[Show abstract][Hide abstract] ABSTRACT: Background
Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.Methods
The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 ¿, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators.Survival analyses were calculated for all patients receiving adjuvant chemotherapy in relation to expression of all makers above.ResultsPatients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 ¿, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 ¿ (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.Conclusions
The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 ¿ negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/¿ irinotecan in stage II/III colorectal cancer.
Journal of Experimental & Clinical Cancer Research 10/2014; 33(1):83. DOI:10.1186/PREACCEPT-1081572601135276 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Our aim was to compare long-term results of adjuvant treatment of colon cancer (CC) and rectal cancer (RC). Adjuvant chemotherapy of CC improved overall survival (OS), whereas that of RC remained at the level achieved by 5-fluorouracil (5-FU). METHODS: We separately conducted 2 identically designed adjuvant trials in CC and RC. Patients were assigned to adjuvant chemotherapy with 5-FU alone, 5-FU + folinic acid (FA), or 5-FU + interferon-alfa. The first study enrolled patients with stage IIb/III CC, and the second study enrolled patients with stage II/III RC. All patients with RC received postoperative irradiation. RESULTS: Median follow-up for all patients with CC (n = 855) and RC (n = 796) was 4.9 years. The pattern and frequency of recurrence differed significantly, especially lung metastases, which occurred more frequently in RC (12.7%) than in CC (7.3%; P < .001). Seven-year OS rates for 5-FU, 5-FU + FA, and 5-FU + IFN-alfa were 54.1% (95% confidence interval [CI], 46.5-61.0), 66.8% (95% CI, 59.4-73.1), and 56.7% (95% CI, 49.3-63.4) in CC and 50.6% (95% CI, 43.0-57.7), 56.3% (95% CI, 49.4-62.7), and 54.8% (95% CI, 46.7-62.2) in RC, respectively. A subgroup analysis pointed to a reduced local recurrence (LR) rate and an increased OS by the addition of FA in stage II RC (n = 271) but not in stage III RC (n = 525). CONCLUSION: FA increased 7-year OS by 12.7 percentage points in CC but was not effective in RC. Based on these results and the pattern of metastases, our results suggest that the chemosensitivity of CC and RC may be different. Strategies different from those used in CC may be successful to decrease the frequency of distant metastases in RC in the future.
Clinical Colorectal Cancer 10/2012; 12(1). DOI:10.1016/j.clcc.2012.07.005 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/aims:
Thymidylate synthase (TS) is an enzyme for DNA-synthesis and the target for 5-fluorouracil whereas cyclin-D1 plays a critical role in the progression of cells through the G1 phase of the cell-cycle. There is evidence that expression of these markers may predict the outcome of patients with colorectal cancers. The aim of this study was to examine the prognostic value of TS and cyclin D1 protein expression in patients with node negative colorectal cancers.
TS and cyclin D1 protein expression from 140 patients with UICC stage I and II colorectal cancer was analyzed by immunhistochemistry in paraffin-embedded primary tumour specimens.
The 1-, 5- and 10-year overall-survival rates were 96%, 86% and 71%, respectively. Tumour stage and recurrence were associated with overall-survival. Low- and high TS immunoreactivity was present in 68 (48%) and 72 (52%) of cancers, respectively. Low- and high cyclin D1 immunoreactivity was present in 98 (70%) and 42 (30%) of the cancers, respectively. Patients (n=72) with high TS expressing tumours had a worse overall-survival than patients (n=68) with low TS expressing colorectal cancers (p=0.011). No difference in overall-survival was seen between patients with high and low cyclin D1 expressing cancers.
TS may be helpful as a prognostic marker in lymph node negative colorectal cancer.
[Show abstract][Hide abstract] ABSTRACT: Gastric cancer is the fourth cancer in incidence worldwide, with a high disease-related death rate. The aim of this study was to evaluate the importance of clinical and pathological factors for the prognosis of gastric cancer patients.
We analysed data from 304 consecutive patients. Clinical and pathological factors and the surgical resection status were analysed by univariate analyses, followed by investigation of important factors using a proportional hazard regression analysis with backward elimination in order to identify important independent prognostic factors.
Univariate analysis revealed that age, pT, pN, M, UICC stage, grading, and resection status were significantly associated with survival. Multivariate analysis identified age, pT, pN, M, and resection status as independent prognostic factors.
Besides age and pathological parameters, radical R0 resection plays an essential role in the management of gastric cancer and should be aimed at, even if extended resection may be necessary.
Anticancer research 05/2012; 32(5):1839-42. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease.
Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I-III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance.
All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p = 0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival.
Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.
