The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NeoCTx) is performed for most patients with colorectal cancer liver metastases (CRCLM). However, chemotherapy-associated liver injury (CALI) has been associated with poor postoperative outcome. To date, however, no clinically applicable and noninvasive tool exists to assess CALI before liver resection. METHODS: Routine blood parameters were assessed in 339 patients before and after completion of NeoCTx and before surgery. The study assessed the prognostic potential of the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), the albumin-bilirubin grade (ALBI), and their combinations. Furthermore, an independent multi-center validation cohort (n = 161) was included to confirm the findings concerning the prediction of postoperative outcome. RESULTS: Higher ALBI, APRI, and APRI + ALBI were found in patients with postoperative morbidity (P = 0.001, P = 0.064, P = 0.001, respectively), liver dysfunction (LD) (P = 0.009, P = 0.012, P < 0.001), or mortality (P = 0.037, P = 0.045, P = 0.016), and APRI + ALBI had the highest predictive potential for LD (area under the curve [AUC], 0.695). An increase in APRI + ALBI was observed during NeoCTx (P < 0.001). Patients with longer periods between NeoCTx and surgery showed a greater decrease in APRI + ALBI (P = 0.006) and a trend for decreased CALI at surgery. A cutoff for APRI + ALBI at - 2.46 before surgery was found to identify patients with CALI (P = 0.002) and patients at risk for a prolonged hospital stay (P = 0.001), intensive care (P < 0.001), morbidity (P < 0.001), LD (P < 0.001), and mortality (P = 0.021). Importantly, the study was able to confirm the predictive potential of APRI + ALBI for postoperative LD and mortality in a multicenter validation cohort. CONCLUSION: Determination of APRI + ALBI before surgery enables identification of high-risk patients for liver resection. The combined score seems to dynamically reflect CALI. Thus, APRI + ALBI could be a clinically relevant tool for optimizing timing of surgery in CRCLM patients after NeoCTx.

Long-term outcomes of patients with 10 or more colorectal liver metastases.

BACKGROUND: Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients. METHODS: The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry. RESULTS: Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor. CONCLUSIONS: Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial.

BACKGROUND: For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting. PATIENTS AND METHODS: OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis. RESULTS: In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively). CONCLUSIONS: Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI. CLINICALTRIALSGOV: NCT00778102.

Variations in genes involved in dormancy associated with outcome in patients with resected colorectal liver metastases.

BACKGROUND: Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy. PATIENTS AND METHODS: Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns. RESULTS: NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively. CONCLUSION: Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.

Variations in genes involved in immune response checkpoints and association with outcomes in patients with resected colorectal liver metastases.

In patients with colorectal liver metastases (CLM), liver resection offers the possibility of cure and long-term survival. The liver is a highly immunogenic organ harboring ~80% of the body's tissue macrophages. Emerging data demonstrate a critical role of the immune response for cancer treatment. We investigated variations within genes involved in immune response checkpoints and their association with outcomes in patients with CLM who underwent neoadjuvant chemotherapy including bevacizumab and liver resection. Single-nucleotide polymorphisms (SNPs) in nine genes (CCL2, CCR2, LAG3, NT5E, PDCD1, CD274, IDO1, CTLA4 and CD24) were analyzed in genomic DNA from 149 patients with resected bevacizumab-pretreated CLM by direct Sanger DNA sequencing, and correlated with response, recurrence-free survival (RFS), overall survival (OS), probability of cure and recurrence patterns. IDO1 (indoleamine 2, 3-dioxygenase) rs3739319 G>A and CD24 rs8734 G>A showed a significant difference in 3-year OS rates. In addition, IDO1 rs3739319 G>A was significantly associated with extrahepatic recurrence. Recursive partitioning analyses revealed that IDO1 rs3739319 G>A was the dominant SNP predicting RFS and OS. Our data suggest that variants within genes involved in immune response checkpoints are associated with outcomes in patients with resected CLM and might lead to improved treatment strategies modulating anti-tumor immune response by targeting novel immune checkpoints.

Plasma thrombospondin 1 as a predictor of postoperative liver dysfunction.

