatic adenocarcinomas (50%) that corresponded to loss of TIMP3-RNA-expression. Promoter hypermethylation was identified in 2 of 34 tumors (6%). It was tumor specific and corresponded to a loss of TIMP3 protein expression. TIMP3 alterations did not correlate with any clinical feature such as tumor size or survival. CONCLUSION TIMP3 seems to play an important role in the tumorigenesis of primary pancreatic adenocarcinomas. In contrast to other tumors, hypermethylation seems not to be the key mechanism for the inactivation of TIMP3. Other methods of gene inactivation need to be identified.

Secretory meningiomas constitute a relatively rare subtype of meningiomas, accounting for only 1.1% at our institution, with a 6:1 predominance of female patients. This study aimed to obtain more information about the immunohistochemical characteristics of this histological entity, and to analyse the effects of histological factors such as the presence of mast cells on the radiological evidence of surrounding tumour oedema that frequently occurred in this subtype of meningioma. Fourteen cases of secretory meningioma were examined. Relevant clinical information was obtained from the patient files. Peritumoural oedema was determined either by CT or MRI scans and graded as small, moderate and severe. In order to perform the quantitative evaluation of mast cells in secretory meningiomas in a comparison with other meningiomas, 14 non-secretory meningiomas were randomly selected and used as a control group. The immunohistochemical staining of carcinoembryonic antigen was positive within the secretory droplets and the cells surrounding them in all cases. Ki 67 (MIB 1) proliferative index mean values were 2.4%, indicating low expression in all secretory meningiomas. Moreover, from our statistical analysis, there is no clear-cut pattern of various types of cytokeratins emerging in secretory meningiomas. The secretory meningiomas were characterized by a significantly increased number of mast cells as compared with non-secretory meningiomas of different grades. As the present clinical findings and laboratory results could not confirm a correlation between mast cell density and radiological evidence of oedema, further studies of mediators are warranted.

We tested the hypothesis that the ability of granulocyte colony-stimulating factor (G-CSF) to prevent death from fecal peritonitis is influenced by the composition of the antibiotic regimen with which it is administered. We used a rodent model of polymicrobial peritoneal contamination and infection and the concept of clinical modeling randomized trials (CMRTs), which includes the conditions of randomized, clinical trials and complex clinical interventions (e.g., anesthesia, volume substitution, antibiotics, surgery, postoperative analgesia). With the peritonitis model we obtained a mortality dose-response curve that was sensitive to antibiotic prophylaxis. G-CSF was most efficacious when it was administered both prophylactically and after the onset of peritonitis. Cefuroxime/metronidazole, ofloxacin/metronidazole, and amoxicillin/clavulanate improved survival in combination with G-CSF best, whereas cefotaxime or ceftriaxone with and without metronidazole did not. G-CSF administration was associated with improved polymorphonuclear neutrophil phagocytosis and enhanced bacterial clearance. Pro-inflammatory cytokine release (tumor necrosis factor-a, interleukin-6, macrophage inflammatory protein-2) was decreased in plasma and in the peritoneal fluid. Their expression was lowered in various organs on the protein and mRNA level. The results were used to design a clinical trial to test the ability of G-CSF to prevent serious infections in patients with colorectal cancer surgery. In this trial G-CSF application and antibiotic prophylaxis were performed with the most effective scheduling and combinations (cefuroxime/metronidazole and ofloxacin/metronidazole) as defined here.

