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.

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.

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.

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.

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.

[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.

Transthoracic high-frequency echocardiographic detection of atherosclerotic lesions in the descending portion of the left coronary artery.

To assess the ability of transthoracic high-frequency two-dimensional echocardiography to detect atherosclerotic lesions in the descending portion of the left coronary artery, 30 consecutive patients with suspected coronary artery disease underwent two-dimensional echocardiographic examination 24 to 96 hours before coronary angiography. The descending portion of the left coronary artery was arbitrarily divided into a mid segment (the portion of the coronary vessel embedded in the anterior interventricular sulcus) and an apical segment (the portion turning around the cardiac apex into the posterior interventricular sulcus). The mid segment was imaged in 24 and the apical segment in 25 of the 30 patients for a total of 49 out of 60 segments (82%). Comparison of the echocardiographically visualized segments with the corresponding angiographic segments indicated that a correct echocardiographic diagnosis of significant stenosis was made in 11 out of 12 segments. There were no false positive results. Thus the sensitivity and specificity of high-frequency transthoracic echocardiography in the detection of significant stenosis in the imaged segments were 92% and 100%, respectively. Compared with angiography, additional information concerning the status of the arterial wall, the presence of calcific plaques, and the cross-sectional extent of the obstructive lesions was obtained by echocardiography in eight patients.

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.

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.).

The value of intraoperative laparoscopic examination of the contralateral inguinal ring during hernia repair in children.

Approximately 40% of children with a clinical unilateral inguinal hernia display a patent processus vaginalis on the contralateral side; half of these children subsequently develop an inguinal hernia. The management of this problem is still controversial. Different strategies to identify patients who profit from an open contralateral exploration have been applied (diagnostic pneumoperitoneum, herniography, ultrasound). The purpose of this study was to evaluate the usefulness of intraoperative laparoscopy in a no-puncture technique through the opened hernia sack. In 75 children (age 6 months to 7 years) with clinical unilateral hernia laparoscopy (5-mm Laparoscope, 30 degrees and 70 degrees ), in cases of wide-open contralateral internal inguinal ring (Type III) an open surgical exploration was performed. Twelve patients (17%) fulfilled the laparoscopic criteria of a Type III ring. The diagnose was confirmed during open contralateral exploration. Seven children (8%) showed a patent but small processus vaginalis with a shallow internal ring. These patients were treated conservatively. In the follow-up period (median 6 months) one subsequent hernia developed. There was no technical failure, and no associated complications were seen. The median time for laparoscopy was 6 minutes. Intraoperative laparoscopy during unilateral hernia repair allows the identification of patients who profit from bilateral open surgery during the same operation with little additional operating time, and so far with no resulting complications. Application of this method may avoid a second hospitalization and operation as well as unnecessary routine bilateral open exploration. As an additional source of information through excellent visualization of the abdominal cavity, this method proved helpful to examine the incarcerated bowel after repositioning.

["No-puncture-laparoscopy" in hernia management in childhood--reliable complement to established therapy concepts]. / "No-puncture-Laparoskopie" während der Hernienversorgung im Kindesalter--sinnvolle Ergänzung eines bewährten Therapiekonzepts.

BACKGROUND: Approximately 50% of children with a clinical unilateral inguinal hernia display a patent processus vaginalis on the contralateral side; half of these children subsequently develop an inguinal hernia. The management of this problem is still controversial. The purpose of this study was to evaluate the usefulness of intraoperative laparoscopy in a non-puncture technique through the opened hernia sack. METHOD: In 112 children (age 6 months to 7 years) with clinical unilateral hernia laparoscopy (5 mm laparoscope, 30 degrees and 70 degrees). In cases of a wide-open contralateral internal inguinal ring (type III) open surgical exploration was performed. RESULTS: Nineteen patients (17%) fulfilled the laparoscopic criteria of a type III ring; the diagnose was confirmed during open contralateral exploration. Fourteen of these patients were younger than two years. The median time for laparoscopy was 6 min (3-11 min). No complications associated with the laparoscopy were observed. CONCLUSIONS: Intraoperative laparoscopy during unilateral hernia repair allows the identification of patients who profit from bilateral open surgery during the same operation with little additional operating time and so far with no resulting complications. Application of this method may avoid a second hospitalization and operation, as well as an unnecessary routine bilateral open exploration. As an additional source of information through excellent visualization of the abdominal cavity, this method proved helpful to examine incarcerated bowel after repositioning.

Surgery and multimodal treatments in pancreatic cancer--a review on the basis of future multimodal treatment concepts.

BACKGROUND: To improve the surgical outcome after resection of pancreatic adenocarcinomas, multimodal treatment concepts need to be applied and improved. In spite of several positive studies, and the fact that multimodality treatment is the standard concept in major centers for pancreatic cancer surgery, a recent trial shed some doubt on the positive effect of adjuvant radiochemotherapy, so that the majority with reservations about multimodal treatment feel confirmed in their opinion that surgical treatment alone is sufficient therapy for resectable pancreatic cancer. The controversy among those for and against adjuvant treatment need an up-to-date review of the indications and results achievable with various treatment modalities. PATIENTS/METHODS: The literature on the indications and results of adjuvant/neoadjuvant therapies in pancreatic cancer was reviewed to provide a solid base for current recommendations and future developments. A special view was concentrated on the biology of the disease in the spontaneous course, after surgery and during/after various palliative and adjuvant/neoadjuvant treatment modalities, to characterize the disease for an optimally targeted treatment in conjunction with surgical removal of the tumor. The results of systemic and regional chemotherapy and radiotherapy either alone or in combination, before, during, and after surgery, were critically analyzed with respect to the oncological possibilities and pitfalls of each treatment method. RESULTS: In two randomized trials, one testing postoperative radiochemotherapy (GITSG), and one postoperative chemotherapy (Bakkevold), the adjuvant treatment achieved a significant prolongation of the median survival time. The 5- and 10-year survival rates were improved in the GITSG study. The EORTC-GITCCG trial could not confirm the benefit of adjuvant radiochemotherapy. This study had a different design than the GITSG trial. Several historical control studies supported the beneficial effect of postoperative radiochemotherapy. In three historical control trials using regional chemotherapy, one with intraoperative radiotherapy, the survival times were improved vs. surgery alone. Intraoperative or postoperative radiotherapy as single modalities might reduce local relapses, but a survival advantage is still debated. Preoperative neoadjuvant radiochemotherapy has several advantages (downstaging, devitalizing margins and lymph node metastases, compatibility of treatment vs. postoperative radiochemotherapy), and does not seem to increase the postoperative morbidity. Several trials have confirmed the feasibility of this concept, but no survival advantage has yet been proven. Systemic and regional chemotherapy is able to downstage primarily nonresectable pancreatic cancers. CONCLUSIONS: Postoperative adjuvant radiochemotherapy with up-to-date protocols can be recommended for routine treatment, if the surgeon or the patient desires to improve the usually remote prognosis after surgery alone. For those being undecisive or against adjuvant therapy, the participation in trials, e.g., ESPAC 1 and 2 studies, is strongly recommended. Regarding our own positive experience with adjuvant regional chemotherapy and in view of the postresectional progression pattern, we currently favour adjuvant radiochemotherapy, with the chemotherapy delivered regionally via the celiac axis. This concept will be tested vs. surgery alone in the ESPAC 2 trial. Neoadjuvant therapies have a great potential, but should be conducted within studies, such as pre-, intra-, or postoperative radiotherapy.

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.

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.