Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07.

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Prioritising sewerage maintenance using inferred sewer age: a case study for Edinburgh.

The reported research project focuses on using a database which contains details of customer contacts and CCTV data for a key Scottish catchment to construct a GIS based sewer condition model. Given the nature of the asset registry, a key research challenge was estimating the age of individual lengths of pipe. Within this context, asset age was inferred using the estimated age of surface developments-this involved overlaying the network in a GIS with historical digital maps. The paper illustrates that inferred asset age can reliably be used to highlight assets which are more likely to fail.

Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer.

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.

A human-curated annotation of the Candida albicans genome.

Recent sequencing and assembly of the genome for the fungal pathogen Candida albicans used simple automated procedures for the identification of putative genes. We have reviewed the entire assembly, both by hand and with additional bioinformatic resources, to accurately map and describe 6,354 genes and to identify 246 genes whose original database entries contained sequencing errors (or possibly mutations) that affect their reading frame. Comparison with other fungal genomes permitted the identification of numerous fungus-specific genes that might be targeted for antifungal therapy. We also observed that, compared to other fungi, the protein-coding sequences in the C. albicans genome are especially rich in short sequence repeats. Finally, our improved annotation permitted a detailed analysis of several multigene families, and comparative genomic studies showed that C. albicans has a far greater catabolic range, encoding respiratory Complex 1, several novel oxidoreductases and ketone body degrading enzymes, malonyl-CoA and enoyl-CoA carriers, several novel amino acid degrading enzymes, a variety of secreted catabolic lipases and proteases, and numerous transporters to assimilate the resulting nutrients. The results of these efforts will ensure that the Candida research community has uniform and comprehensive genomic information for medical research as well as for future diagnostic and therapeutic applications.

Sebaceous carcinoma of the breast.

We report on a rare distinctive variant of infiltrating ductal carcinoma characterized by sebaceous differentiation of tumor cells. The neoplasm was identified in a lumpectomy specimen from a 45-year-old woman with extensive metastatic disease. In addition to conventional in situ and invasive ductal components, approximately half of the tumor cells exhibited a phenotype resembling tumors of the sebaceous skin appendage with coarsely vacuolated cytoplasm and peripherally displaced nuclei. The sebaceous moiety was also present in the distant metastatic deposits. There was no evidence of mucin production by tumor cells. Ultrastructurally, empty-appearing non-membrane bound vacuoles attested to the sebaceous cells' lipid content. The immunoprofile of the lesion included positivity for cytokeratin and epithelial membrane antigen. Vimentin, S100 protein and carcinoembryonic antigen were not expressed. Most tumor cell nuclei reacted with antibodies to oestrogen and progesterone receptors but failed to show overexpression of the HER2/neu protein. The MIB-1 labeling index averaged 16%. At variance with sebaceous breast carcinomas on record, the present case is notable for its prolonged clinical course.

[Anagrelide in control of myeloproliferative thrombocythemia: long-term experiences in 6 patients]. / Anagrelide zur Kontrolle der myeloproliferativen Thrombozythämie: Langzeiterfahrung bei 6 Patienten.

Symptomatic or asymptomatic chronic elevation of platelet count can be observed in all forms of myeloproliferative disorders (MPD). Benefits and limitations of the traditional platelet-reducing agents, such as radioactive phosphorus, alkylating agents, hydroxyurea and interferon alpha, are well known and have been largely described. Anagrelide (Agrelin) is an additional newer drug with a selective platelet-lowering effect. We describe our own long-term experience in 6 patients with MPD who were treated with anagrelide as part of a compassionate-use protocol between April 1991 and August 1997. The median duration of therapy was 54 months (range 17 to 75 months), with an overall response rate of 100% (complete and partial response for at least 4 weeks). The initial median platelet count of 1211 x 10(9)/l (range 847 to 2050 x 10(9)/l) was reduced rapidly and lastingly to 570 x 10(9)/l (range 216 to 667 x 10(9)/l) at the time of the last control. Under treatment with anagrelide 4 of the 6 patients showed a reduction of disease-associated symptoms or complications. Adverse reactions were generally mild and transitory, and no interruption or cessation of therapy was required. Development of drug resistance or late adverse events were not observed. Treatment with anagrelide is effective, safe and in our opinion easy to administer. It also appears to be suitable for long-term administration.

[Successful syngeneic transplantation using G-CSF-stimulated peripheral hematopoietic progenitor cells combined with post-transplant administration of G-CSF in a patient with acute lymphatic leukemia]. / Erfolgreiche syngene Transplantation mit G-CSF-stimulierten peripheren hämatopoietischen Vorläuferzellen (PBPC), kombiniert mit posttransplantärer Verabreichung von G-CSF bei einem Patienten mit akuter lymphatischer Leukämie.

A 45-year-old male with acute lymphoblastic leukemia in first remission was successfully transplanted with G-CSF (filgrastim)-mobilized syngeneic PBPC (peripheral blood progenitor cells). Conditioning regimen consisted of high-dose etoposide, cyclophosphamide and total body irradiation. For PBPC mobilization the patient's healthy syngeneic brother was subcutaneously stimulated with 16 micrograms/kg/day G-CSF for 5 consecutive days. Only mild adverse effects (myalgia, transient changes of laboratory test) were observed. PBPC-apheresis was performed three times without complications on days 4, 5 and 6 after the start of G-CSF application. The unmanipulated PBPC (total 5.75 x 10(8)/kg mononucleated cells) were transfused immediately after each collection. Engraftment under administration of G-CSF (5 micrograms/kg/day subcutaneously) from day 0 to +12 was very rapid. Neutrophils exceeded 1.0 x 10(9)/l on day +9, platelet counts reached 50 x 10(9)/l on day +13. On day +27 the patient was discharged from the hospital with normal blood counts except mild anemia (Hb 9.5 g%). Bone marrow aspiration was repeatedly normocellular with normal differential count and no leukemia. We demonstrate that G-CSF-mobilized syngeneic PBPC transplantation after myeloblative chemoradiotherapy results in rapid and so far stable hematologic reconstitution with an actual follow-up of more than 15 months. This experience may be of relevance for future allogeneic G-CSF-mobilized PBPC transplantation.

