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Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Center experience in liver transplantation (LTX): management of dermal side effects caused by sirolimus.

INTRODUCTION: Sirolimus improves post transplant maintenance therapy in LTX. Dermal side effects causing pain and discomfort can limit patients' compliance. The package insert mentions such skin disorders as acne and rash. One case of sirolimus-induced leucocytoclastic vasculitis is reported in the literature. METHODS: From July 1998 to October 2003, Sirolimus was implemented in the immunosuppressive protocol in 23 out of 60 liver recipients. Sirolimus target levels are between 3 and <10 ng/dl. Combination with a calcineurinblocker and/or MMF (mycophenolate mofetil) depending on liver function and creatinine is standard. Weekly patient monitoring in the first month after discharge included physical examination, blood samples and immunosuppresant trough levels. Biopsies were taken from untypical efflorescences. RESULTS: Three patients with non-specific effloresces were reported: one with leucocytoclastic vasculitis and one with exfoliate forearm dermatitis required change of medication while one perivascular lymphocytic eosinophilic dermatitis subsided after dose reduction. In three cases of mouth ulcer, trough levels exceeded 10 ng/dl and in six patients acne diminished after dose reduction. Eighteen out of 23 patients are still receiving sirolimus. Reasons for removal from the study were incompliance and incompatibility. Two patients died. DISCUSSION: Immunosuppressants inevitably produce side effects in TX recipients. The positive management of troublesome side effects contributes importantly to compliance and patient survival.

Acne Vulgaris↗

Clinical and serological follow-up in dogs with visceral leishmaniosis treated with allopurinol and sodium stibogluconate.

Seven dogs with parasitologically proven clinical visceral leishmaniosis (Leishmania infantum infection) were treated with a combination of allopurinol and sodium stibogluconate. The dogs received first orally 15 mg/kg of allopurinol every 12 h until the clinical signs improved, in the following 1 month period allopurinol at same dose and subcutaneously 30 mg/kg of sodium stibogluconate combination were given daily and at the end of the combined treatment, allopurinol was continued alone at the same dose till the end of 8 months. During the treatment period, dogs were supported by additional proteins, vitamins, and minerals. A long acting insecticide (collar or drop) was also used in order to prevent further parasite transmission. Follow-up was maintained by clinical, clinicopathological evaluation, and parasitological examination of lymph node, serology using the indirect immunofluorescent antibody test (IFAT). Before treatment commenced, the most important clinical signs were exfoliative dermatitis, ulcerations, peripheral lymhadenopathy, pale mucous membranes, weight loss, and ocular lesions. Clinicopathological findings included commonly anaemia, hyperproteinaemia, hyperglobulinaemia and hypoalbuminaemia. Before the treatment, amastigotes were seen in six of the seven dogs by examination of lymph node aspiration, and IFAT-titers were positive in all dogs. At the end of 8 months treatment, remission of clinical signs, restoration to normal of clinicopathological abnormalities were noticed. Lymph node aspiration was performed on three out of the seven dogs at the end of the treatment because of the very small sizes of the lymph nodes, and no amastigotes were observed. Although the mean IFAT-titer of the dogs were significantly (P < 0.001) lower compared with pretreatment, IFAT-titers of dogs were still positive. No relapses occurred during treatment period and a 6-24-month duration after the end of therapy. Based on the above results, long-term use of allopurinol combined with sodium stibogluconate together with support treatment concluded to have enough therapeutic efficacies in the treatment of dogs with visceral leishmaniosis. Observations of the cases for possible relapses were still going on and insecticide application was carefully carrying on in order preventing a possible re-infection.

Allopurinol↗

Venomous bites to the external genitalia: an unusual cause of acute scrotum.

The acute scrotum generates a long list of differential diagnoses. An unusual etiology includes insect envenomation, which typically is an acute process with rapid onset of symptomatologies. Two patients with genital envenomation are reported. We review the reported cases at our institution with all types of bites and stings. Symptoms of pain and pruritus, and signs of ecchymosis and edema preceding exfoliating dermatitis were evident in both cases. Mild analgesics and antihistamines promoted resolution in each instance.

