Impact of BCL-2 Expression on Course of Disease in Neuroblastoma.

OBJECTIVE: The antiapoptotic BCL-2 protein has implications for maturation and differentiation of neural tissue and acts as a strong modulator of carcinogenesis in different tumors. Recent research focuses not only on its benefit as a prognostic factor, but also as a potential therapeutic target. The role of BCL-2 in neuroblastoma, the most common extracranial solid tumor in childhood, remains controversial. The aim of our study was to determine the gene expression level of BCL-2 in a large cohort of neuroblastoma patients and its correlation with clinical parameters. METHODS: Tumor samples and clinical data were collected from 100 neuroblastoma patients treated according to the NB2004 protocol of the German Society of Pediatric Oncology and Hematology. BCL-2 gene expression levels were measured by quantitative reverse transcription polymerase chain reaction and correlated with clinical parameters. RESULTS: BCL-2 expression was detected in all tumor samples. Relative BCL-2 expression levels were higher in females versus males (1.839 vs. 1.342; p = 0.0143), in patients with low versus high International Neuroblastoma Staging System stage (2.051 vs. 1.463; p = 0.0206), in nonmetastatic versus metastatic disease (1.801 vs. 1.342; p = 0.0242), as well as in patients without presurgical chemotherapy (2.145 vs. 1.402; p = 0.0016), but was not associated with overall survival and MYCN amplification. CONCLUSION: Our study demonstrates the ubiquitous expression of BCL-2 in neuroblastoma and suggests the possibility for targeted therapy with BCL-2 inhibitors, even in lower-stage neuroblastoma. It also underlines the need for further research on concomitant genetic alterations for a better understanding of the impact of BCL-2 on this pediatric tumor type.

Total Psoas Muscle Area as a Marker for Sarcopenia Is Related to Outcome in Children With Neuroblastoma.

Background: Sarcopenia describes a generalized loss of skeletal muscle mass, strength, or function. Determined by measuring the total psoas muscle area (tPMA) on cross-sectional imaging, sarcopenia is an independent marker for poor post-surgical outcomes in adults and children. Children with cancer are at high risk for sarcopenia due to immobility, chemotherapy, and cachexia. We hypothesize that sarcopenic children with neuroblastoma are at higher risk for poor post-operative outcomes. Patients and Methods: Retrospective analysis of children with neuroblastoma ages 1-15 years who were treated at our hospital from 2008 to 2016 with follow-up through March 2021. Psoas muscle area (PMA) was measured from cross-sectional images, using computed tomography (CT) and magnetic resonance imaging (MRI) scans at lumbar disc levels L3-4 and L4-5. tPMA is the sum of the left and right PMA. Z-scores were calculated using age- and gender-specific reference values. Sarcopenia was defined as a tPMA z-score below -2. A correlation of tPMA z-scores and sarcopenia with clinical variables and outcome was performed. Results: One hundred and sixty-four children with workup for neuroblastoma were identified, and 101 children fulfilled inclusion criteria for further analysis, with a mean age of 3.92 years (SD 2.71 years). Mean tPMA z-score at L4-5 was -2.37 (SD 1.02). Correlation of tPMA z-score at L4-5 with weight-for-age z-score was moderate (r = 0.54; 95% CI, 0.38, 0.66). No association between sarcopenia and short-term outcome was observed. Sarcopenia had a sensitivity of 0.82 (95% CI, 0.62-0.93) and a specificity of 0.48 (95% CI 0.36-0.61) in predicting 5-year survival. In a multiple regression analysis, pre-operative sarcopenia, pre-operative chemotherapy in the NB2004 high-risk group, unfavorable tumor histology, and age at diagnosis were associated with 5-year survival after surgery, with hazard ratios of 4.18 (95% CI 1.01-17.26), 2.46 (95% CI 1.02-5.92), 2.39 (95% CI 1.03-5.54), and 1.01 (95% CI 1.00-1.03), respectively. Conclusion: In this study, the majority of children had low tPMA z-scores and sarcopenia was a risk factor for decreased 5-year survival in children with neuroblastoma. Therefore, we suggest measuring the tPMA from pre-surgical cross-sectional imaging as a biomarker for additional risk stratification in children with neuroblastoma.

