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3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) has been developed for imaging cell proliferation and findings correlate strongly with the Ki-67 labelling index in breast cancer. The aims of this pilot study were to define objective criteria for [18F]FLT response and to examine whether [18F]FLT-PET can be used to quantify early response of breast cancer to chemotherapy. Seventeen discrete lesions in 13 patients with stage II–IV breast cancer were scanned prior to and at 1 week after treatment with combination 5-fluorouracil, epirubicin and cyclophosphamide (FEC) chemotherapy. The uptake at 90 min (SUV90) and irreversible trapping ( K i) of [18F]FLT were calculated for each tumour. The reproducibility of [18F]FLT-PET was determined in nine discrete lesions from eight patients who were scanned twice before chemotherapy. Clinical response was assessed at 60 days after commencing FEC. All tumours showed [18F]FLT uptake and this was reproducible in serial measurements (SD of mean % difference = 10.5% and 15.1%, for SUV90 and K i, respectively; test–retest correlation coefficient ≥0.97). Six patients had a significant clinical response (complete or partial) at day 60; these patients also had a significant reduction in [18F]FLT uptake at 1 week. Decreases in K i and SUV90 at 1 week discriminated between clinical response and stable disease ( p = 0.022 for both parameters). In three patients with multiple lesions there was a mixed [18F]FLT response in primary tumours and metastases. [18F]FLT response generally preceded tumour size changes. [18F]FLT-PET can detect changes in breast cancer proliferation at 1 week after FEC chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Cyclin D1 is an important regulator of G1-S phase cell cycle transition and has been shown to be important for breast cancer development. GSK3â phosphorylates cyclin D1 on Thr-286, resulting in enhanced ubiquitylation, nuclear export and degradation of the cyclin in the cytoplasm. Recent findings suggest that the development of small-molecule cyclin D1 ablative agents is of clinical relevance. We have previously shown that the histone deacetylase inhibitor trichostatin A (TSA) induces the rapid ubiquitindependent degradation of cyclin D1 in MCF-7 breast cancer cells prior to repression of cyclin D1 gene (CCND1) transcription. TSA treatment also resulted in accumulation of polyubiquitylated GFP-cyclin D1 species and reduced levels of the recombinant protein within the nucleus. Results: Here we provide further evidence for TSA-induced ubiquitin-dependent degradation of cyclin D1 and demonstrate that GSK3â-mediated nuclear export facilitates this activity. Our observations suggest that TSA treatment results in enhanced cyclin D1 degradation via the GSK3â/CRM1-dependent nuclear export/26S proteasomal degradation pathway in MCF-7 cells. Conclusion: We have demonstrated that rapid TSA-induced cyclin D1 degradation in MCF-7 cells requires GSK3â-mediated Thr-286 phosphorylation and the ubiquitin-dependent 26S proteasome pathway. Drug induced cyclin D1 repression contributes to the inhibition of breast cancer cell proliferation and can sensitize cells to CDK and Akt inhibitors. In addition, anti-cyclin D1 therapy may be highly specific for treating human breast cancer. The development of potent and effective cyclin D1 ablative agents is therefore of clinical relevance. Our findings suggest that HDAC inhibitors may have therapeutic potential as small-molecule cyclin D1 ablative agents. [ABSTRACT FROM AUTHOR]

Background: The cyclin D1 proto-oncogene is an important regulator of G1 to S-phase transition and an important cofactor for several transcription factors in numerous cell types. Studies on neonatal cardiomyocytes and postmitotic neurons indicate that the activity of cyclin D1 may be regulated through its cytoplasmic sequestration. We have demonstrated previously, that TSA induces the ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells. Additional studies were initiated in order to further investigate the effect of TSA on cyclin D1 regulation using sub-cellular fractionation techniques. Results: Our studies revealed cyclin D1 to be localized predominantly within the cytoplasmic fraction of all cell lines tested. These observations were confirmed by confocal microscopy. GSK3â was found to be localized within both the nucleus and cytoplasm throughout the cell cycle. Inhibition of GSK3â or CRM1-dependent nuclear export resulted in only modest nuclear accumulation, suggesting that the cytoplasmic localization of cyclin D1 results from the inhibition of its nuclear import. Conclusion: We have shown by several different experimental approaches, that cyclin D1 is in fact a predominantly cytoplasmic protein in mammalian cancer cell lines. Recent studies have shown that the cytoplasmic sequestration of cyclin D1 prevents apoptosis in neuronal cells. Our results suggest that cytoplasmic sequestration may additionally serve to regulate cyclin D1 activity in mammalian cancer cells. [ABSTRACT FROM AUTHOR]

Chylous pleural effusion, or chylothorax, usually results from obstruction to or disruption of the thoracic duct. Malignant etiologies are the most common cause of chylothorax, lymphoma accounting for the majority of non-traumatic chylous effusions. We report an unusual case of bilateral chylothorax associated with a retrosternal toxic multinodular goiter in a patient with non-Hodgkin's lymphoma. An ablative dose of 131I was administered with apparent initial clinical improvement. The pathogenesis of chylothorax and therapeutic considerations are discussed. [ABSTRACT FROM AUTHOR]

Purpose: d -Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of d-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of d-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for d-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μ M. Predominant circulating metabolites were perillic acid (Cmax 20.7 ± 13.2 to 71 ± 29.3 μ M ), dihydroperillic acid (Cmax 16.6 ± 7.9 to 28.1 ± 3.1 μ M ), limonene-1,2-diol (Cmax 10.1 ± 8 to 20.7 ± 8.6 μ M ), uroterpenol (Cmax 14.3 ± 1.5 to 45.1 ± 1.8 μ M ), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of d-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions: d-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the article "Severe hypocalcaemia after being given intravenous bisphophonate," by Rajesh Peter and colleagues in the February 7, 2004 issue.