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Background: New treatment strategies for locally advanced head and neck squamous cell carcinoma combine induction chemotherapy and chemoradiation. Identifying the predictors of outcome in sequentially treated patients is critical for focusing therapeutic research. In this analysis, the authors evaluated human papillomavirus type 16 (HPV-16) status and the expression levels of a defined set of biomarkers to identify predictors of response to this treatment modality.Methods: In total, 114 patients with oropharyngeal cancer (OPC) who were treated on the TAX 324 trial (cisplatin and fluorouracil with or without docetaxel in patients with locally advanced head and neck squamous cell carcinoma) had pretreatment biopsy specimens that were evaluable for HPV-16 DNA and immunohistochemical expression of the following biomarkers: beta-tubulin II (βT-II), glutathione S-transferase (GST-π), p53, and B-cell lymphoma 2 (Bcl-2). Patients were categorized into risk groups based on their HPV status and biomarker expression levels.Results: Patients with high-risk OPC were defined by HPV-negative status and either elevated expression of βT-II or levels of at least 2 of the other 3 adverse markers (elevated GST-π, elevated p53, or low Bcl-2). All other HPV-negative patients were categorized as moderate risk. In total, 55 patients were HPV-positive, and 59 patients were HPV-negative, with 34 were categorized as high risk and 25 categorized as moderate risk. The median survival for HPV-positive patients was not reached. The median survival was 44.2 months for moderate-risk patients (95% confidence interval, 20.9 months to not reached) and 12.1 months for high-risk patients (95% confidence interval, 7.5-19.7 months). The 24-month survival rate was 89% for HPV-positive patients, 67% for moderate-risk patients, and 29% for high-risk patients (P < .0001).Conclusions: The molecular data set in this study readily differentiated between 2 distinct groups of patients with locally advanced, HPV-negative OPC. This risk-stratification strategy may serve as a guide for treatment selection. [ABSTRACT FROM AUTHOR]

Background: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models.Experimental Design: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment.Results: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model.Conclusions: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment. [ABSTRACT FROM AUTHOR]

Bladder cancer is among the most prevalent malignancies, and is characterised by frequent tumour recurrences and localised inflammation, which may promote tissue invasion and metastasis. Microarray analysis was used to compare gene expression in normal bladder urothelium with that in tumours at different stages of progression. The innate immune response gene, interferon-stimulated gene 15 kDa (ISG15, GIP2), was highly expressed at all stages of bladder cancer as compared to normal urothelium. Western blotting revealed a tumour-associated expression of ISG15 protein. ISG15 exhibited a stage-associated expression, with significantly (P<0.05) higher levels of ISG15 protein in muscle-invasive T2-T4 tumours, compared with normal urothelium. Although ISG15 is involved in the primary immune response, ISG15 expression did not correlate with bladder inflammation. However, immunohistochemical staining revealed expression of ISG15 protein in both cancer cells and stromal immune cells. Interestingly, a significant fraction of ISG15 protein was localised to the nuclei of tumour cells, whereas no nuclear ISG15 staining was observed in ISG15-positive stromal cells. Taken together, our findings identify ISG15 as a novel component of bladder cancer-associated gene expression. [ABSTRACT FROM AUTHOR]

The Eastern Cooperative Oncology Group (ECOG) performed a phase 2 study in B-cell chronic lymphocytic leukemia (CLL) of oral theophylline, a methylxanthine that inhibits cyclic nucleotide phosphodiesterases, thereby inducing the intracellular accumulation of cyclic adenosine monophosphate (cAMP). In 25 patients with Rai stages 0–1, theophylline, 200mg given orally every 12h was well tolerated. There was one complete response after 22.5 months of treatment, which continues at 27 + months, and 18 other patients had stable disease. In vitro exposure of patients' lymphocytes to aminophylline (75–250 μg/ ml), the soluble form of theophylline, resulted in dose- and time-dependent induction of apoptosis in 9/20 patients studied. Apoptosis was documented flow-cytometrically by monitoring the expression of bcI-2 and bax, forward light scatter, fluorescence intensity of binding of CD45 antibody, and the binding of annexin. Patients whose leukemic lymphocytes were susceptible to apoptosis induction by aminophylline in vitro experienced a significantly longer progression-free survival than patients whose cells were resistant to the drug in culture (P= 0.025). This suggests that in a CLL population treated with theophylline, induction of an apoptotic response to the drug in vitro is prognostic for absence of clinical progression. [ABSTRACT FROM AUTHOR]

Background. Reports of the usefulness of ultrasonography in the diagnosis of hepatic veno-occlusive disease (HVOD) have presented conflicting results.¶Objective. To determine the usefulness of gray-scale or Doppler ultrasonographic measurements in the diagnosis of HVOD in pediatric patients undergoing BMT.¶Materials and methods. We prospectively obtained 202 serial sonograms on 48 patients and examined the association between the clinical diagnosis of HVOD (McDonald criteria) and eight ultrasound parameters, including the hepatic artery resistive index (HARI), direction and velocity of portal venous flow, and thickness of the gall bladder wall.¶Results. HVOD developed in 29 of the 48 patients. The portal venous velocity increased after BMT in the group without HVOD and decreased in the group with HVOD; this difference was significant (P = 0.01). However, there was a great deal of variability in velocity measurements for individual patients. The mean HARI was 0.64 in the group with HVOD and 0.63 in the group without HVOD, and there was no difference between the two groups in the pattern of change in HARI relative to the day of BMT (P = 0.4). There was also no significant difference in thickness of the gallbladder wall between the two groups (P = 0.6).¶Conclusion. No ultrasound parameter studied was as useful as the McDonald criteria for diagnosing HVOD. [ABSTRACT FROM AUTHOR]