Paravasation with cyclophosphamide - Case report of tissue necrosis in a patient with primary breast cancer

Background: Paravasation is a rare but severe complication of treatment with cytotoxic agents. Some anticancer drugs are considered to be of high toxicity (vesicant), some are merely irritant, and some are regarded as nearly non-toxic to healthy tissue as is the case with cyclophosphamide. Case Report: In this report, we present the first case of severe tissue damage caused by a paravasation of cyclophosphamide in a breast cancer patient receiving chemotherapy. Conclusion: Therefore, every attending oncological physician should be aware of the possibility of severe tissue damage as a consequence of cyclophosphamide paravasation

A phase I trial of beta-all-trans-retinoic acid delivered via a collagen sponge and a cervical cap for mild or moderate intraepithelial cervical neoplasia.

A phase I trial was conducted of the vitamin A derivative beta-all-trans-retinoic acid (vitamin A acid; TRA), delivered via a collagen sponge and cervical cap for mild or moderate intraepithelial cervical neoplasia. On the basis of known skin and mucosal membrane toxicity, a concentration of 0.05% TRA in a cream-based vehicle was selected as the starting dose and was escalated later with the use of a modified Fibonacchi scale. The delivery device and the TRA were changed daily for 4 days, and side effects were assessed on days 1, 2, 3, 4, 8, and 30 by clinical and colposcopic examination. Vaginal, cervical, and systemic toxicity were evaluated in 35 patients. No dose-related systemic effects were found; mild cervical inflammation increased in many patients at higher doses. Unacceptably high vaginal toxicity was reached at a TRA concentration of 0.484%. A concentration of 0.372% TRA is recommended for use in phase II trials in mild and moderate cervical intraepithelial neoplasia

Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial.

BackgroundRetinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%.PurposeThis randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN.MethodsAnalyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test.ResultsRA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible.ConclusionsA short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects.ImplicationsA derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible

Ambulatory chemotherapy : past, present and future

Ambulatory chemotherapy allows the delivery of short and extended chemotherapy infusions through a portable pump from the comfort of patients’ homes. It is essential to offer it for suitable candidates to ensure both their safety and the success of the treatment session. This requires a delicate balance between clinical assessment and patient acceptance. The two main components of this treatment modality are the pump and the access device. There are several pump designs and mechanisms on the market, with the latest being the portable disposable elastomeric one. Clinicians along with a multidisciplinary medical team often decide upon the type of access device; patients are also involved whenever shared decision making is practiced. Despite some reports of pump programming errors or malfunctions, research is underway to find innovative solutions to support its use

Understanding and meeting the needs of those using growth hormone injection devices

BACKGROUND: Recombinant human growth hormone (r-hGH) is used to treat: growth hormone deficiency in children and adults; children born small for gestational age; Turner's syndrome; and chronic renal failure. r-hGH is administered by daily subcutaneous injection and may be given using a number of different administration devices. The aim of this survey was, firstly, to identify which attributes of an r-hGH administration device are considered most important to physicians, teenage patients, parents of young children requiring GH and nurses who have experience of r-hGH administration, and, secondly, to determine how they rate existing devices in each of these key attributes. METHODS: The opinions of 67 individuals with experience in r-hGH administration were captured in discussion sessions. Parents, physicians and nurses were asked to rate 19 device attributes by completing a questionnaire, and to rank four different r-hGH administration devices (including a conceptual electronic device) in order of preference. RESULTS: Reliability, ease of use, lack of pain during injection, safety in use, storage, and number of steps in preparation before use, during use and after were considered to be the five most desirable attributes of an r-hGH administration device. An electronic device was preferred to an automatic, multi-dose injection device, a needle-free injection device or a manual, ready-to-use, disposable injection device. CONCLUSION: In the opinion of physicians, nurses and parents using r-hGH injection devices, an ideal device must combine reliability with simplicity, while delivering treatment with minimal pain. An electronic device, which combines many of the most useful features of existing devices with novel functions, was the preferred option for r-hGH administration

Interferon-α resistance in renal carcinoma cells is associated with defective induction of signal transducer and activator of transcription 1 which can be restored by a supernatant of phorbol 12-myristate 13-acetate stimulated peripheral blood mononuclear cells