Antibiotic prophylaxis is used in many surgical procedures but there are frequent cardiovascular instabilities following antibiotics in perioperative period. A clinic modelling randomised trial (CMRT) in pigs was developed to compare the effects of 2 commonly used antibiotic combinations on cardiovascular stability during major surgery.Thirty pigs (both sexes) were randomised into 3 groups, receiving either saline (placebo), co-amoxiclav or cefuroxime/metronidazole in clinically relevant doses as antibiotic prophylaxis. A laparotomy was performed and the abdomen remained open. Surgical complications were simulated by removing one third of the blood volume. For fluid resuscitation, 500 ml hetastarch (HAES(TM)) were infused rapidly (therapy of complication) and polymyxin B (15 mg/kg bodyweight) was applied for induction of histamine release reactions (complication of therapy). The main end points were histamine release reactions, these were classified by 2 blinded investigators.Neither cardiovascular changes nor histamine release reactions were detected immediately after the administration of antibiotics or placebo alone. Plasma histamine concentrations increased after bleeding in the co-amoxiclav group (p0.05). After fluid resuscitation and induction of anaphylactoid reactions, the median histamine release and cardiovascular changes were not significantly different between the groups. However, the incidence of typical histamine release related reactions differed significantly between the groups: 8/10 for the controls, 6/10 in the co-amoxiclav and 2/10 in the cefuroxime/metronidazole group (p0.05).The stability and reproducibility of this model clearly demonstrated the concept of a 'clinic modelling randomised trial' as a useful tool. Antibiotic prophylaxis influences the organism's capability to cope with intraoperative bleeding and fluid resuscitation problems. Indeed antibiotic prophylaxis may be beneficial. These effects of antibiotics could only be demonstrated in complex surgical models. Thus new antibiotics should be investigated in complex animal models prior to prospective randomised clinical trials or usage in clinical practice.

Patients undergoing anaesthesia and surgery frequently complain about postoperative nausea and vomiting (PONV). Whether pretreatment with H1 and H2 blocking agents reduces the incidence of PONV remains controversial. To answer this question, we performed a randomised, prospective, placebo-controlled clinical study to evaluate the efficacy of a premedication with H1 and H2 receptor antagonists.1149 patients (both sexes) undergoing surgery were randomly assigned to three treatment groups and one control group. Patients in the treatment groups were premedicated with the following H1 + H2 receptor antagonists:Group 1 (n = 335): 5 mg/kg cimetidine i.v. + 0.1 mg/kg dimetindene i.v. 20 min before induction of anaesthesiaGroup 2 (n = 337): 1.25 mg/kg ranitidine i.v. + 0.1 mg/kg dimetindene i.v. 20 min before induction of anaesthesiaGroup 3 (n = 316): 300 mg ranitidine p.o. + 0.1 mg/kg dimetindene i.v. 1 to 2 h before induction of anaesthesiaGroup 4 (n = 161): 20 ml saline solution i.v. 20 min before induction of anaesthesiaPatients from the treatment groups 1, 2 and 3 received regional or general anaesthesia depending on the clinical decision. All control patients received general anaesthesia consisting of fentanyl, a thiobarbiturate, enflurane, nitrous oxide, oxygen, and vecuronium.The incidence of nausea and vomiting was 8.5%, 6.8% and 5.4% in patients from the treatment groups (1, 2 and 3) who underwent general anaesthesia (n = 545), with no statistically significant differences between groups. The incidence of nausea and vomiting in the control group (n = 161) was 28.3% (nausea) and 27.5% (vomiting), respectively. In patients who underwent regional anaesthesia (n = 443), the incidence of nausea and vomiting was 2.5% and 1.1%, respectively.Premedication with H1 and H2 blocking agents significantly reduces the incidence of postoperative nausea and vomiting.

Migration of the tibial component in total knee arthroplasty (TKA) is subject of many studies using roentgen stereophotogrammetric analysis (RSA). In previous studies of cemented and uncemented tibial components, high migration values were found. Improvements in cementing technique, prosthetic design and pre-coating techniques reduced these values as shown in more recent studies.A total of 35 patients were initially included in the study and operated on between 12/1999 and 10/2000. All patients received a NexGen TKA cemented into the proximal tibia using Palamed G bone cement. The implants and the tibial metaphysis were marked with standard tantalum markers. Radiostereometric analysis was performed post-operatively and after 3, 6 and 12 months using a standard digital radiostereometric analysis. Functional parameters were assessed using the Knee Society Score (KSS) clinical rating system.There were no complications and failures within the first year. After 1 year radiostereometric measurements of the translational parameters along and the rotational parameters around the x-, y- and z-axis revealed: X-Trans -0.19 mm, Y-Trans +0.02 mm, Z-Trans +0.08 mm, X-Rot +0.26 degrees, Y-Rot -0.35 degrees, Z-Rot +0.09 degrees. The maximum total point motion was +0.96 mm and the mean maximum subsidence was -0.23 mm. Except for anterior-posterior, medio-lateral stability and extension leg all endpoints of the KSS clinical rating system showed a significant improvement.After 12 months, the use of Palamed G bone cement in total knee arthroplasty was demonstrated to be safe. Both the clinical and radiostereometric results were good and comparable to the results reported in other RSA studies in cemented total knee arthroplasty.