BACKGROUND: Liver regeneration following liver resection involves a complex interplay of growth factors and their antagonists. Thrombospondin 1 has recently been identified as a critical inhibitor of liver regeneration by the activation of transforming growth factor ß1 in mice, and preliminary data seem to confirm its relevance in humans. This study aimed to confirm these observations in an independent validation cohort. METHODS: Perioperative circulating levels of thrombospondin 1 were measured in patients undergoing liver resection between January 2012 and September 2013. Postoperative liver dysfunction was defined according to the International Study Group of Liver Surgery and classification of morbidity was based on the criteria by Dindo et al. RESULTS: In 85 patients (44 major and 41 minor liver resections), plasma levels of thrombospondin 1 increased 1 day after liver resection (mean 51·6 ng/ml before surgery and 68·3 ng/ml on postoperative day 1; P = 0·001). Circulating thrombospondin 1 concentration on the first postoperative day specifically predicted liver dysfunction (area under the receiver operating characteristic (ROC) curve 0·818, P = 0·003) and was confirmed as a significant predictor in multivariable analysis (Exp(B) 1·020, 95 per cent c.i. 1·005 to 1·035; P = 0·009). Patients with a high thrombospondin 1 concentration (over 80 ng/ml) on postoperative day 1 more frequently had postoperative liver dysfunction than those with a lower level (28 versus 2 per cent) and severe morbidity (44 versus 15 per cent), and their length of hospital stay was more than doubled (19·7 versus 9·9 days). CONCLUSION: Thrombospondin 1 may prove a helpful clinical marker to predict postoperative liver dysfunction as early as postoperative day 1.

Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study).

BACKGROUND: Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation. PATIENTS AND METHODS: Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012. RESULTS: Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%). CONCLUSIONS: This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for 'conversion' treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional 'line of therapy' in those patients who are not cured. CLINICAL TRIAL NUMBER: NCT00153998, www.clinicaltrials.gov.

The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022.

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

Neoadjuvant bevacizumab persistently inactivates VEGF at the time of surgery despite preoperative cessation.

BACKGROUND: When anti-VEGF (vascular endothelial growth factor) antibody bevacizumab is applied in neoadjuvant treatment of colorectal cancer patients with liver metastasis, 5-6 weeks between last bevacizumab dose and liver resection are currently recommended to avoid complications in wound and liver regeneration. In this context, we aimed to determine whether VEGF is inactivated by bevacizumab at the time of surgery. METHODS: Fifty colorectal cancer patients with liver metastases received neoadjuvant chemotherapy ± bevacizumab supplementation. The last dose of bevacizumab was administered 6 weeks before surgery. Plasma, subcutaneous and intraabdominal wound fluid were analysed for VEGF content before and after liver resection (day 1-3). Immunoprecipitation was applied to determine the amount of bevacizumab-bound VEGF. RESULTS: Bevacizumab-treated individuals showed no increase in perioperative complications. During the entire monitoring period, plasma VEGF was inactivated by bevacizumab. In wound fluid, VEGF was also completely bound by bevacizumab and was remarkably low compared with the control chemotherapy group. CONCLUSION: These data document that following a cessation time of 6 weeks, bevacizumab is fully active and blocks circulating and local VEGF at the time of liver resection. However, despite effective VEGF inactivation no increase in perioperative morbidity is recorded suggesting that VEGF activity is not essential in the immediate postoperative recovery period.

KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab.

BACKGROUND: The prognostic value of KRAS mutation in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab before liver resection is unclear. METHODS: The KRAS and BRAF status of resected CLM was assessed in prospectively studied patients. Mutations were correlated with recurrence-free and overall survival. Only patients with remaining vital tumour cells in the resected specimen and those without disease progression were analysed; those with progressive disease did not undergo resection. RESULTS: A total of 60 patients were enrolled. Fifteen (25 per cent) had a KRAS mutation, but none of the 60 patients had a BRAF mutation. The radiological response to neoadjuvant chemotherapy including bevacizumab, assessed according to the Response Evaluation Criteria In Solid Tumours, was partial in 52 patients (87 per cent) and the remaining eight had stable disease. The partial response rate was similar in patients with a KRAS mutation and those with the wild-type gene (12 of 15 versus 40 of 45 patients; P = 0·400). KRAS mutation had a negative prognostic effect on recurrence-free survival (hazard ratio (HR) 2·48, 95 per cent confidence interval 1·26 to 4·89; P = 0·009) and overall survival (HR 3·51, 1·30 to 9·45; P = 0·013). CONCLUSION: This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM.

Value of hepatic venous pressure gradient measurement before liver resection for hepatocellular carcinoma.

