Injection-site granulomas resulting from the administration of both leuprorelin acetate and goserelin acetate for the treatment of prostatic cancer.

Although injection-site granulomas caused by leuprorelin acetate have been reported, there have been no reports of granulomas caused by both leuprorelin acetate and goserelin acetate. An 81-year-old man presented with subcutaneous nodules of the abdominal wall and upper arm, where 11.25 mg of leuprorelin acetate had been injected for the treatment of prostate cancer. Because of these nodules, treatment was changed to goserelin acetate. Nevertheless, he presented with another subcutaneous nodule at the injection site. Histological examination showed that these nodules consisted of numerous giant cells that were CD3-positive T lymphocytes and CD68-positive histiocytes associated with granulomatous changes. The granulomas had likely been caused by delayed-type hypersensitivity to leuprorelin acetate injection. The granuloma that formed after goserelin acetate injection might thus have developed owing to the immunogenicity of the previous leuprorelin acetate injections. The patient underwent surgical castration. The present case suggests that both leuprorelin acetate and goserelin acetate can cause injection-site disorders.     

A comparison of three gonadotrophin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study

The use of gonadotrophin-releasing hormone analogues (GnRHa) has resulted in improved pregnancy rates in in-vitro fertilization (IVF) treatment cycles. Traditionally, short-acting analogues have been employed because of concerns over long-acting depot preparations causing profound suppression and luteal phase defects adversely affecting pregnancy and miscarriage rates. We randomized 60 IVF patients to receive a short-acting GnRHa, nafarelin or buserelin, or to receive a depot formulation, leuprorelin, all commenced in the early follicular phase and compared their effects on hormonal suppression and clinical outcome. We found that on day 15 of administration there was a significant difference in the suppression of oestradiol from initial concentrations, when patients on buserelin were compared with patients on nafarelin or leuprorelin (54 versus 72 and 65%; P < 0.05) and also in the number of patients satisfactorily suppressed, (80 versus 90 and 90%; P < 0.05), though there were no differences between the analogues by day 21. Similarly there was no difference in hormonal suppression during the stimulation phase or in implantation, pregnancy or miscarriage rates in comparing the three agonists. We conclude that with nafarelin and leuprorelin, stimulation with gonadotrophins may begin after 2 weeks of suppression and that long-acting GnRHa are as effective as short-acting analogues with no detrimental effects on the luteal phase.     

Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard?/Depo-Eligard?) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study

Introduction

The 1-, 3- and 6- month biodegradable polymer matrix depot formulations of leuprorelin acetate (Eligard^®/Depo-Eligard^®, Astellas Pharma Inc/BV) were shown to reduce testosterone and prostate-specific antigen levels and to be well tolerated in patients with advanced prostate cancer in several clinical trials. This study aimed at evaluating the efficacy, safety and tolerability of the 1- and 3-month leuprorelin acetate depot formulations in daily clinical practice.

Material and methods

A prospective, open-label, non-interventional, phase IV study (MANTA) was conducted in 243 Belgian prostate cancer patients who had been prescribed the 1-month (7.5 mg) or 3-month (22.5 mg) leuprorelin acetate depot formulation. Patients were followed for at least 3 months.

Results

Median serum prostate-specific antigen levels were reduced by 95% from 12.0 ng/ml at baseline to 0.60 ng/ml after a median follow-up time of 132 days, while median testosterone levels were reduced by 94% from 360 ng/dl to 20 ng/dl. Partial or complete treatment response was observed in 83% of patients at the final visit (according to the physician''s assessment). Ninety-two patients (37.86%) experienced treatment-emergent adverse events, with injection site-related reactions, hot flushes and tumor flare being the most common ones. Overall safety and tolerability of the leuprorelin acetate depot formulation were rated as good or excellent by 90% of physicians.

Conclusions

These data are consistent with efficacy and tolerability results from clinical trials. They confirm that the 1- and 3-month leuprorelin acetate depot formulations are well tolerated and reliably lower serum prostate-specific antigen and testosterone levels in routine clinical practice.     