Objective: The perioperative use of colloidal plasma substitutes is still under discussion. We therefore conducted a prospective randomised study with three commonly used plasma substitutes to examine their histamine releasing effects in 21 volunteers. Material or subjects: 21 male volunteers were enrolled in this prospective, randomised, controlled clinical study. Endpoints were the incidence of early and late histamine release and the time course of the release kinetics. Normovolemic hemodilution technique was used with hydroxyethyl starch (n = 6), human albumin (n = 6) and polygeline (n = 9). Measurement and observation period was 240 min after the start of the plasma substitute infusion. Heart rate, blood pressure, SaO2, clinical symptoms/signs and plasma histamine were measured during the observation period. Results: The incidence of histamine release over the whole observation period in all three groups was 100%. Histamine release occurred frequently in all three groups until 30 min (50%–78%) and up to 240 min (late release reaction: 67%–83%) after the start of infusion. Surprisingly even hydroxyethyl starch, which is regarded as a generally safe and effective plasma substitute, caused high incidences of late histamine release (67%). Histamine release is a well known side effect of polygeline and – to a lesser extent – also of albumin, but was a novel finding for hydroxyethyl starch. Conclusions: We demonstrated for the first time histamine releasing effects of hydroxyethyl starch over a long period of time after administration. This perioperatively and for intensive care possibly relevant finding should make clinicians aware of late side effects not yet connected with the clinical use of these colloidal plasma substitutes.

Background Use of a standardized meal stimulation test has been recommended for the early diagnosis of pancreaticoduodenal endocrine tumours (PETs) in patients with multiple endocrine neoplasia type 1 (MEN 1). The diagnostic value of this test was re-evaluated. Methods In a prospective, controlled trial 58 standardized meal stimulation tests (563 kcal) were performed in 12 patients with MEN 1 and histologically, biochemically and/or radiologically confirmed PETs (group 1), 11 carriers of an MEN 1 mutation with no evidence of PETs (group 2) and in 27 healthy controls (group 3). Serum pancreatic polypeptide (PP) and gastrin concentrations were measured before and during the test meal. Results Patients in group 1 had significantly higher mean basal serum PP and gastrin concentrations than patients in group 2 and controls (P < 0·05). In all three groups an increase in serum PP was observed after meal stimulation, but there was no significant difference between the groups. No increase in gastrin level was found in any of the groups after meal stimulation. Conclusion The standardized meal stimulation test does not reliably indicate the presence of PETs in patients with MEN 1, whereas raised basal serum PP and gastrin levels do. The expensive and time-consuming meal test can be excluded from MEN 1 screening programmes.

Background and aim: New biological response modifiers are usually tested in reductionistic, pharmacological animal models by the determination of mechanistic endpoints (mortality rate, cellular/physiological parameters). In the meantime, quality of life had become an important endpoint in clinical trials but adequate animal experiments are very rare. The aim of this study was to demonstrate alterations in the behavioural response of septic rats due to a prophylaxis with cytokine (G-CSF) plus antibiotics. Methods: Sickness behaviour (locomotor activity, circadian rhythms of blood pressure, heart rate and temperature) was determined by the use of radio telemetry. Complex animal experiments in rats were performed including anaesthesia, antibiotic and G-CSF prophylaxis, volume substitution, laparotomy, contamination and infection with human faecal suspension and postoperative analgesia. Results: Prior to infection, rats showed circadian rhythm in locomotor activity, blood pressure, heart rate and temperature. Sham operation did not alter these parameters significantly. Immediately after abdominal contamination and infection, locomotor activity was strongly reduced and circadian rhythm was lost in all parameters. Body temperature showed a continuous rise, peaking 38 h after infection. Untreated animals died in 63% (8/14) of cases. Antibiotic prophylaxis blunted the febrile response and markedly reduced mortality to 20% (2/10) or 0% (0/10) using G-CSF plus antibiotics. Blood pressure and heart rate were increased in parallel with the rise in temperature. These early physiological changes were not prevented by prophylaxis, but normal behaviour was restored faster with G-CSF plus antibiotic prophylaxis. Conclusions: In septic rats, sickness behaviour (locomotor activity) is significantly improved in parallel to the mortality rate by a prophylaxis with G-CSF plus antibiotics. Sickness behaviour can be considered as an equivalent to human quality of life.

