LRP1/CD91 is up-regulated in monocytes from patients with haemophilia A: a single-centre analysis.

The low-density lipoprotein receptor-related protein 1 (LRP1) is an ubiquitously expressed endocytic receptor that, among its several functions, is involved in the catabolism of coagulation factor VIII (FVIII) and in the regulation of its plasma concentrations. Although LRP1/CD91 polymorphisms have been associated with increased FVIII levels and a consequent thrombotic risk, no data are available on LRP1/CD91 expression in patients with inherited FVIII deficiency. With the aim of elucidating this issue, 45 consecutive patients with haemophilia A (HA) (18 severe, 5 moderate and 22 mild HA) were enrolled in this cross-sectional, single-centre survey. The LRP1/CD91 mean fluorescence intensity (MFI) in monocytes from HA patients was significantly higher than that detected in 90 healthy blood donors (105 vs. 67, P < 0.001). This over-expression was independent of hepatitis C virus infection status and varied according to the severity of the haemophilia, being higher in patients with more severe FVIII deficiency. In conclusion, our study documents for the first time that LRP1/CD91 is over-expressed on monocytes from HA patients, with the intensity of expression varying according to the severity of the FVIII deficiency. Further studies are needed to assess the clinical implications of these findings.

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.

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.

Bionomy of Anicla mahalpa Schaus, 1898 (Lepidoptera: Noctuidae: Noctuinae), in the laboratory.

The genus Anicla Grote, 1874 is composed of eleven species; their larvae are harmful, mainly to native and cultivated grasses, but up to now, there is information available of only two species. This study aims at detailing the bionomy of A. mahalpa Schaus; the data were obtained from a laboratory rearing under the following settings: 20 +/- 2 masculineC, 70 +/- 10% relative humidity and 12 hours of photoperiod. Larvae were fed on ryegrass, Lolium multiflorum Lam. (Poaceae). The results expressed by the mean and respective standard error for the periods of each phase, in days, were the following: egg 6.00 +/- 0.00, larva 36.47 +/- 0.44, pre-pupa 5.23 +/- 0.21, pupa 23.60 +/- 0.37, and adult: longevity 15.24 +/- 0.75 with pre-egg-laying-periods of 5.29 +/- 0.32; egg-laying period, 9.64 +/- 0.81, and post-egg-laying period, 0.71 +/- 0.27 days. The mean number of egg-laying cycles per female was 7.36 +/- 0.20 and 2,014.21 +/- 78.93 eggs per female. Eggs, which are subspheric, have a diameter of 0.76 +/- 0.01 mm; larvae passed through six instars; their head capsules width, provided a mean ratio of growth of 1.482. Pupae presented a mean width and length of 6.07 +/- 0.06 and 17.24 +/- 0.19 mm, respectively and weight of 0.33 +/- 0.01 g.

Bionomy of Anicla mahalpa Schaus, 1898 (Lepidoptera: Noctuidae: Noctuinae), in the laboratory / Bionomia de Anicla mahalpa Schaus, 1898 (Lepidoptera: Noctuidae: Noctuinae), em laboratório

The genus Anicla Grote, 1874 is composed of eleven species; their larvae are harmful, mainly to native and cultivated grasses, but up to now, there is information available of only two species. This study aims at detailing the bionomy of A. mahalpa Schaus; the data were obtained from a laboratory rearing under the following settings: 20 ± 2 ºC, 70 ± 10 percent relative humidity and 12 hours of photoperiod. Larvae were fed on ryegrass, Lolium multiflorum Lam. (Poaceae). The results expressed by the mean and respective standard error for the periods of each phase, in days, were the following: egg 6.00 ± 0.00, larva 36.47 ± 0.44, pre-pupa 5.23 ± 0.21, pupa 23.60 ± 0.37, and adult: longevity 15.24 ± 0.75 with pre-egg-laying-periods of 5.29 ± 0.32; egg-laying period, 9.64 ± 0.81, and post-egg-laying period, 0.71 ± 0.27 days. The mean number of egg-laying cycles per female was 7.36 ± 0.20 and 2,014.21 ± 78.93 eggs per female. Eggs, which are subspheric, have a diameter of 0.76 ± 0.01 mm; larvae passed through six instars; their head capsules width, provided a mean ratio of growth of 1.482. Pupae presented a mean width and length of 6.07 ± 0.06 and 17.24 ± 0.19 mm, respectively and weight of 0.33 ± 0.01 g.