Acute Disease↗

Diphenylhydantoin-induced hypersensitivity reaction with interstitial nephritis.

A 10-year-old black girl had an episode of diphenylhydantoin(DPH)-induced exfoliative dermatitis, lymphadenopathy, hepatitis, peripheral eosinophilia, and transient renal failure. The findings of specific lymphocyte sensitization of DPH, a clinically typical delayed hypersensitivity reaction, multinucleated histiocytes in the renal interstitium, and negative renal immunofluorescence studies for immune reactants indicate that the child's renal injury was at least partially cell-mediated.

Autoantigens↗

Mobile genetic elements and bacterial toxinoses: the superantigen-encoding pathogenicity islands of Staphylococcus aureus.

It is a remarkable observation that virtually all bacterial toxins associated with specific clinical conditions (toxinoses) are encoded by mobile (and therefore variable) genetic elements. Remarkably, these rarely, if ever, carry determinants of antibiotic resistance. Examples are the toxins responsible for diphtheria, anthrax, tetanus, botulism, cholera, toxic shock, scarlet fever, exfoliative dermatitis, food poisoning, travelers' diarrhea, shigella dysentery, necrotizing pneumonia, and others. A recently discovered example of this phenomenon is the family of related staphylococcal pathogenicity islands encoding superantigens (SAgs). These are 15-20kb elements that occupy constant positions in the chromosomes of toxigenic strains, and are characterized by certain phage-related features, namely genes encoding integrases, helicases, and terminases, and the presence of flanking direct repeats. The prototype, SaPI1 of Staphylococcus aureus, encodes TSST-1 plus two newly described SAgs, SEK and SEL. Other members of the family encode enterotoxins B (SaPI3) and C (SaPI4), plus at least two other SAgs each. SaPI1 and SaPI2, also encoding TSST-1, are excised and induced to replicate by certain staphylococcal phages, and are then encapsidated at high efficiency into phage-like infectious particles with heads about 1/3 the size of the helper phage heads, commensurate with the sizes of the respective genomes. This results in transfer frequencies of the order of 10(8)/ml, and is presumably responsible for the spread of these elements as well as for their acquisition in the first place. In the absence of a helper phage, these two islands are highly stable; neither excision, loss, or transfer occurs at detectable frequency. Several general implications of this phenomenon will be discussed. One is that the determinants of these toxins have been imported from other species and therefore are not components of the basic genome of the extant producing organisms. This raises the question of the biological (adaptive?) roles of these toxins. Another is that the toxin-carrying units can spread among different (though probably related) species. An interesting question is that of the biological basis for the separation of toxin and resistance determinants.

Animals↗

[Iatrogenic acrodermatitis enteropathica-like syndrome in leucinosis].

INTRODUCTION: Leucinosis (maple syrup urine disease) is a metabolic disorder caused by an enzymatic deficiency involved in the degradative pathways of the three branched-chain amino acids. We report an observation of acrodermatitis enteropathica-like syndrome induced by essential amino acid deficiency in a child with leucinosis. CASE REPORT: A child with leucinosis was referred to our hospital for exfoliative dermatitis of the perioral and anogenital regions associated with diarrhea and pancytopenia. The diagnosis of iatrogenic acrodermatitis enteropathica-like syndrome was confirmed after screening showing isoleucine deficiency. Rapid response was observed after adequate isoleucine supplementation. DISCUSSION: The acrodermatitis enteropathica-like eruption in our patient was due to an iatrogenic amino acid nutritional imbalance. Our observation underlines the risk of using a branched-chain amino acid-free formula without adequate supplementation of deficient amino acids. In addition, dietary insufficiency of isoleucine, associated with the treatment of organic aciduria should be added to the causes of acrodermatitis enteropathica-like syndrome.

Acrodermatitis↗

A randomised, blinded, placebo-controlled clinical trial with allopurinol in canine leishmaniosis.