BACKGROUND: Portal hypertension associated with liver cirrhosis increases the risk of postoperative complications after liver resection for hepatocellular carcinoma (HCC). This study assessed the role of preoperative hepatic venous pressure gradient (HVPG) assessment in identifying portal hypertension. METHODS: All patients who underwent liver resection for HCC between January 2000 and December 2009 at the Department of General Surgery, Medical University Vienna, were analysed retrospectively. HVPG was assessed prospectively in a subset of patients before liver resection. The influence of this assessment on postoperative complications was investigated. RESULTS: A total of 132 patients were enrolled, of whom 39 underwent HVPG measurement. Mean(s.d.) HVPG was 6·4(3·0) and 4·3(1·4) mmHg in patients with and without postoperative complications respectively (P = 0·028). Complication rates differed significantly at a cut-off HVPG value of 5 mmHg: 11 of 21 patients with a gradient of 1-5 mmHg developed complications versus 12 of 14 patients with a higher value (P = 0·045). HVPG exceeding 5 mmHg was associated with worse liver fibrosis (P = 0·004), higher rates of postoperative liver dysfunction (5 of 13 versus 1 of 18; P = 0·022) and ascites (7 of 14 versus 3 of 21; P = 0·022), and a longer hospital stay (median (range) 11 (7-26) versus 8 (4-20) days; P = 0·034). Overall postoperative morbidity did not differ between patients who had preoperative HVPG assessment and those who did not (P = 0·142). CONCLUSION: Preoperative HVPG assessment predicted liver fibrosis and postoperative complications.

Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009.

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC.

Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel.

The past 5 years have seen the clear recognition that the administration of chemotherapy to patients with initially unresectable colorectal liver metastases can increase the number of patients who can undergo potentially curative secondary liver resection. Coupled with this, recent data have emerged that show that perioperative chemotherapy confers a disease-free survival advantage over surgery alone in colorectal cancer (CRC) patients with initially resectable liver disease. The purpose of this paper is to build on the existing knowledge and review the issues surrounding the use of chemotherapy +/- targeted agents combined with surgery in the treatment of CRC patients with liver metastases, with a view to providing clinical recommendations. An international panel of 21 experts in colorectal oncology comprising liver surgeons and medical oncologists reviewed the available evidence. In a major change to clinical practice, the panel's recommendation was that the majority of patients with CRC liver metastases should be treated up front with chemotherapy, irrespective of the initial resectability status of their metastases.

The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008.

This article summarizes the expert discussion on the management of hepatocellular carcinoma (HCC), which took place during the 10th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, June 2008. A multidisciplinary approach to a patient with HCC is essential, to guarantee optimal diagnosis and staging, planning of surgical options and selection of embolisation strategies or systemic therapies. In many patients, the underlying cirrhosis represents a challenge and determines therapeutic options. There is now robust evidence in favour of systemic therapy with sorafenib in patients with advanced HCC with preserved liver function. Those involved in the care for patients with HCC should be encouraged to participate in well-designed clinical trials, to increase evidence-based knowledge and to make further progress.

Lymph node ratio after curative surgery for intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is rare but its incidence is rising worldwide. The value of lymph node dissection for ICC is under discussion; the current staging systems do not differentiate between numbers of involved nodes. METHODS: Ninety-three patients who underwent laparotomy for ICC between 1997 and 2007 were identified retrospectively; 46 who underwent curative resection and systematic lymphadenectomy around the hepatoduodenal ligament were analysed further. Univariable and multivariable regression analysis was performed to identify prognostic factors. RESULTS: Tumour size and advanced tumour stage were associated with worse overall and recurrence-free survival in univariable analysis. An increased ratio of positive to total harvested lymph nodes (LNR) was also prognostic for adverse outcome in lymph node-positive patients: crude hazard ratio 8.93 (95 per cent confidence interval (c.i.) 1.52 to 32.50) for overall survival and 8.76 (1.96 to 39.22) for recurrence-free survival. Adjusted hazard ratios for LNR in multivariable regression analysis were 9.81 (1.52 to 43.44) and 10.63 (2.04 to 55.31) respectively. The total number of retrieved lymph nodes was not related to survival or recurrence. CONCLUSION: LNR appears to be a good prognostic factor for survival or recurrence after curative resection for ICC.

Selective resection of colorectal liver metastases.

