[Vasculitis of the celiac artery as a presentation of Takayasu's arteritis]. / Vasculitis del tronco celíaco como presentación de arteritis de Takayasu.

Takayasu arteritis is an idiopathic and chronic granulomatous vasculitis manifested in the form of panaortitis, of unknown etiology, even though an autoimmune origin is postulated. It is progressive and generates, in adults and children, segmental stenosis, occlusion, dilation and / or aneurysms. Isolated gastrointestinal vasculitis without systemic involvement is rare. This case leads us to take into account the atypical abdominal manifestation of Takayasu arteritis in the differential diagnosis of a frequent symptom, such as epigastralgia, and to highlight the role currently played by non-invasive imaging methods for its diagnosis.

La arteritis de Takayasu es una vasculitis idiopática y granulomatosa crónica que se manifiesta en forma de panaortitis, de etiología desconocida, aunque se postula un origen autoinmune. Es progresiva y genera, tanto en adultos como en niños, estenosis segmentaria, oclusión, dilatación y/o aneurismas. La vasculitis aislada gastrointestinal sin afectación sistémica es rara. Este caso lleva a tener en cuenta la manifestación abdominal atípica de la arteritis de Takayasu en el diagnóstico diferencial de un síntoma frecuente, como la epigastralgia, y a destacar el rol que ocupan en la actualidad los métodos de imágenes no invasivos para su diagnóstico.

Vasculitis del tronco celíaco como presentación de arteritis de Takayasu / Vasculitis of the celiac artery as a presentation of Takayasu's arteritis

La arteritis de Takayasu es una vasculitis idiopática y granulomatosa crónica que se manifiesta en forma de panaortitis, de etiología desconocida, aunque se postula un origen autoinmune. Es progresiva y genera, tanto en adultos como en niños, estenosis segmentaria, oclusión, dilatación y/o aneurismas. La vasculitis aislada gastrointestinal sin afectación sistémica es rara. Este caso lleva a tener en cuenta la manifestación abdominal atípica de la arteritis de Takayasu en el diagnóstico diferencial de un síntoma frecuente, como la epigastralgia, y a destacar el rol que ocupan en la actualidad los métodos de imágenes no invasivos para su diagnóstico.

Takayasu arteritis is an idiopathic and chronic granulomatous vasculitis manifested in the form of panaortitis, of unknown etiology, even though an autoimmune origin is postulated. It is progressive and generates, in adults and children, segmental stenosis, occlusion, dilation and / or aneurysms. Isolated gastrointestinal vasculitis without systemic involvement is rare. This case leads us to take into account the atypical abdominal manifestation of Takayasu arteritis in the differential diagnosis of a frequent symptom, such as epigastralgia, and to highlight the role currently played by non-invasive imaging methods for its diagnosis.

A phase I, dose-finding study of sunitinib combined with cisplatin and 5-fluorouracil in patients with advanced gastric cancer.

Background This phase I, open-label, dose-escalation study examined the safety, maximum tolerated dose (MTD), and pharmacokinetics of sunitinib plus chemotherapy in patients with advanced gastric cancer. Patients and methods Sunitinib (25 or 37.5 mg/day, Schedule 2/1: 2 weeks on treatment/1 week off) plus chemotherapy (fixed starting doses of cisplatin 80 mg/m(2) and 5-fluorouracil [5-FU] 4,000 mg/m(2)) was administered to patients with advanced gastric cancer who had not received prior therapy for metastatic disease. Results Thirty-four patients were enrolled and received sunitinib 25 mg/day (n = 24) or 37.5 mg/day (n = 10) plus chemotherapy. No dose-limiting toxicity (DLT) was reported in the sunitinib 37.5 mg cohort. However, repeated patterns of myelosuppression beyond the first cycle led to investigation of sunitinib 25 mg/day. This was the MTD, and one DLT (grade 3 mucosal inflammation) was reported. The combination had an acceptable adverse event profile; generally of grade 1/2. There was no evidence of a pharmacokinetic drug-drug interaction between sunitinib and 5-FU. Six patients (26 %) receiving the MTD had a partial response and eight patients experienced stable disease ≥3 months. Conclusions Sunitinib plus cisplatin 80 mg/m(2) and 5-FU 4,000 mg/m(2) were combinable and adverse events were manageable. The MTD of sunitinib was established as 25 mg/day on Schedule 2/1.

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer.