Lymphatic Leakage after Surgery for Neuroblastoma: A Rare Complication?

INTRODUCTION: Neuroblastoma is the most common extracranial solid tumor in infancy. It is responsible for around 15% of all oncological deaths during childhood. Due to its retroperitoneal location, neuroblastoma is invasively growing directly in and around the lymphatic duct. Consecutively, lymphatic leakage (LL) after surgery for neuroblastoma is a known complication. The purpose of this study is the investigation of frequency and impact of this complication. MATERIAL AND METHODS: Between February 2003 and December 2016, 204 patients with neuroblastoma received surgical treatment in our department. A retrospective analysis for macroscopical extent of resection, duration of drainage postsurgery, maximum amount of fluid drained in 24 hours, MYCN amplification status, therapeutic options for LL, follow-up status, and overall survival was performed. RESULTS: A total of 40% of patients (82/204) showed LL to some extent. In patients with MYCN amplification, LL was seen significantly more often than in patients without MYCN amplification status (p = 0.019). LL was also significantly correlated with extent of surgery (p = 0.005). Follow-up status and overall survival were significantly inversely associated with LL (p = 0.004 and p = 0.0001). LL was self-limiting in all cases. There was a trend toward shorter duration of LL if either no special therapy was chosen or total parenteral nutrition (TPN) was administered (p = 0.0603). CONCLUSION: We show that LL in neuroblastoma is a common complication of tumor resection and occurring more often than anticipated. Since, in our study cohort, all cases of LL were self-limiting, we question the indication for invasive therapy besides supporting measures.

Implication of Image-Defined Risk Factors for the Extent of Surgical Resection and Clinical Outcome in Patients with Pelvic Neuroblastoma.

INTRODUCTION: Pelvic neuroblastoma (NB) is a rare entity and occurs in 2 to 5% of all NBs. Surgery in the pelvic area is-even for the experienced oncological surgeon-technically challenging, as injuries of bladder and/or rectal innervation may carry lifelong consequences for the patient. Several studies have proven the impact of image-defined risk factors (IDRFs) for outcome, complications and extent of resection in NB; however, the specific role of IDRF in pelvic NB has not been investigated yet. MATERIALS AND METHODS: Patient charts were retrospectively evaluated for International Staging System stage, IDRF status, MYCN amplification, and outcome parameters. RESULTS: Between 2003 and 2019, 277 NBs were surgically resected in the department of pediatric surgery of Dr. von Hauner Children's Hospital. Out of these, 11 patients (3.9%) had pelvic NB. Evaluation of the preoperative imaging showed two patients without IDRF (stage L1) and eight patients in stage L2. One patient had stage M according to distant metastasis. Patients without IDRF underwent complete macroscopical resections, whereas complete tumor removal was not possible without mutilation in patients with IDRF. At time point of diagnosis, only patients with IDRF had functional neurological problems. Three patients developed perioperative complications; all of them had at least one IDRF. Three patients developed local recurrence during the course of the disease, all of them had at least one IDRF. CONCLUSION: Our results indicate on a preliminary level the importance of IDRF as a prognostic tool for surgical removal of pelvic NB.