Operative release of the impingement syndrome. Indication, technique, results.

We examined the long-term results of two different methods of shoulder decompression (Neer acromioplasty and resection of the coracoacromial ligament) after an average observation period of 8 years. Clinical and radiological features were evaluated in 48 patients with 50 treated shoulders, as was the subjective result of the treatment in 58 patients with 61 operated joints. Pain was substantially eased in 93% (acromioplasty) and 100% (ligamentary resection), mobility improved in 76% and 83%, respectively. A favourable result was achieved in 86% of the acromioplasty cases and in 75% of the ligament resection cases. In one-third of the shoulders, an increasing degeneration of joint structures could be demonstrated radiologically; the degree depended on the severity of the initial rotator cuff injury, not on the method of shoulder decompression. The differences between both surgical methods examined were not statistically significant, but acromioplasty provides a superior extension of the subacromial space and protection for the reconstructed rotator cuff tendons. Our results compare favourably with other published studies. The methods described are suitable for the treatment of subacromial impingement.

A novel bioreactor design for in vitro reconstruction of in vivo liver characteristics.

We have constructed a bioreactor aimed at imitating the three-dimensional micro- and macroenvironment of the liver. In vivo hepatocytes are arranged in plates of cell monolayers and are specifically attached with both sinusoidal surfaces to the space of Disse which contains extracellular matrix. Nonparenchymal cells are located on the other side of the space of Disse toward the sinusoid. For supporting monolayer hepatocytes with bipolar attachment to the extracellular matrix, we used a double gel culture technique that sandwiches hepatocytes between two layers of collagen. In double gel cultures, albumin production increases during an adaptive period to the in vitro environment. In contrast to conventional single gel hepatocytes, double gel hepatocytes maintain expression of sinusoidal microvilli and a polyhedric cell shape in culture as seen by transmission electron microscopy. Albumin production in the bioreactor was stable. The organotypical bioreactor concept is an example of organ mimicry and may provide the basis for the organ-otypical development of a full-sized hybrid artificial liver.

[The role of MRT in detecting the cause of therapy-refractory partial complex epilepsy]. / Zur Rolle der MRT beim Nachweis der Ursache therapierefraktärer partiell-komplexer Epilepsien.

MRT is of considerable significance in the investigation of epilepsy because of its ability to render soft tissue contrast for the demonstration of structural lesions. The present retrospective study consists of an analysis of MRT findings in operatively confirmed, circumscribed temporal tumours and in hippocampal sclerosis. The examinations were performed under standard conditions using T1- and T2-weighted spin-echo sequences of the head and coronal T2-weighted gradient-echo sequences of the brain stem. The diagnosis of tumours was extremely accurate (22/23) and specific (18/23) whereas hippocampal sclerosis could not be satisfactorily demonstrated (5/18). The use of intravenous contrast medium did not provide any advantages.

Ventricular fibrillation in a patient with exercise-induced anaphylaxis, normal coronary arteries, and a positive ergonovine test.

Exercise-induced anaphylaxis (EIA) is a rare form of physical allergy. Although histamine release is a feature of EIA, and histamine provocation of coronary spasm has been described, serious cardiac arrhythmias in EIA have not been reported. Exercise-induced anaphylaxis was diagnosed in a survivor of out-of-hospital cardiac arrest due to ventricular fibrillation after ECG signs of coronary spasm. Coronary artery disease was excluded. Ergonovine provocation induced coronary spasm in this patient. This is, to the authors' knowledge, the first description of ventricular fibrillation in EIA, possibly due to coronary spasm.

The influence of methanol on the interactions of calcium with the pyridine nucleotides.

The interactions of calcium with NAD+, NADH, NADP+ and NADPH in a 50% (by volume) methanol/water mixture (pH 7, 25 degrees C) were studied by calorimetry. The association constants for 1:1 complex formation were found to be 6.6 +/- 0.2, 270 +/- 76, 18 +/- 3 and 98 +/- 10 for NAD+, NADH, NADP+ and NADPH, respectively. Comparing these to the association constants for an aqueous system reveals that as the polarity of the solvent system is decreased the interactions involving NAD+, NADP+ and NADPH are all decreased. In contrast, the interaction involving NADH is markedly increased. All the interactions were found to be endothermic.

The equilibrium constants and enthalpy changes for the esterification of glycine by ethanol in water and ethanol- water mixtures.

Equilibrium constants, defined on the basis of the moles of all reactants and products including water, were found to be 4.6, 1.0 and 0.8 for the esterification of the glycinc cation at 20 degrees in a dilute aqueous sytem, and systems having 0.5 : 1 and 1 : 1 molar ratios of ethanol to water, respectively. When corrections were made for deviations from ideality a value of 5 +/- 1 was obtained for all three systems. Enthalpy changes were determined calorimetrically for the dilute aqueous and equimolar ethanol-water systems, and in each case was close to 1 kcal mole(-). The entropy change was calculated as 6 cal mole(-1) deg(-1).DeltaG(0') for the hydrolysis of the glycine ethyl ester cation at 20 degrees and pH 7 was calculated as -7.5 kcal mole(-1).