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Effects of intralesional versus ip administration of cisplatin on squamous cell carcinoma of mice.

The effects of intralesional versus ip administration of cisplatin (total, 24 mg/kg) given on different schedules were studied using transplantable squamous cell carcinoma of mice. The size of the tumor in the control group increased approximately 60 times at the end of the experiments, whereas it decreased to 0.04 of the initial volume following a single intralesional injection of cisplatin. The ratio of treated/control mice was 0%. The comparable values in the groups with intralesional cisplatin at 3- and 1-week intervals were 7% and 20%, respectively. The responses of the tumor to cisplatin in the ip groups were lower than those of the intralesional groups and were not dependent on the schedule of administration. Toxic deaths were less frequently encountered in the intralesional groups of animals. Platinum concentration in tumors of the intralesional group was two to five times higher than that of the ip group 15 minutes to 96 hours after injection of 12 mg/kg of cisplatin, whereas the concentration in sera of the intralesional group remained lower than that of the ip group until 48 hours after the injection. The results indicate that the intralesional route produces a good response of tumor to cisplatin by maintaining high levels of the non-protein-bound form of the agent in the tumor tissue that cannot be provided by other routes of administration.

Animals↗

Adrenal suppression after corticosteroid injection of periocular hemangiomas.

Two infants with symptomatic periocular hemangiomas received 1-ml intralesional injections of a 50:50 mixture of triamcinolone acetonide (40 mg/ml) and betamethasone (8 mg/ml). Both developed adrenal suppression as evidenced by the immediate depression of their serum cortisol and adrenocorticotrophic hormone levels. One patient remained adrenal suppressed for five months and, concurrently, her growth rate and weight dropped from normal to below the fifth percentile. Adrenal suppression should be added to the growing list of complications caused by the corticosteroid injection of periocular hemangiomas.

Adrenal Cortex Hormones↗

Intralesional cidofovir for recurrent laryngeal papillomas: preliminary report.

This is a preliminary report of an ongoing study to test the efficacy of intralesional injections of the antiviral drug cidofovir in adults with recurrent laryngeal papillomas in whom multiple other treatments have previously failed. This study has been designed to include 10 to 20 patients, a number sufficient to either prove or disprove the safety and efficacy of this agent. This report conveys information on the first three patients enrolled in the trial. Each patient received an overall dose of 5 to 10 ml of cidofovir, at a concentration of 4.17 mg/ml, intralesionally at 2- to 4-week intervals. The approximate volume injected into each wart was 0.2 to 0.5 ml. Biopsies of the lesion sites were obtained at the initiation and completion of therapy. No other treatment was given. Resolution of lesions was monitored by videolaryngoscopy and still photography 1 to 2 weeks after each treatment. In time, the lesions resolved in all three patients, although all three later experienced a minor recurrence. We conclude that intralesional cidofovir appears to be a promising new treatment for controlling--and perhaps at higher dosages curing--refractory laryngeal papillomas, while causing little or no injury to laryngeal structures.

Adult↗

Antitumor activity of Listeria monocytogenes on a guinea pig fibrosarcoma.

Listeria monocytogenes-mediated tumor inhibition was studied in strain 13 guinea pigs by using a methylcholanthrene-induced fibrosarcoma (MCA-1). Mixtures of Listeria and tumor cells in ratios of 1:100, 1:200, or 1:400 (Listeria:MCA-1 cells) led to significant suppression of tumor growth. Intralesional injection of tumors on day 6 posttransplantation led to the regression of a highly significant number of tumors. Animals receiving injections of Listeria, either in a mixture with tumor cells or intralesionally, displayed enhanced skin test reactivity to a tumor extract. Tumor regressors were resistant for at least 2 to 3 months after the initial transplant to rechallenge with MCA-1 cells. Thus, with this particular tumor-host system, Listeria was successfully employed as an antitumor agent with no visibly detrimental side effects to the host.

Animals↗

Subcutaneous Administration of a Replication-Competent Adenovirus Expressing HSV-tk to Cotton Rats: Dissemination, Persistence, Shedding, and Pathogenicity.

