Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

Advantages of a multi-state approach in surgical research: how intermediate events and risk factor profile affect the prognosis of a patient with locally advanced rectal cancer.

BACKGROUND: Standard survival analysis fails to give insight into what happens to a patient after a first outcome event (like first relapse of a disease). Multi-state models are a useful tool for analyzing survival data when different treatments and results (intermediate events) can occur. Aim of this study was to implement a multi-state model on data of patients with rectal cancer to illustrate the advantages of multi-state analysis in comparison to standard survival analysis. METHODS: We re-analyzed data from the RCT FOGT-2 study by using a multi-state model. Based on the results we defined a high and low risk reference patient. Using dynamic prediction, we estimated how the survival probability changes as more information about the clinical history of the patient becomes available. RESULTS: A patient with stage UICC IIIc (vs UICC II) has a higher risk to develop distant metastasis (DM) or both DM and local recurrence (LR) if he/she discontinues chemotherapy within 6 months or between 6 and 12 months, as well as after the completion of 12 months CTx with HR 3.55 (p = 0.026), 5.33 (p = 0.001) and 3.37 (p < 0.001), respectively. He/she also has a higher risk to die after the development of DM (HR 1.72, p = 0.023). Anterior resection vs. abdominoperineal amputation means 63% risk reduction to develop DM or both DM and LR (HR 0.37, p = 0.003) after discontinuation of chemotherapy between 6 and 12 months. After development of LR, a woman has a 4.62 times higher risk to die (p = 0.006). A high risk reference patient has an estimated 43% 5-year survival probability at start of CTx, whereas for a low risk patient this is 79%. After the development of DM 1 year later, the high risk patient has an estimated 5-year survival probability of 11% and the low risk patient one of 21%. CONCLUSIONS: Multi-state models help to gain additional insight into the complex events after start of treatment. Dynamic prediction shows how survival probabilities change by progression of the clinical history.

Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP).

BACKGROUND: To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. PATIENTS AND METHODS: Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. RESULTS: Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). CONCLUSION: Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

Factors influencing the course of acute appendicitis in adults and children.

PURPOSE: Our aim was to determine predictive factors for the diagnosis and postoperative complications of acute appendicitis. MATERIALS AND PATIENTS: Data sets of 1,439 consecutive adults and children who had an appendectomy between 1999 and 2008 were retrospectively analyzed. RESULTS: A mild acute appendicitis was present in 50 % (n = 722) and a severe acute appendicitis in 25 % (n = 355) of the patients. No signs of any pathology were found in 6 % (n = 82). Gender, white blood count (WBC), C-reactive protein (CRP), and ultrasound (US) examination were important indicators of mild acute and severe acute appendicitis in adults and children. Postoperative complications occurred in 16 % (237/1,439), mainly consisting of wound infections (8 %, n = 122) and bowel dysfunction (5 %, n = 76). Sixty-two patients (4.3 %) required reoperations. One patient died (1/1,439, 0.07 % mortality rate). Age, pathology, and the presence of bacteria in the intraoperative swab were important predictive factors for postoperative complications in adults and children. Time since onset of symptoms and type of operation were also associated with postoperative complications among adults. Complications developed in 21 and 9 % of the adults (155/754 and 10/125) who had open and laparoscopic surgery, respectively. CONCLUSIONS: Besides history and clinical examination, WBC, CRP, and US examination remain important factors for diagnosing acute appendicitis. Complications are related to the pathology, presence of bacteria, and type of operation. Early diagnosis within 48 h may be important. A laparoscopic procedure in adults may also cause fewer wound infections.

Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Adjuvant chemoradiotherapy of advanced resectable rectal cancer: results of a randomised trial comparing modulation of 5-fluorouracil with folinic acid or with interferon-α.