Aluminium-induced granulomas after inaccurate intradermal hyposensitization injections of aluminium-adsorbed depot preparations

BACKGROUND: The development of persistent subcutaneous nodules at the injection sites of aluminium-adsorbed hyposensitization solutions is rare. These nodules have been interpreted as a delayed, granulomatous hypersensitivity reaction to aluminium. We report for the first time a case of persistent intradermal granulomas that developed at the sites of inaccurate intradermal, instead of subcutaneous, hyposensitization injections. METHODS: An intradermal nodule was excised and processed for histopathology, scanning electron microscopy, and X-ray microanalysis. Intradermal and patch tests with aluminium hydroxide were performed. RESULTS: Histologically, the nodule presented a pattern of granulomatous inflammatory reaction surrounding foci of necrotic tissue. Scanning electron microscopy and X-ray microanalysis revealed deposits of aluminium within the granulomas. Patch tests with aluminium hydroxide were negative, and intradermal tests caused persistent intradermal granulomas. Subsequent hyposensitization therapy in our department with the usual subcutaneous injections of aluminium-adsorbed allergen extracts was well tolerated by the patient. CONCLUSIONS: Local toxic effects of aluminium may be crucial in the development of persistent intradermal injection-site granulomas. Such intradermal nodules may develop even if the subcutaneous route is well tolerated. We conclude that inaccurate intradermal injections of aluminium-containing solutions have to be strictly avoided.     

Is High-Dose Leuprorelin Acetate Effective and Safe in Asian Men with Prostate Cancer? An Open-Label,Non-Comparative,Multi-Center Clinical Trial

Purpose

Leuprorelin is a well known luteinizing hormone releasing hormone agonist. However, there are insufficient data on the efficacy and safety of high dose leuprorelin acetate, especially in Asian patients with prostate cancer. We aimed to investigate the safety and efficacy of leuprorelin acetate 22.5 mg administered at three-month intervals in patients with prostate cancer.

Materials and Methods

In an open, prospective clinical trial enrolling 47 patients, we aimed to assess the efficacy and safety of leuprorelin acetate 22.5 mg in treating patients with histologically confirmed prostate cancer. The primary objective of this study was to evaluate the efficacy of the leuprorelin acetate 22.5 mg in producing and maintaining castration levels of testosterone over a 6-month follow-up period and to determine its safety profile.

Results

All 42 patients achieved serum testosterone levels within the castration range by 4 weeks. A breakthrough response was observed in one of 36 patients by 8 weeks. However, this patient was medically castrated by 12 weeks. There were no significant prostate-specific antigen (PSA) or testosterone changes according to clinical stage or body mass index. Twenty adverse events (AEs) in 15 of 42 patients (35.7%) were observed during this study. The most common AEs were hot flushes (n=4, 20.0%) with mild intensity, pain (n=2, 10.0%), and infection (n=2, 10.0%). No patient withdrew from the study due to AEs.

Conclusion

Leuprorelin acetate 22.5 mg was shown to be effective and safe in Asian patients with prostate cancer, even though sexual function decreased.     

History of clinical studies on hypothalamic hormone analogs in Mexico

Early clinical trials in Mexico with analogs of luteinizing hormone-releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Extensive clinical studies were carried out at IMSS with agonists of LH-RH, both in men and woman. All subjects responded to LH-RH agonists with a release of LH and FSH, but repeated administration of these analogs, initially aimed at stimulation of fertility (thought to stimulate fertility), was later shown to result in inhibition due to desensitization of pituitary gland and downregulation of LH-RH receptors. Various clinical investigations with LH-RH antagonists were also carried out. This included the first demonstration that LH-RHantagonists can suppress LH and FSH and sex steroid secretion in men and women. Various studies in Mexico with early LH-RH antagonists aimed at the development of new contraceptive methods were reviewed. Modern LH-RH antagonist Cetrorelix was shown to be effective in men and women and useful in treatment of uterine leiomyomas and benign prostatic hyperplasia. Major oncological studies were also carried out with agonist D-Trp6-LH-RH and antagonist Cetrorelix in men with prostate cancer, which demonstrated therapeutic efficacy of both types of analogs. Some endocrine studies with early analogs of somatostatin were also cited and a clinical trial with somatostatin analog vapreotide in patients with relapsed prostate cancer was reviewed. All these studies played a major role in introducing analogs of hypothalamic-releasing hormones into clinical medicine.     

Post-vaccination granuloma due to aluminium hydroxide

Post-vaccination granulomas a well-known reaction due to aluminium adsorbed vaccines. We report three cases of children who developed subcutaneous nodules at the site of a previous injection of Tetracoq*vaccine (tetanus, diphtheria, Bordetella pertussis, poliovirus). Histologically, the lesions were characterized by a necrotizing granulomatous reaction with eosinophilic crystalline material. This material stained positively with the solochrome cyanine stain and was pink-purple. This aluminium stain enabled diagnosis of post-immunization injection-site reaction due to aluminium.     