Since human adenoviruses replicate only in human cells, toxicology studies with adenoviral vectors are hampered by the lack of a permissive nonhuman host. Before a replication-competent adenoviral vector expressing HSV-tk (Ad.OW34) can be used in clinical studies for intratumoral injections in patients with cutaneous lesions of head and neck cancer or intralesional injection for in situ vaccination strategy in advanced metastatic melanoma patients, risks have to be estimated in animal studies. In an attempt to assess potential toxicology, dissemination, persistence and shedding, we injected Ad.OW34 subcutaneously into cotton rats. (Sigmodon hispidus), which are considered a semi-permissive host for human adenoviruses. The animals underwent one or two subcutaneous injection cycles with 2.3 x 10(12) viral particles/kg each or a single course with 6.9 x 10(13) viral particles/kg and were analyzed at defined time points for histopathological changes in the brain, heart, lungs, spleen, liver, kidneys, ovaries, and skin. Additionally, these tissues as well as urine, feces, mouth, and skin swabs were analyzed at multiple time points by real-time quantitative polymerase chain reaction for the presence of vector sequences. The only significant treatment-related histopathologic finding was dermatitis with mild acanthosis at the site of vector injection. All other tissues evaluated were within normal limits or showed changes that were most likely incidental or spontaneous in nature. Vector sequences were detected in the skin at the injection site and to a lesser extent in the liver, spleen, and lungs. In addition, small amounts of vector DNA were detected in the ovaries. The vector sequences were rapidly cleared and the absence of viral sequences in the excreta and swabs of the majority of animals suggest that there was no significant replication of the vector in this host. The administration of Ad.OW34 was also associated with mild hyperamylasemia, lymphocytosis, and granulocytosis; however, we did not observe any clinical signs of illness or death in the experimental animals over the course of the study.

Adenoviruses, Human↗

Recombinant interferon alfa-2b in plaque-phase mycosis fungoides. Intralesional and low-dose intramuscular therapy.

A two-part clinical trial was conducted to determine the therapeutic efficacy of recombinant interferon alfa-2b in plaque-phase mycosis fungoides. In an initial randomized double-blind study, each of six patients had two representative plaques injected intralesionally with 1 X 10(6) U of recombinant interferon alfa-2b per site and two control plaques injected with placebo three times weekly for four consecutive weeks. Complete clinical regression of disease was observed at ten of 12 recombinant interferon alfa-2b sites compared with one of 12 placebo-treated sites four weeks after treatment with injections was stopped. Subsequently, in an open-labeled study, five of these patients were treated intramuscularly with 5 X 10(6) U of recombinant interferon alfa-2b three times weekly for four weeks and two patients were treated with a second, more extended course of therapy lasting 12 to 16 weeks. Three of the five patients treated systemically showed some improvement overall, but the responses were judged not to be clinically significant. The differential response observed from intralesional and intramuscular injections may be related to differences in concentration of recombinant interferon alfa-2b achieved in lesional skin by the two methods of administration.

Adult↗

Triamcinolone acetonide injection for laryngeal stenosis.

Three cases with acquired laryngeal stenosis have been presented. They were treated by percutaneous intralesional injection of triamcinolone acetonide using mirror laryngoscopy. The laryngeal airway and the phonation have been satisfactory for a period of two to six years of close follow-up.

Adult↗

Nonsurgical treatment of basal cell carcinomas with intralesional 5-fluorouracil/epinephrine injectable gel.

BACKGROUND: To develop a nonsurgical treatment alternative for basal cell carcinomas (BCCs), we evaluated intralesional sustained-release chemotherapy with 5-fluorouracil/epinephrine injectable gel (5-FU/epi gel). OBJECTIVE: To optimize the dose and treatment schedule, we compared the safety, tolerance, and efficacy of six treatment regimens of 5-FU/epi gel in patients with BCCs. METHODS: Two doses and four treatment schedules of 5-FU/epi gel were compared in an open-label, randomized study of 122 patients with biopsy-proven BCCs. One BCC per patient was treated for up to 4 to 6 weeks, then observed for 3 months at which time the tumor site was completely excised for histologic examination. RESULTS: Overall, 91% of evaluable treated tumors (106 of 116) in all regimens had histologically confirmed complete tumor resolution. No clinically significant treatment-related systemic adverse events occurred. The best response rate, tolerance, and patient compliance with assigned dose were in patients receiving 0.5 ml of 5-FU/epi gel three times a week for 2 weeks. The complete response rate based on histologic assessment in this group was 100%. CONCLUSION: Results demonstrate that treatment of BCC with 5-FU/epi gel is both safe and effective, may result in histologically confirmed complete response rates comparable to surgery, and provides a nonsurgical treatment alternative in selected patients.