BACKGROUND: This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1-6. Efficacy was a secondary objective. RESULTS: Thirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n=1), grade 4 neutropenia (n=4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n=1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5-79.7). CONCLUSIONS: The MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.

Brostallicin (PNU-166196)--a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells.

Defects in DNA mismatch repair (MMR) are associated with a predisposition to tumorigenesis and with drug resistance owing to high mutation rates and failure to engage DNA-damage-induced apoptosis. DNA minor groove binders (MGBs) are a class of anticancer agents highly effective in a variety of human cancers. Owing to their mode of action, DNA MGB-induced DNA damage may be a substrate for DNA MMR. This study was aimed at investigating the effect of loss of MMR on the sensitivity to brostallicin (PNU-166196), a novel synthetic alpha-bromoacrylic, second-generation DNA MGB currently in Phase II clinical trials and structurally related to distamycin A. Brostallicin activity was compared to a benzoyl mustard derivative of distamycin A (tallimustine). We report that the sensitivities of MLH1-deficient and -proficient HCT116 human colon carcinoma cells were comparable after treatment with brostallicin, while tallimustine resulted in a three times lower cytotoxicity in MLH1-deficient than in -proficient cells. MSH2-deficient HEC59 parental endometrial adenocarcinoma cells were as sensitive as the proficient HEC59+ch2 cells after brostallicin treatment, but were 1.8-fold resistant after tallimustine treatment as compared to the MSH2-proficient HEC59+ch2 counterpart. In addition, p53-deficient mouse fibroblasts lacking PMS2 were as sensitive to brostallicin as PMS2-proficient cells, but were 1.6-fold resistant to tallimustine. Loss of neither ATM nor DNA-PK affected sensitivity to brostallicin in p53-deficient mouse embryonic fibroblasts, indicating that brostallicin-induced cytotoxicity in a p53-deficient genetic background does not seem to require these kinases. These data show that, unlike other DNA MGBs, MMR-deficient cells retain their sensitivity to this new alpha-bromoacrylic derivative, indicating that brostallicin-induced cytotoxicity does not depend on functional DNA MMR. Since DNA MMR deficiency is common in numerous types of tumours, brostallicin potentially offers the advantage of being effective against MMR-defective tumours that are refractory to several anticancer agents.

Blood glutathione as a surrogate marker of cancer tissue glutathione S-transferase activity in non-small cell lung cancer and squamous cell carcinoma of the head and neck.

The identification of markers predicting the response to therapy is of the utmost importance in oncology. Several authors have suggested that increased levels of glutathione (GSH) and glutathione S-transferase (GST) activity might be meaningful predictors of poor responsiveness to chemotherapy in several human cancers, but the biological assays have not been standardised and published studies show conflicting evidence. The aim of the present study was to select a validated panel of tests to assess the GST/GSH system in a clinical setting. Matched blood and tissue samples (normal and malignant) from 52 cancer patients with either non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (SCCHN) were investigated. GSH levels and GST activity were higher in cancer tissues than in matched normal tissues in both malignancies. The difference was statistically significant in NSCLC (P=0.0004 and P=0.0002, for GSH and GST, respectively) and borderline in SCCHN (P=0.03 and P=0.02, for GSH and GST, respectively). Moreover a strong correlation was found between the GSH level in whole blood and GST activity in cancer tissue in both malignancies (P=0.003, r=0.53 in NSCLC, P<0.0001, r=0.89 in SCCHN). In conclusion, reliable and robust methods for routine use in tissue extracts and in whole blood have been validated. Our finding regarding the GSH level in blood indicates that circulating GSH could have a clinical relevance as a surrogate marker of GST activity in tumour tissue.

Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study.

PURPOSE: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer. PATIENTS AND METHODS: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m(2) IV, epirubicin 50 mg/m(2) IV, and fluorouracil 500 mg/m(2) IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles. RESULTS: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P =.01) and in the assessable subset (66% v 52%, respectively; P =.005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P =.0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P =.01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P =.23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF. CONCLUSION: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.

Plant sources of acid stable lipases: potential therapy for cystic fibrosis.

