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S Kubicka

Publications and source records attributed to S Kubicka.

At least 19 recordsLinked to original sources
PubMed2007

[Systemic treatment of liver and biliary tumors].

Hepatocellular carcinoma (HCC) is generally difficult to treat. This is primarily due to the reduced liver function of most patients and the low sensitivity of liver cancer cells to chemotherapy. This has been demonstrated in many clinical trials. Molecular therapies might represent an improvement in the systemic treatment of patients with HCC. In addition to anti-angiogenic drugs, compounds which interfere with specific signal transduction cascades have shown promising results in smaller trials. There are only limited numbers of studies about the systemic treatment options for biliary cancers. To date, the best response rates have been achieved with combination chemotherapies containing platinum analogues and gemcitabine. In the absence of larger clinical phase III trials, no standard chemotherapy for biliary cancers exists today.

Angiogenesis Inhibitors↗
PubMed2005

Chemoocclusion vs chemoperfusion for treatment of advanced hepatocellular carcinoma: a randomised trial.

AIMS: Transarterial chemoembolization (TACE) can be associated with considerable toxicity and treatment-associated mortality. Transient transarterial chemoocclusion (TACO) using degradable starch microspheres (DSM) has been proposed as a potentially safer alternative while maintaining anti-tumour efficiency. In a randomised phase II trial TACO was compared to transarterial chemoperfusion without DSM (TACP). METHODS: Seventy-four patients with advanced HCC were randomised to two treatment arms: (i) TACO (600-1200 mg DSM) and (ii) TACP. In both arms regional chemotherapy consisted of cisplatin (100 mg/m2) and doxorubicin (60 mg/m2). Both arms were corresponding in terms of age, gender, liver performance state, and tumour-stage. A maximum of six treatment cycles was applied in monthly intervals. Follow-up was performed in terms of tumour response, time to progression, survival and quality of life. RESULTS: Tumour response rates did not differ significantly between the two treatment arms, however, there was a tendency towards higher response rates in the TACO arm (TACO vs TACP): partial response: 26 vs 9%, stable disease: 41 vs 55%, progressive disease: 33 vs 36%. Time to tumour progression (32 vs 27 weeks), and overall survival (60 vs 69 weeks) were not significantly different. Grade 4 adverse events were rare in both arms and treatment-associated mortality was not observed. In addition, there was no significant difference in terms of quality of life under therapy (EORTC). CONCLUSION: TACO with DSM did not improve response or survival significantly compared to TACP in advanced non-resectable HCC.

Aged↗
PubMed2005

Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child-Pugh score B or C) and a score of >2. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received.

Adolescent↗
PubMed2005

Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces hepatic steatosis in viral hepatitis and after alcohol intake.

BACKGROUND AND AIMS: Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in transformed cells and is considered as an agent for cancer therapy. As there is evidence that TRAIL is also essential for apoptosis in animal models of liver injury, we investigated the role of TRAIL in viral hepatitis and after alcohol consumption. METHODS: Expression of TRAIL was determined by western blot analysis in the liver of patients with chronic hepatitis C virus (HCV) infection as well as in experimental acute adenoviral hepatitis and after alcohol intake in the liver of mice. To investigate the effect of FasL and TRAIL expression, we used low dose adenoviral gene transfer. Apoptosis and steatosis were assessed by TUNEL and fat red staining, and by caspase assays. RESULTS: TRAIL was overexpressed in the liver of patients with HCV associated steatosis while acute adenoviral hepatitis resulted in upregulation of TRAIL-DR5. In contrast with FasL, TRAIL expression was harmless to healthy livers. However, in virally infected livers, TRAIL expression induced apoptosis and steatosis whereas expression of FasL only resulted in apoptosis of hepatocytes without steatosis. After alcohol intake, TRAIL expression led to hepatic steatosis, without apoptosis of hepatocytes, indicating that TRAIL mediated apoptosis and steatosis may be independently modulated after viral infection and alcohol intake. In viral hepatitis and after alcohol intake, Ad-TRAIL mediated steatosis can be inhibited by injection of a neutralising TRAIL antibody. CONCLUSIONS: We identified TRAIL as a new mediator of hepatic steatosis in viral hepatitis and after alcohol intake. Consequently, TRAIL mediated hepatotoxicity has to be considered in patients with viral hepatitis and alcoholic liver disease.

Alcohol Drinking↗
PubMed2004

[Prognosis of hepatocellular carcinoma according to new staging classifications].