Immunological castration by a totally synthetic vaccine: modification of biological properties of LH-RH after conjugation to adjuvant-active muramyl peptide

Recently, we demonstrated that immunological castration of male mice can be obtained by immunization with Luteinizing Hormone-Releasing Hormone (LH-RH) directly coupled to NAcMur-L-Ala-D-isoGln-L-Lys (MDP-Lys) without carrier and Freund's Complete Adjuvant (FCA) but in the presence of Polyvinyl-Pyrrolidone (PVP). In the present report, we have observed that: (a) immunization by the conjugate, LH-RH-MDP-Lys, was very effective even in absence of PVP, and this conjugate was more active than other conjugates containing MDP coupled to LH-RH fragments; (b) a strong secondary response could be observed by the administration of free LH-RH suggesting that the endogenous secretion of LH-RH might elicit a boosting effect; (c) administration of MDP-Lys coupled to LH-RH decreased the pyrogenicity of the glycopeptide; (d) such a conjugation also decreased the hormonal activity of the antigen although it enhanced its immunogenicity. These results show that a conjugate (2000 dalton) of a decapeptide hormone with a synthetic adjuvant glycopeptide can induce immunological castration in mice after administration in saline. The immunopharmacological properties of the conjugate and its conditions of efficacy suggest that such an approach could find clinical application.     

Spotlight on glatiramer acetate in relapsing-remitting multiple sclerosis

Glatiramer acetate (Copaxone) is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS). In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5% and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS. The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions. In conclusion, glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.     

The small blue cell dilemma associated with tamoxifen therapy

CONTEXT: Several endometrial diseases, such as endometrial hyperplasia, endometrial carcinoma, and endometrial polyps, have been reported to be associated with tamoxifen administration. We recently observed a high incidence of distinctive small blue cells in Papanicolaou tests of women who had received tamoxifen treatment for breast carcinoma. OBJECTIVES: To define the characteristics of these small blue cells, to identify the patient population in which they are found, and to determine the clinical significance and possible etiology of these findings. DESIGN: A total of 154 Papanicolaou tests from 60 patients with a clinical history of tamoxifen therapy were reviewed retrospectively. RESULTS: Small blue cells were found in 40% of Papanicolaou tests from patients who received tamoxifen therapy. Patients with small blue cells in their Papanicolaou tests were an average of 9 years older at the time tamoxifen therapy was initiated than those without. Among the available follow-up surgical biopsies, no malignant diagnoses were made. CONCLUSIONS: We conclude that these distinctive small blue cells are found more frequently in older patients and most probably represent proliferative reserve cells of cervical/vaginal epithelium resulting from the estrogenic agonist effect of tamoxifen. More importantly, they are nonneoplastic in nature.     

The granuloma in Crohn's disease. A bioptical study

Serial sections of 1434 colonic and rectal biopsies of 347 patients with Crohn's disease were performed. The relationship between the incidence of granulomas and the inflammatory alterations of the mucosa and some clinical parameters was studied. The presence of granulomas depends on the severity of inflammatory alterations and not on the site of the biopsy. The number of granulomas per mm3 increases from caecum to rectum. The incidence of granulomas decreases with age, duration of illness and under a conservative therapy. If several biopsies, taken at the same or at different times, are studied, granulomas can be found in 40-50% of these patients.     

Invasive carcinoma of the breast with granulomatous response

Three patients are described who had invasive ductal carcinoma associated with noncaseating epithelioid granulomas. Multinucleated giant cells, predominantly of Langhans' type, were present in the granulomas. The granulomas were restricted to the carcinoma, and no granulomatous response was evident in regional lymph nodes. None of the patients had clinical evidence of systemic granulomatous disease, although one patient subsequently was found to have hepatic portal granulomas. This uncommon tissue response to neoplasm is distinct from carcinomas with osteoclast-like multinucleated giant cells. Similarly, the process differs from the granulomas presenting in axillary lymph nodes that drain a carcinoma.     