O gênero Anicla Grote, 1874 é composto por onze espécies cujas lagartas são nocivas principalmente a gramíneas nativas e cultivadas, entretanto, até o momento só existem informações a respeito de duas espécies. Este estudo objetivou detalhar a bionomia de A. mahalpa Schaus cujos dados foram obtidos a partir de uma criação laboratorial feita sob condições de 20 ± 2 ºC, 70 ± 10 por cento UR e 12 horas de fotofase. As lagartas foram alimentadas com azevém, Lolium multiflorum Lam. (Poaceae). Os resultados expressos pela média e pelo respectivo erro-padrão para os períodos de cada fase, em dias, foram: ovo 6,00 ± 0,00; larva 36,47 ± 0,44; pré-pupa 5,23 ± 0,21; pupa 23,60 ± 0,37 e adulta: longevidade 15,24 ± 0,75 com períodos de pré-oviposição 5,29 ± 0,32; oviposição 9,64 ± 0,81 e pós-oviposição 0,71 ± 0,27 dias. O número médio de posturas por fêmea foi 7,36 ± 0,20 e de ovos por fêmea, 2.014,21 ± 78,93. Os ovos, de formato subesférico, apresentam diâmetro de 0,76 ± 0,01 mm; as lagartas passaram por seis ínstares cujas médias da largura das cápsulas cefálicas proporcionaram razão média de crescimento de 1,482. As pupas apresentaram em média largura e comprimento 6,07 ± 0,06 e 17,24 ± 0,19 mm, respectivamente, e peso de 0,33 ± 0,01 g.

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.

Anorectal amelanotic melanoma.

OBJECTIVE: Anorectal melanoma is a rare, highly malignant tumour with a poor 5 year survival of 10%. Most anorectal melanomas have gross and/or histologic pigmentation, however about 30% of anorectal melanomas are amelanotic. METHOD: We report three cases of amelanotic anorectal melanomas and integrate our data with six case reports of amelanotic malignant melanoma from the literature. Further we compare clinicopathological data and clinical outcome with large series of anorectal melanomas (both, amelanotic and pigmentated). RESULTS: There were seven females and two males, of median age 62 years (range: 45-75 years). Rectal bleeding was the leading symptom in all cases with a mean duration of 4 months before diagnosis. Eight of nine patients developed distant metastases. Median survival was 14 months (range: 3-60 months). A tumour thickness of < 4 mm was correlated with long-term disease-free survival, whereas tumour thickness of 4 mm or more was correlated with systemic recurrence. CONCLUSION: Early diagnosis is key for efficient treatment and improved survival rate for patients with this unusual variant of melanoma. There is no difference in terms of age, time of diagnosis, stage and survival between pigmented and amelanotic anorectal melanoma.

[Rare cause of recurring necrotising pancreatitis]. / Seltene Ursache einer rezidivierenden, nekrotisierenden Pankreatitis.

BACKGROUND: Necrotising pancreatitis may develop as a consequence of pancreatic duct obstruction by stones, tumors or in the presence of a pancreas divisum. Alcohol and nicotine are regarded as risk factors for the disease becoming chronic. PATIENT AND COURSE OF THE DISEASE: A 63-year-old female patient with suspected cystadenocarcinoma of the pancreas tail, which was resolved as a pancreatic pseudocyst, was treated for recurrent pancreatitis for 2 years. A tumor in the pancreas head was only detected on a follow-up CT after resection of a complicating liver abscess. In retrospect, progressive pancreatic duct anomalies were visible on previous scans. Partial duodenopancreatectomy confirmed the presence of a pancreas head carcinoma. CONCLUSION: Continuous critical re-evaluation of all potential causes of pancreatitis including rare conditions, such as a tumor, is required particularly if pancreatitis recurs over a long period. Re-evaluation of studies over time and of findings apart from the actual main focus of the complication, in this case pancreatitis of the pancreas tail, may help to detect the underlying disease instead of just treating the consequences.

Biological aspects of Hylesia metapyrrha (Lepidoptera; Saturniidae; Hemileucinae), in laboratory.