Additive value of transarterial embolization to systemic sirolimus treatment in kaposiform hemangioendothelioma.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor in children, which can be accompanied by life-threatening thrombocytopenia, referred to as Kasabach-Merritt phenomenon (KMP). The mTOR inhibitor sirolimus is emerging as targeted therapy in KHE. As the sirolimus effect on KHE occurs only after several weeks, we aimed to evaluate whether additional transarterial embolization is of benefit for children with KHE and KMP. Seventeen patients with KHE and KMP acquired from 11 hospitals in Germany were retrospectively divided into two cohorts. Children being treated with adjunct transarterial embolization and systemic sirolimus, and those being treated with sirolimus without additional embolization. Bleeding grade as defined by WHO was determined for all patients. Response of the primary tumor at 6 and 12 months assessed by magnetic resonance imaging (MRI), time to response of KMP defined as thrombocyte increase >150 × 103 /µL, as well as rebound rates of both after cessation of sirolimus were compared. N = 8 patients had undergone additive embolization to systemic sirolimus therapy, sirolimus in this group was started after a mean of 6.5 ± 3 days following embolization. N = 9 patients were identified who had received sirolimus without additional embolization. Adjunct embolization induced a more rapid resolution of KMP within a median of 7 days vs 3 months; however, tumor response as well as rebound rates were similar between both groups. Additive embolization may be of value for a more rapid rescue of consumptive coagulopathy in children with KHE and KMP compared to systemic sirolimus only.

Vessel adherent growth represents a major challenge in the surgical resection of neuroblastoma and Is associated with adverse outcome.

PURPOSE: Neuroblastoma (NB) is the most common extracranial, solid tumor in childhood, with a peak incidence in children under 6 years of age. Due to its variable course of disease, which ranges from spontaneous regression to metastatic spread, NB still represents a significant therapeutic challenge. Strikingly, a certain number of NBs intraoperatively show vessel adhesion and/or infiltrative growth, which is often not visible in pre-operative imaging. We proposed the term unexpected vessel infiltration of NB (UVIN) to denote this phenomenon. UVIN represents a major surgical challenge. METHODS: In this study, we determined frequency and clinical relevance of UVIN in a cohort of 100 NB-patients with subsequent correlation to several unfavorable characteristics of disease. RNA expression levels of MYCN and its co-regulated antisense transcript MYCNOS to identify markers was measured by PCR. RESULTS: We found UVIN to be present in 34% of cases and significantly correlated with incomplete resection, MYCN amplification, complications, neoadjuvant therapy, tumor grade and MYCNOS expression levels. MYCN expression levels showed no significant results with UVIN. CONCLUSION: Collectively, our data show that UVIN represents a frequent surgical problem associated with a poor outcome in NB patients. MYCN and MYCNOS seem to be no appropriate markers for UVIN. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level III.

Expression of Truncated Neurokinin-1 Receptor in Childhood Neuroblastoma is Independent of Tumor Biology and Stage.

BACKGROUND: Neuroblastoma is an embryonal malignancy arising from the aberrant growth of neural crest progenitor cells of the sympathetic nervous system. The tachykinin receptor 1 (TACR1) - substance P complex is associated with tumoral angiogenesis and cell proliferation in a variety of cancer types. Inhibition of TACR1 was recently described to impede growth of NB cell lines. However, the relevance of TACR1 in clinical settings is unknown. PATIENTS AND METHODS: We investigated gene expression levels of full-length and truncated TACR1 in 59 neuroblastomas and correlated these data with the patients' clinical parameters such as outcome, metastasis, International Neuroblastoma Staging System (INSS) status, MYCN proto-oncogene, bHLH transcription factor (MYCN) status, gender and age. RESULTS: Our results indicated that TACR1 is ubiquitously expressed in neuroblastoma but expression levels are independent of clinical parameters. CONCLUSION: Our data suggest that TACR1 might serve as a potent anticancer target in a large variety of patients with neuroblastoma, independent of tumor biology and clinical stage.

Complete surgical resection improves outcome in INRG high-risk patients with localized neuroblastoma older than 18 months.