Policies and procedures related to weak D phenotype testing and Rh immune globulin administration. Results from supplementary questions to the Comprehensive Transfusion Medicine Survey of the College of American Pathologists

OBJECTIVE: To determine and evaluate policies and procedures related to weak D phenotype testing and terminology and the administration of Rh immune globulin in selected clinical situations. Design, Setting, and Participants.-Institutions participating in the College of American Pathologists 1999 J-A Comprehensive Transfusion Medicine Survey program were asked to respond to a series of supplementary questions related to weak D phenotype testing and Rh immune globulin administration. More than 3500 institutions and transfusion services participated. RESULTS: Most supplementary questions elicited more than 3000 responses. Despite no clinical or regulatory mandate, 58. 2% of transfusion services routinely perform an antiglobulin test for the weak D phenotype in patients who test negative with anti-D reagents. Significant differences were found concerning the transfusion of blood components to patients with the weak D phenotype and the administration of Rh immune globulin to these individuals. At least one patient with the weak D phenotype with anti-D alloantibody formation was observed during a 12-month period by 31.8% of transfusion services. CONCLUSIONS: Significant variability concerning policies and procedures related to weak D typing and terminology was found in this survey. Transfusion of blood components to patients with the weak D phenotype and the administration of Rh immune globulin also demonstrated variations. Anti-D alloantibody formation by patients with the weak D phenotype may not be as rare as previously thought. Additional study related to the clinical significance of these results is warranted.     

Acute mediastinitis,mediastinal granuloma,and chronic fibrosing mediastinitis: A review

Acute mediastinitis is a rare infection that carries high morbidity and mortality. They are complications seen most often with deep sternal wound infections from surgeries with median sternotomies, oropharyngeal and odontogenic infections and esophageal perforations. These conditions should be promptly recognized and treated. Mediastinal granulomas are focal, mass-like lesions commonly resulting from prior granulomatous infections. They are regarded as benign, self-resolving lesions however can cause complications by compression of adjacent mediastinal structures. Chronic fibrosing mediastinitis is a rare, diffuse fibroinflammatory process most often seen with granulomatous infections and carries a worse prognosis than mediastinal granulomas especially when adjacent mediastinal structures are compromised. In this review, we discuss the epidemiology, etiology, clinical presentation, treatment and prognosis of acute mediastinitis, mediastinal granulomas, and chronic fibrosing mediastinitis.     

A Case of Mental Retardation with Paraphilia Treated with Depot Leuprorelin

Paraphilia is a psychiatric disease that has been difficult to cure. However, recently developed therapeutic methods hold promise. The patient was a 20-yr-old male with chief complaints of continuous masturbation, genital exposure, and aggressive behavior that started 2 yr ago. We administered leuprorelin 3.6 mg intramuscular injection per month, a depot gonadotrophin-releasing hormone analogue, to this patient who a severe mentally retardation with paraphilia. The clinical global impression (CGI)-severity, CGI-improvement and aberrant behavior checklist were performed. After one month, we observed significant improvement in symptoms, such as decreases of abnormal sexual behavior and sexual desire. The GnRH analogues are suggested to be used as an alternative or supplementary therapeutic method for sexual offenders after clinical studies.

Graphical Abstract

相似文献   

Endoscopic and bioptic study of the upper gastrointestinal tract in Crohn's disease patients

In the present study, virtually all of 225 patients suffering from Crohn's disease of the lower gastrointestinal tract (small and/or large bowel) were subjected to endoscopic examination of the upper gastrointestinal tract (esophagus, stomach, duodenum); while histologic examination of the upper gastrointestinal tract was performed in a portion of the patients (54 initial esophageal, 221 initial gastric and 210 initial duodenal examinations). Statistical evaluation of the findings from the upper gastrointestinal tract revealed that: Endoscopic lesions were observed in the esophagus of 15%, the stomach of 49%, and the duodenum of 34% of the 225 Crohn's disease patients. Of the 54 patients from which esophageal biopsies were taken, 31 (57%) revealed histopathologic alterations. Of the 221 patients from which gastric biopsies were obtained, 60% revealed histopathologic alterations; the rate was 53% in the 210 patients from which duodenal biopsies were taken. Calculated from the present data, noncaseating granulomas, i.e., Crohn's disease, were present only in the stomach of 29.4% of the patients, only in the duodenum in 3.4% of patients, and in both the stomach and duodenum in 4.9% of patients. Gastric granulomas were confined to the region of the stomach body and fundus in 3.4% of the patients from which gastric biopsies were obtained and to the antrum in 15.6% of the respective patients. Both gastric regions were involved in 8.3% of the respective patients. The incidence of gastric granulomas was significantly increased in young patients, patients with enterocolic manifestations of Crohn's disease, and those with brief duration of disease. Patient sex or previous drug therapy had no effect on the incidence of granulomas. The most frequent endoscopic findings in the stomach of patients with Crohn's disease were mucosal edema, mucosal redness, and acute or chronic erosions. Only chronic erosions were of significant predictive value for the presence of granulomas, i.e., diagnosis of Crohn's disease. The most frequent endoscopic lesion in the duodenum was mucosal redness, followed by mucosal edema and aphthous lesions. Ulcers, stenosis, and mucosal redness had significant predictive values for the presence of granulomas.     

