Evofosfamide, a new horizon in the treatment of pancreatic cancer.

Evofosfamide, also formerly known as TH-302, is an investigational hypoxia-activated prodrug and is used to target cancerous cells under hypoxic conditions, which is a feature possessed by multiple solid tumors including pancreatic tumors. Gemcitabine, a cytotoxic agent, has for many years been the standard first-line treatment for metastatic pancreatic cancer in patients. In recent years, combination chemotherapeutic therapies have provided a new avenue for molecular targeting by increasing the probability of eliminating the cancer and minimizing the likelihood of resistance. We have evaluated multiple studies in an effort to shed light on an emerging prodrug, evofosfamide, which operates by selectively targeting the tumor hypoxic compartment. A web-based literature search was performed through PubMed and Google Scholar using the keywords 'evofosfamide', 'TH-302,' and 'pancreatic tumor.' Of the available results, 53 relevant studies were reviewed and summarized. Chemotherapeutic agents such as evofosfamide, which targets tumor hypoxia, are new agents against cancer cells. Current experience with these agents is limited as additional and longer prospective studies are needed to further evaluate the clinical efficacy and postmarketing safety profile.

Cardiomyopathy Associated With Targeted Therapy for Breast Cancer.

BACKGROUND: Chemotherapeutic agents directed against human epidermal growth factor receptor 2 (HER-2) have significantly improved the prognosis of patients who are positive for this receptor. However, cardiomyopathy remains as a common adverse effect of using these agents. MATERIALS AND METHODS: Literature search was conducted via PubMed using the keywords of "Trastuzumab Cardiomyopathy," "Lapatinib Cardiomyopathy" and "Pertuzumab Cardiomyopathy," which provided 104 results. These articles were then screened for relevance to the targeted subject based on their title and abstracts. Case reports and articles that were not discussing any aspect of cardiomyopathy secondary to targeted therapy for breast cancer and articles not in English were eliminated. After elimination, a bibliography search among selected articles was done and a total of 46 articles were identified. The collected articles were then meticulously analyzed and summarized. RESULTS: The use of human epidermal growth factor receptor 2 (HER-2) receptor targeted chemotherapy in breast cancer is limited because of a higher incidence (19-22%) of cardiomyopathy. The incidence of cardiomyopathy is not dose dependent and in most cases it is reversible after discontinuation of the drug and treatment with heart failure medications. Severe adverse outcomes including death or permanent disability are rare. CONCLUSION: HER-2 targeted chemotherapy for breast cancer has a higher incidence of associated reversible cardiomyopathy. Patients should be monitored by serial echocardiography starting at the beginning of the treatment and followed by every 3 months until the completion of chemotherapy. Co-ordination between oncologists and cardiologists is needed to develop evidence-based protocols to prevent, identify, monitor and treat trastuzumab-induced cardiomyopathy.

Dermatotoxic effects of orally administered ciprofloxacin in sweating and nonsweating animal models.

CONTEXT: Some drugs, such as ciprofloxacin (CFX), that are excreted in sweat may produce some effects/toxicities in the skin structure. In order to differentiate the dermatotoxic effects of drugs due to excretion in sweat, it is essential to perform simultaneous studies in sweating and nonsweating animal models. OBJECTIVE: To determine the dermatotoxic effects of CFX in sweating (goats) and nonsweating (rabbits) animals and to determine whether there is a relationship between dermatotoxicity and the blood CFX concentration. MATERIALS AND METHODS: CFX was administered orally at the dose rate of 20 mg/kg body weight to goats (n = 16) and rabbits (n = 16) for 1 and 2 weeks, while control animals were given vehicle (water). Skin biopsies were taken after 1- and 2-week administration of CFX and processed histologically. Similarly, the CFX concentration in the plasma samples was analyzed by high-performance liquid chromatography (HPLC). RESULTS: Mean ± standard error (SE) epidermal thickness (µm) was 26.2 ± 0.2, 38.6 ± 2.05, and 37.8 ± 1.8 for the control, 1-week-treated, and 2-week-treated goats and 16.06 ± 2.39, 50.67 ± 6.61, and 34.03 ± .12 for the control, 1-week-treated, and 2-week-treated rabbits, respectively. Mean ± SE epidermal cell layers were 2.08 ± 0.08, 3.42 ± 0.16, and 3.25 ± 0.21 in the control, 1-week-treated, and 2-week-treated goats and 1 ± 0, 3.08 ± 0.37, and 1.83 ± 0.35 in the control, 1-week-treated, and 2-week-treated rabbits, respectively. Mean ± SE plasma concentration (µg/mL) of CFX was 0.37 ± 0.06 and 0.30 ± 0.05 in the 1- and 2-week-treated goats and 0.13 ± 0.04 and 0.14 ± 0.09 in the 1- and 2-week-treated rabbits, respectively. CONCLUSION: Microscopically, increases in epidermal thickness, number of cell layers, and cell infiltration were observed in both sweating and nonsweating animals, indicating that the dermatotoxic effects may not be due to CFX excretion in sweat. No relationship was found between dermatotoxicity and blood CFX concentration in both animal models.