International Journal of Colorectal Disease 03/2012; 27(10):1369-76. DOI:10.1007/s00384-012-1456-0 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High-level microsatellite instability (MSI-H) has been reported as a prognostic marker in colon cancer. We here analysed the prognostic significance of MSI and mutations of the Beta2-Microglobulin (B2M) gene, which occur in about 30% of MSI-H colon cancer, in the cohort of the prospective FOGT-4 (Forschungsruppe Onkologie Gastrointestinale Tumoren, FOGT) trial.
Microsatellite instability status was determined using standard protocols (NCI/ICG-HNPCC panel and CAT25) in 223 colon cancer lesions. Beta2-Microglobulin mutation status was evaluated by exon-wise sequencing in all MSI-H lesions.
Patients with MSI-H (n=34) colon cancer presented with a significantly lower risk of relapse after 12 months of follow-up compared with MSS (n=189) colon cancer patients (5 year time to relapse: MSI-H 0.82 vs MSS 0.66, P=0.03). No significant difference in overall survival was detected. Beta2-Microglobulin mutations were identified in 10 (29.4%) out of 34 MSI-H colon cancers and were associated with a complete absence of disease relapse or tumour-related death events (P=0.09).
The risk of late disease relapse was significantly lower in patients with MSI-H compared with MSS colon cancer. Moreover, B2M mutations may contribute to the favourable outcome of MSI-H colon cancer patients and should therefore be evaluated as a potential prognostic marker in future clinical trials.
British Journal of Cancer 02/2012; 106(6):1239-45. DOI:10.1038/bjc.2012.53 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Translational control mediated by non-coding microRNAs (miRNAs) plays a key role in the mechanism of cellular resistance to anti-cancer drug treatment. Dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS, TS) are two of the most important targets for antifolate- and fluoropyrimidine-based chemotherapies in the past 50 years. In this study, we investigated the roles of miR-215 in the chemoresistance to DHFR inhibitor methotrexate (MTX) and TS inhibitor Tomudex (TDX).
The protein levels of both DHFR and TS were suppressed by miR-215 without the alteration of the target mRNA transcript levels. Interestingly, despite the down-regulation of DHFR and TS proteins, ectopic expression of miR-215 resulted in a decreased sensitivity to MTX and TDX. Paradoxically, gene-specific small-interfering RNAs (siRNAs) against DHFR or TS had the opposite effect, increasing sensitivity to MTX and TDX. Further studies revealed that over-expression of miR-215 inhibited cell proliferation and triggered cell cycle arrest at G2 phase, and that this effect was accompanied by a p53-dependent up-regulation of p21. The inhibitory effect on cell proliferation was more pronounced in cell lines containing wild-type p53, but was not seen in cells transfected with siRNAs against DHFR or TS. Moreover, denticleless protein homolog (DTL), a cell cycle-regulated nuclear and centrosome protein, was confirmed to be one of the critical targets of miR-215, and knock-down of DTL by siRNA resulted in enhanced G2-arrest, p53 and p21 induction, and reduced cell proliferation. Additionally, cells subjected to siRNA against DTL exhibited increased chemoresistance to MTX and TDX. Endogenous miR-215 was elevated about 3-fold in CD133+HI/CD44+HI colon cancer stem cells that exhibit slow proliferating rate and chemoresistance compared to control bulk CD133+/CD44+ colon cancer cells.
Taken together, our results indicate that miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX. The findings of this study suggest that miR-215 may play a significant role in the mechanism of tumor chemoresistance and it may have a unique potential as a novel biomarker candidate.
Molecular Cancer 04/2010; 9:96. DOI:10.1186/1476-4598-9-96 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, high-throughput microRNA (miRNA) expression analysis revealed that the expression of miR-140 was associated with chemosensitivity in osteosarcoma tumor xenografts. Tumor cells ectopically transfected with miR-140 were more resistant to methotrexate and 5-fluorouracil (5-FU). Overexpression of miR-140 inhibited cell proliferation in both osteosarcoma U-2 OS (wt-p53) and colon cancer HCT 116 (wt-p53) cell lines, but less so in osteosarcoma MG63 (mut-p53) and colon cancer HCT 116 (null-p53) cell lines. miR-140 induced p53 and p21 expression accompanied with G(1) and G(2) phase arrest only in cell lines containing wild type of p53. Histone deacetylase 4 (HDAC4) was confirmed to be one of the important targets of miR-140. The expression of endogenous miR-140 was significantly elevated in CD133(+hi)CD44(+hi) colon cancer stem-like cells that exhibit slow proliferating rate and chemoresistance. Blocking endogenous miR-140 by locked nucleic acid-modified anti-miR partially sensitized resistant colon cancer stem-like cells to 5-FU treatment. Taken together, our findings indicate that miR-140 is involved in the chemoresistance by reduced cell proliferation through G(1) and G(2) phase arrest mediated in part through the suppression of HDAC4. miR-140 may be a candidate target to develop novel therapeutic strategy to overcome drug resistance.