AIMS: Safety of liver surgery for colorectal cancer liver metastases after neoadjuvant chemotherapy has to be re-evaluated. PATIENTS AND METHODS: Two hundred Patients were prospectively analyzed after surgery for colorectal cancer liver metastases between 2001 and 2004 at our institution. Special emphasis was given to perioperative morbidity and mortality under modern perioperative care. RESULTS: There was no in-hospital mortality and the perioperative morbidity was 10% (20/200). Four patients had to be reoperated due to bile leak or intraabdominal abscess. The remainder either had infectious complications or pleural effusion and/or ascites requiring tapping. Variables strongly associated with decreased survival were T, N, G and UICC (International Union against cancer) classification of the primary, hepatic lesions>5 cm and elevated tumour markers. Short disease free interval and neoadjuvant chemotherapy without response predicted impaired recurrence free survival (RFS). Multivariate analysis revealed lymph node status and differentiation of the primary, presence of extrahepatic tumour and gender as factors associated with decreased survival. Administration of neoadjuvant chemotherapy was not associated with higher postoperative morbidity or prolonged hospital stay. CONCLUSIONS: Modern dissection techniques and improved perioperative care contributed to a very low rate of surgery-related morbidity (10%) and a zero percent mortality which was also observed in patients pretreated with neoadjuvant chemotherapy prior to resection. Liver resection in experienced hands has become a safe part in the potentially curative attempt of treating patients with metastatic colorectal cancer.

Expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu in patients with gallbladder cancer.

BACKGROUND: To improve the prognosis of gallbladder cancer (GC) patients, a better understanding of the mechanisms of tumor development and progression is essential. The deregulation of cell cycle control is a critical step in the development of cancer. The purpose of this study was to investigate the expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu in an unselected GC patient population and to assess the association of these markers with p27(Kip1) expression, p53 gene mutation status and clinical parameters of the patients. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissues from 55 operated GC patients were used to determine the expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu with immunohistochemistry. RESULTS: Expression of p21(Wafl/Cip1) was observed in 28%, of p57(Kip2) in 19% and of HER2/neu in 13% of the patients. Absence of p57(Kip2) expression was significantly associated with T3/T4 stage (p = 0.01), positive lymph nodes (p = 0.02) and advanced UICC stages (p = 0.05). HER2/neu expression significantly correlated with advanced T stages (p = 0.02). In the total patient population, p21(Wafl/Cip1), p57(Kip2) and HER2/neu had no impact on survival of the patients. Among patients with a mutated p53 gene, those without p21(Wafl/Cip1) expression had a prolonged survival compared to patients with p21(Wafl/Cip1) expression (p = 0.004). Moreover, in p27(Kip1)-positive patients, those without p21(Wafl/Cip1) expression had a longer survival than those with p21(Wafl/Cip1) expression (p = 0.003). CONCLUSION: In the subgroup of patients with a mutated p53 gene or in p27(Kip1)-positive patients, absence of p21(Wafl/Cip1) expression may be associated with longer survival of GC patients. Therefore, further analyses of this protein in larger patient populations are warranted.

HER 2/neu protein expression in colorectal cancer.

BACKGROUND: Conflicting data exist about the prevalence of HER-2/neu overexpression in colorectal cancer ranging from 0 to 83 %. In our study we tried to clarify the extent of expression and its relationship to clinicopathological parameters. METHODS: This study involved 77 specimens of malignant colorectal cancer lesions of surgically resected patients. HER-2/neu immunohistochemistry was performed using the Hercep-Test Kit. RESULTS: Out of 77 specimens, 56 were Her-2/neu negative (70%), 20 (26%) showed a barely immunostaining (1+), only 1 (1%) was moderately (2+) and 2 (3%) were strongly positive (3+). Her-2/neu staining (moderately and strongly positive) was only detected in primary tumours of patients with confirmed metastases. No relationship was found between membranous HER-2 expression and patients' gender or differentiation. The median survival time of patients with positive HER-2/neu immunostaining was 21 versus 39 months in patients without HER-2/neu expression (p = 0.088). CONCLUSION: The c-erbB protein expression was observed in colorectal cancer but rarely in the therapeutic range (2+ and 3+). There was no significant association with tumour grade, gender, localization of the primary tumour or survival. These data indicate that c-erbB-2 is unlikely to play a major role in the therapeutic management of colorectal cancer.