Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection.

Bevacizumab (Avastin™; rhuMab VEGF), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has seen increased use in the perioperative treatment of colorectal and pancreatic cancer. Little is known, however, regarding its impact on surgical outcomes in patients undergoing resection. The objective of this review was to examine if the addition of bevacizumab to existing neoadjuvant regimens increases morbidity after cancer resection.

Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy.

BACKGROUND: Patients treated with epidermal growth factor receptor inhibitors (EGFRIs) frequently experience dermatologic toxic effects. Whereas the impact of these effects on quality of life and EGFRI dosing has been described, their impact on physical health has not been ascertained. We examined the prevalence of infections that complicate dermatologic toxic effects of EGFRIs. METHODS: We used retrospective chart review methods to analyze 221 patients who were treated in the Skin and Eye Reactions to Inhibitors of EGFR and Kinases clinic, a referral clinic for dermatologic toxic effects of cancer therapies. We reviewed results of bacterial cultures, histopathologic assessment of biopsy samples, and immunohistochemical staining of skin specimens for viral pathogens that were recorded in the patients' medical records. Associations between patient demographic and treatment characteristics and the development of infections were examined using the Fisher exact test. All statistical tests were two-sided. RESULTS: Eighty-four (38%) of the 221 patients showed evidence of infection at sites of dermatologic toxic effect. Fifty (22.6%) of the 221 patients had cultures positive for Staphylococcus aureus, and 12 (5.4%) of the 221 patients cultured positive for methicillin-resistant S aureus. Less frequent infections included herpes simplex (3.2%), herpes zoster (1.8%), and dermatophytes (10.4%). The seborrheic region was the most prevalent site of infection, and patients with leukopenia had higher risk for infection than patients who did not have leukopenia (P = .005). Demographic factors and associated treatments were not associated with the occurrence of a dermatologic infection (P > or = .05). CONCLUSIONS: Patients with dermatologic toxic effects following treatment with EGFRIs have a high prevalence of cutaneous infections. Most notably, bacterial infections developed at sites previously affected by dermatologic toxic effects, with leukopenic patients being at greater risk.

A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization.

Chemoembolization and other ablative therapies are routinely utilized in downstaging from United Network for Organ Sharing (UNOS) T3 to T2, thus potentially making patients transplant candidates under the UNOS model for end-stage liver disease (MELD) upgrade for hepatocellular carcinoma (HCC). This study was undertaken to compare the downstaging efficacy of transarterial chemoembolization (TACE) versus transarterial radioembolization. Eighty-six patients were treated with either TACE (n = 43) or transarterial radioembolization with Yttrium-90 microspheres (TARE-Y90; n = 43). Median tumor size was similar (TACE: 5.7 cm, TARE-Y90: 5.6 cm). Partial response rates favored TARE-Y90 versus TACE (61% vs. 37%). Downstaging to UNOS T2 was achieved in 31% of TACE and 58% of TARE-Y90 patients. Time to progression according to UNOS criteria was similar for both groups (18.2 months for TACE vs. 33.3 months for TARE-Y90, p = 0.098). Event-free survival was significantly greater for TARE-Y90 than TACE (17.7 vs. 7.1 months, p = 0.0017). Overall survival favored TARE-Y90 compared to TACE (censored 35.7/18.7 months; p = 0.18; uncensored 41.6/19.2 months; p = 0.008). In conclusion, TARE-Y90 appears to outperform TACE for downstaging HCC from UNOS T3 to T2.

A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma.