BACKGROUND: Although several studies have been conducted on the role of surgery in localized neuroblastoma, the impact of surgical timing and extent of primary tumor resection on outcome in high-risk patients remains controversial. METHODS: Patients from the German neuroblastoma trial NB97 with localized neuroblastoma INSS stage 1-3 age > 18 months were included for retrospective analysis. Imaging reports were reviewed by two independent physicians for Image Defined Risk Factors (IDRF). Operation notes and corresponding imaging reports were analyzed for surgical radicality. The extent of tumor resection was classified as complete resection (95-100%), gross total resection (90-95%), incomplete resection (50-90%), and biopsy (<50%) and correlated with local control rate and outcome. Patients were stratified according to the International Neuroblastoma Risk Group (INRG) staging system. Survival curves were estimated according to the method of Kaplan and Meier and compared by the log-rank test. RESULTS: A total of 179 patients were included in this study. 77 patients underwent more than one primary tumor operation. After best surgery, 68.7% of patients achieved complete resection of the primary tumor, 16.8% gross total resection, 14.0% incomplete surgery, and 0.5% biopsy only. The cumulative complication rate was 20.3% and the surgery associated mortality rate was 1.1%. Image defined risk factors (IDRF) predicted the extent of resection. Patients with complete resection had a better local-progression-free survival (LPFS), event-free survival (EFS) and OS (overall survival) than the other groups. Subgroup analyses showed better EFS, LPFS and OS for patients with complete resection in INRG high-risk patients. Multivariable analyses revealed resection (complete vs. other), and MYCN (non-amplified vs. amplified) as independent prognostic factors for EFS, LPFS and OS. CONCLUSIONS: In patients with localized neuroblastoma age 18 months or older, especially in INRG high-risk patients harboring MYCN amplification, extended surgery of the primary tumor site improved local control rate and survival with an acceptable risk of complications.

Survival of metastatic gastric cancer: Significance of age, sex and race/ethnicity.

BACKGROUND: Despite the success of modern chemotherapy in the treatment of large bowel cancers, patients with metastatic gastric cancer continue to have a dismal outcome. Identifying predictive and prognostic markers is an important step to improving current treatment approaches and extending survival. METHODS: Extracting data from the US NCI's Surveillance, Epidemiology, and End Results (SEER) registries, we compared overall survival for patients with metastatic gastric cancer by gender, age, and ethnicity using Cox proportional hazards models. 13,840 patients (≥ 18 years) were identified from 1988-2004. Males and females were categorized by age grouping and ethnicity. RESULTS: 19% of Hispanic patients were diagnosed < 45 years of age as compared to 5.5% of Caucasians. Caucasian patients and men were more likely to be diagnosed with tumors in the gastric cardia (P<0.001). In our survival analysis, we found that women had a lower risk of dying as compared to men (P<0.001). Overall survival diminished with age (P<0.001). The median overall survival was 6 months in patients of ≤ 44 years old as compared to 3 months in patients 75 years and older. Gender differences in overall survival significantly varied by race and tumor grade/differentiation (P for interaction = 0.003 and 0.005, respectively). CONCLUSION: This is the largest study of metastatic gastric cancer patients from the SEER registry to show that age, gender, and tumor location are significant independent prognostic factors for overall survival in patients with metastatic gastric cancer.

Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models.

Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, is known to possess tumorigenic and proangiogenic properties. Overexpression of IL-8 has been detected in many human tumors, including colorectal cancer (CRC), and is associated with poor prognosis. The goal of our study was to determine the role of IL-8 overexpression in CRC cells in vitro and in vivo. We stably transfected the IL-8 cDNA into two human colon cancer cell lines, HCT116 and Caco2, and selected IL-8-secreting transfectants. Real-time RT-PCR confirmed that IL-8 mRNA was overexpressed in IL-8 transfectants with 45- to 85-fold higher than parental cells. The IL-8-transfected clones secreted 19- to 28-fold more IL-8 protein than control and parental cells as detected by ELISA. The IL-8 transfectants demonstrated increased cellular proliferation, cell migration and invasion based on functional assays. Growth inhibition studies showed that IL-8 overexpression lead to a significant resistance to oxaliplatin (p < 0.0001). Inhibition of IL-8 overexpression with small interfering RNA reversed the observed increases in tumorigenic functions and oxaliplatin resistance, suggesting that IL-8 not only provides a proliferative advantage but also promotes the metastatic potential of colon cancer cells. Using a tumor xenograft model, IL-8-expressing cells formed significantly larger tumors than the control cells with increased microvessel density. Together, these findings indicate that overexpression of IL-8 promotes tumor growth, metastasis, chemoresistance and angiogenesis, implying IL-8 to be an important therapeutic target in CRC.

Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study).

BACKGROUND: To test whether intratumoral gene expression levels and germline polymorphisms predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab and bevacizumab plus irinotecan (CBI) vs. cetuximab and bevacizumab (CB)(BOND2). PATIENTS AND METHODS: Genomic DNA was extracted for genotyping from 65 patients (31: CBI arm and 34: CB arm). Thirty five patients had tissue samples available for the gene expression assay (18: CBI arm and 17: CB arm). RESULTS: High intratumoral gene expression levels of EGFR, VEGFR2 and NRP1 were associated with longer overall survival (OS) in patients receiving combined monoclonal antibodies with or without irinotecan. FCGR3A V158F, CyclinD1 A870G and EGFR R497K polymorphisms are associated with clinical outcome in patients received combined cetuximab and bevacizumab. CONCLUSIONS: Intratumoral gene expression levels of EGFR, VEGFR2 and NRP as well as polymorphisms in FCGR3A, CyclinD1 and EGFR could predict clinical outcome in mCRC patients enrolled in BOND2, independent of KRAS mutation status.

Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients.

PURPOSE: The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti-epidermal growth factor receptor-targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144). EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded (FFPE) tissue samples of 130 drug-refractory mCRC patients enrolled in IMC-0144, a phase II clinical trial of cetuximab monotherapy, were analyzed. gDNA was extracted from dissected FFPE tumor tissue, and KRAS mutation status and six potentially functional IGF1 and IGF1R polymorphisms were analyzed using direct DNA sequencing or PCR-RFLP. Tumor response analysis was based on recursive partitioning, and survival analyses were based on univariate and multivariate hazard regression models. RESULTS: In univariate and multivariate analyses, five IGF pathway single-nucleotide polymorphisms were significantly associated with progression-free survival (PFS) and/or overall survival (OS). In multivariate combined risk allele analysis, the additive model for PFS and OS was significantly associated with the number of risk alleles in wt KRAS patients (P = 0.001 and P = 0.02, respectively). In addition, wt KRAS patients harboring IGF1 rs2946834 A/A genotype had a 50% objective response rate compared with 0% for A/G genotype. CONCLUSIONS: These results indicate that IGF1 pathway polymorphisms are potential predictive/prognostic molecular markers for cetuximab efficacy in wt KRAS mCRC patients. Prospective biomarker-embedded clinical trials are warranted to validate our findings. Clin Cancer Res; 16(22); 5591-602. ©2010 AACR.

Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus.

OBJECTIVE: The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms. SUMMARY BACKGROUND DATA: Systemic tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis will help to better define tumor stage, indicate disease progression, identify novel therapeutic targets, and monitor response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal growth factor (EGF) have been shown to mediate the regulation of local and early-onset angiogenesis, and in turn may impact the process of tumor growth and disease progression. METHODS: We investigated tissue samples from 239 patients with localized EA treated with surgery alone. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism and 5'-end [gamma-P] ATP-labeled polymerase chain reaction methods. RESULTS: PAR-1 -506 ins/del (adjusted P value=0.011) and EGF +61 A>G (adjusted P value=0.035) showed to be adverse prognostic markers, in both univariate and multivariable analyses. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted P value<0.001). CONCLUSION: This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence.

Gender disparities in metastatic colorectal cancer survival.

