mFOLFOX6 versus mFOLFOX6 + aflibercept as neoadjuvant treatment in MRI-defined T3-rectal cancer: a randomized phase-II-trial of the German Rectal Cancer Study Group (CAO/ARO/AIO 0214).

BACKGROUND: Neoadjuvant chemotherapy is an option for patients with locally advanced rectal cancer at low risk for local recurrence. This randomized phase II trial investigated whether the addition of aflibercept to modified FOLFOX6 (mFOLFOX6) could improve the rates of centrally confirmed pathological complete remissions (pCR) and (disease-free) survival in magnetic resonance imaging (MRI)-staged cT3 rectal cancer. PATIENTS AND METHODS: Patients with rectal cancer fulfilling the following criteria were included: lower border of tumor >5 cm and <16 cm from anal verge; circumferential resection margin >2 mm and T3-tumor with a maximum infiltration of 10 mm, as determined by MRI. Patients were randomized 1 : 2 to six cycles mFOLFOX6 ± aflibercept. Surgery was scheduled 4 weeks after chemotherapy. Primary endpoint was the rate of centrally confirmed pCR. The study was designed to detect an improvement of pCR from 10% to 27% (power 80%, type I error 20%). RESULTS: A total of 119 randomized patients started treatment (39 patients mFOLFOX6, arm A, and 80 mFOLFOX + aflibercept, arm B). The incidence of all grade adverse events was similar in both arms, however, adverse events grade ≥3 were more than twice as high in the experimental arm due to hypertension. Surgical complications were comparable. Aflibercept did not improve the pCR rate (arm A 26% versus arm B 19%, P = 0.47) and more patients in arm B had node positivity. With a median follow-up of 40.1 months, the 4-year disease-free survival was 83% in arm A and 85% in arm B (P = 0.82). Only two patients in arm A and one patient in arm B developed local recurrence. CONCLUSIONS: In patients with locally advanced rectal cancer and MRI-defined low risk of local recurrence, neoadjuvant mFOLFOX6 + aflibercept was feasible and did not compromise surgery. Survival data were favorable in both arms, but pCR rates were not increased by the addition of aflibercept.

Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings.

BACKGROUND: ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy. PATIENTS AND METHODS: Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences. RESULTS: Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49-0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56-0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53-0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71-1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266). CONCLUSIONS: Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.

Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group.

BACKGROUND: This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m(2)/day 1 plus capecitabine 1000 mg/m(2) bid/days 1-14 or with irinotecan 200 mg/m(2)/day 1 plus capecitabine 800 mg/m(2) bid/days 1-14 both every 21 days. The primary end point was 6 months progression-free survival (PFS). RESULTS: A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx-bevacizumab: n = 127; mCapIri-bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%-84%) and 84% (95% CI, 77%-90%). Median PFS and OS were 10.4 months (95% CI, 9.0-12.0) and 24.4 months (95% CI, 19.3-30.7) with CapOx-bevacizumab, and 12.1 months (95% CI, 10.8-13.2) and 25.5 months (95% CI, 21.0-31.0) with mCapIri-bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx-bevacizumab and in 16% with mCapIri-bevacizumab. CONCLUSIONS: Both, CapOx-bevacizumab and mCapIri-bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.

S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma-final results of the randomized AIO MATEO phase II trial.

PURPOSE: Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. DESIGN: MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints. RESULTS: From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%). CONCLUSIONS: S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

Endocavitary contrast enhanced ultrasound (CEUS)--work in progress.

PURPOSE: To demonstrate the benefit concerning localisation, measurement and visualisation of complications of drained fluid collections in the abdomen by applying ultrasound contrast agent via drainage catheters. In addition, to investigate the usefulness of CEUS in applying the agents in the biliary tract or when given orally. MATERIALS AND METHODS: A single drop of SonoVue® was added to 0.9 % saline solution and instilled via drainage catheters. Location, dimensions and complications of drained fluid collections were recorded and compared to the results of sonographic examination using saline solution alone and fluoroscopic examination using iodinated contrast agents. The biliary system was visualised by applying the solution via nasobiliary drains or via ERC catheterisation. Orally administered solutions consisted of one drop of SonoVue® in 50 ml aqua. RESULTS: Admixture of an ultrasound contrast agent to saline solution facilitates position monitoring of the drains in fluid collections and provides reliable information on the dimensions of the drained collection. Complications like fistulae to the biliary system, blood vessels, small or large intestine or to the peritoneal cavity are precisely displayed. The biliary system is shown in detailed description. Orally administered, the contrast agent is visible after intake long unto the colon. Insufficient anastomoses or spontaneous perforations become detectable. CONCLUSION: The application of ultrasound contrast agents via drainage catheters provides substantial information on location and dimensions of drained fluid collections and their communication with surrounding organ structures. The biliary system can be visualised. Oral administration is feasible and provides important additional information.

Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study.

BACKGROUND: Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned analyses of the influence of tumor biomarkers on treatment outcome were carried out. PATIENTS AND METHODS: Patients received weekly cetuximab (400 mg/m(2) on day 1, subsequently 250 mg/m(2)) plus irinotecan (80 mg/m(2)) and a 24-hour continuous infusion of folinic acid (200 mg/m(2)) and 5-FU (1500 mg/m(2)) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD). RESULTS: The most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months [95% confidence interval (CI) 7.1-15.6] and 16.5 months (95% CI 11.7-30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression. CONCLUSION: Cetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.

Peripapillary duodenal varices as a rare cause of severe bleeding in a patient with no other signs of portal hypertension--successful endoscopic treatment with cyanoacrylate injection.

Duodenal varices (DVs) are a rare cause of upper gastrointestinal bleeding and rather suspected in patients with portal hypertension. Bleeding DVs are difficult to manage and often fatal due to delayed diagnosis. We report on a 71-year-old patient with massive upper gastrointestinal haemorrhage, who did not show any clinical signs of portal hypertension; however, he had a history of duodenal segmental resection 8 years before. The source of bleeding could not be detected with different imaging methods such as angiography and computed tomography. Upper gastrointestinal endoscopy finally revealed DVs, which were located just adjacent to the papilla. After endoscopic injection therapy with n-butyl 2-cyanoacrylate the bleeding stopped immediately and the patient soon stabilised. Despite the peripapillar localisation no signs of pancreatitis or cholestasis occurred; during 10-month follow-up a marked regression of the varices without further signs of variceal bleeding was observed.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

[Differentiated therapy of liver tumors]. / Differenzialtherapie von Lebertumoren.

Focal nodular hyperplasia is a polyclonal hyperplasia of liver cells as a result of locally enhanced blood flow because of vessel malformations. Only symptomatic FNH is an indication for resection or enucleation. In contrast to FNH growth of adenoma is dependent on sexual hormones. Solitary HNFalpha-inactivated and inflammatory adenomas larger than 5 cm should be removed because of risk of tumor rupture or bleeding, while beta-catenin mutated adenomas should be surgically removed at any stage because of risk of malignant transformation. The prognosis of patients with HCC is dependent on the tumor stage, but also on the liver function. Resection is the treatment of choice for HCC in patients without liver cirrhosis. Patients with liver cirrhosis and early HCC without extrahepatic metastasis can be successfully treated by liver transplantation. If transplantation is not possible these tumors should be removed by local percutaneous ablation. Transarterial chemoembolization is an effective treatment for more advanced HCC in patients with good liver function. Studies showed that the multikinase inhibitor sorafenib significantly improves survival of patients with advanced or metastatic HCC in child A cirrhosis. The only curative option for patients with intrahepatic cholangiocarcinomas is surgical resection. Patients with unresectable cholangiocarcinomas should be treated with a chemotherapy consisting of Gemcitabine-Cisplatin-combination.

[Multimodality therapy of colorectal cancer]. / Multimodale Therapie des kolorektalen Karzinoms.

Adjuvant chemotherapy for resected stage III colon cancer is indicated for all patients, including elderly patients >70 years. In general, adjuvant oxaliplatin-fluoropyrimidine chemotherapy should be started within 6 weeks after tumor resection and should be given for a period of 6 months. However, patients aged >70 should receive fluoropyrimidine mono-chemotherapy. This mono-therapy, but not an oxaliplatin-based combination, can also be considered for patients with standard risk stage II tumors without microsatellite instability. In stage II patients with a high risk constellation adjuvant oxaliplatin-fluoropyrimidine combination therapy should be considered. Patients with stage II and III rectal cancer require neoadjuvant radiochemotherapy with fluoropyrimidine followed by adjuvant fluoropyrimidine treatment. There is no role for the use of VEGF- or EGFR-antibodies in the adjuvant therapy of colon cancer or in neoadjuvant therapy of rectal cancer. The prognosis of patients with primary resectable colorectal liver metastases may be improved by adjuvant or perioperative chemotherapy, while neoadjuvant systemic chemotherapy frequently facilitates potential curative resection of initially non-resectable liver metastases.