BACKGROUND: Standard adjuvant chemoradiotherapy of rectal cancer still consists of 5-fluorouracil (5-FU) only. Its cytotoxicity is enhanced by folinic acid (FA) and interferon-α (INFα). In this trial, the effects of FA and IFNα on adjuvant 5-FU chemoradiotherapy in locally advanced rectal cancer were investigated. METHODS: Patients with R(0)-resected rectal cancer (UICC stage II and III) were stratified and randomised to a 12-month adjuvant chemoradiotherapy with 5-FU, 5-FU+FA, or 5-FU+IFNα. All patients received levamisol and local irradiation with 50.4 Gy. RESULTS: Median follow-up was 4.9 years (n=796). Toxicities (WHO III+IV) were observed in 32, 28, and 58% of patients receiving 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. No differences between the groups were observed for local or distant recurrence. Five-year overall survival (OS) rates were 60.3% (95% confidence interval (CI): 54.3-65.8), 60.4% (54.4-65.8), and 59.9% (53.0-66.1) for 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. A subgroup analysis in stage II (pT3/4pN0) disease (n=271) revealed that the addition of FA tended to reduce the 5-year local recurrence (LR) rate by 55% and increase recurrence-free survival and OS rates by 12 and 13%, respectively, relative to 5-FU alone. CONCLUSIONS: Interferon-α cannot be recommended for adjuvant chemoradiotherapy of rectal cancer. In UICC stage II disease, the addition of FA tended to lower LR and increased survival. The addition of FA to 5-FU may be an effective option for adjuvant chemoradiotherapy of UICC stage II rectal cancer.

[Evaluation of an objective structured clinical examination (OSCE) in surgery and orthopedics by medical students]. / Studentische Evaluation einer objektiven, strukturierten klinischen Prüfungsmethode (OSCE) im Fach Chirurgie und Orthopädie.

BACKGROUND: The objective structured clinical exam (OSCE) has become an established form of examination. However, for general and orthopedic surgery it has barely been evaluated. Therefore, the present study was performed to analyze the OSCE in surgery by the students of the University of Ulm. MATERIAL AND METHODS: In total 304 medical students undertaking the OSCE were included in the study. The students were asked to fill out a standardized questionnaire which contained different evaluation parameters, such as test adequacy, comprehensibility, balance, difficulty, atmosphere and clinical relevance as well as self-assessment and overall rating. RESULTS: In the overall rating the OSCE was rated as having a clinical relevance. The preferred preparation strategies were the clinical traineeship and standard medical textbooks. Altogether, the OSCE was chosen as the preferred future examination method, followed by multiple choice testing and clinical practical examination. CONCLUSION: The evaluation of the OSCE by the medical students at the University of Ulm showed a high acceptance rate as well as a high clinical relevance.

[Quality criteria for treatment of colorectal cancer. From a surgeon's viewpoint]. / Qualitätsanforderungen zur Behandlung des Kolon- und Rektumkarzinoms. Aus chirurgischer Sicht.

The surgeon is the key "prognosis factor" for colorectal cancer. For this reason quality criteria were recently established (including minimum numbers) in order to treat patients who are entitled to the best quality of care and to improve the prognosis. The aim of this study was to critically discuss the existing demands on the surgeon based on the current literature and our own results and to formulate evidence-based quality criteria for surgical clinics. After reviewing the current literature criteria were compiled, discussed and finally presented in a summarized form. These are based on current developments on the diagnostic and therapy of large intestine and colorectal carcinoma. New developments of the German Cancer Society for planning of organ centers are incorporated. The quintessence of our study is that the number of cases alone is not decisive for the success of therapy. Important are the application of the correct surgical-oncology operation procedure, adherence to standards and the training of surgeons. Following the S3 guidelines stage-oriented therapy should additionally be carried out in a structured sequence. This includes an interdisciplinary decision making on the diagnostic and therapy strategy (tumor board). The organization structure of the hospital (teams, tumor board, emergency care with intensive care unit, emergency diagnostic and options for interventional measures) can be more important than the hospital case numbers alone. These demands which have been evaluated from published data and own results are designed to raise the therapy of colorectal cancer to the best possible level of quality and to effect a further improvement in the prognosis.

Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression.

BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell-cell and cell-matrix interactions. In cancer, SPARC can be not only associated with a highly aggressive phenotype, but also acts as a tumour suppressor. The aim of this study was to characterise the function of SPARC and its modulation by fibroblast growth factor receptor (FGFR) 1 isoforms in pancreatic ductal adenocarcinoma (PDAC). METHODS AND RESULTS: Exogenous SPARC inhibited growth, movement, and migration. ShRNA inhibition of endogenous SPARC in ASPC-1 and PANC-1 cells resulted in increased anchorage-dependent and -independent growth, transwell migration, and xenograft growth as well as increased mitogenic efficacy of fibroblast growth factor (FGF) 1 and FGF2. Endogenous SPARC expression in PANC-1 cells was increased in FGFR1-IIIb over-expressing cells, but decreased in FGFR1-IIIc over-expressing cells. The up-regulation of endogenous SPARC was abrogated by the p38-mitogen-activated protein kinase inhibitor SB203580. SPARC was detectable in conditioned medium of pancreatic stellate cells (PSCs), but not PDAC cells. Conditioned medium of PDAC cells reduced endogenous SPARC expression of PSCs. CONCLUSION: Endogenous SPARC inhibits the malignant phenotype of PDAC cells and may, therefore, act as a tumour suppressor in PDAC. Endogenous SPARC expression can be modulated by FGFR1-III isoform expression. In addition, PDAC cells may inhibit endogenous SPARC expression in surrounding PSCs by paracrine actions.

Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells.

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.

Value of MDCT in preoperative local staging of rectal cancer for predicting the necessity for neoadjuvant radiochemotherapy.

PURPOSE: Neoadjuvant therapy may reduce local rectal cancer recurrence after total mesorectum extirpation. This study was performed to assess whether multi-detector row CT (MDCT) is capable of reliably differentiating UICC I (surgery) from UICC II-IV (neoadjuvant therapy). MATERIALS AND METHODS: 29 patients underwent preoperative MDCT of the abdomen in a portal venous phase. Two blinded readers independently evaluated the datasets on a dedicated workstation using axial and coronal reformations. Local tumor extension (T), nodal status (N) and distant metastases (M) were evaluated and the UICC stage was determined. Findings were correlated with postoperative histology. RESULTS: Histologically, 9 patients were UICC I; 20 UICC > I (II: 7; III: 11; IV: 2). Reader 1 correctly identified 3 / 9 as UICC I, overstaged 6 / 9, and correctly staged 20 / 20 as UICC > I. Reader 2 correctly identified 4 / 9 as UICC I, overstaged 5 / 9, understaged 4 / 20 and correctly staged 16 / 20 as UICC > I (PPV UICC I 100 % [50 %] reader 1 [reader 2], NPV 77 % [76 %], accuracy 79 % [69 %]). Reasons for overstaging by reader 1 (reader 2) included false-positive lymph nodes (LN) in 5 (5), overgrading T 1 tumors as T 3 in 1(0), and T overgrading in 4 / 5 (2 / 5) patients with false-positive LN. CONCLUSION: MDCT failed to reliably identify UICC I in rectal cancer patients. Therefore, a strategy based solely on MDCT to identify patients who would benefit from neoadjuvant therapy does not seem appropriate.

[Lay assessment of health care services using therapy for rectal cancer as an example]. / Vergleichende bewertung von gesundheitsleistungen durch laien am beispiel der therapie des rektumkarzinoms.

AIM: Multimodal treatment strategies make the assessment of health care services very difficult even for experts and almost impossible for lay persons. The aim of this project was to present complex data from scientific publications in a simplified way so that all essential information is preserved, but still assessable by lay persons and to compare their assessments with the recommendations of experts. METHODS: Using the surgical treatment of rectal cancer with or without preoperative radiation as an example, the aims of treatment as well as the "outcomes" (actually intended study endpoints) and "outputs" (surrogate parameters) were defined, identified and presented graphically for five key studies of neoadjuvant treatment. RESULTS: German lay persons (n = 59) favoured in the majority of the cases (93 %) surgical treatment without preoperative radiation. Lay persons assessed the results in a similar manner to other groups (physicians, health care workers, and health care politicians) and lay persons of other cultural backgrounds. Altogether, the participants (n = 152) favoured surgical treatment without preoperative therapy in 86 % of the cases (653 of 760). This lay assessment did not correlate with the assessments and recommendations of the scientific societies responsible for the guidelines. CONCLUSIONS: Complex scientific results can be prepared in such a way that their assessment by lay persons is feasible. Lay persons orientate their assessment according to the outcomes, while the recommendations of the guidelines are more directed by the outputs. These different viewpoints should be taken more into consideration for the development of guidelines than they are now.

Prognostic factors influencing the survival of patients with colon cancer receiving adjuvant 5-FU treatment.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Quality for the data basis of evidence-based medicine: rectal cancer and preoperative 5 x 5 irradiation]. / Qualität der Datengrundlage zu Evidence-based Medicine--Rektumkarzinom und präoperative 5 x 5 Bestrahlung.