Adult↗

Refractory pretibial myxoedema with response to intralesional insulin-like growth factor 1 antagonist (octreotide): downregulation of hyaluronic acid production by the lesional fibroblasts.

We report a case of refractory pretibial myxoedema (PTM) with Graves' disease in which there was a good clinical response to intralesional injection of the insulin-like growth factor 1 (IGF-1) antagonist octreotide. Intralesional octreotide (200 microg once daily) dramatically improved the tumorous lesions of PTM after 4 weeks, and the lesions remained stable even after reducing the dose to 200 microg once weekly. The amount of hyaluronic acid (HA) in the lesional skin decreased to 5.8 microg mg-1 dry weight from 16.3 microg mg-1 dry weight after 4 weeks of octreotide treatment. IGF-1 showed a dose-dependent stimulatory effect on HA secretion by both normal and patient's fibroblasts at higher concentrations in vitro. Octreotide significantly suppressed IGF-1 induced-HA secretion by the patient's fibroblasts, but not by normal fibroblasts, which suggests that expression of IGF-1 receptor on fibroblasts, or its affinity for IGF-1, are upregulated in PTM, resulting in the oversecretion of HA. These results might suggest that octreotide improves PTM through downregulation of HA production by lesional fibroblasts.

Down-Regulation↗

Augmentation of cytotoxicity of lymphokine activated killer cells on ovarian tumor cells by various biological response modifiers.

The effect of combining lymphokine activated killer (LAK) cells with either recombinant interleukin-2 (rlL-2), recombinant interferon-alpha (rIFN-alpha), recombinant tumor necrosis factor (rTNF) or streptococcal preparation OK-432 were assessed, using Raji, 2 kinds of cultured ovarian lines (PA-1 and SKOV-3), and 7 fresh ovarian tumor lines. LAK cells were generated by culturing peripheral blood lymphocytes (PBL) with rIL-2 for 3-5 days. The simultaneous combination of LAK cells with rIFN alpha or OK-432 augmented the cytotoxicity of LAK cells. The susceptibility of tumor cells to LAK cells also increased after the pretreatment of tumor cells with OK-432. These results suggest that the simultaneous injection of LAK cells with rIFN-alpha or OK-432 and the intralesional injection of OK-432 prior to the adoptive transfer of LAK cells may be a beneficial combination treatment for LAK treatment.

Biological Products↗

Lipomas treated with subcutaneous deoxycholate injections.

BACKGROUND: Lipomas are benign neoplasms of mature fat cells. Current treatments are invasive and carry the risk of scarring. Injections of phosphatidylcholine solubilized with deoxycholate, a bile salt, have been used to reduce unwanted accumulations of fat. Recent in vitro and ex vivo investigations indicate that deoxycholate alone causes adipocyte lysis. OBJECTIVE: We sought to report our experience treating lipomas using subcutaneous deoxycholate injections. METHODS: A total of 6 patients presenting with 12 lipomas were treated with intralesional injections of sodium deoxycholate (1.0%, 2.5%, and 5.0%) at intervals of 2 to 20 weeks. Tumor size, cutaneous reactions, and patients' subjective responses were recorded before and after treatment. RESULTS: All lipomas decreased in size (mean area reduction, 75%; range, 37%-100%) as determined by clinical measurement (with ultrasound confirmation in one lipoma) after an average of 2.2 treatments. Several lipomas fragmented or became softer in addition to decreasing in volume. Adverse effects, including transient burning, erythema, and local swelling, were associated with higher deoxycholate concentrations but resolved without intervention. There was no clear association between deoxycholate concentration and efficacy. CONCLUSIONS: Our clinical experience supports our laboratory investigations demonstrating that deoxycholate, rather than phosphatidylcholine, is the active ingredient in subcutaneously injected formulas used to treat adipose tissue. This small series suggests that low concentration deoxycholate may be a relatively safe and effective treatment for small collections of fat. However, controlled clinical trials will be necessary to substantiate these observations.

