Non-small-cell lung cancer vaccine therapy: a concise review.

Lung cancer is the leading cause of cancer deaths in the United States and throughout the world; globally, there are more than 1.1 million deaths each year. Treatment modalities currently employed are significantly limited; 50% of patients experience disease recurrence after surgery, and less than a quarter of patients respond to systemic chemotherapy. These statistics have fueled the search for a safer, more effective treatment modality. Despite significant advances in our understanding of the molecular basis of cancer immunology, many obstacles remain. However, encouraging clinical results in patients immunized with autologous tumor cell vaccines expressing granulocyte macrophage colony-stimulating factor strongly advocate further investigation of immunotherapy in non-small-cell lung cancer (NSCLC). Further studies are needed to demonstrate whether these novel therapies can potentially complement or even replace current therapeutic approaches. We present a review of the various vaccine-based strategies employed to target and treat NSCLC.     

Impact of non-alcoholic fatty liver disease on chronic hepatitis B.

BACKGROUND: The impact of superimposed non-alcoholic fatty liver disease (NAFLD) is well established in patients with chronic hepatitis C (CH-C), but the impact in patients with chronic hepatitis B (CH-B) is less clear. Aim: This study aims to evaluate the prevalence of NAFLD in patients with CH-B and the association with viral and host factors, particularly in patients with metabolic syndrome (MS). DESIGN: Data from patients with CH-B was obtained from our databases. Patients with excessive alcohol use were excluded. Hepatitis B virus (HBV) genotyping by INNO-LIPA was available for some patients. The presence of MS was defined according to the Adult Treatment Panel III (ATP III). All biopsies were read by two hepatopathologists using Metavir, modified histologic activity index (MHAI), as well as a NAFLD pathologic protocol. Patients were classified as (1) those without NAFLD; (2) those with simple hepatic steatosis; (3) and those with superimposed non-alcoholic steatohepatitis (NASH). Factors associated with superimposed NAFLD, its subtypes, and hepatic fibrosis were also analysed. RESULTS: Subjects included 153 HBV patients [66% male, age 50.5+/-27.5 years, body mass index 24.7+/-3.7 kg/m(2), waist 83.2+/-10.9 cm; 8.5% Caucasian, 67% Asian, aspartate aminotransferase (AST) 63.2+/-88.2 IU/l, alanine aminotransferase (ALT) 98.6+/-164.6 IU/l, glucose 111.6+/-50.5 mg/dl, HBV-DNA 1.8 x 10(8)+/-1.9 x 10(6) copies/ml, 7% with MS, 13% with diabetes, 20% with arterial hypertension and 8.5% with dyslipidaemia]. Liver biopsy was available for 64 subjects [19% had superimposed NAFLD, 13% had superimposed NASH, 86% had some degree of fibrosis, and 39% had advanced fibrosis (Ishak >3)]. Patients with HBV and superimposed NASH were significantly older (55 vs. 42 years, P=0.008), more likely to have hypertension (63% vs. 15%, P=0.006) and dyslipidaemia (50% vs. 8%, P=0.006), and had a larger waist circumference (92 vs. 83 cm, P=0.03). The presence of fibrosis was associated with higher waist circumference (84 vs. 80 cm, P=0.03), higher HBV-DNA (1.9 x 10(8) vs. 5 x 10(6) copies/ml, P=0.005), and elevated ALT >40 IU/l (73.6% vs. 33.3%, P=0.02). CONCLUSIONS: The components of MS (obesity, hypertension, and dyslipidaemia) are associated with the presence of NASH in patients with CH-B. The presence of hepatic fibrosis seems to be associated with known host and viral factors as well as the presence of abdominal obesity.     

Cytokeratin 7 and 20 staining for the diagnosis of lung and colorectal adenocarcinoma

The origin of metastatic adenocarcinoma lesions can sometimes be difficult to diagnose. The objectives of our study were to establish the cytokeratin staining pattern of primary and metastatic lung and colorectal adenocarcinomas, and to determine if this helps to identify the site of origin of metastatic lesions. We reviewed a total of 102 tissue samples from patients in our tumour registry, with either primary or metastatic lung or colorectal adenocarcinoma. Tissue sections were stained for cytokeratin 7 and 20 and read as positive or negative for staining. Clinical and radiologic information was reviewed from computerised charts. The cytokeratin 7+/cytokeratin 20- pattern characterised 96% (29 out of 30) of primary and 95% (21 out of 22) of metastatic lung adenocarcinomas. All the primary (26), and 88% (21 out of 24) of metastatic colorectal adenocarcinomas stained cytokeratin 7-/cytokeratin 20+. Samples from a variety of metastatic sites were evaluated for cytokeratin 7 and 20 staining. Out of the 102 samples, in 95% (97 out of 102) of the cases, the cytokeratin 7 and cytokeratin 20 staining pattern characterised and differentiated between lung and colorectal adenocarcinoma. Primary and metastatic lung adenocarcinomas show a cytokeratin 7+/cytokeratin 20- staining pattern, while colorectal adenocarcinomas stain cytokeratin 7-/cytokeratin 20+. Cytokeratin staining is helpful in the diagnostic differentiation of metastatic lesions from these two common primaries, and assists in determining the site of origin of metastatic lesions.     

A phase I and pharmacokinetic study of VNP40101M,a new alkylating agent,in patients with advanced or metastatic cancer

Summary Purpose: VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion. Study design: The starting dose was 3 mg/m² every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m². Beyond 100 mg/m², dose increments were 25%. Initially, 1–2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related grade 2 adverse event, all dose levels required assessment of 3–6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose. Results: Twenty-six patients in 13 dose levels ranging from 3–305 mg/m² were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m², six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes. Conclusions: The MTD and recommended dose for phase II trials is 305 mg/m² every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.Supported by Vion Pharmaceuticals, Inc.     

A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer

PHY906 is a novel Chinese herbal preparation that has been used in the Orient for over 1800 years to treat a wide range of gastrointestinal side effects including diarrhea, abdominal cramps, vomiting, fever, and headache. Preclinical and clinical studies were conducted to further investigate the biologic and clinical activities of this herbal medicine. To ensure standardization and maintain interbatch reliability of PHY906, high performance liquid chromatography (HPLC) was used to establish a "chemical fingerprint" of PHY906. In vivo preclinical studies using the murine Colon 39 tumor model showed that PHY906 protected against the weight loss associated with irinotecan treatment. In the presence of PHY906, mice were able to tolerate otherwise lethal doses of irinotecan. Significantly improved antitumor activity and overall survival were observed in animals treated with the combination of irinotecan and PHY906 versus irinotecan alone. The combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) also resulted in at least additive antitumor activity with no increased host toxicity. Based on these in vivo studies, a phase I multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over study of PHY906 as a modulator of the weekly, bolus regimen of irinotecan, 5-FU, and LV (IFL) in the first-line treatment of patients with advanced colorectal cancer (CRC) was conducted. The specific objectives of this clinical trial were to determine the safety and tolerability of PHY906 when administered concomitantly with the bolus, weekly IFL regimen. Treatment with PHY906 did not alter the pharmacokinetics of 5-FU, irinotecan, or the irinotecan metabolite SN-38.     

Utility of <Superscript>18</Superscript>F-fluoroestradiol (<Superscript>18</Superscript>F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy

Background

Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. ¹⁸F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes ¹⁸F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen.

Methods

Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with ¹⁸F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with ¹⁸F-FES 1–5 days post administration of Z-endoxifen.

Results

Statistically significant changes (p?=?0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration.

Conclusion

F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.