PURPOSE: Combination chemotherapy results in a significant survival advantage in patients with advanced gastric cancer compared to best supportive care. Nevertheless, the prognosis remains poor with a median survival of 8-10 months. Topoisomerase-I inhibitors such as irinotecan have activity in advanced gastric cancer. Pegamotecan may offer significant advantages over other topoisomerase-I inhibitors due to its prolonged circulating half-life, tolerability and passive tumour accumulation. PATIENTS AND METHODS: This was a non-randomised, multi-centre, two-step Fleming design phase II study. Eligible patients with locally advanced (inoperable) or metastatic gastric or gastro-oesophageal adenocarcinoma, with measurable disease, ECOG performance status < or =2, with adequate haematological, renal and hepatic function, who had received < or =1 prior chemotherapy regimen for advanced disease, were treated with 7,000 mg/m(2) of pegamotecan as a 1-h infusion every 21 days until disease progression or unacceptable toxicity. The primary efficacy measure was the objective response rate. RESULTS: Five of the 35 patients recruited into this study had a partial response (14.3%), with a median time to progression of 11.9 weeks (95% CI: 6.6, 13.1), and median overall survival of 38.1 weeks (95% CI: 29.0, 47.3). Grade 3/4 toxicities included neutropenia in 6 (17.1%) patients, thrombocytopenia in 4 (11.4%), fatigue in 8 (22.9%), nausea in 6 (17%), vomiting in 6 (17%) and anorexia in 4 (11.4%) patients. There were no episodes of febrile neutropenia and no toxic deaths. CONCLUSIONS: Pegamotecan has activity in this patient population and was generally well-tolerated. The favourable rate of haematological toxicities and diarrhoea compared with irinotecan in similar studies suggests that pegamotecan could be combined with other active agents in further studies in this disease.

Fibrosis, portal hypertension, and hepatic volume changes induced by intra-arterial radiotherapy with 90yttrium microspheres.

PURPOSE: To identify changes in hepatic parenchymal volume, fibrosis, and induction of portal hypertension following radioembolization with glass microspheres for patients with metastatic disease to the liver. RESULTS: In our series of sequential bilobar (n = 17) treatments, a mean decrease in liver volume of 11.8% was noted. In this group, a mean splenic volume increase of 27.9% and portal vein diameter increase of 4.8% were noted. For patients receiving unilobar treatments (n = 15), mean ipsilateral lobar volume decrease of 8.9%, contralateral lobar hypertrophy of 21.2%, and a 5.4% increase in portal vein diameter were also noted. These findings were not associated with clinical toxicities. CONCLUSION: (90)Yttrium radioembolization utilizing glass microspheres in patients with liver metastases results in changes of hepatic parenchymal volume and also induced findings suggestive of fibrosis and portal hypertension. Further studies assessing the long-term effects are warranted.

Investigating the possible role of benthic macroinvertebrates and zooplankton in the life cycle of the haplosporidian Bonamia ostreae.

Bonamia ostreae is a protistan parasite of the European flat oyster, Ostrea edulis. Though direct transmission of the parasite can occur between oysters, it is unclear if this represents the complete life cycle of the parasite, and the role of a secondary or intermediate host or carrier species cannot be ruled out. In this preliminary study, benthic macroinvertebrates and zooplankton from a B. ostreae-endemic area were screened for the presence of parasite DNA, using polymerase chain reaction (PCR). Eight benthic macroinvertebrates and nineteen grouped zooplankton samples gave positive results. Certain species, found positive for the parasite DNA, were then used in laboratory transmission trials, to investigate if they could infect naïve oysters. Transmission of B. ostreae was effected to two naïve oysters cohabiting with the brittle star, Ophiothrix fragilis.

Microfauna associated with amoebic gill disease in sea-farmed Atlantic salmon, Salmo salar L., smolts.

A study of microfauna, associated with pathological changes in the gills of Atlantic salmon, Salmo salar L., was conducted over 2001-2002. Monthly samples of 1(+) salmon smolts were taken, protozoan populations were quantified and gill health was assessed histologically. Protozoan densities were correlated with pathological changes, in order to determine their possible role in lesions in the gills. The most severe gill tissue changes were observed in summer/autumn and the least in spring. A diverse polyphyletic protozoan community was observed colonizing the gills, including Neoparamoeba sp., other amoebae, scuticociliates, Ichthyobodo-like flagellates, trichodinid ciliates and prostomatean ciliates. The earlier gill tissue changes in the gill were not always associated with the presence of these microorganisms, whereas amoebae (other than Neoparamoeba sp.), Ichthyobodo-like flagellates and trichodinid ciliates correlated with augmenting gill lesions. Neoparamoeba sp. was present, but its abundance did not correlate with the disease. This study suggests that a diversity of protozoans including Ichthyobodo-like flagellates, trichodinid ciliates and amoebae other than Neoparamoeba sp. are involved in the aetiology of amoebic gill disease in the Irish situation.