Adult↗

Active specific immunotherapy against occult brain metastasis.

We determined whether lyophilized High Five (H5) insect cells engineered to produce IFN-beta (H5BVIFN-beta) could induce systemic immunity against occult brain metastases. C3H/HeN mice were injected s.c. with syngeneic UV-2237M fibrosarcoma or K-1735M2 melanoma cells. Intralesional injection of 2 x 10(6) lyophilized H5BVIFN-beta cells produced complete regression of the s.c. tumors. Six weeks later, UV-2237M fibrosarcoma cells or K-1735M2 melanoma cells were injected into the internal carotid artery of naive or treated mice. UV-2237M brain metastases developed in naive mice or mice cured of K-1735M2 tumors but not in mice cured of UV-2237M tumors. Similarly, K-1735M2 brain metastases developed in naive mice or mice cured of UV-2237M fibrosarcomas but not in mice cured of K-1735M2 melanoma. In the next set of studies, mice were injected s.c. with UV-2237M fibrosarcoma cells. On day 7, UV-2237M fibrosarcoma cells or K-1735M2 cells were implanted into the internal carotid artery, and on day 10, the s.c. tumors were injected with lyophilized H5BVIFN-beta. Both the s.c. tumors and the occult brain metastases produced from carotid injections were eradicated in a tumor-specific manner. The regression of the brain metastases was abrogated by depletion of CD4(+) or CD8(+) cells from immunized mice. These results demonstrate that specific systemic immunity can be induced by lyophilized H5BVIFN-beta and that the resultant immune response can eliminate established brain metastasis.

Animals↗

Intramuscular beta-interferon treatment for severe vulvar vestibulitis.

Seven patients with vulvar vestibulitis associated with human papillomavirus (HPV) infection were treated with intramuscular (IM) injections of human beta-interferon. The IM route was chosen to avoid painful intralesional injections. Complete remission of symptoms was achieved in three patients who received 45 x 10(6) IU of beta-interferon; they remained asymptomatic for a duration of 6-18 months following treatment. Of the four patients who received only 30 x 10(6) IU, two had complete remission of dyspareunia, but in one it recurred after 18 months; one had some relief; and one did not respond. Two patients who did not show complete remission of the disease and the one with recurrence subsequently underwent perineoplasty. The IM treatment was well tolerated and resulted in a satisfactory response in a selected group of patients. There is evidence to suggest that a total dose of 45 x 10(6) IU is preferable to a dose of 30 x 10(6).

Adolescent↗

Treatment of basal cell carcinoma with intralesional interferon.

Eight patients with basal cell carcinomas were treated with recombinant alpha-2 interferon. Each patient had a biopsy-proved basal cell carcinoma of the nodular or superficial type that was injected intralesionally three times a week for 3 weeks (9 total injections) with 1.5 X 10(6) IU (0.15 ml) of alpha-2 interferon per injection (total dose, 13.5 X 10(6) IU). Excisional biopsy 2 months after completion of therapy revealed no evidence of basal cell carcinoma in any patient. Minimal side effects were observed. In these eight patients alpha-2 interferon was therefore an effective and safe modality of treatment. The encouraging results of this pilot study suggest that additional evaluation of interferon in the treatment of basal cell carcinoma is warranted.

Basal Cell Carcinoma↗

Intratumoral echo-guided injection of interleukin-2 and lymphokine-activated killer cells in hepatocellular carcinoma.

Interleukin-2 has proved to be effective for the intralesional treatment of tumors of the bladder. There are examples in literature of hepatocellular carcinoma (HCC) treatment with lymphokine-activated killer (LAK) cells infused in the hepatic artery. We decided to check the effects of echo-guided intralesional injection of these cells in this disease. We treated 5 patients with inoperable hepatocellular carcinoma, following cirrhosis; in 4 cases the mass had a diameter less than 3 cm (small HCC) while in the remaining case it measured 7 cm. Tumor size remained unchanged in 3 of the 4 small HCC, and increased only slightly in the other (over a period of 10 months). This would appear to indicate that treatment halted neoplasm growth or at least slowed it down. The echo pattern of the lesions changed, with a constant reduction in echogenicity. Finally, in multiple control biopsies, fibrosis, present in only one case before treatment, was found fairly constantly after treatment. There were no significant side effects, apart from slight water retention in one patient. On the basis of our preliminary results, we consider it worthwhile continuing this study to establish the most suitable IL-2 doses and analyze in more detail the modifications induced in the neoplasm.