VSV virotherapy improves chemotherapy by triggering apoptosis due to proteasomal degradation of Mcl-1.

Overexpression of myeloid cell leukemia 1 protein (Mcl-1), an anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member, contributes to chemotherapy resistance of tumors. The short half-life of Mcl-1 makes it an interesting target for therapeutic agents that negatively interfere with cellular protein biosynthesis, such as oncolytic viruses. Vesicular Stomatitis Virus (VSV) has been established as the oncolytic virus that efficiently disrupts de novo protein biosynthesis of infected cells. Here, we show that after VSV infection, Mcl-1 protein levels rapidly declined, whereas the expression of other members of the Bcl-2 family remained unchanged. Mcl-1 elimination was a consequence of proteasomal degradation, as overexpression of a degradation-resistant Mcl-1 mutant restored Mcl-1 levels. Mcl-1 rescue inhibited apoptosis and thereby confirmed that Mcl-1 downregulation contributes to VSV-induced apoptosis. In vitro, VSV virotherapy in combination with chemotherapy revealed an enhanced therapeutic effect compared with the single treatments, which could be reverted by Mcl-1 rescue or RNA interference (RNAi)-mediated knockdown of pro-apoptotic Bax and Bak proteins. Finally, in a tumor mouse model, combinations of doxorubicin and VSV showed a superior therapeutic efficacy compared with VSV or doxorubicin alone. In summary, our data indicate that VSV virotherapy is an attractive strategy to overcome tumor resistance against conventional chemotherapy by elimination of Mcl-1.

Treatment decisions in metastatic colorectal cancer - Beyond first and second line combination therapies.

Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has reached up to 30months in recent clinical trials of first line therapies. Following disease progression after the standard in both, 1st and 2nd line, combination chemotherapy with monoclonal antibodies, many patients maintain a good performance status and a significant proportion is motivated to undergo further therapy. Choices of treatment beyond the second line setting for mCRC are therefore becoming increasingly important. New options have entered the therapeutic field recently: Regorafenib is a multikinase inhibitor approved for mCRC patients who have progressed on chemotherapy (including fluoropyrimidines, irinotecan, and oxaliplatin), plus VEGF inhibitor(s) and - if RAS wild-type - an anti-EGFR inhibitor. Regorafenib significantly improved OS, compared to placebo, in two phase III trials (CORRECT and CONCUR) in mCRC patients. Trifluridine/Tipiracil, an oral fluoropyrimidine, also resulted in significantly improved OS when compared to placebo in the phase III RECOURSE trial, which was conducted in a similar patient population to CORRECT. Reintroduction of previously administered therapy is another valid and commonly used approach, especially for those regimens which were discontinued before progression, e.g. if associated with cumulative toxicities, such as peripheral neuropathy or due to treatment breaks. Re-challenge of drugs to which patients developed resistance is also feasible although evidence for this strategy is limited.

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.

Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials.

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55-0.75) and OS (HR 0.83; 95%-CI, 0.76-0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41-3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression.

In the Solt-Faber model DENA and 2-Acetaminofluorene (AAF) treatment combined with hepatectomy induces hepatocellular carcinoma in rats. In this model AAF blocks proliferation of hepatocytes, while oval cells restore liver mass. Here we studied the molecular mechanism involved in blocking AAF-dependent cell cycle progression of hepatocytes. AAF inhibits cell proliferation of hepatocytes shown by the lack of Cyclin E expression before the G1/S phase restriction point. Immunfluorescence studies revealed that Cyclin E positive signals were restricted to oval cells, while hepatocytes remained negative. Additionally, AAF treatment induces strong nuclear p53 expression which is associated with increased p21 mRNA levels. Inhibition of active Cyclin/CdK (cyclin dependent kinase) complexes is reflected in AAF-treated animals by decreased RB expression and phosphorylation. The decrease in RB expression and phosphorylation, which is essential in triggering DNA synthesis and Cyclin A expression, leads to a deficiency in transcriptionally active E2F complex formation after hepatectomy. Thus, two molecular explanations are evident to account for AAF-dependent cell cycle progression of hepatocytes in vivo: first, induction of p53 expression which leads to higher p21 mRNA levels, and second, a lack of Cyclin E expression at the G1/S phase restriction point after hepatectomy.

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.

Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.

PURPOSE: Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS: The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS: Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION: In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

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.