A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.

BACKGROUND: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. RESULTS: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CONCLUSIONS: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12609000294257.

Observation of narrow-band terahertz coherent Cherenkov radiation from a cylindrical dielectric-lined waveguide.

We report experimental observation of narrow-band coherent Cherenkov radiation driven by a subpicosecond electron bunch traveling along the axis of a hollow cylindrical dielectric-lined waveguide. For an appropriate choice of dielectric wall thickness, a short-pulse beam current profile excites only the fundamental mode of the structure, producing energetic pulses in the terahertz range. We present detailed measurements showing a narrow emission spectrum peaked at 367 + or - 3 GHz from a 1 cm long fused silica capillary tube with submillimeter transverse dimensions, closely matching predictions. We demonstrate a 100 GHz shift in the emitted central frequency when the tube wall thickness is changed by 50 microm. Calibrated measurements of the radiated energy indicate up to 10 microJ per 60 ps pulse for an incident beam charge of 200 pC, corresponding to a peak power of approximately 150 kW.

The prevalence of avascular necrosis in patients treated with chemotherapy for testicular tumours.

To study the prevalence of avascular necrosis in patients receiving chemotherapy for testicular cancer we invited 103 consecutive patients treated by chemotherapy to attend for MRI scan of the hips. Four of 47 (9% (CI 2-20%)) patients scanned and 4/103 (3.8% (CI 1-10%)) of patients invited to participate in the study had evidence of avascular necrosis. As not all patients in the study had completed the at risk period this equates to a 3-year actuarial risk of 6.3% (95% confidence limits (CI) 2.4-16.1). These data suggest that avascular necrosis is an uncommon but significant complication of chemotherapy including steroids as anti-emetics.

Efficiency of searching the grey literature in palliative care.

A systematic review into palliative care team effectiveness was undertaken which has, inherent in its methodology, grey literature searching. Over 100 letters were written to a systematically chosen range of service providers, commissioners, and experts in combination with requests for information in six UK national cancer/palliative care organization newsletters. In addition, the System for Information on Grey Literature (SIGLE ) database was searched. As a result, 25 document hard copies were received. The documents were, in all but one case (this one study was also highlighted by the SIGLE search), not relevant as they were predominated by annual reports, service descriptions, and needs assessments. In terms of obtaining unpublished studies for possible inclusion in the review, this comprehensive search was unsuccessful and, therefore, it would appear that grey literature searching is not a useful tool in palliative care systematic reviews.

Dissimilatory sulfite reductase (desulfoviridin) of the taurine-degrading, non-sulfate-reducing bacterium Bilophila wadsworthia RZATAU contains a fused DsrB-DsrD subunit.

A dissimilatory sulfite reductase (DSR) was purified from the anaerobic, taurine-degrading bacterium Bilophila wadsworthia RZATAU to apparent homogeneity. The enzyme is involved in energy conservation by reducing sulfite, which is formed during the degradation of taurine as an electron acceptor, to sulfide. According to its UV-visible absorption spectrum with maxima at 392, 410, 583, and 630 nm, the enzyme belongs to the desulfoviridin type of DSRs. The sulfite reductase was isolated as an alpha2beta)gamma(n) (n > or = 2) multimer with a native size of 285 kDa as determined by gel filtration. We have sequenced the genes encoding the alpha and beta subunits (dsrA and dsrB, respectively), which probably constitute one operon. dsrA and dsrB encode polypeptides of 49 (alpha) and 54 kDa (beta) which show significant similarities to the homologous subunits of other DSRs. The dsrB gene product of B. wadsworthia is apparently a fusion protein of dsrB and dsrD. This indicates a possible functional role of DsrD in DSR function because of its presence as a fusion protein as an integral part of the DSR holoenzyme in B. wadsworthia. A phylogenetic analysis using the available Dsr sequences revealed that B. wadsworthia grouped with its closest 16S rDNA relative Desulfovibrio desulfuricans Essex 6.

Biochemical and molecular characterization of taurine:pyruvate aminotransferase from the anaerobe Bilophila wadsworthia.