[Show abstract][Hide abstract] ABSTRACT: Interleukin-13 (IL-13) is an anti-inflammatory cytokine produced in cells of hematopoetic origin. It is not known whether pancreatic cancer cells produce IL-13 or whether IL-13 can modulate pancreatic cancer cell growth and influence the frequency of lymph node metastases.
Cell growth and signaling were analyzed by cell counting, colorimetric proliferation assays, fluorescent-activated cell sorting, and in vitro kinase activity assays. IL-13 expression and secretion were determined by Northern blot analysis and enzyme-linked immunosorbent assay, respectively. Localization of IL-13 and its transmembrane receptor (IL-4R) in primary pancreatic ductal adenocarcinoma (PDAC) was characterized by immunohistochemistry.
IL-13 enhanced the growth of ASPC-1, CAPAN-1, and COLO-357 cells. This was associated with enhanced p44/42 mitogen-activated protein kinase (MAPK) phoshorylation. In contrast to p44/42 MAPK, phosphatidylinositol 3-kinase activity was also induced in IL-13-unresponsive MIA PaCa-2, PANC-1, and T3M4 cells. All cells expressed and secreted IL-13. Neutralizing IL-13 antibodies inhibited the growth of ASPC-1 and CAPAN-1 cells. Immunohistochemical analysis of resected primary ductal adenocarcinoma specimens revealed high levels of IL-13 in 30 of 70 cases and its transmembrane receptor (IL-4R) in 28 of 70 cases, respectively. Fifteen of 16 specimens (94%) exhibiting high IL-13 and IL-4R coexpression had lymph node metastases, while only 30 of the remaining 54 samples (56%) had positive lymph nodes (p = 0.0134).
IL-13 can act as an autocrine growth factor in PDAC. Endogenous expression of IL-13 in conjunction with IL-4R in the cancer cells seems to facilitate lymph node metastasis.
International Journal of Colorectal Disease 09/2008; 24(1):57-67. DOI:10.1007/s00384-008-0550-9 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anorectal melanoma is a rare, highly malignant tumour with a poor 5 year survival of 10%. Most anorectal melanomas have gross and/or histologic pigmentation, however about 30% of anorectal melanomas are amelanotic.
We report three cases of amelanotic anorectal melanomas and integrate our data with six case reports of amelanotic malignant melanoma from the literature. Further we compare clinicopathological data and clinical outcome with large series of anorectal melanomas (both, amelanotic and pigmentated).
There were seven females and two males, of median age 62 years (range: 45-75 years). Rectal bleeding was the leading symptom in all cases with a mean duration of 4 months before diagnosis. Eight of nine patients developed distant metastases. Median survival was 14 months (range: 3-60 months). A tumour thickness of < 4 mm was correlated with long-term disease-free survival, whereas tumour thickness of 4 mm or more was correlated with systemic recurrence.
Early diagnosis is key for efficient treatment and improved survival rate for patients with this unusual variant of melanoma. There is no difference in terms of age, time of diagnosis, stage and survival between pigmented and amelanotic anorectal melanoma.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Necrotising pancreatitis may develop as a consequence of pancreatic duct obstruction by stones, tumors or in the presence of a pancreas divisum. Alcohol and nicotine are regarded as risk factors for the disease becoming chronic. PATIENT AND COURSE OF THE DISEASE: A 63-year-old female patient with suspected cystadenocarcinoma of the pancreas tail, which was resolved as a pancreatic pseudocyst, was treated for recurrent pancreatitis for 2 years. A tumor in the pancreas head was only detected on a follow-up CT after resection of a complicating liver abscess. In retrospect, progressive pancreatic duct anomalies were visible on previous scans. Partial duodenopancreatectomy confirmed the presence of a pancreas head carcinoma. CONCLUSION: Continuous critical re-evaluation of all potential causes of pancreatitis including rare conditions, such as a tumor, is required particularly if pancreatitis recurs over a long period. Re-evaluation of studies over time and of findings apart from the actual main focus of the complication, in this case pancreatitis of the pancreas tail, may help to detect the underlying disease instead of just treating the consequences.
Der Chirurg 04/2008; 79(3):252-7. · 0.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adjuvant chemotherapy is recommended for stage III colon cancer. The aim of this study was to identify important prognostic factors among patients with colon cancer receiving adjuvant 5-FU-based treatment.