A total of 45 non-uremic dogs, with clinical signs indicating leishmaniosis, entered the study. Diagnosis was confirmed by indirect immunofluorescence assay (IFA) on serum and polymerase chain reaction (PCR) on bone marrow samples. The dogs were randomly allocated into Group A (n=37) that received allopurinol (10mg/kg B.W., per os, twice daily) for 4 consecutive months, and Group B (n=8) that were placebo-treated. Clinical signs were scored just before and at monthly intervals throughout the study period, in a blinded and independent fashion. Complete blood count, serum biochemistry profile, urinalysis, lymph node and bone marrow parasitology, IFA and enzyme-linked immunosorbent assay (ELISA) serology and bone marrow PCR were carried out at the beginning and at the end of the trial. A total of three Group A and one Group B dogs died of end stage kidney disease that developed during the trial. In Group A animals that endured the trial there was a significant improvement in the general body condition, conjunctivitis, peripheral lymphadenopathy, splenomegaly, masticatory muscle atrophy, ulcerative stomatitis, epistaxis, exfoliative dermatitis, cutaneous ulcerations, blepharitis and nasodigital hyperkeratosis. The same observation was made for anemia, lymphopenia, hyperproteinemia, hyperglobulinemia, hyperphosphatemia, increased alkaline phosphatase activity and the low albumin/globulin ratio. By contrast, no improvement of any kind was seen in Group B dogs. Lymph node and bone marrow parasite numbers were significantly decreased in Group A animals. In Group B, that occurred only in the lymph nodes. Apart from remission of clinical signs and restoration to normal of clinicopathological abnormalities, allopurinol did not eliminate Leishmania organisms, as the PCR result on bone marrow was still positive in all the dogs that finished the trial.

Allopurinol↗

Desensitization to imatinib in patients with leukemia.

BACKGROUND: Imatinib mesylate is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and hypereosinophilic syndrome. Imatinib is associated with a variety of adverse cutaneous reactions, including urticaria, maculopapular exanthem, generalized exanthematous pustulosis, exfoliative dermatitis, and Stevens-Johnson syndrome. OBJECTIVE: To evaluate the safety and efficacy of oral desensitization by administering incremental dosages of imatinib mesylate to patients with leukemia who have had rashes associated with prior exposure. METHODS: Ten patients with leukemia and imatinib-associated recurrent rash underwent a 4-hour outpatient oral desensitization procedure. Beginning with 10 ng, we administered oral imatinib elixir in increasing dosages every 15 minutes. Patient outcomes were monitored by a return clinic visit and by telephone follow-up for a median of approximately 3 years. RESULTS: No episodes of anaphylaxis or serious adverse effects occurred during or immediately after desensitization. Four patients (all with urticaria) had no recurrence of rash after desensitization, and 4 had recurrent rash that resolved after temporary glucocorticosteroid and antihistamine administration. Two patients developed a recurrent rash 5 hours and several days after the procedure and were unable to resume therapy. CONCLUSION: This oral desensitization protocol appears to help some leukemic patients with recurrent rash tolerate imatinib mesylate, thus permitting continuation of this life-prolonging therapy. These findings suggest that some adverse cutaneous reactions to imatinib may be due to a hypersensitivity mechanism rather than a pharmacologic effect.

Administration, Oral↗

Drug allergy in a general hospital: Results of a novel prospective inpatient reporting system.