PURPOSE: Previous studies have shown that estrogen prevents colon cancer in postmenopausal women, indicating a role in colorectal cancer carcinogenesis and tumor progression. We investigated the interactions between sex, age, ethnicity, and year of diagnosis on overall survival (OS) in patients with metastatic colorectal cancer (MCRC). EXPERIMENTAL DESIGN: We screened 52,882 patients with MCRC from 1988 to 2004, using the Surveillance Epidemiology and End Results registry. Age at diagnosis, sex, ethnicity, tumor location, year of diagnosis, OS, and cancer-specific survival were evaluated using Cox proportional hazards model. The models were adjusted for marital status, tumor site, tumor differentiation, and treatment with radiation and/or surgery. RESULTS: We observed that younger women (18-44 years old) with MCRC lived longer than younger men (17 months versus 14; P < 0.0001, log-rank test). In contrast, older women (55 years and older) had significantly worse OS than older men (7 months versus 9; P < 0.0001, log-rank test). In multivariate analysis, we found that gender discrepancies have widened in recent years; young women diagnosed after 2000 have improved cancer-specific survival, compared to men (hazard ratio, 0.778; 95% confidence interval, 0.669-0.904), but those diagnosed before 2000 benefit less (hazard ratio, 0.931; 95% confidence interval, 0.821-1.056). CONCLUSION: As one of the largest data sets analyzed to establish that younger women with MCRC survive longer than younger men, hormonal status not only seems to play an important role in the development and pathogenesis of colorectal cancer but also may be of prognostic significance. These data warrant further studies to determine the role of estrogen in colorectal cancer.

Thymidylate synthase gene variations: predictive and prognostic markers.

Since its introduction more than 50 years ago by Heidelberger et al., the fluoropyrimidine 5-fluorouracil (5-FU) has remained the mainstay of therapeutic regimens used in the treatment of colorectal cancer and other human malignancies, with single-agent response rates of 20% to 25% in advanced disease stage. Pharmacogenomics has emerged as a useful tool to address interindividual gene variations by analyzing the interplay of host and tumor genotype and drug efficacy and toxicity. Having a reliable panel of prognostic and predictive markers will be critical in selecting an individualized and tailored chemotherapy regimen based on the particular tumor and host genotype. Although conflicting results have been reported, higher thymidylate synthase (TS) protein and mRNA expression levels in tumors have generally been associated with poor clinical outcome in patients treated with 5-FU-based chemotherapy regimens. However, the cause of the variability in TS expression still remains not fully understood, although several germ-line polymorphisms seem to affect the expression of TS, some of which have been found to have an effect on prognosis and the probability of response to 5-FU-based chemotherapy. This review will provide an update on pharmacogenomic studies of TS that were aimed at elucidating their role as prognostic and predictive markers.

Polymorphisms in interleukin 1 beta and interleukin 1 receptor antagonist associated with tumor recurrence in stage II colon cancer.

PURPOSE: Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage II colon cancer who are more likely to benefit from adjuvant chemotherapy. Interleukin 1 beta (IL1B) and interleukin 1 receptor antagonist (IL1RN) have been shown to play a critical role in the early onset of tumor-associated angiogenesis. In this study, we tested whether eight functionally significant polymorphisms within six genes of the angiogenesis pathway [IL1B, IL1RN, vascular endothelial growth factor A (VEGFA), VEGF receptor 2, interleukin-8, cyclooxygenase-2] will predict the risk of tumor recurrence in stage II colon cancer patients treated with 5-fluorouracil based adjuvant chemotherapy. EXPERIMENTAL DESIGN: Blood samples were obtained from 109 patients with stage II colon cancer at the University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism protocols. RESULTS: Patients harboring the IL1RN/IL1B 1-T-C (IL-1RN variable number tandem repeats (VNTR)/IL1B C+3954T/C-511T) haplotype were at greatest risk of developing tumor recurrence [relative risk (RR): 2.72, 95% confidence interval (CI): 1.22-6.08] (adjusted P=0.015). In addition, IL1B +3954 any T (RR: 2.78, 95% CI: 0.99-7.83) (adjusted P=0.043), IL1RN VNTR (RR: 6.09, 95% CI: 1.11-33.4) (adjusted P=0.038), and VEGFA -634 any C (RR: 2.91, 95% CI: 1.13-7.48) (adjusted P=0.026) were shown to be adverse prognostic markers, in both univariate and multivariable analyses. CONCLUSION: Polymorphisms in IL1B, IL1RN, and VEGFA as well as IL1B/IL1RN haplotype analysis may serve as molecular markers for tumor recurrence in stage II colon cancer, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.