The aim of this work was to study biological aspects and the life cycle of Hylesia Metapyrrha in a laboratory. Laboratorial breeding was made at 25 +/- 1 degrees C, 70 +/- 10% UR and 14 hours of photophase, feeding the larvae with guava leaves (Psidium guayava L. - Myrtaceae). Time was evaluated on the days of all the development stages; morphometry was evaluated in millimeters and the pupas mass in grams. The eggs were disposed in groups and covered by urticating abdominal hair. The incubation period lasted 52 days. The larvae, with gregarious habits, presented background black coloration, yellowish scoli and two orange longitudinal lines above and below the spiracles, during the development which lasted an average period of 74.59 days and went through seven instars. The pre-pupa and the pupa stages lasted on average 8.82 and 50.56 days, respectively; the female pupae presented a duration, weight and size which was significantly bigger. The adult stage lasted on average 5.50 days with periods of pre, post and oviposition of 2.30, 1.90 and 1.00 days, respectively. This study broadens the knowledge of the immature stages, biological, morphological and behavioral aspects, until then restricted to the morphology and to registers of the occurrence of the adult forms.

Biological aspects of Hylesia metapyrrha (Lepidoptera; Saturniidae; Hemileucinae), in laboratory

The aim of this work was to study biological aspects and the life cycle of Hylesia Metapyrrha in a laboratory. Laboratorial breeding was made at 25 ± 1 °C, 70 ± 10 percent UR and 14 hours of photophase, feeding the larvae with guava leaves (Psidium guayava L. - Myrtaceae). Time was evaluated on the days of all the development stages; morphometry was evaluated in millimeters and the pupaÆs mass in grams. The eggs were disposed in groups and covered by urticating abdominal hair. The incubation period lasted 52 days. The larvae, with gregarious habits, presented background black coloration, yellowish scoli and two orange longitudinal lines above and below the spiracles, during the development which lasted an average period of 74.59 days and went through seven instars. The pre-pupa and the pupa stages lasted on average 8.82 and 50.56 days, respectively; the female pupae presented a duration, weight and size which was significantly bigger. The adult stage lasted on average 5.50 days with periods of pre, post and oviposition of 2.30, 1.90 and 1.00 days, respectively. This study broadens the knowledge of the immature stages, biological, morphological and behavioral aspects, until then restricted to the morphology and to registers of the occurrence of the adult forms.

O presente estudo objetivou estudar aspectos biológicos e o ciclo de vida de Hylesia metapyrrha em laboratório. Para tanto, foi realizada uma criação laboratorial a 25 ± 1 °C, 70 ± 20 por cento UR e 14 horas de fotofase, alimentando-se as lagartas com folhas de goiabeira (Psidium guajava L - Myrtaceae). Para todas as fases de desenvolvimento, foram avaliados o tempo em dias, a morfometria em milímetros e, para as pupas, a massa, em gramas. Também foram feitas observações sobre características morfológicas e etológicas. Os ovos, de formato subcilíndrico, são dispostos em grupos e recobertos por cerdas abdominais urticantes, o período de incubação foi de 52,00 dias. As lagartas, de hábito gregário, apresentam coloração de fundo negra, escolos amarelados e duas linhas longitudinais laranja dispostas acima e abaixo dos espiráculos, durante o desenvolvimento que teve um período médio de 74,59 dias, passaram por sete ínstares. As fases de pré-pupa e pupa duraram em média 8,82 e 50,56 dias, respectivamente, sendo que as pupas do sexo feminino apresentaram duração, peso e tamanho significativamente maiores que as dos machos. A fase adulta durou em média 5,50 dias, com períodos de pré, pós e oviposição de 2,30, 1,90 e 1,00 dias, respectivamente. Este estudo amplia os conhecimentos sobre as fases imaturas, aspectos biológicos, morfológicos e comportamentais até então restritos apenas à morfologia e registros da ocorrência das formas adultas.

Treatment of Barrett's esophagus with argon plasma coagulation and antireflux surgery. A retrospective analysis.

BACKGROUND/AIMS: The aim of this study was to assess the efficacy and the results of ablation of Barrett'esophagus by endoscopic argon plasma coagulation (APC) followed by fundoplication. METHODOLOGY: Between January 1999 and December 2004, 21 patients with histological proven, short BE and scheduled for fundoplication, were treated by APC. Treatment was repeated until histological confirmation of complete ablation was obtained. All patients underwent surgical correction of reflux by Nissen fundoplication. Response to treatment was assessed at follow up with endoscopy every 6 to 12 months. RESULTS: BE ablation was obtained in all patients after a mean of 3.6 APC sessions. There was no mortality and morbidity was 19% (4/21 patients). All patients underwent 360 degrees Nissen fundoplication as antireflux procedure. There was no operative mortality and no major complications requiring re-operation. Mean postoperative hospital stay was 7.9 days. Postoperatively 17/21 patients had at least one endoscopic control. The mean observation time was 17.5 months. Recurrence of Barrett epithelium was observed in 6 patients at a mean of 9.6 months after fundoplication. CONCLUSIONS: Our results show that the combination of APC and fundoplication is a safe and effective treatment option for most patients with uncomplicated BE. Although no cancer development was observed, larger studies with a longer follow up are required to assess the impact of APC on cancer risk.