BACKGROUND AND OBJECTIVE: We investigated prognostic factors and survival of patients with hepatocellular carcinoma (HCC) in North-Germany. Established staging systems (Child-Pugh, Okuda and UICC classification) were compared with new prognostic scores from Italy (CLIP) and Spain (BCLC). PATIENTS AND METHODS: The clinical course of 62 consecutive patients (34-82 years, 48 males, 14 females) with HCC observed in the Medical School of Hannover from October 1996 to September 1998 were retrospectively analyzed. The patients were classified according to the staging systems of Child Pugh, Okuda, UICC, CLIP and BCLC. Follow-up ended on December 31 (st) 2001. RESULTS: Overall median survival was 11,3 (1 - 59,5) months. At univariate analysis (log-rank test) Okuda, UICC, CLIP and BCLC Score were each associated with a shorter survival. In contrast Child Pugh score provided no significant prognostication. By multiple regression analysis (Cox regression analysis), only the CLIP and UICC score and chronic hepatitis B infection were shown to be independent risk factors. CONCLUSION: Our investigations indicate, that the CLIP and UICC classifications identified those patients with the best prognosis and they, as well as chronic hepatitis C, were shown to be independent risk factors.

Adult↗
PubMed2004

SiRNA based strategies for inhibition of apoptotic pathways in vivo--analytical and therapeutic implications.

Apoptosis is a genetically controlled mechanism of cell death which is important for embryogenesis, metamorphosis, tissue homeostasis and tumor regression of multicellular organisms. In normal cells as well as in transformed cells signals released from the cytoplasm and/or the cell membrane can trigger the activation of caspases which in turn cleave many cellular substrates, leading to the characteristic morphology of apoptosis. Systematic analysis and dissection of apoptotic pathways was obtained by the use of knock out or transgenic organisms, expressing dominant active or negative proteins. The use of antisense oligonucleotides (ASO) for analysis of apoptotic pathways was commonly restricted to cultured cells, because of the low efficacy of ASO in in vivo experiments. In order to investigate the contribution of specific apoptotic pathways in the onset and maintenance of disease in vivo experiments are needed. This approach allows the analysis of apoptotic pathways within their physiological/pathophysiological environment. The combination of recent advances in in vivo gene delivery with siRNA technique for efficient gene silencing provides new, unique possibilities to study apoptotic pathways thereby evaluating new molecular therapeutic strategies in vivo. In this minireview we will focus on the use of RNA interference for analytical and therapeutical suppression of apoptotic pathways in vivo with special consideration of the liver.

Animals↗
PubMed2004

[Cholangiocellular and gallbladder carcinoma].

Risk factors for cholangiocellular and gallbladder carcinomas are bile stones and chronic inflammation of the biliary system. Gallbladder cancer and intrahepatic cholangiocellular carcinomas can be diagnosed with a high sensitivity by ultrasonography, CT and MRI, while the most sensitive diagnostic methods for perihilar or distal cholangiocellular carcinomas are ERC or MRC. The only curative option for patients with gallbladder- or bile duct cancer is surgical resection. Outside clinical studies there is currently no indication for neoadjuvant or adjuvant chemotherapy or radiochemotherapy. Gallbladder and bile duct carcinomas are moderately chemotherapy-sensitive tumors. The objective response rates in phase II studies with 5-FU or gemcitabine monochemotherapy are between 10 - 30 %. Higher response rates between 20 - 50 % have been observed in phase II studies with combination chemotherapy, in particular with the combination of gemcitabine/cisplatin. Because of the low incidence of gallbladder and bile duct carcinomas there are currently no large phase III trails investigating the impact of chemotherapy on survival and quality of life or comparing the activity of different chemotherapy protocols. Patients in good general physical conditions or with tumor-associated symptoms should be treated with palliative chemotherapy (whenever possible in clinical studies), while chemotherapy should be avoided in patients with severe non-tumor-associated morbidity. Endoscopic procedures, such as PTC- or ERC-stenting and photodynamic therapy, are important supportive therapies which can help to maintain the bile flow and consequently improve survival and quality of life of patients with malignant bile duct obstructions.

Animals↗
PubMed2003

Increasing sensitivity of morphological diagnosis in hepatocellular carcinoma (HCC) by combination of cytological and fine-needle histological examination after ultrasound guided fine needle biopsy.