Bilophila wadsworthia RZATAU is a Gram-negative bacterium which converts the sulfonate taurine (2-aminoethanesulfonate) to ammonia, acetate and sulfide in an anaerobic respiration. Taurine:pyruvate aminotransferase (Tpa) catalyses the initial metabolic reaction yielding alanine and sulfoacetaldehyde. We purified Tpa 72-fold to apparent homogeneity with an overall yield of 89%. The purified enzyme did not require addition of pyridoxal 5'-phosphate, but highly active enzyme was only obtained by addition of pyridoxal 5'-phosphate to all buffers during purification. SDS/PAGE revealed a single protein band with a molecular mass of 51 kDa. The apparent molecular mass of the native enzyme was 197 kDa as determined by gel filtration, which indicates a homotetrameric structure. The kinetic constants for taurine were: Km = 7.1 mM, Vmax = 1.20 nmol.s-1, and for pyruvate: Km = 0.82 mM, Vmax = 0.17 nmol.s-1. The purified enzyme was able to transaminate hypotaurine (2-aminosulfinate), taurine, beta-alanine and with low activity cysteine and 3-aminopropanesulfonate. In addition to pyruvate, 2-ketobutyrate and oxaloacetate were utilized as amino group acceptors. We have sequenced the encoding gene (tpa). It encoded a 50-kDa peptide, which revealed 33% identity to diaminopelargonate aminotransferase from Bacillus subtilis.

The utility of tumour markers in assessing the response to chemotherapy in advanced bladder cancer.

In patients with advanced bladder cancer receiving chemotherapy, early assessment of response can avoid unnecessary toxicity. The aim of this study was to assess the role of tumour markers in monitoring response. Serum levels of one or more of markers beta human chorionic gonadotrophin (betahCG), carcinoembryomic antigen (CEA), CA125 and CA19.9 were measured in 74 patients with advanced bladder cancer receiving chemotherapy from 1992 to 1997. Forty-three of 74 (58%) of patients had at least one raised marker (1.5 times upper limit of normal range). This was more common in patients with extra-pelvic disease than in those with disease confined to the pelvis (P = 0.002). Thirty-eight of 78 (49%) assessable patients had a radiological response. Neither clinical response (P = 0.81) nor survival (P = 0.16) differed between marker-negative and marker-positive patients. Clinical response was strongly related to marker response in the 35 comparable patients (P = 0.0001). No patient had a clinical response without response of at least one marker. Ninety per cent of patients who achieved a marker response had done so by 8 weeks. Monitoring of tumour markers in patients with advanced bladder cancer can help predict the response to chemotherapy.

Squamous cell carcinoma of the thyroid: outcome of treatment in 16 patients.

AIMS AND METHODS: Squamous cell carcinoma of the thyroid is very rare and has a poor prognosis. Treatment and outcome were retrospectively analysed in a consecutive series of 16 patients treated at the Royal Marsden Hospital, with the aim of establishing guidelines for management. RESULTS: Twelve of the 16 patients had locoregional disease only at presentation and four had distant metastases. Eight of the 16 underwent surgery and four were given post-operative radiotherapy. Radiotherapy alone was used in six patients unsuitable for surgery. Median survival was 16 months. There were three long-term survivors; each had localized disease treated with surgery and post-operative radiotherapy. Patients treated with surgery alone all developed local recurrence. Two of six patients treated with radiotherapy alone had a partial response but all subsequently developed progressive local disease. Chemotherapy was used in two patients with no response. CONCLUSIONS: Long-term survival is possible if disease is diagnosed early and is completely resected. Surgery should be followed by radical dose radiotherapy.

Desulfonispora thiosulfatigenes gen. nov., sp. nov., a taurine-fermenting, thiosulfate-producing anaerobic bacterium.

Strain GKNTAUT has been described as a bacterium able to ferment the organosulfonate taurine (2-aminoethanesulfonate) quantitatively to acetate, ammonia and thiosulfate, an unusual metabolic product. This novel fermentation has now also been observed in four independent isolates from two continents. All five organisms were strictly anaerobic, Gram-positive, motile, spore-forming bacteria. Enrichments with isethionate (2-hydroxyethanesulfonate) and cysteate (2-amino-3-sulfopropionate), in contrast, yielded bacteria that disproportionated the sulfonate to sulfate and sulfide. The phylogenetic location of the taurine fermenters was analysed on the basis of 16S rDNA sequences. Strain GKNTAUT (= DSM 11270T = ATCC 700533T) is described as the type strain of a new genus and species, for which the name Desulfonispora thiosulfatigenes gen. nov., sp. nov. is proposed.

Stage IV endometrial carcinoma: a 10 year review of patients.