[An unusual foreign body in the upper gastrointestinal tract causing nonspecific abdominal pain]. / Ungewöhnlicher Fremdkörper im oberen Gastrointestinaltrakt als Ursache eines unklaren Abdomens.

The risk of penetration of vena cava filters through the wall of the vena cava is estimated to be as high as 25%, although clinical symptoms are observed far less frequently in patients with this complication. Due to the close relationship between vena cava and duodenum, the latter can be injured by dislocated filters. We describe the presentation, evaluation, and treatment of a patient with a cava filter protruding into the duodenum, and we review the literature.

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.

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.

Surgery, radio- and chemotherapy for multimodal treatment of rectal cancer.

The possibilities and results of multimodal treatment in rectal cancer were reviewed with respect to the results of surgical treatment only. Based on the results of 4 studies, reducing local relapse rates and increasing long term survival rates significantly, postoperative radiochemotherapy (RCT) + chemotherapy (CT) should remain the recommended standard for R0 resected UICC II and III rectal cancers. The addition of RT to adjuvant CT reduces local relapses without significant impact on survival (NSABP R-02). Vice versa, the addition of CT to RT or an improved CT in the RCT-concept prolongs survival. Preoperative neoadjuvant radiotherapy (RT) reduced local relapse rates in 9 studies, and extended survival in one study that evaluated all eligible patients. Preoperative RT reduced local relapse rates in addition to total mesorectal excision (TME) but did not extend survival. The preoperative RCT + CT downstages resectable and nonresectable tumors and induces a higher sphincter preservation rate. Phase III data justifying its routine use in all UICC II + III stages are not yet available. This treatment may be routinely applied in nonresectable primary tumors or local relapses. Preoperative RCT (or RT) may evolve as standard, if the patient selection is improved and postoperative morbidity and long term toxicity reduced. Intraoperative RT could be added to this concept or be used together with preoperative/postoperative RT at the same indications. Postoperative adjuvant RT reduced local relapses significantly in a single trial, and no impact on survival time is reported. Since postoperative RT is inferior to preoperative RT, this treatment cannot be recommended, if RT is chosen as a single treatment modality in adjunction to surgery. The results of local tumor excisions may be improved with pre- or postoperative RCT + CT. In the future, multimodal treatment of rectal cancer might be more effective, if individualized according to prognostic factors.

Regional chemotherapy of non-resectable liver metastases from colorectal cancer - literature and institutional review.

BACKGROUND: Cure is possible by resecting colorectal isolated liver metastases. In non-resectable isolated colorectal liver metastases (CRLM), regional chemotherapy has been advocated to optimize the disease control in the liver in order to improve the results of the alternative, systemic chemotherapy. The drugs are delivered by means of hepatic artery infusion (HAI) via ports or pumps; pharmacological modifications of the hepatic arterial blood-flow-like HAI with starch microspheres or stop-flow and perfusion techniques were applied to improve HAI. METHODS: We reviewed the literature and report our progress, up to May 1999, in analyzing the validity of HAI for CRLM therapy. RESULTS: In the majority of phase-II and -III trials, the response rates to HAI were significantly higher than those from systemic chemotherapy, and local disease control could be achieved even when HAI was used second line to systemic chemotherapy. The meta-analysis of randomized trials comparing HAI with either systemic chemotherapy (five trials) or, optionally, either 5-fluorouracil (FU) or symptomatic treatment (two trials) showed a significant advantage of HAI in response (41% vs 14%, P<10(-10)) and median survival time (15 months vs 11 months, P<0.0009). The active anabolite of 5-FU, 5-fluordeoxyuridine (5-FUDR), the drug of choice for HAI in those trials, may cause severe hepatotoxicity. To avoid this toxicity, we developed a HAI protocol using mitoxantrone, 5-FU plus folinic acid (FA) and mitomycin C (MFFM). The response rates of HAI with 5-FU plus FA or MFFM were 45% and 66%, the interim median survival times 19.8 months and 27.4 months. 5-Year survivors were observed in all our protocols. Since no severe hepatotoxicity occurred, 9 of 74 patients were resected after response to HAI with 5-FU plus FA or MFFM, without surgical mortality and with survival times from 2+ months to 58+ months. CONCLUSION: The high response rates, the long survival times, the possibility of achieving 5-year-survival either by HAI alone or by resection after down staging with HAI all sum up to the evidence that HAI could be the primary choice of treatment for CRLM. Phase-III trials are conducted to compare the protocols with optimal regional versus systemic chemotherapy.