Dynamics of innate immune response in Gallus domesticus using two methods of induced molting.

The aim of this study was to compare the ability of laying hen abdominal macrophages during the second production cycle by using two different methods of induced molting. Two groups of Single Comb White Leghorn hens were induced to molt at the end of their first production cycle using feed restriction and ZnO supplementation. Macrophages were isolated from the abdomen and in vitro cytotoxic ability, at which point macrophage bactericidal moiety nitric oxide (NO) was recorded. Serum IgM and IgG titers against sheep red blood cells (SRBC) were determined at various stages: before molting (BM), 5% production level (5P), peak production stage (PP) and at the end of production (EP) level after fast and Zn-induced molt. Macrophages adherence percentage remained unaffected (p< or =0.05) during all production cycles, whereas the macrophage engulfment percentage and engulfment/cell was significantly higher (p< or =0.05) at PP in both fast and Zn-induced molted groups, as compared to all other studied stages. Macrophage NO production was increased (p< or =0.05) at PP and after SRBC and lipopolysaccrides (LPS) stimulus, when molted with ZnO supplementation. Serum total antibody titer against SRBC increased serum IgG and IgM titers during the second production cycle by Zn-induced molt. However, molting stress greatly reduced IgG and IgM production at the 5P stage. Serum Zn concentration increased with the onset of production but decreased at the EP stage irrespective of their molting regimes. Our results validate the strengthened innate and acquired immune response during the second production cycle after Zn-induced molting instead of fasting.

Predicting outcome based on Swenerton score in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation: implications for patient selection.

The aim of this study was to study the effectiveness of the Swenerton score in assessing extent of disease as an independent prognostic and predictive factor in patients with metastatic breast cancer (MBC) who receive high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplant (AHSCT). Two-hundred thirty-two patients with MBC underwent HDCT. Extent of disease was assessed quantitatively using the Swenerton score. A retrospective analysis was performed using Cox proportional hazards regression and logistic regression models. One hundred three (44%) patients had a complete response (CR) after HDCT. Bone marrow as source of hematopoietic stem cells, hormone-receptor-negative status, and visceral involvement correlated with both worse overall survival (OS) and progression-free survival (PFS). Short disease-free interval, multiple sites of metastatic disease, and less than 50% reduction in the Swenerton Score during induction chemotherapy correlated with worse OS. Patients in CR at the time of HDCT had better PFS than patients in partial response, stable disease, or progressive disease. Fifty-six patients who underwent conversion to CR after HDCT had a similar median OS (not reached v 74 months; P =.51) and PFS duration (22 v 44 months; P =.15) as patients who received HDCT after a CR to standard-dose chemotherapy (SDCT). Conversion to CR was predicted by a >/=50% reduction in the Swenerton score during SDCT (odds ratio [OR] 3.32, P <.01) and soft-tissue disease (OR 4.08, P <.01). The presence of multiple metastatic sites predicted decreased probability of conversion to CR (OR 0.34, P <.01). The Swenerton score provides a thorough estimate of disease extent, and reduction of Swenerton score by SDCT is potentially useful for selecting the optimal candidates for HDCT trials who may achieve long-term disease control.

A detailed evaluation of cardiac toxicity: a phase II study of doxorubicin and one- or three-hour-infusion paclitaxel in patients with metastatic breast cancer.

PURPOSE: This Phase II study was designed to determine the efficacy and toxicity of combination doxorubicin and paclitaxel as front-line treatment for metastatic breast cancer. EXPERIMENTAL DESIGN: Eligible patients had no prior anthracycline or taxane therapy and normal cardiac function. They were treated with bolus doxorubicin 60 mg/m2, followed by paclitaxel 200 mg/m2, as either 1- or 3-h infusions for six to seven cycles. Single-agent paclitaxel was continued thereafter. Serial multiple gated acquisition scans were performed, and endomyocardial biopsies were performed for consenting patients. RESULTS: Eighty-two patients were enrolled with a median age of 53 years (range, 32-78 years). Of 79 evaluable patients, 58.2% had an objective response (3.8% complete response + 54.4% partial response), 34.2% had stable disease, and 7.6% had progressive disease. With median follow-up of 37.5 months, median time to progression was 7 months; median survival was 31 months. Multiple gated acquisition scans were performed in 82 of 82 patients at baseline, 75 of 82 patients at a total doxorubicin dose of 60-180 mg/m2, 62 of 68 patients at 200-300 mg/m2, 18 of 52 patients at 310-360 mg/m2, and 4 of 8 patients at 420 mg/m2. Median ejection fractions were 62.5, 60, 57.5, 52.5, and 32%, respectively. Fifteen of 82 (18.3%) patients had a decrease in ejection fraction > or = 15% to an absolute ejection fraction < or = 50%. Eight of these 15 patients (53%) developed clinical congestive heart failure: 4 of 8 (50%) who received a total doxorubicin dose of 420 mg/m2 versus 4 of 74 (5.4%) who received a dose < or = 360 mg/m2 (P = 0.002). CONCLUSIONS: When the doxorubicin dose exceeds 360 mg/m2, the combination of bolus doxorubicin and paclitaxel presents unacceptable cardiac risk.