UNLABELLED: Increasing sensitivity of morphological diagnosis by combination of cytological and fine-needle histological examination after ultrasound guided fine needle biopsy in hepatocellular carcinoma (HCC). AIM: We investigated the factors which may affect the sensitivity of morphological diagnostics (cytology and fine-needle histology) in HCC after ultrasound guided biopsy. METHOD: In 62 patients, an ultrasound guided cytological (n = 62) and fine-needle histological (n = 45) biopsy was performed. In addition, the smears were investigated by cytophotometry (n = 62). RESULTS: Considering each method separately, the sensitivity of both cytological and histological diagnostics was about 80%. The sensitivity could be raised to 89% by combining the two methods. In seven patients, the HCC could not be primarily confirmed morphologically. In nine patients, the result of histological and cytological investigation was not congruent. With regard to the size of the biopsied lesion, tumor stage, cytophotometric finding and survival these 16 patients (group A) were compared with the 46 patients in whom the HCC could be primarily confirmed morphologically (group B). The statistical analysis did reveal a significantly lower percentage of tumors with diploid or tetraploid (euploid) cells in group B. Euploid tumors were significantly more highly differentiated. In patients with euploid tumors, the sensitivity of the cytological investigation was 67% and respectively 75% of the histological investigation. The sensitivity could be raised to 82% in this population by combining the two investigations. On the other hand in aneuploid tumors, the sensitivity could only be increased from 93% and 88% respectively to 97% by combining cytology and fine-needle histology. SUMMARY: Our investigations show that the sensitivity of morphological diagnostics can be raised especially in the highly differentiated HCC with a physiological DNA content by combination of cytological and fine-needle histological investigations.

Adult↗
PubMed2003

Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer.

BACKGROUND: and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation. METHODS: To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation. RESULTS: Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma-high grade dysplasia with minimal invasive growth-compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells. CONCLUSIONS: These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.

Adenoma↗
PubMed2001

Ras adenoviruses modulate cyclin E protein expression and DNA synthesis after partial hepatectomy.

Ras-genes encode for proteins important for transmitting extracellular signals from the cytoplasm to the nucleus. In this study we investigated the impact of Ras on cell cycle progression after hepatectomy by using adenoviral vectors (adv) expressing beta-galactosidase (beta-gal), a dominant-negative (Ras N17) or a dominant-active (Ras 61L) form of H-Ras. Partial hepatectomy was performed in mice treated with the different adenoviruses and cell cycle progression was studied by analysing factors involved in cell cycle control during liver regeneration. After hepatectomy, adv Ras 61L increases DNA synthesis significantly in comparison to the other treatment groups. Higher Ras activity results in an early increase of transcriptional active E2F-3, which is associated with higher cyclin E, but almost unchanged cyclin D protein expression. However, Northern blot analysis and cyclin E promoter experiments indicate that, besides transcriptional mechanisms also post-transcriptional mechanisms are involved in regulating cyclin E protein expression after partial hepatectomy in mice treated with adv Ras 61L. Cyclin E phosphorylation studies demonstrate that adv Ras 61L results in hypophosphorylation of cyclin E compared to the control group at early time points after hepatectomy, when cyclin E protein expression strongly increases and there is only a minor effect on cyclin E mRNA levels. Our experiments indicate adv Ras 61L in vivo increases Cyclin E expression by higher transcription via E2F and a post-transcriptional mechanism. These mechanisms result in an earlier activation of an active CDK2/Cyclin E complex which, in turn, triggers DNA synthesis.

Adenoviridae↗
PubMed2001

Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure.

Con A administration results in dose-dependent immune-mediated liver injury. Cytokines are important to determine the outcome of liver failure in this model, and especially TNF-alpha and IFN-gamma directly contribute to hepatocyte damage. The intracellular pathways of these two cytokines, which eventually result in tissue destruction, are not well defined. Here we used anti-IFN-gamma Abs and adenoviral vectors that express molecules inhibiting distinct TNF-alpha-dependent pathways in hepatocytes to better understand the relevance of specific intracellular signaling cascades for Con A-induced liver failure. We show that activation of TNF-alpha- and IFN-gamma-dependent intracellular pathways occurs prior to the influx of immune-activated cells into the liver and that anti-TNF-alpha and anti-IFN-gamma neutralizing Abs cannot block infiltration of these cells. Blocking experiments with Abs and adenoviral vectors showed that NF-kappaB activation and the Fas-associated death domain protein/caspase 8 cascade in hepatocytes during Con A-induced liver failure have no impact on tissue injury. Additionally, STAT1 activation alone after Con A injection in liver cells does not result in liver damage. In contrast, IFN-gamma-dependent expression of IFN regulatory factor-1 and TNF-alpha-dependent activation of c-Jun N-terminal kinase in liver cells correlates with liver cell damage after Con A injection. Therefore, our experiments indicate that 11418690

Adaptor Proteins, Signal Transducing↗
PubMed2001

Autoregulation enables different pathways to control CCAAT/enhancer binding protein beta (C/EBP beta) transcription.

