Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer

Background

3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma.

Methods

Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000?mg/m² on days 1, 8, and 15 every 28?days) 1?h after completing a 4-h infusion of 3-AP given at a dose of 105?mg/m² in patients with normal liver function (stratum A) or 80?mg/m² if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B.

Results

Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3?C4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24?h after 3-AP therapy showed increased R2 mRNA expression by in situ RT?CPCR, suggesting RR inhibition.

Conclusions

Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.     

Combined treatment with Bevacizumab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients

Background Bevacizumab, a monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), has produced promising results when combined with chemotherapy in the treatment of advanced colorectal cancer (CRC). The aim of the present study was to define the immunological profile of metastatic CRC patients at baseline and following chemotherapy with either irinotecan/5-fluorouracil/leucovorin (IFL) alone or IFL in combination with.bevacizumab (B-IFL). Methods Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HD) (n = 20) and patients (n = 40) were tested for T-cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and cytokine production following stimulation with anti-CD3 mAb. Results,PBMCs obtained from CRC patients prior to treatment exhibited lower auto-MLR responses and low production of IL-2, IFN-γ, IL-12 and IL-18 cytokines, whereas IL-4 and IL-10 cytokines were increased as compared to HD (p < 0.001, for all parameters) following in vitro stimulation with anti-CD3 mAb. During treatment, and in particular in week 12 of evaluation, IL-2 (p < 0.001 for both IFL and B-IFL groups), IFN-γ (p < 0.001 for IFL and p = 0.001 for B-IFL), IL-12 (p < 0.001 for both IFL and B-IFL) and IL-18 (p < 0.001 for both IFL and B-IFL) production, as well as auto-MLR responses increased (p < 0.001 for both IFL and B-IFL), whereas IL-4 (p < 0.001 for IFL and p = 0.001 for B-IFL) and IL-10 [p < 0.001 for IFL and p = 0.067 (non-significant) for B-IFL] production decreased over baseline in the two treatment groups, yet their respective values never reached those of HD. Moreover, IL-2, IFN-γ production, and auto-MLR were higher in the B-IFL over the IFL treatment group (p < 0.001, p < 0.04, p < 0.001, respectively). Conclusion Our study demonstrates that the abnormal immune parameters observed in metastatic CRC patients at presentation can substantially improve during treatment with either IFL or B-IFL. The immune parameters examined can provide a sensitive and valuable tool for monitoring immune function in CRC patients, and could be applied as surrogate markers predicting treatment-related outcome.     

A 57-year-old female with a cerebellar mass

A 57-year-old female presented with recurrent episodes of nausea and vomit, as well as instability during walking. The patient had a history of uterine leiomyosarcoma, for which she underwent a hysterectomy and oophorectomy 8 months ago. CT scan revealed a calcified mass that was located in the left cerebellar hemisphere which was resected. Histologically, multiple tissue fragments displayed infiltration of cerebellar tissue by polymorphic spindle-shaped cells. The Ki-67 proliferation index was approximately 20%. The morphological and immunohistochemical data, in association with the past clinical history, were consistent with cerebellar metastasis of uterine leiomyosarcoma. Although adjuvant radiotherapy was introduced, the patient died of cardiopulmonary arrest 6 weeks after the surgical procedure. The present case adds to the body of literature being the second report of uterine leiomyosarcoma metastatic to the cerebellum.     

The role of the fat mass and obesity associated gene (<Emphasis Type="Italic">FTO</Emphasis>) in breast cancer risk

Background  

Obesity has been shown to increase breast cancer risk. FTO is a novel gene which has been identified through genome wide association studies (GWAS) to be related to obesity. Our objective was to evaluate tissue expression of FTO in breast and the role of FTO SNPs in predicting breast cancer risk.     

Lipodystrophy: pathophysiology and advances in treatment

Lipodystrophy is a medical condition characterized by complete or partial loss of adipose tissue. Not infrequently, lipodystrophy occurs in combination with pathological accumulation of adipose tissue at distinct anatomical sites. Patients with lipodystrophy exhibit numerous metabolic complications, which indicate the importance of adipose tissue as an active endocrine organ. Not only the total amount but also the appropriate distribution of adipose tissue depots contribute to the metabolic state. Genetic and molecular research has improved our understanding of the mechanisms underlying lipodystrophy. Circulating levels of hormones secreted by the adipose tissue, such as leptin and adiponectin, are greatly reduced in distinct subpopulations of patients with lipodystrophy. This finding rationalizes the use of these adipokines or of agents that increase their circulating levels, such as peroxisome proliferator-activated receptor γ (PPARγ) agonists, for therapeutic purposes. Other novel therapeutic approaches, including the use of growth hormone and growth-hormone-releasing factors, are also being studied as potential additions to the therapeutic armamentarium. New insights gained from research and clinical trials could potentially revolutionize the management of this difficult-to-treat condition.