Stage IV endometrial cancer is uncommon, often occurs in elderly patients and has a poor prognosis, which makes the choice of treatment difficult. 18 patients with stage IV endometrial cancer presenting over a 10 year period, between 1987 and 1997, were reviewed with regard to mode of treatment and response. The mean age was 65 years. Five had disease confined to the pelvis and 13 had extra pelvic disease. 15 of 18 patients had a total abdominal hysterectomy (TAH). One patient received radiotherapy alone and five received post-operative radiotherapy. Overall freedom from pelvic symptoms was achieved in seven of 18 patients. All seven had undergone TAH and two had received post-operative radiotherapy. Progestogens were given to 13 patients. Six received progestogens alone, without radiotherapy or chemotherapy. Of these, two responded, one for 9 months and one with verified lung metastases, who had a complete response, is still alive at 6.5 years. Eight patients received chemotherapy, with single agent cisplatin or carboplatin AUC 6. Three patients responded, one for 4.5 years. The overall median survival was 12 months from diagnosis. Actuarial 5 year survival was 15% (CI 3-36). There was no significant survival difference for, hormone therapy or chemotherapy. Stage IV endometrial cancer has a poor prognosis but durable response can be achieved in some patients.

Avascular necrosis in patients treated with BEP chemotherapy for testicular tumours.

Avascular necrosis (AVN) is known to occur after combination chemotherapy for lymphomas and leukaemias that includes high dose corticosteroids, but it has been reported rarely in patients with solid tumours. We describe five recent cases in young men with testicular tumours (three of which were of good prognosis), who had been treated with chemotherapy using dexamethasone as an antiemetic. Dexamethasone is a low cost and effective antiemetic, but it may be responsible for inducing AVN in patients receiving chemotherapy for solid tumours. A prospective survey of the frequency of AVN is justified to quantify the extent of the problem.

Different therapeutic approaches and outcome in the treatment of pterygium.

PURPOSE: This study was initiated to investigate the role of different therapeutic modalities in the outcome of the surgical treatment of pterygium. METHODS: The results of treatment of pterygia with a variety of surgical techniques were studied in 56 eyes (49 patients) operated on at Bristol Eye Hospital during a period of five years. The surgical techniques included simple excision; bare sclera; conjunctival autograft; sliding conjunctival flap; lamellar keratoplasty and penetrating keratoplasty. Twelve eyes received additional beta irradiation in a fractionated total dose of 40 Gys. RESULTS: The incidence of recurrence was 23.2% for the 43 treated primary pterygia, and 23% for the 13 recurrent pterygia. All recurrences occurred between 2.5 and 11 months postoperatively. None of the 11 cases where additional beta irradiation was used showed any recurrence or other complication within the study period. In the recurrent pterygia group, the cases treated with a combination of surgical excision and beta irradiation, showed significantly lower recurrence rate (p < 0.001) compared to those cases treated with surgical excision alone. CONCLUSIONS: Beta irradiation as a complement to surgical treatment of pterygium, is successful in treating high risk cases such as reoperations, whereas for the majority of primary pterygia surgical excision alone is adequate. Additionally, follow up of one year will reveal any recurrences.

Magnetic resonance imaging of the whole spine in suspected malignant spinal cord compression: impact on management.

Patients with suspected malignant spinal cord compression may present with a misleading sensory level or have multiple levels of compression that are not apparent clinically or on imaging of a limited area of the spine. To estimate how often this occurs and to evaluate a policy of magnetic resonance imaging (MRI) of the whole spine for any patient with suspected cord compression, data from 127 patients who had undergone MRI scans of the whole spine were reviewed. In 85 of 127 scans, there was evidence of compression of or impingement upon the spinal cord. A sensory level was present in 47 of these 85 patients, but in 12/47 (26%) the sensory level was four or more segments below or three or more segments above the actual lesion. Multiple levels of compression or impingement were found in 33 of 85 (39%) patients; in 24 of these, more than one region (cervical/thoracic/lumbar) of the cord was involved. For 32 patients who commenced radiotherapy to a treatment volume based on clinical criteria before the MRI scan was available, the radiotherapy fields needed modification in 16 (50%) as a result of the MRI findings. The results support a policy of MRI of the whole spine in any patient with suspected malignant spinal cord compression.

Treatment of chronic iliac artery occlusions by means of percutaneous endovascular stent placement.

PURPOSE: A retrospective evaluation of outcomes in patients with chronic iliac occlusions treated with insertion of metallic endovascular stents, without previous thrombolysis, on an intention-to-treat basis. MATERIALS AND METHODS: Seventy-two patients with chronic iliac occlusion underwent attempted stent placement from either the ipsilateral or contralateral femoral artery. There were 49 men and 23 women. Mean age was 63.1 years (range, 39-88 years). A total of 89 stents were deployed in 67 patients. Follow-up was from 24 to 69 months (mean, 37.5 months). RESULTS: Stents were successfully deployed in 67 patients (93%), with two early failures, giving a primary success rate of 90%. There were five significant and four insignificant procedural complications. There were four late failures (all within the first year) and four non-stent-related deaths. CONCLUSION: Endovascular stent placement offers an alternative to surgery in the treatment of chronic iliac occlusions.