The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.

Tumors arising from the pancreatic islet cells are rare and represent a heterogeneous group of benign or malignant lesions. Most tumors present with well characterized syndromes, whereas others appear to be nonfunctioning. The clinical features of 11 men and 7 women with nonfunctioning islet cell carcinomas operated on between 1983 and 1998 were reviewed. The median patient age was 53.5 years (range 26-74 years). The most frequent presenting symptoms were abdominal pain (13 patients), weight loss (7 patients), and obstructive jaundice (4 patients). Gut hormone profiles were normal in all patients. Abdominal sonography and computed tomography localized the tumor in 17 patients, and correct prediction of an endocrine tumor was achieved in 12 patients. Six of seven patients showed a hypervascular tumor upon angiography, and seven of eight patients preoperatively had positive somatostatin receptor scintigraphy. At operation, regional or distant metastases were present in 15 (83%) and 6 (33%) patients, respectively. Eleven patients underwent potentially curative resections, and the remaining seven patients were managed palliatively by resection (four patients) or bypass procedures (three patients). Three patients had up to three more resection for metastases. Eight patients received postoperative octreotide, interferon alpha therapy, or both. The overall cumulative 5- and 10-year survival rates were 65.4% and 49.1%, respectively. Of the 11 patients who underwent curative resection, 10 were alive after a median follow-up of 63 months (range 7-180 months), but only 5 are free from disease. Although surgical cure is rare in nonfunctioning islet cell carcinomas, significant long-term palliation can be achieved in a large proportion of patients with an aggressive surgical approach and, when indicated, additional medical therapy.

Background Kirsten rat sarcoma virus ( KRAS ) wild-type status determined using a locked nucleic acid (LNA)-mediated quantitative polymerase chain reaction (qPCR) clamping assay (LNA assay) predicted response to therapy in the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study. A companion KRAS diagnostic tool has been developed for routine clinical use (QIAGEN therascreen kit) (QIAGEN Manchester Ltd, Manchester, UK). We wanted to assess the concordance between the validated US Food and Drug Administration (FDA)-approved therascreen assay and the LNA assay in determining the KRAS status of a subset of patients enrolled in the CRYSTAL study. Patients and Methods DNA extracted from paraffin-embedded tumor sections was tested for KRAS status using the therascreen assay. Efficacy data from the CRYSTAL study were assessed to determine if the overall survival (OS) hazard ratio for cetuximab in patients identified as having KRAS wild-type status using the therascreen assay was equivalent to that in patients identified as KRAS wild-type using the LNA assay. This was determined by assessing if the concordance between the therascreen assay and the LNA assay met the minimum threshold (prespecified as 0.8) to achieve a significant difference in the OS hazard ratio in favor of the cetuximab + FOLFIRI (5-fluorouracil, leucovorin [folinic acid], irinotecan) arm in the KRAS wild-type population as identified using the therascreen assay. Results Of the 148 samples determined to be KRAS wild-type (therascreen assay), 141 (95.3%) samples were also KRAS wild-type (LNA assay) and 7 samples (4.7%) were KRAS mutant (LNA assay). The prespecified primary concordance measure p was 141/148 = 0.953 (95% confidence interval [CI], 0.905-0.981). The concordance was statistically significantly higher than the prespecified threshold of 0.8 for concordance between the therascreen assay and the LNA assay. Consistent with the concordance exceeding the prespecified threshold, the OS hazard ratio (cetuximab + FOLFIRI arm vs. FOLFIRI arm) in the KRAS wild-type population, determined by the therascreen assay, supported a significant benefit for cetuximab (ie, the 95% CI excluded 1) and was comparable to the OS hazard ratio observed in the CRYSTAL study KRAS wild-type population (LNA assay) even after adjustment for potentially confounding baseline variables. Conclusion These results support the utility of the therascreen assay for identifying patients who may benefit from cetuximab therapy for metastatic colorectal cancer.