Downstaging by regional chemotherapy of non-resectable isolated colorectal liver metastases.

AIMS: To improve the course of isolated non-resectable colorectal liver metastases (CRLM) by hepatic arterial infusion treatment. Patients with CRLM have a worse prognosis than those whose liver metastases are resectable. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases with 5-fluorouracil+folinic acid (5-FU+FA) i.v. may result in median survival times of 6.4-14.3 months. Hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (5-FUDR) has been demonstrated in a meta-analysis of randomized trials to be superior to i.v. treatment/palliative care (median survival 15 vs. 10 months). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver cirrhosis. We have developed a stepwise protocol for HAI in CRLM, which is superior to HAI with 5-FUDR and to systemic chemotherapy. METHODS: Between 1982 and 1997, 168 CRLM patients were treated within the following protocols. In protocol A, 48 CRLM patients received HAI with 5-FUDR. In protocol B, 46 patients received 5-FUDR i.a. (HAI)+i.v. In protocol C 5-FU+FA were delivered via HAI in 24 patients with CRLM. In protocol D, based on in vitro phase II studies and the results of protocol C, mitoxantrone and mitomycin C were added to 5-FU+FA (MFFM). Fifty (50) CRLM patients received HAI with HFFM. RESULTS: The response rates, median survival time, systemic toxicity and SC rate were: 42%, 20.8 months, 0-19% and 38% for protocol A; 46%, 20.8 months, 0-20% and 41% for protocol B; 45%, 19.8 months, 4-25% and 0% for protocol C; and 66%, 27.4 months, 2-26% and 0% for protocol D. The surgically placed ports for HAI in protocols C and D functioned in 90%, 82% and 76% of patients, 6, 9, and 11 months after beginning HAI. Quality of life in protocol D was high. Nine patients from protocols C and D with either partial (PR, seven patients) or complete (CR, two patients) remissions received a secondary liver resection without hospital mortality, and seven of nine patients are alive 2-58 months after liver resection. The other two died 11 and 22 months after resection. CONCLUSIONS: Optimal treatment of CRLM was found to be protocol D: HAI with MFFM. The results of this protocol, including high remission rate, long median survival time, good port function, good quality of life and, interestingly, the possibility of downstaging and resecting primarily non-resectable metastases, seem to be superior to HAI with 5-FUDR or 5-FU+FA and to systemic chemotherapy with 5-FU+FA. This hypothesis is currently being examined in a phase III study (HAI with MFFM vs. 5-FU+FA i.v.).

Serum and correspondent tissue measurements of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF-R). Clinical relevance in pancreatic cancer and chronic pancreatitis.

CONCLUSION: The results of this study show that routine measurements of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF-R) cannot improve screening for pancreatic cancer despite the frequently present tissue overexpression. Both values fail to reveal this malignancy in a serum test. Patients with chronic pancreatitis exhibit no or very low concentrations of EGF. In cases where preoperative diagnosis is difficult the noninvasive EGF and EGF-R serum measurements may be helpful in discriminating between pancreatic cancer and chronic pancreatitis. BACKGROUND: EGF and EGF-R are frequently overexpressed in the tissue of patients suffering from ductal pancreatic cancer and to lesser degree in patients with chronic pancreatitis. The aim of this study was to determine the value of serum measurements in these patients to detect malignant pancreatic disease. In cases of pancreatic cancer, the tissue expression of EGF and EGF-R was evaluated by immunohistochemistry. METHOD: Thirty-five patients with chronic pancreatitis and 31 patients with pancreatic cancer were evaluated; 71 patients admitted for routine surgery (hernia repair, cholecystectomy, goiter surgery) served as controls. RESULTS: EGF and EGF-R values were not significantly different in pancreatic cancer as compared to controls and did not correlate with other tumor markers (CA 19-9, carcinoembryonic antigen [CEA], tumor polypeptide antigen [TPA]) or with the stage of the disease. Fourteen patients (67%) with pancreatic cancer displayed tissue overexpression for EGF and 11 patients for EGF-R (52%). These patients, however, also failed to exhibit any significant pathological changes in serum concentration. In chronic pancreatitis, EGF and EGF-R were significantly decreased as compared to pancreatic cancer and controls. This was an unexpected finding. There was a positive correlation to clinical exocrine insufficiency.