Annually 25,000 people are diagnosed with rectal cancer in Germany. Neoadjuvant short-term radiotherapy is recommended for advanced local disease and is able to reduce by half the local recurrence rates even under high quality surgical conditions. However, the prognosis is not affected by neoadjuvant short-term radiotherapy. Key problems of neoadjuvant short-term radiotherapy are late toxic effects including faecal incontinence, sexual dysfunction, gastrointestinal symptoms, cardiovascular diseases as well as an increased frequency of secondary malignancies. Therefore, any overstaging has to be avoided by using high quality pretreatment diagnostics. The prognosis is associated with the quality of surgery. Therefore, rectal cancer surgery should be performed in specialised centres only. In our opinion, there is presently no indication for short-term preoperative radiotherapy in rectal cancer due to its lack of influence on prognosis and the resulting late toxicities.

Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions.

Interleukin-4 (IL-4) is an immunomodulatory cytokine, which can inhibit the growth of tumour cells. Pancreatic cancer cells and tissues express high levels of IL-4 receptors. The aim of this study was to characterise the effects of IL-4 on the growth and signalling pathways of pancreatic cancer cells. Cell growth was determined by cell counting and MTT assays in association with fluorescence-activated cell sorter analysis, IL-4 expression using ELISA and real-time PCR techniques, and signal transduction using immunoprecipitation or immunoblot analysis. We now report for the first time that IL-4 significantly enhanced the growth of five out of six cultured pancreatic cancer cell lines in a dose-dependent manner in association with an increased fraction of cells in S-phase. Surprisingly, all six cell lines expressed endogenous IL-4, and IL-4 was detectable in the supernatant. Incubating cells with neutralising IL-4 antibodies resulted in a significant inhibition of basal growth in three cell lines, including IL-4-unresponsive MIA PaCa-2 cells, which however expressed the highest endogenous IL-4 levels. Interleukin-4 enhanced activity of MAPK, Akt-1, and Stat3 in IL-4-responsive, but not in IL-4-unresponsive MIA PaCa-2 cells; however, IL-4 enhanced tyrosine phosphorylation of insulin receptor substrate-1 and -2 in all cell lines. Our results demonstrate for the first time that pancreatic cancer cells produce IL-4 and that IL-4 can act as a growth factor in pancreatic cancer cells. Together with the observation that neutralising IL-4 antibodies can inhibit the growth of these cells, our results suggest that IL-4 may act as an autocrine growth factor in pancreatic cancer cells and also give rise to the possibility that cancer-derived IL-4 may suppress cancer-directed immunosurveillance in vivo in addition to its growth-promoting effects, thereby facilitating pancreatic tumour growth and metastasis.

Colon cancer: survival after curative surgery.

Several new aspects have evolved during the past years concerning factors that influence survival in surgically and medically treated colon cancer patients that are relevant to the treating team for the treatment strategy and patient's choice. The 5-year-survival rates dependent on UICC stages/substages (I: 68%-100%, II: 58%-90%, III: 33%-76%, IV: <5%-9%) show remarkable variations between published reports, surgical hospital units, individual surgeons, and continents (USA vs Europe). Those variations may be due to surgical techniques, training status, hospital and individual case volume, and, also, referral patterns and statistical evaluation methods. Survival times and cure rates are significantly improved by adjuvant chemotherapy in UICC III and in substages of UICC II (e.g. UICC II B) by 5%-12%, when compared with surgical controls. In three recently published trials standard adjuvant chemotherapy was further improved by increased survival rates, e.g. from 59% to 71% in stage III and IIB patients. Molecular and genetic factors, such as thymidylate synthase (TS), microsatellite instability (MSI) or loss of chromosome 18q/"DCC" might have an independent impact on prognosis in the spontaneous course, and TS could help to better select patients for adjuvant chemotherapy.

A longterm follow-up study of thymidylate synthase as a predictor for survival of patients with liver tumours receiving hepatic arterial infusion chemotherapy.

AIMS: Thymidylate synthase (TS) is a key-enzyme for DNA synthesis and targeted by fluoropyrimidines (FPs). High TS ratios are associated with resistance to systemic FP-based chemotherapy. The aim of this study was to report the influence of TS ratios on primary tumour response to FP-based HAI and long-term follow-up of patients with isolated non-resectable liver tumours in part from a previously published study. METHODS: Fifty-one consecutive patients with liver tumours receiving HAI with available tumour tissue for TS quantitation were studied between 1991 and 2001. Liver metastases were from colorectal origin in 41 patients and other primary sites in 6 patients. Four patients had primary liver cancers. Tumour tissue was obtained at laparotomy for the intraarterial infusion device implantation. TS mRNA quantitation was performed by RT-PCR using beta-actin as internal standard. RESULTS: The median TS ratio was 2.2 with high variation among tumours ranging from 0.1 to 27. Twenty-two out of 51 patients responded to HAI. The median TS ratio of the responders was 1.6 and more than two-fold lower than the ratio of the non-responders with 3.3 (p < 0.01). In the subgroup with TS3.0 only four out of 22 patients responded. No patients with very high TS ratios >or=4.5 ( n = 13) responded to HAI. Median survival was 20 months (range: 3-109). Patients with TS-ratios 3.0 with 27%. CONCLUSION: TS seems to be a predictive and prognostic factor for patients with isolated non-resectable liver tumours receiving FP-based HAI. Patients with very high TS ratios do not seem to benefit from FP-based HAI.