Therapy of selected human malignancies with interferon-α is widely accepted but often complicated by the emergence of interferon-α resistance. Interferon is a pleiotropic cytokine with antiproliferative, antitumour, antiviral and immunmodulatory effect; it signals through the Jak-STAT signal transduction pathway where signal transducer and activator of transcription 1 plays an important role. Here we report both, a lack of signal transducer and activator of transcription induction in interferon-α resistant renal cell carcinoma cells and signal transducer and activator of transcription 1 reinduction of phorbol 12-myristate 13-acetate-stimulated peripheral blood mononuclear cells supernatant. Preliminary experiments on the identification of the molecules that reinducing signal transducers and activators of transcription 1 indicate that interferon-γ may be the responsible candidate cytokine, but several others may be involved as well. This work provides the basis for therapeutic strategies directed at the molecular modulation of interferon-α resistance in human neoplasms

Pichia pastoris versus Saccharomyces cerevisiae:a case study on the recombinant production of human granulocyte-macrophage colony-stimulating factor

BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is a glycoprotein that has been approved by the FDA for the treatment of neutropenia and leukemia in combination with chemotherapies. Recombinant hGM-CSF is produced industrially using the baker's yeast, Saccharomyces cerevisiae, by large-scale fermentation. The methylotrophic yeast, Pichia pastoris, has emerged as an alternative host cell system due to its shorter and less immunogenic glycosylation pattern together with higher cell density growth and higher secreted protein yield than S. cerevisiae. In this study, we compared the pipeline from gene to recombinant protein in these two yeasts. RESULTS: Codon optimization in silico for both yeast species showed no difference in frequent codon usage. However, rhGM-CSF expressed from S. cerevisiae BY4742 showed a significant discrepancy in molecular weight from those of P. pastoris X33. Analysis showed purified rhGM-CSF species with molecular weights ranging from 30 to more than 60 kDa. Fed-batch fermentation over 72 h showed that rhGM-CSF was more highly secreted from P. pastoris than S. cerevisiae (285 and 64 mg total secreted protein/L, respectively). Ion exchange chromatography gave higher purity and recovery than hydrophobic interaction chromatography. Purified rhGM-CSF from P. pastoris was 327 times more potent than rhGM-CSF from S. cerevisiae in terms of proliferative stimulating capacity on the hGM-CSF-dependent cell line, TF-1. CONCLUSION: Our data support a view that the methylotrophic yeast P. pastoris is an effective recombinant host for heterologous rhGM-CSF production

Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice

The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol. Its oral bioavailability is very low due to the action of P-glycoprotein in the gut wall and CYP450 in gut wall and liver. However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed. We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF’s) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF’s without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself. Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor EL-ethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF’s maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels

Intensification of Antiretroviral Therapy with a CCR5 Antagonist in Patients with Chronic HIV-1 Infection: Effect on T Cells Latently Infected

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4+ T cells in chronically HIV-1-infected patients receiving antiretroviral therapy. Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation. Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4+ or CD8+ counts, although a significant decrease was found in the proportion of HLA-DR+/CD38+ CD4+ and CD8+ T-cells. LPS and sCD14 levels increased. Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results

Recombinant Mouse PAP Has pH-Dependent Ectonucleotidase Activity and Acts through A1-Adenosine Receptors to Mediate Antinociception

Prostatic acid phosphatase (PAP) is expressed in nociceptive neurons and functions as an ectonucleotidase. When injected intraspinally, the secretory isoforms of human and bovine PAP protein have potent and long-lasting antinociceptive effects that are dependent on A1-adenosine receptor (A1R) activation. In this study, we purified the secretory isoform of mouse (m)PAP using the baculovirus expression system to determine if recombinant mPAP also had antinociceptive properties. We found that mPAP dephosphorylated AMP, and to a much lesser extent, ADP at neutral pH (pH 7.0). In contrast, mPAP dephosphorylated all purine nucleotides (AMP, ADP, ATP) at an acidic pH (pH 5.6). The transmembrane isoform of mPAP had similar pH-dependent ectonucleotidase activity. A single intraspinal injection of mPAP protein had long-lasting (three day) antinociceptive properties, including antihyperalgesic and antiallodynic effects in the Complete Freund's Adjuvant (CFA) inflammatory pain model. These antinociceptive effects were transiently blocked by the A1R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (CPX), suggesting mPAP dephosphorylates nucleotides to adenosine to mediate antinociception just like human and bovine PAP. Our studies indicate that PAP has species-conserved antinociceptive effects and has pH-dependent ectonucleotidase activity. The ability to metabolize nucleotides in a pH-dependent manner could be relevant to conditions like inflammation where tissue acidosis and nucleotide release occur. Lastly, our studies demonstrate that recombinant PAP protein can be used to treat chronic pain in animal models