The pathologic spectrum of gastrointestinal and hepatic histoplasmosis

We characterized the pathologic spectrum of lesions in gastrointestinal and hepatic histoplasmosis by studying cases of disseminated disease in immunocompromised and immunocompetent patients from endemic and nonendemic areas. We evaluated 56 specimens from 52 patients with H&E and silver stains. Of these patients, 43% presented with gastrointestinal rather than pulmonary symptoms. Thirty-one percent had gastrointestinal lesions, 10% had liver lesions, and 43% had both. Gross gastrointestinal features included ulcers (49% of patients), nodules (21%), hemorrhage (13%), obstructive masses (6%) and normal mucosa (23%). Microscopic gastrointestinal findings included diffuse lymphohistiocytic infiltration (83%), ulceration (45%), lymphohistiocytic nodules (25%), or minimal inflammatory reaction (15%) but only rare well-formed granulomas (8.5%). The most common hepatic finding was portal lymphohistiocytic inflammation; discrete hepatic granulomas were seen in less than 20% of involved livers. The pathologist must be aware of the broad range of gastrointestinal and hepatic lesions produced by histoplasmosis and, in particular, that well-formed granulomas are rare. Given the appropriate clinical context, histoplasmosis should be considered in both immunocompetent and immunocompromised patients, regardless of pulmonary symptoms, in nonendemic as well as endemic areas.     

A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts

Cytomegalovirus is a major viral pathogen in patients who undergo renal transplantation, and cytomegalovirus disease is difficult to treat. We therefore conducted a randomized, placebo-controlled, double-blind trial of acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts from cadavers. Acyclovir was given orally in doses of 800 to 3200 mg per day, according to the patients' estimated level of renal function. Patients took the first dose of either acyclovir or placebo six hours before transplantation and continued to take the assigned medication for 12 weeks. Of 118 patients enrolled in the study, 104 completed at least 30 days on the study medication and were included in our analysis of the results. During the first year after transplantation, 4 of 53 patients (7.5 percent) in the acyclovir group had symptomatic cytomegalovirus disease, as compared with 15 of 51 (29 percent) in the placebo group (P = 0.002). There was a single case of cytomegalovirus pneumonia in the acyclovir group, as compared with nine in the placebo group. The greatest prophylactic benefit of acyclovir was observed among seronegative patients who had received a kidney from a seropositive donor; only one of six such patients in the acyclovir group had cytomegalovirus disease, as compared with all seven in the placebo group. Acyclovir decreased the incidence of documented cytomegalovirus infection (with or without symptomatic disease) to 36 percent from 61 percent among the patients who received the placebo (P = 0.011). Among the patients who received acyclovir, the rates of recovery of virus from the blood and urine were significantly reduced, but the rate of viral shedding from the pharynx was not significantly different from that in the placebo group. There were no differences between the groups in the frequency of adverse events or in the rate of survival of either grafts or patients. We conclude that the oral administration of acyclovir, beginning before the transplantation of a renal allograft from a cadaver, reduces the rate of cytomegalovirus infection and disease without affecting the survival rate of either grafts or patients.     

Wegener's granulomatosis masquerading as unilateral sinusitis

Wegener's Granulomatosis (WG) is a rare, multi-system disease of unknown aetiology. The disease is characterised by necrotizing granulomas and vasculitis of the upper and lower respiratory tracts and kidneys. The sinonasal region may be the first area to manifest this systemic condition. If the disease is diagnosed early and treated appropriately, involvement of the lungs and kidneys may be averted. Left untreated, the disease may prove rapidly fatal. A low threshold of clinical suspicion must be maintained. We report a case, of a middle aged patient who presented with unilateral sinusitis secondary to a large obstructive nasal mass. Anti neutrophil cytoplasmic antibody (ANCA) titres helped confirm the diagnosis of WG. Unilateral sinusitis with a nasal mass, is a very unusual presentation of WG, and emphasises the importance of a low threshold of suspicion for patients presenting with atypical sinonasal symptoms.