Environmental risk factors associated with amoebic gill disease in cultured salmon, Salmo salar L., smolts in Ireland.

A 2-year study was carried out on amoebic gill disease (AGD) involving monthly samples of 1+ Atlantic salmon, Salmo salar L., smolts, histological assessment of the gills and analysis of environmental data. Gill pathology was seen before amoebae could be detected microscopically. These changes in gill integrity were associated with marine environmental conditions, particularly elevated ammonium, nitrite and chlorophyll levels. The results suggest that the environmental changes predispose salmon to colonization by amoebae and ciliates. High densities of histophagous scuticociliates were observed in the gills during periods of advanced gill pathology. A number of different amoebae were observed in close association with gill pathology. Neoparamoeba was not seen in high densities, nor was it associated with gill pathology, indicating that Neoparamoeba may not be the primary agent of the AGD in Irish salmonid culture.

Small subunit ribosomal DNA characterization of an unidentified aurantiactinomyxon form and its oligochaete host Tubifex ignotus.

In this study, the small subunit (18S) ribosomal DNA gene from an aurantiactinomyxon form of unknown taxonomic position (A1) and from its aquatic oligochaete host (Tubifex ignotus) were characterized. Molecular sequence information on A1 was obtained to allow comparisons of this gene with known sequences from known myxosporean forms, and therefore to investigate possible relationships between this organism and its alternate myxosporean stage. Sequence data for the oligochaete host, together with morphological features, will allow reliable identification of this species in the future. Sequence data derived from the 18S DNA gene and data from other related or non-related organisms were analyzed and used to construct a phylogenetic tree. Phylogenetic studies provided an insight into the taxonomic position of A1. Sequence similarities within the 18S rDNA A1 gene and compared organisms indicated that A1 was most closely related to members of the sub-order Variisporina (Myxidium lieberkuehni [Ml] and Sphaerospora oncorhynchi [So]). Clustering of the 3 organisms in the same branch was well supported by high bootstrap values (81%). A1 showed higher similarities with sequences of Ml (approximately 80%) than with So (approximately 79%). Myxosporean sequence analysis indicated that phylogenetic arrangements do not support traditional classification based on morphological criteria of the spores, but rather support arrangement by tissue location. Marine actinosporeans Triactinomyxon sp. and Tetraspora discoidea were found to be associated with Platysporinid myxosporeans, supporting previous findings. In this study, 18S rDNA sequence data are generated for first time for the aquatic oligochaete T. ignotus. Phylogenetic 18S rDNA gene analyses performed with T. ignotus support and confirm existing morphological and molecular phylogenetic studies. Paraphyly of the Tubificidae family was noticed.

Lysozyme activity and protein concentration in the haemolymph of the flat oyster Ostrea edulis (L.).

Lysozyme activity and protein concentration in the haemolymph of the flat oyster Ostrea edulis were investigated. These biochemical constituents of the haemolymph could be an indication of the physiological condition and vitality of the defence system of an animal. Haemolymph protein and lysozyme in oysters were examined over an 18 month period to determine their relationship with the strain of oyster, the season, the site, and parasitism by Bonamia ostreae. Haemolymph protein concentration exhibited seasonal fluctuations and varied between strains. Levels of protein in oysters highly infected with B. ostreae were slightly depressed but not significantly so. Haemolymph lysozyme varied greatly between individuals but no correlation was found between lysozyme levels and infection of oysters by B. ostreae.

Actinosporean infections in oligochaetes in a river system in southwest Ireland with descriptions of three new forms.