BACKGROUND: Drug allergies are unpredictable immunologic adverse effects, usually immunoglobulin E-mediated immediate hypersensitivity or T-cell-mediated delayed hypersensitivity. There is a paucity of accurate prospective data on drug allergy in hospitalized patients. OBJECTIVE: To describe the incidence, manifestations, and outcome of drug allergy in hospitalized patients. METHODS: All newly developed cases, confirmed or suspected, of drug allergy in inpatients using a network-based electronic notification system. Each notification was evaluated by an allergist-immunologist during the same admission. RESULTS: From December 1, 1997 to December 31, 1999, 366 cases were reported from a total of 90,910 admissions. After review, only 210 cases were verified to have drug allergy. Antimicrobials and anti-epileptic drugs comprised 75% of the drug allergies reported. Cutaneous eruptions were the most common clinical presentation (95.7%), with maculopapular rash being the most common morphology. Systemic manifestations occurred in 30%, of which hepatitis was the most common. Serious adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized exfoliative dermatitis occurred in 11 (5.2%) patients. There was no case of anaphylaxis attributable to drug allergy. After adjusting for underreporting, the incidence of drug allergy in our hospitalized patients was 4.20 per 1,000 (95% confidence interval [CI] 2.93 to 5.46), drug allergy developing during the course of inpatient treatment 2.07 per 1,000 (95% CI 1.45 to 2.69), and mortality attributable to drug allergy 0.09 per 1,000 (95% CI 0.06 to 0.12) hospitalizations. CONCLUSIONS: A network-based, allergist-immunologist-verified, surveillance system enables more accurate labeling of drug allergy. The incidence of drug allergy and mortality in hospitalized patients is low.

Adolescent↗

Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS).

Since the first description by Saltzstein in 1959, the denomination of drug-induced pseudolymphoma was used to describe two cutaneous adverse drug reactions with a histological picture mimicking malignant lymphoma. On the basis of clinical presentation, this term includes two different patterns: (1) hypersensitivity syndrome which begins acutely in the first 2 months after the initiation of the drug and associates fever, a severe skin disease with characteristic infiltrated papules and facial edema or an exfoliative dermatitis, lymphadenopathy, hematologic abnormalities (hypereosinophilia, atypical lymphocytes) and organ involvement such as hepatitis, carditis, interstitial nephritis, or interstitial pneumonitis. The cutaneous histological pattern shows a lymphocytic infiltrate, sometimes mimicking a cutaneous lymphoma, and the mortality rate is about 10%. When organ involvement exists, corticosteroids are often prescribed with dramatic improvement. Relapses may occur. (2) drug-induced pseudolymphoma which has a more insidious beginning with nodules and infiltrated plaques appearing several weeks after the beginning of the drug without constitutional symptoms. A pseudolymphoma pattern is seen on cutaneous histological slides. Complete improvement is usual after drug withdrawal, but a delayed lymphoma is possible. To decrease the ambiguity of the denomination of hypersensitivity syndrome, we propose the term of DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).

Anticonvulsants↗

Disseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus.

BACKGROUND: In the pre-AIDS era disseminated histoplasmosis was rare and the cutaneous manifestations thereof were reported infrequently. A range of unusual clinical manifestations of disseminated cutaneous histoplasmosis (DCH) in AIDS patients has been documented, but the cutaneous histopathological descriptions are short and incomplete. In addition, the histopathological spectrum of AIDS-associated DCH is poorly recognized. METHODS: This is a prospective 32-month study of all HIV positive patients diagnosed with histoplasmosis in the Departments of Anatomical Pathology and Dermatology, Nelson R. Mandela School of Medicine and King Edward VIII Hospital, Durban, South Africa. Clinical distribution and morphology of the individual skin lesions and CD4+ lymphocyte counts in the peripheral blood were analysed in relation to the histopathological features of biopsied lesional tissue. Ultrastructural examination of tissue retrieved from the wax blocks of three cases that exhibited dermal karyorrhexis and collagen necrosis was undertaken. Fungal culture of lesional skin tissue was undertaken in all patients. RESULTS: Twenty-one biopsies of papules (7), nodules (4), plaques (5), erythema multiforme-like lesions (2), vasculitic lesions (2) and exfoliative dermatitis (1) from 14 patients were examined. Of four biopsies (CD4 range: 120-128 cells/mm3) one and three demonstrated necrotizing and non-necrotizing granulomatous inflammation with a paucity of intrahistiocytic microorganisms. Seven biopsies (CD4 range: 2-56 cells/mm3) demonstrated diffuse dermal and intravascular accumulation of histiocytes densely parasitized by Histoplasma capsulatum var. capsulatum. Vasculitis, karyorrhexis or collagen necrosis was not present. Ten biopsies (CD4 range: 2-72 cells/mm3) demonstrated diffuse dermal karyorrhexis, collagen necrosis and interstitial, extracellular H. capsulatum var. capsulatum. Histiocytic disintegration and nuclear fragmentation and release of intact microorganisms and intact and ruptured lysosomes were identified ultrastructurally. Leucocytoclastic vasculitis was present in two biopsies of vasculitic clinical morphology. Microbiological culture confirmed histoplasmosis in all cases. Three patients died before treatment was commenced. Two patients died within the first two days of induction of therapy. Nine patients demonstrated dramatic healing of the cutaneous lesions. CONCLUSIONS: Despite the clinicopathological spectrum of DCH and the attendant host immunocompromise, timely and appropriate treatment of DCH may be lifesaving and allows rapid healing of skin lesions. A high index of clinical suspicion and skin biopsies and culture are crucial for accurate diagnosis.