Data sets of 855 colon cancer patients treated between 1992 and 1999 within a multicenter adjuvant trial comparing 5-FU modulation with folinic acid or interfereron-alpha were examined. Backward elimination in a proportional hazards model was used to identify prognostically relevant clinical and pathological factors.
Tumor recurrence (p<0.001), duration of adjuvant treatment (p<0.001), tumor substage (p=0.004), age (p=0.005), grading (p=0.016), treatment-related toxicity (p=0.021), and treatment (p=0.031) were identified in descending order of importance as prognostic factors for overall survival.
Adjuvant 5-FU-based treatment should be performed for at least 6months with a stepwise adjustment of 5-FU doses until toxicity >WHO II. Substages should be reported separately and used for stratification in future trials due to their broad variation in outcome. In the future, this may result in adjuvant treatment of stage III colon cancer adjusted for the risk of substages.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 02/2008; 34(12):1316-21. DOI:10.1016/j.ejso.2008.01.019 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies from our laboratory have identified a number of genes associated with chemosensitivity to 5-fluorouracil (5-FU) using an in vitro colon cancer cell line model. In this study, the in vivo significance of several marker genes in terms of prognostic potential was evaluated using colorectal cancer patient samples. Eight marker genes were selected based on their functional roles and significant fold changes in expression. They are SERTA domain containing 1 (SEI1), ribonucleotide reductase M2 polypeptide (RRM2), origin recognition complex, subunit 6 homolog-like (ORC6L), eukaryotic translation initiation factor 4E (EIF4E), thymidylate synthase (TS), SET and MYND domain containing 3 (SMYD3), Dickkopf homolog 4, and methyl-CpG binding domain protein 4 (MBD4). Forty-eight snap frozen clinical colorectal samples (24 normal and 24 paired colorectal cancer patient samples) were selected with detailed clinical follow-up information. cDNAs were synthesized and the expression levels of marker genes were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using the two-tailed paired Wilcoxon test. Survival curves were plotted according to the method of Kaplan-Meier and compared using the log-rank test. Based on the quantitative expression analysis, RRM2 (p=0.0001; 95% CI, 2.0-4.5), ORC6L (p=0.0001; 95% CI, 1.8-4.6), EIF4E (p=0.0002; 95% CI, 0.3-0.9), TS (p=0.0005; 95% CI, 0.7-2.2) and SMYD3 (p=0.0001; 95% CI, 0.8-1.5) were overexpressed in tumor tissues. However, the expression of SEI1 was decreased in tumors (p=0.02; 95% CI, 0.1-1.3), consistent with the function of SEI1 as a potential tumor suppressor. Kaplan-Meier survival analysis indicated that MBD4 is a significant prognostic factor for patient survival (p=0.03). MBD4 was a key protein involved in DNA methylation. The expression of TS was associated with tumor stage as it had a significantly higher expression level in UICC stage I and II compared to stage IV patients (p=0.03). MBD4 may be a potential novel prognostic marker for predicting patient survival for colorectal cancer.
[Show abstract][Hide abstract] ABSTRACT: HintergrundDie nekrotisierende Pankreatitis kann eine schwere Komplikation einer Pankreasgangabflussstörung z.B. durch Steine, Tumorstenose
oder bei Pancreas divisum sein. Alkohol- und Nikotinkonsum gelten als Risikofaktoren der Chronifizierung.
Patientin und VerlaufBei einer 63-jährigen Patientin mit o.g. Risikofaktoren, einem Pancreas divisum und vermeintlichem zystischen Pankreasschwanztumor,
der sich als Pseudozyste bei einer Pankreatitis herausstellte, erfolgte eine 2-jährige Behandlung rezidivierender Pankreatitisschübe.
Erst bei der Behandlung eines komplizierenden Leberabszesses fiel in einer CT eine malignitätssuspekte, zum Aufstau des Pankreashauptganges
führende Pankreaskopfraumforderung auf. Retrospektiv waren Gangveränderungen schon auf Voraufnahmen sichtbar. Die partielle
Duodenopankreatektomie bestätigte das Pankreaskopfkarzinom.
SchlussfolgerungGerade eine lange Zeit rezidivierende Pankreatitis erfordert, auch seltene Ursachen wie einen Tumor in Betracht zu ziehen.
Hilfreich dafür ist – abgesehen von der Fokussierung auf die aktuelle jeweilige Komplikation, hier der Pankreasschwanzpankreatitis
–, die vermeintlich unerheblichen Befunde des restlichen Organs nicht außer Acht zu lassen.