Aged↗

Ablation of tumor cells in vivo by direct injection of HSV-thymidine kinase retroviral vector and ganciclovir therapy.

The introduction of therapeutic genes into proliferating tumor cells in vivo by direct intralesional injection of retroviral vectors can provide an effective and valuable approach for the treatment of a variety of solid tumor types. Efficient transduction of tumor cells in situ by direct injection was demonstrated using a retroviral vector containing the beta-galactosidase (beta-gal) gene. Ablation therapy in vivo was demonstrated using a retroviral vector containing the Herpes simplex virus thymidine kinase gene (HSV-TK) to deliver the TK gene into the murine colorectal tumor cell line CT26. Ablation of CT26 tumor cells in situ was achieved by directly injecting high-titer HSV-TK retroviral vector preparations into the site of tumor cell inoculation followed by intraperitoneal (i.p.) delivery of ganciclovir (GCV). This gene therapy strategy demonstrated a markedly lower rate of tumor progression, with several complete regressions, compared to animals in control groups. We also demonstrated that resistance to subsequent challenges with unmodified CT26 cells and an enhanced cellular immune response is associated with tumor regression in immunocompetent animals. Our results demonstrate the feasibility of direct in situ administration of HSV-TK retroviral vectors for the treatment of cancer and suggest that a cellular immune response may be elicited by this therapy.

Animals↗

[Sarcoidal granulomas following injections of botulic toxin A (Botox) for corrections of wrinkles].

BACKGROUND: The introduction of foreign material into the skin can lead to sarcoidal reactions. Such a reaction is reported, consecutive to injections of botulic toxin A (Botox). CASE REPORT: A 57-year-old woman, noticed the occurrence of frontal and glabellar nodules, 3 weeks after the injection of botulic toxin A (Botox), for the correction of wrinkles. Histopathological examination revealed a sarcoidal granuloma. Clinical and biological investigations were negative, ruling out the hypothesis of systemic sarcoidosis. The lesion could be reproduced experimentally by an intradermal injection of botulic toxin A on the volar aspect of the forearm. Corticosteroids per os associated with intralesional injections of triamcinolone acetonide were followed by a complete regression of the nodules. DISCUSSION: The occurrence of sarcoidal granulomas at the sites of injection of botulic toxin A (Botox(R)) has not been reported - so far - in the literature. Systemic sarcoidosis has been ruled out. The sarcoidal reaction has been reproduced experimentally by the intradermal injection of botulic toxin A, but not by saline. This leads to think that the sarcoidal reaction was provoked by antigenic stimulation, comparable to the Kveim reaction, and did not correspond to "scar sarcoidosis".

Botulinum Toxins, Type A↗

Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF.

Past studies in animal models with gene-transfected tumour cells have suggested that GM-CSF may have a role in immunotherapy of tumours as a result of the effects it has on antigen-presenting cells. The present (phase I) studies were carried out to examine whether intralesional injections of GM-CSF induce regression of subcutaneous metastases in patients with melanoma and influence lymphoid infiltrates in and around the metastases. Thirteen patients had 15-50 mg doses of GM-CSF injected into two subcutaneous metastases. In each case one metastasis received only five injections before excision whereas the other received weekly injections up to 6 months. Partial regression of injected and/or non-injected metastases was seen in three patients. The metastases from the responding patients that were treated with intralesional GM-CSF had marked increases and high absolute numbers of T cell infiltrates into the tumour, particularly of the CD4 T cell subset. There was an increase in IL-2R expression on the T cells and an increase in the number of Langerhans' cells infiltrating the tumours. The best predictors of clinical responses therefore appeared to be high relative increases and high absolute numbers of CD4+ T cells and Langerhans' cells within the treated tumour. These results provide support for further exploration of the role of GM-CSF in immunotherapy of human melanoma.

Adult↗