Sediment samples were collected in April, June and August 1998 from a river in southwest Ireland. A total of 1,836 oligochaete specimens were collected from these sediments, and examined for actinosporean infections. Actinosporean-infected oligochaetes have been determined, symptoms and course of infection have been considered and the spores released from them have been described. Spore characteristics for each actinosporean were defined and the prevalence of infection in each oligochaete species was also determined. The overall prevalence of infection with actinosporeans within the oligochaete sample was approximately 2%. Seven types were distinguished, belonging to echinactinomyxon, aurantiactinomyxon and neoactinomyxum forms, from Tubifex ignotus, Lumbriculus variegatus and Limnodrilus hoffmeisteri, and compared with actinosporean types previously reported in the literature. Three of these forms have not been previously described, while the other 4 are morphologically and morphometrically similar to known forms. These actinosporeans may be stages in myxozoan life cycles.

Impact of the copepod Mytilicola orientalis on the Pacific oyster Crassostrea gigas in Ireland.

Infections of a population of Crassostrea gigas by the copepod Mytilicola orientalis were examined at an oyster growing site at Dungarvan, County Waterford, Ireland. Twenty-one samples, each consisting of 20 to 30 oysters have been examined over 2 yr. Condition, sex, reproductive stage, length, weight, glycogen content and other parasite burdens of the oysters were examined in relation to the degree of infection of M. orientalis; 14.38% of oysters were infested. Mean abundance was 0.6 oyster(-1) The maximum number of copepods in an oyster was 20. M. orientalis had no effect on condition, growth, sex, stage or glycogen content of the oyster but correlated with shell burrowing by Polydora sp.

The role of carcinoembryonic antigen monitoring in management of colorectal cancer.

Carcinoembryonic antigen (CEA) is an important tool in the management of colorectal cancer. Its use as a prognostic indicator in resectable disease remains controversial but may be improved with molecular detection of the antigen. In monitoring patients after resection, CEA can be the first sign of a potentially curable recurrence. It can also be useful in assessing tumor response in patients being treated for metastases without easily measurable disease. CEA alone cannot dictate the type or duration of treatment but may be used in addition to standard monitoring tests.

The effect of intermittent steroid therapy on anti-sperm antibody levels.

Sperm-bound antisperm antibody levels were measured in 10 males in subfertile partnerships who were treated with high dose intermittent prednisolone therapy over a period up to 9 months. Antibody levels fell in all patients during therapy, although a transient rise occurred after 2-4 months. There were low treatment complication rates. Four pregnancies occurred during the treatment of the 10 patients. There was no correlation between pregnancy and change in antibody.

The current position of poikilotherms.

The major research themes in poikilotherm leukaemias, and their progress over the past two years are reviewed. Despite the fact that poikilotherms represent 99% of the animal world including man, background knowledge on most poikilotherm species is sparse. Furthermore, haemic systems in many poikilotherms have functions different to those of homeotherms. Most progress is being made in relation to lethal blood mutant neoplasms in Drosophila, leukaemias of farmed salmonids among the fishes, and among shellfish, the hemic sarcomas of bivalves. The hypothesis that epizootic neoplasia in fish and shellfish populations could be indicative of environmental pollution is being refined in the light of recent studies; environmental xenobiotics are no longer considered to play a primary aetiological role in either lymphomas and leukaemias of fish or haemic sarcomas of bivalves, although xenobiotics may have a primary role in other poikilotherm neoplasms.

Atmospheric pollution.

After a brief exposition of the structure and constituents of the atmosphere, this review paper discusses the nature of the criteria by which a particular material present as the result of human activity is to be regarded as a pollutant. The pollutants or potential pollutants likely to be found in urban air are noted, and the procedures for setting air-quality standards are outlined by way of two examples, ozone and lead. The provisional character of air-quality standard is emphasized. Special attention is given to photochemical smog as being a form of air pollution endemic to urbanized countries with warm climates like that of Australia. The characteristics of photochemical smog are discussed, and figures are presented to illustrate its prevalence in several Australian cities over the past few years. Finally, reference is made to research on the role of hydrocarbon emissions in the formation of smog conducted by the writer and his colleagues in the Commonwealth Scientific and Industrial Research Organization (CSIRO).