Exogenous lipase used in the treatment of pancreatic insufficiency may be destroyed by stomach acid. This study was undertaken to search for a readily available source of acid stable lipase. Eleven plant sources (avocado, walnut, pinenut, coconut, lupin, lentils, chickpea, mungbean, oats, castor beans and eggplant) were screened for lipolytic activity using a newly developed radio-isotopic labelled substrate method. The results obtained by this method were confirmed by thin layer chromatography. Two of the sources (castor bean and dehulled oats) showed significant lipolytic activity at pH 5.6, castor beans containing 1.5 U/mg of extracted solid and oats 400-1200 U/mg of extracted solid. Castor beans are difficult to obtain and so may be an impractical commercial source of lipase; however, oats are abundant. If simple methods of enzyme purification and concentration can be developed, oats may prove to be a practical source of acid stable lipase for use in the treatment of patients with pancreatic insufficiency, especially those who have cystic fibrosis.

Comparative studies of UV-induced DNA cleavage by analogues of iodoHoechst 33258.

Following the earlier demonstration that iodo-Hoechst 33258 sensitizes DNA and cells to UVA, presumably mediated by formation of a carbon-centred radical on the ligand upon dehalogenation, three isomeric analogues of iodo-Hoechst 33258 have now been studied. The isomers differ in the location of the iodine atom in the phenyl ring of the ligand, relative to the site of attachment of the bibenzimidazole moiety, and are accordingly denoted ortho-, meta- and para-iodoHoechst. Comparison of the ligands with respect to induction of DNA ssb in pBR322 DNA revealed a wide range of activity; (D37's vary by a factor of 37), decreasing in the order: ortho- > meta- and para- > iodoHoechst 33258. Preliminary dehalogenation studies suggest that the higher activity of the ortho isomer results more from increased cross-section for dehalogenation than from increased efficiency of strand breakage per dehalogenation event. However, the chemistry of strand breakage by the ortho-isomer is distinctive, and tentatively assigned to initial attack at the 1'-deoxyribosyl carbon; the other two isomers, like iodo-Hoechst 33258, attack the 5'-carbon. The results are discussed in terms of the spectrum of DNA strand breakage chemistry associated with ionizing radiation, and the potential of DNA strand breaking agents such as the iodoHoechst compounds to study the chemical and biological consequences of the different subclasses of initial DNA damage.

Cholelithiasis of the ovary.

BACKGROUND: Laparoscopic cholecystectomy is becoming a popular surgical option in the management of gallstone disease. Reports on complications of this procedure have usually focused on prolonged operative time, bleeding, and infections. We describe a case of cholelithiasis of the ovary following laparoscopic cholecystectomy. CASE: A 70-year-old woman, para 5-0-0-5, presented with a 2-month history of a pelvic mass following a laparoscopic cholecystectomy. Exploratory laparotomy demonstrated a 4 x 4-cm para-ovarian cyst as well as multiple rectal and pelvic implants. Pathologic findings confirmed gallstones of the ovary and pelvic peritoneum. These gallstones elicited mesothelial proliferation, local hemorrhage, and adhesion formation. CONCLUSION: The pathologic consequences of pelvic cholelithiasis can be marked. This was demonstrated in a postmenopausal woman, but has direct implications for the premenopausal patient as well. Our experience suggests that gallstones lost during laparoscopic cholecystectomy should be removed if possible.

Production and characterization of neutralizing monoclonal antibody to a human rotavirus strain with a "super-short" RNA pattern.

A neutralizing monoclonal antibody, B37:1, against a human rotavirus (B37) with a "super-short" RNA pattern was derived. The antibody gave serotype-specific reactions with a panel of standard rotaviruses and was reactive in an enzyme immunoassay. Epidemiological studies of this new human serotype should now be possible.

Derivation of neutralizing monoclonal antibodies to human rotaviruses and evidence that an immunodominant neutralization site is shared between serotypes 1 and 3.

Neutralizing monoclonal antibodies were derived to human rotaviruses RV-4 (serotype 1), RV-5 (serotype 2), and ST-3 (serotype 4). By enzyme immunoassay and fluorescent focus neutralization, eight of the antibodies appeared to be specific for the immunizing serotype, and so have potential as reagents for rotavirus serotyping by enzyme immunoassay. Seven of these were shown by Western blotting, enzyme immunoassay for antibody additivity, and reaction with rotavirus reassortants, to be directed against the major outer capsid glycoprotein. The remaining serotype-specific antibody immunoprecipitated the 84-kD outer capsid protein. One antibody reacted with all serotype 1 and 3 rotaviruses but not with serotypes 2 or 4. When tested with virus mutants, this antibody recognized an immunodominant determinant of neutralization shared between serotypes 1 and 3 on the major outer shell glycoprotein. Our results suggest that two outer capsid proteins possess determinants of neutralization, and that viruses of different serotypes may share immunodominant neutralization sites.