Adult↗

Childhood pemphigus.

BACKGROUND: Five children with pemphigus are reported: three with pemphigus vulgaris, one with pemphigus vegetans, and one with pemphigus foliaceus. Only one case of juvenile pemphigus vegetans has been published in the literature. MATERIALS AND METHODS: All three patients with pemphigus vulgaris were treated with oral corticosteroid; in two cases, azathioprine was added for steroid-sparing effect. The patient with pemphigus vegetans had a clinical presentation resembling pemphigus vulgaris, but the lesions in the perianal area healed as hypertrophic granulation tissue. He was treated with oral corticosteroid, azathioprine, and intralesional corticosteroid. The patient with pemphigus foliaceus presented with exfoliative dermatitis, and was treated with oral corticosteroid; methotrexate was added later for steroid-sparing purposes RESULTS: The patients were followed up for 1-4 years; the prognosis of childhood pemphigus is good. CONCLUSIONS: Long-term follow-up is needed to detect flaring of the disease and the side-effects of immunosuppressive drugs.

Adolescent↗

Skin allograft in the treatment of toxic epidermal necrolysis (TEN).

BACKGROUND: TEN is a severe form of exfoliative dermatitis. Its course is acute and its outcome fatal in 40% of cases. Wound cover to prevent fluid/protein loss and infections and to control pain, is the first step, as for burns. Skin allograft can be successfully used for this purpose. OBJECTIVE: We report two cases of TEN with de-epithelialization of 50 and 70% of the total body surface area. The patients were given support therapy and treated with human glycerol-preserved skin allografts for wound cover. METHODS: Patients were grafted with glycerol-preserved donor skin, obtained from a skin bank. RESULTS: Re-epithelization of treated areas was complete in 8 days; pain relief was obtained soon after the graft. CONCLUSIONS: Glycerol-preserved skin allograft is an effective treatment in extensive skin loss, for its barrier and analgesic effect. Quality standards of this product ensure safety and simplicity of use at limited cost.

Aged↗

Transfusion-associated graft-versus-host disease: report of an occurrence following the administration of irradiated blood.

Patients who are heavily immunosuppressed, such as those undergoing intensive anti-cancer chemotherapy, are at risk for development of accidental engraftment and graft-versus-host disease when they undergo transfusion with cellular blood components, a condition known as transfusion-associated graft-versus-host disease (TA-GVHD). To prevent this complication, it is routine to irradiate such blood components prior to their transfusion, although the minimum irradiation dose required is uncertain. The development of probable TA-GVHD is reported in a 10-year-old child following transfusions of platelets and packed red cells that had been irradiated at a nominal dose of 15 Gy. The transfusions were given during treatment for relapse of acute myeloid leukemia. Although the child developed complications including exfoliative dermatitis, delayed bone marrow regeneration, renal failure requiring dialysis, and respiratory failure requiring assisted respiration, she recovered from the episode of TA-GVHD after treatment with high-dose methylprednisolone and antithymocyte globulin. However, her leukemia relapsed, and she died. This experience suggests that the irradiation of cellular blood components at a nominal dose of 15 Gy prior to their transfusion to heavily immunosuppressed patients may be insufficient to prevent TA-GVHD.

Blood↗