CCAAT/enhancer binding protein beta (C/EBP beta) also named liver-enriched transcriptional activating protein (LAP) is a member of the C/EBP family of transcription factors and is involved in hepatocyte-specific gene expression and in the process of tissue differentiation. The activity of LAP/C/EBP beta can be regulated at the transcriptional and posttranslational level or by protein-protein interaction with other transcription factors. In this study we show that LAP/C/EBP beta can stimulate its own transcription. Deletion analysis of the rat LAP/C/EBP beta promoter in luciferase reporter gene experiments demonstrated that the region located between nucleotide -121 to -71, comprising two recently characterized cAMP responsive element (CRE)-like elements, is important for autoregulation. Gel shift experiments using oligonucleotides with overlapping point mutations identified the sequence GCAATGA (beta-site) adjacent to and partially overlapping the first CRE-like site as core motif for LAP/C/EBP beta binding. Analysis of a mutated beta-site in reporter gene experiments showed the functional relevance of this site for autoregulation. The composite C/EBP beta-CRE-element in the promoter enables synergistic activation of transcription by LAP/C/EBP beta and the protein kinase A (PKA)/cAMP responsive element binding protein (CREB) pathway in a cell-type specific manner. In hepatoma cells nuclear factor kappa B (NF-kappa B) increased autoregulation and therefore could mediate enhanced activation during inflammatory responses. In summary, our results demonstrated that the assembly of the three binding sites in the promoter and thus the interaction between LAP/C/EBP beta and members of the CREB or NF-kappa B family allows the control of LAP/C/EBP beta gene transcription as a response to different stimuli in a tissue specific manner.

Animals↗
PubMed2001

[Adjuvant chemotherapy in liver malignancy for improving operability].

Complete tumor resection is the only curative option for patients with colorectal liver metastases. Hepatic resection is frequently not possible for technical reasons: because of large tumors, multiple or bilateral metastases, or tumors that are too close to vessels. In these cases chemotherapy might downstage the tumor volume and facilitate secondary curative resection in patients initially not eligible for curative surgery. Treatment with fluorouracil (5-Fu) alone has resulted in disappointing response rates of about 10-20% in patients with colorectal liver metastases, which make these protocols useless in the neoadjuvant setting. Because regional chemotherapy into the hepatic arteria results in significantly higher response rates (40-50%), some studies have documented some success in secondary curative surgery after regional chemotherapy of initially unresectable colorectal liver metastases. However, regional chemotherapy is invasive and therefore not standard therapy for every patient with colorectal liver metastases. Recently new exciting treatment options have become available for colorectal cancer. Combinations of chemotherapy consisting of irinotecan and 5-Fu/FA or oxaliplatin and 5-Fu/FA result in response rates of 50% and can be considered a new standard first-line chemotherapy for patients with metastatic colorectal cancer. Recently, two encouraging retrospective studies have been published with chronomodulated chemotherapy of oxaliplatin and 5-Fu/FA in the setting of neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases. With this multidisciplinary approach, antitumor activity of chemotherapy appears to be translated into a long-term survival benefit and some patients with initially unresectable colorectal liver metastases can potentially be cured. As a consequence, on the premises of close cooperation between surgeons and internists, more patients with metastatic colorectal cancer will be cured in the future.

Chemotherapy, Adjuvant↗
PubMed2001

Improved prognosis following peritonectomy procedures and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from appendiceal carcinoma.