BackgroundNecrotising pancreatitis may develop as a consequence of pancreatic duct obstruction by stones, tumors or in the presence
of a pancreas divisum. Alcohol and nicotine are regarded as risk factors for the disease becoming chronic.
Patient and course of the diseaseA 63-year-old female patient with suspected cystadenocarcinoma of the pancreas tail, which was resolved as a pancreatic pseudocyst,
was treated for recurrent pancreatitis for 2 years. A tumor in the pancreas head was only detected on a follow-up CT after
resection of a complicating liver abscess. In retrospect, progressive pancreatic duct anomalies were visible on previous scans.
Partial duodenopancreatectomy confirmed the presence of a pancreas head carcinoma.
ConclusionContinuous critical re-evaluation of all potential causes of pancreatitis including rare conditions, such as a tumor, is required
particularly if pancreatitis recurs over a long period. Re-evaluation of studies over time and of findings apart from the
actual main focus of the complication, in this case pancreatitis of the pancreas tail, may help to detect the underlying disease
instead of just treating the consequences.
Der Chirurg 01/2008; 79(3):252-257. DOI:10.1007/s00104-007-1415-4 · 0.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the efficacy and the results of ablation of Barrett'esophagus by endoscopic argon plasma coagulation (APC) followed by fundoplication.
Between January 1999 and December 2004, 21 patients with histological proven, short BE and scheduled for fundoplication, were treated by APC. Treatment was repeated until histological confirmation of complete ablation was obtained. All patients underwent surgical correction of reflux by Nissen fundoplication. Response to treatment was assessed at follow up with endoscopy every 6 to 12 months.
BE ablation was obtained in all patients after a mean of 3.6 APC sessions. There was no mortality and morbidity was 19% (4/21 patients). All patients underwent 360 degrees Nissen fundoplication as antireflux procedure. There was no operative mortality and no major complications requiring re-operation. Mean postoperative hospital stay was 7.9 days. Postoperatively 17/21 patients had at least one endoscopic control. The mean observation time was 17.5 months. Recurrence of Barrett epithelium was observed in 6 patients at a mean of 9.6 months after fundoplication.
Our results show that the combination of APC and fundoplication is a safe and effective treatment option for most patients with uncomplicated BE. Although no cancer development was observed, larger studies with a longer follow up are required to assess the impact of APC on cancer risk.
[Show abstract][Hide abstract] ABSTRACT: Thymidylate synthase (TS) is an important enzyme for DNA synthesis and the target for 5-fluorouracil (5-FU). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas.
TS expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies.
The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours.
Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis.
International Journal of Colorectal Disease 02/2007; 22(1):49-55. DOI:10.1007/s00384-006-0111-z · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The functions of non-coding microRNAs (miRNAs) in tumorigenesis are just beginning to emerge. Previous studies from our laboratory have identified a number of miRNAs that were deregulated in colon cancer cell lines due to the deletion of the p53 tumor suppressor gene. In this study, the in vivo significance of some of these miRNAs was further evaluated using colorectal clinical samples. Ten miRNAs (hsa-let-7b, hsa-let-7g, hsa-miR-15b, hsa-miR-181b, hsa-miR-191, hsa-miR-200c, hsa-miR-26a, hsa-miR-27a, hsa-miR-30a-5p and hsa-miR-30c) were evaluated for their potential prognostic value in colorectal cancer patients. Forty eight snap frozen clinical colorectal samples (24 colorectal cancer and 24 paired normal patient samples) with detailed clinical follow-up information were selected. The expression levels of 10 miRNAs were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using a two tailed paired Wilcoxon test. A Kaplan-Meier survival curve was generated followed by performing a Logrank test. Among the ten miRNAs, hsa-miR-15b (p = 0.0278), hsa-miR-181b (p = 0.0002), hsa-miR-191 (p = 0.0264) and hsa-miR-200c (p = 0.0017) were significantly over-expressed in tumors compared to normal colorectal samples. Kaplan-Meier survival analysis indicated that hsa-miR-200c was significantly associated with patient survival (p = 0.0122). The patients (n = 15) with higher hsa-miR-200c expression had a shorter survival time (median survival = 26 months) compared to patients (n = 9) with lower expression (median survival = 38 months). Sequencing analysis revealed that hsa-miR-181b (p = 0.0098) and hsa-miR-200c (p = 0.0322) expression were strongly associated with the mutation status of the p53 tumor suppressor gene. Some of these miRNAs may function as oncogenes due to their over-expression in tumors. hsa-miR-200c may be a potential novel prognostic factor in colorectal cancer.