Conversion of locally inoperable primary rectal cancer with multiple liver metastases to an option for cure after local down-staging and hepatic arterial infusion chemotherapy.

AIMS: This case report presents a patient with local unresectable primary rectal cancer and multiple synchronous liver metastases. METHODS: The treatment consisted of primary tumor resection after down-staging by local irradiation followed by hepatic arterial infusion chemotherapy. RESULTS: The patient is now without any signs of tumor growth 44 months after beginning of treatment.

Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5-fluorouracil, folinic acid, and mitomycin C may prolong survival.

BACKGROUND: Regional chemotherapy of isolated, nonresectable colorectal liver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5-Fluorodeoxyuridine (5-FUDR) has been the drug studied in most Phase II and III trials. The meta-analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5-FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5-fluorouracil (5-FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5-FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5-FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM. PATIENTS AND METHODS Between February 1993 and August 2000, 63 patients with CRLM were treated with HAI using mitoxantrone, 5-FU with FA, and mitomycin C (MFFM) via port catheters with a protocol planing up to 11 cycles of treatment. Toxicity and response were analyzed according to World Health Organization (WHO) criteria, and survival was analyzed according to Kaplan-Meier. All patients were treated with more than two HAI cycles. RESULTS: The objective response rate (complete remission and partial remission) was 54% and primary intrahepatic progression (progressive disease) occurred in 4.8%, whereas in 41.3% of the patients the intrahepatic disease was evaluated as no change. Median survival times from the first diagnosis of CRLM or start of HAI were 25.7 months and 23.7 months, respectively, and 7 patients lived longer than 40 months. Grade 3 toxicity according to WHO occurred in 34.9%, and Grade 4 occurred in 3.2%. No toxic death or SC occurred. CONCLUSIONS: Our new HAI protocol with MFFM seems to be superior to HAI with 5-FUDR, 5-FU with FA, and systemic chemotherapy with 5-FU and FA at acceptable toxicity. Currently, HAI with MFFM is compared with systemic chemotherapy using 5-FU and FA intravenously in a randomized Phase III trial.

Expression of the IIIc variant of FGF receptor-1 confers mitogenic responsiveness to heparin and FGF-5 in TAKA-1 pancreatic ductal cells.

BACKGROUND: Fibroblast growth factors (FGFs) contribute to angiogenesis and mitogenesis by binding to tyrosine kinase receptors termed FGF receptors (FGFRs). FGF-5 is a secreted FGF that is believed to preferentially act via the IIIc splice variant of FGFR-1. Human pancreatic ductal carcinoma cells express FGF-5 and FGFR-1IIIc, implying a potential for autocrine growth modulation. AIM: In this study we investigated the importance of FGFR-1 IIIc expression for FGF-5 mitogenic signaling in a pancreatic ductal cell line. METHODS: A cDNA encoding FGFR-1 IIIc was expressed in the well-differentiated TAKA-1 Syrian hamster pancreatic ductal cell line. RESULTS: TAKA-1 cells secrete FGF-5, but were found not to express FGFR-1 and to be unresponsive to exogenous FGF-5. In contrast, TAKA-1 clones expressing FGFR-1 IIIc were growth stimulated in the presence of FGF-5 and displayed enhanced mitogen-activated protein kinase (MAPK) activity in the presence of FGF-5. PD98059, an inhibitor of this pathway, inhibited FGF-5-induced growth in these clones. CONCLUSION: Our data demonstrate that FGFR-1 IIIc can mediate FGF-5-induced mitogenesis via the MAPK pathway in pancreatic ductal cells, and suggest that expression of FGFR-1 IIIc in conjunction with FGF-5 may contribute to the pathobiology of human pancreatic cancer.