AIMS: The prognosis of patients with peritoneal carcinomatosis from gastrointestinal malignancies is poor. The aim of this study was to analyse the results of multimodality treatment for peritoneal carcinomatosis of appendiceal carcinoma. PATIENTS AND METHODS: From 07/95 to 01/00, 17 patients (13 males, 4 female, median age 58 years) underwent peritonectomy procedures in combination with intraperitoneal hyperthermic chemotherapy. Surgical, pathological and survival data were analysed retrospectively. RESULTS: All patients had undergone previous surgical treatment and one patient had received chemotherapy. In all patients peritonectomy procedures, as described by Sugarbaker, were performed with the aim of achieving a macroscopically complete cytoreduction (range 2-6, median 4 procedures per patient). Following resection, open hyperthermic intraperitoneal chemotherapy with cisplatin was performed. Eleven patients had postoperative complications (predominantly "non-surgical") and two patients died postoperatively. The 4-year survival rate was 75%. Complete cytoreducion had a statistically significant positive influence on long-term survival. CONCLUSIONS: In selected patients (WHO status 0/1, minimal residual disease, no distant metastases, complete cytoreduction), the prognosis for patients with peritoneal carcinomatosis of appendiceal origin can be improved by peritonectomy procedures and hyperthermic intraperitoneal chemotherapy. Postoperative morbidity may be increased due to "non-surgical" complications.

Adult↗
PubMed2001

Evidence for the decreased expression of the latent TGF-beta binding protein and its splice form in human liver tumours.

BACKGROUND: Recently, a splice form of the latent TGF-beta binding protein (LTBP-1) was identified in the liver lacking potential important sequences for matrix association and proteinase cleavage (LTBP-1D, -1delta53). For a better understanding of the unknown (patho)physiological role, the expression levels of LTBP-1D and LTBP-1 (full length) were investigated in normal and malignant human liver on the mRNA and protein level. METHODS: Normal liver (5 specimens), hepatocellular carcinoma (4 specimens) and fibrolamellar carcinoma (2 specimens) were examined by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry, for which specific antibodies were generated. RESULTS: The mRNA levels of LTBP-1/-1D in malignant liver tissues are decreased in comparison to normal liver--more so in HCC than in FLC. This finding was confirmed by a strong decrease of immunostaining of LTBP-1/-1D in neoplastic parenchymal cells of HCC and FLC. However, the intensity of LTBP-1 (full length) protein staining was increased in the extracellular matrix of the carcinomas, while LTBP-1D was not detectable in the matrix. CONCLUSION: Since TGF-beta is known to be over-expressed in liver tumours, the results suggest its enhanced synthesis without binding to LTBP-1. This probably influences the availability of bioactive TGF-beta in the tumour tissue. The missing matrix localization of LTBP-1D indicates that the hinge region containing a heparin-binding site is essential for the binding of LTBP-1 in the extracellular matrix. LTBP-1D may fulfil specific functions for the latency of matrix-unbound TGF-beta.

Carcinoma, Hepatocellular↗
PubMed2001

K-ras mutations in the bile of patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: The development of cholangiocarcinoma (CCC) is a complication of primary sclerosing cholangitis (PSC). To date, no reliable factors have been described which can define those PSC patients at high risk for the development of CCC and the clinical diagnosis of CCC in PSC patients is difficult. Therefore, molecular markers of cholangiocarcinogenesis, such as K-ras mutations, may improve the early diagnosis of CCC or the timing of liver transplantation. METHODS: K-ras mutations were analysed by enriched polymerase chain reaction/restriction fragment length polymorphism in the bile fluid of 56 PSC patients and 20 patients with other cholestatic diseases. To assess the value of K-ras mutations as a risk factor for cholangiocarcinogenesis, patients were prospectively investigated over a mean period of 31.5 months. RESULTS: In contrast with the control group, 17 (30%) patients with PSC revealed K-ras mutations in bile fluid. The mean Mayo score was not significantly different between PSC patients with (mean score 0.70) and without (mean score 0.13; p=0.2) K-ras mutations. In contrast with the group of PSC patients without K-ras mutations, four CCCs and two dysplasia were diagnosed in the group of patients with K-ras mutations during the follow up investigation (p<0.001). CONCLUSIONS: Our results indicate that K-ras mutations in bile fluid of PSC patients represent frequent early events during cholangiocarcinogenesis. However, most of the PSC patients with K-ras mutations remained tumour free after a long follow up investigation which is in agreement with the fact that these mutations are not specific for malignancy but may also occur in normal bile duct mucosa or in dysplasias. Therefore, analysis of K-ras mutations in bile should not be used for diagnosis of CCC in PSC patients. However, the results of our prospective follow up investigation indicate that K-ras mutations in bile fluid of PSC patients have to be considered as risk factors for the development of CCC which may have implications for the timing of liver transplantation.

Adult↗