Taurine reduction in anaerobic respiration of Bilophila wadsworthia RZATAU.

Organosulfonates are important natural and man-made compounds, but until recently (T. J. Lie, T. Pitta, E. R. Leadbetter, W. Godchaux III, and J. R. Leadbetter. Arch. Microbiol. 166:204-210, 1996), they were not believed to be dissimilated under anoxic conditions. We also chose to test whether alkane- and arenesulfonates could serve as electron sinks in respiratory metabolism. We generated 60 anoxic enrichment cultures in mineral salts medium which included several potential electron donors and a single organic sulfonate as an electron sink, and we used material from anaerobic digestors in communal sewage works as inocula. None of the four aromatic sulfonates, the three unsubstituted alkanesulfonates, or the N-sulfonate tested gave positive enrichment cultures requiring both the electron donor and electron sink for growth. Nine cultures utilizing the natural products taurine, cysteate, or isethionate were considered positive for growth, and all formed sulfide. Two clearly different pure cultures were examined. Putative Desulfovibrio sp. strain RZACYSA, with lactate as the electron donor, utilized sulfate, aminomethanesulfonate, taurine, isethionate, and cysteate, converting the latter to ammonia, acetate, and sulfide. Strain RZATAU was identified by 16S rDNA analysis as Bilophila wadsworthia. In the presence of, e.g., formate as the electron donor, it utilized, e.g., cysteate and isethionate and converted taurine quantitatively to cell material and products identified as ammonia, acetate, and sulfide. Sulfite and thiosulfate, but not sulfate, were utilized as electron sinks, as was nitrate, when lactate was provided as the electron donor and carbon source. A growth requirement for 1,4-naphthoquinone indicates a menaquinone electron carrier, and the presence of cytochrome c supports the presence of an electron transport chain. Pyruvate-dependent disappearance of taurine from cell extracts, as well as formation of alanine and release of ammonia and acetate, was detected. We suspected that sulfite is an intermediate, and we detected desulfoviridin (sulfite reductase). We thus believe that sulfonate reduction is one aspect of a respiratory system transferring electrons from, e.g., formate to sulfite reductase via an electron transport system which presumably generates a proton gradient across the cell membrane.

The assimilation of sulfur from multiple sources and its correlation with expression of the sulfate-starvation-induced stimulon in Pseudomonas putida S-313.

Conditions were optimized for the batch growth of Pseudomonas putida S-313 under sulfur-limited conditions. P. putida grew exponentially with sulfate as the sole source of sulfur, and growth was concomitant with the utilization of sulfate until it was exhausted. A further 20% of protein was synthesized after the apparent disappearance of sulfate. A mass balance for the utilized sulfate in cell material was calculated, given the observed molar growth yield of about 3.6 kg protein (mol S)-1 and a sulfur content of 0.41% S in dry matter. Similar data were obtained for growth with cysteine and thiocyanate. The organism also grew exponentially with 4-toluenesulfonate (TS) as sulfur source, essentially as observed with sulfate, except that negligible protein formation after exhaustion of TS was observed. Similar data were also obtained with 4-nitrocatecholsulfate (NCS) and ethanesulfonate. Any substrate pair selected from sulfate, cysteine and thiocyanate was utilized simultaneously, and although one of the pair of substrates was always preferred, growth continued at the same rate when only one substrate remained. Growth after substrate exhaustion was observed. Any substrate pair selected from TS, NCS and ethanesulfonate gave similar data, but with less growth after exhaustion of the sulfur sources. If a mixed substrate pair was chosen from the two groups, the sulfur source from the first-named group was initially used exclusively, and the second source of sulfur was utilized subsequently, after a lag phase. The data are considered to reflect the control of scavenging for sulfur and of distribution of sulfur in the cell exerted by the sulfate-starvation-induced stimulon.

Comparison of mitozantrone and epirubicin in advanced breast cancer.

Forty chemotherapy naive patients with metastatic or locally advanced breast cancer were treated in a randomized trial comparing mitozantrone 14 mg/m2 with epirubicin 75 mg/m2 given intravenously at 3-weekly intervals. There was a 40% (95% confidence interval (CI) 8-72; P = 0.013) higher partial response rate with epirubicin (11/18) than with mitozantrone (4/19). Epirubicin caused significantly more alopecia (difference 76%; 95% CI 57-96; P < 0.0001) and nausea/vomiting (difference = 38%; 95% CI 10-67; P = 0.01). Three patients who received long courses of epirubicin experienced cardiac failure; two were proved to have cardiomyopathy. The median survival for the epirubicin and mitozantrone groups were 9.5 and 8 months respectively. Thus, although epirubicin gave a higher response rate it also caused more toxicity.