Pharmacogenomics and -genetics in colorectal cancer.

Despite recent progress in our knowledge about the development and therapy of colorectal cancer (CRC), it still remains one of the major cancer related deaths throughout the world. With the introduction of new cytotoxic and targeting agents a significant improvement in progression-free and overall survival has been achieved. However, a significant percentage (40-50%) of patients do not experience beneficial effects and suffer from severe toxicities. It will be critical to identify molecular markers, which may help to assess therapeutic response and outcome in CRC. Validation of predictive and prognostic molecular markers will enable oncologists to tailor patient specific treatment strategies for the individual patient according to the molecular profile of both the patient and their tumor. Individualized therapy will help to improve therapeutic efficacy and to minimize toxicities and therapeutic expenses.

Frequent down-regulation of pim-1 mRNA expression in non-small cell lung cancer is associated with lymph node metastases.

Pim kinases are emerging as important mediators of cytokine signalling pathways in hematopoietic cells, and contribute to the progression of certain leukemias and solid tumors. The mRNA expression of pim-1, a putative oncogenic serine-threonine kinase, was determined in non-small cell lung cancer (NSCLC) patients. Sixty-eight patients with potentially curative resections (R0 resections) for NSCLC in histopathological stages I-IIIA were included. An analysis of pim-1 mRNA expression was performed on paired tumor and normal lung tissue samples by quantitative real-time reverse transcriptase-PCR (RT-PCR) standardized for beta-actin. Pim-1 expression in the tumor (median 0.28) was significantly down-regulated (p<0.0001) compared to the paired normal tissue (median 4.96). Immunohistochemistry showed a strong expression of Pim-1 protein in the normal respiratory epithelium and a lower expression in the tumor cells. A significant association between the pim-1 down-regulation and occurrence of lymph node metastases (p=0.05) was detected. The down-regulation of pim-1 mRNA was demonstrated for 59 out of 68 lung cancer patients (86.8%). Down-regulation occurs already in the early stage of NSCLC and is either directly involved in the lymphatic progression in NSCLC or represents a surrogate marker.

Targeting metastatic colorectal cancer in 2008: a long way from 5-FU.

Colorectal cancer is one of the leading causes of cancer-related death worldwide, with almost 20% of all patients presenting with metastatic disease at the time of their diagnosis. The treatment regimens and options of metastatic colorectal cancer have significantly changed in the last 10 years, leading to an improvement of response rates to about 50%, progression-free survival of about 10 months, and overall survival reaching over 2 years. Beside US Food and Drug Administration approval of the cytotoxic agents irinotecan (Camptosar), oxaliplatin (Eloxatin), and capecitabine (Xeloda), the increasing understanding of molecular pathways that comprise the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy. The biologic agent bevacizumab (Avastin), an inhibitor against vascular endothelial growth factor, and cetuximab (Erbitux) and panitumumab (Vectibix), monoclonal antibodies to epidermal growth factor receptor, have demonstrated their efficacy in clinical trials. This article reviews the mechanisms of action and possible markers of resistance, and summarizes data on the clinical efficacy of targeting agents.

Stem cells in colon cancer.

The concept that cancer might arise from a rare population of cells with stem cell-like properties was proposed 150 years ago. Increasing evidence during the past 2 decades suggests the existence of a small subgroup of cells in cancer that are responsible for tumor growth and proliferation. Stem cells have self-renewing properties; thus, they are appealing candidates for generating the malignant phenotype. Although the concept of stem cells in leukemia has received significant attention for more than the past decade, over the past several years, expression of several surface markers on cancer cells has led to identification of tumor-initiating cells in several solid tumors, including melanoma, brain, breast, prostate, liver, pancreatic, ovarian, and recently, colon cancer. This review will provide an update of the biologic basis of the stem cell model and possible targets for the treatment of colon cancer.