Idiopathic granulomatous mastitis: A diagnostic and therapeutic challenge.

BACKGROUND: Idiopathic granulomatous mastitis is a rare benign breast disease of women of reproductive age. It usually presents as a painful mass. Since the etiology is unclear, directed diagnosis and management is lacking. METHODS: This is a retrospective chart review of 14 patients, over twelve years (2004-2016), identified through query of pathology findings. RESULTS: Two asymptomatic patients were diagnosed after oncologic breast resection following neoadjuvant chemotherapy. The remaining twelve patients were young (31.7 years, range 23-43 years), predominantly non-white (50% African/African-American, 36% Hispanic, 7% Asian), pregnant within the last five years (86%), with no prior granulomatous disease. Evaluation included breast imaging, microbial cultures and staining, and biopsy. Treatment included antibiotics (57%), corticosteroids (21%), methotrexate (7%), and/or surgery (71%). Imaging suggests segmental masses, possibly abscess. CONCLUSION: Granulomatous mastitis is uncommon, and difficult to diagnose and manage. We review our experience, the literature, and propose an algorithm for diagnosis and management.

Calcium and vitamin D metabolism in sarcoidosis.

BACKGROUND: Sarcoidosis associated hypercalcemia (SAHC) may be secondary to excessive levels of 1,25-(OH)2 vitamin D3 produced by autonomous 1-alpha-hydroxylase activity within the granulomas.  The frequency, treatment, and consequences of hypercalcemia remain unclear. STUDY DESIGN AND METHODS: Two patient cohorts were studied.  In Cohort 1, the prevalence of hypercalcemia in 1606 sarcoidosis patients seen during a six year period was analyzed along with treatment and outcome. Cohort 2 consisted of  261 sarcoidosis patients with measured 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 levels. In forty patients, serial levels of 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 were measured at least three months apart without change in therapy. RESULTS: SAHC was identified in 97 of 1606 (6%) of patients studied and additional nine (0.6%) patients had primary hyperparathyroidism. Post treatment follow up was available in 86 SAHC patients. Hypercalcemia improved in >90% of patients, including eight patients treated solely with vitamin D supplement withdrawal. Renal insufficiency, documented in 41 (42%) of SAHC patients, improved with hypercalcemia treatment.  In 80% of Cohort 2 patients low 25-(OH) vitamin D3 levels were measured with only one patient having a low 1,25(OH)2 vitamin D3 level. Elevated 1,25(OH)2 vitamin D3 levels, which were measured in 11% of patients, were higher for those with a history of hypercalcemia. CONCLUSION: Sarcoidosis associated hypercalcemia, which is often accompanied by renal insufficiency, responds to treatment of sarcoidosis and withdrawal of vitamin D supplementation. Measurement of serum vitamin 1,25(OH)2 vitamin D3 appears to best evaluate vitamin D status in sarcoidosis patients.

Effect of obesity on patient-reported outcomes in sarcoidosis.

OBJECTIVES: To assess the impact of high body mass index (BMI) on patient-reported outcomes in sarcoidosis patients and healthy persons. METHODS: In this case-control study, we investigated symptoms of fatigue and dyspnoea, health status, BMI and spirometric tests in 184 sarcoidosis patients and the same number of sex- and age-matched healthy subjects. Fatigue was assessed using the fatigue scale (FS), dyspnoea was determined by the baseline dyspnoea index (BDI) and health status was measured using the respiratory-specific St George's Respiratory Questionnaire (SGRQ). RESULTS: There were significantly more subjects with increased BMI (≥25 kg/m(2)) among the sarcoidosis patients than among the healthy volunteers ((2) 37.675, P < 0.01). Sarcoidosis patients also had a greater probability of having a higher BMI (P < 0.01, OR 1.18, 95%CI 1.071.3). We found significantly lower BDI scores and forced expiratory volume in 1 s/forced vital capacity, as well as higher total SGRQ and total FS scores in sarcoidosis patients than in healthy individuals (P < 0.01 for all differences). CONCLUSION: Sarcoidosis significantly reduces patients' health status, both independently and also due to increased BMI. Reduction in BMI may contribute to improved spirometry results and health status of patients with sarcoidosis.

Management of ocular sarcoidosis.

BACKGROUND: A step wise approach to the use of cytotoxic and anti-tumor necrosis factor (TNF) antibodies has been developed for managing chronic sarcoidosis. OBJECTIVES: To provide a summary of our experience with immunosuppressive agents especially methotrexate and the anti-tumor necrosis factor antibodies in treating chronic ocular sarcoidosis. STUDY DESIGN AND METHODS: This was a retrospective review of 1587 sarcoidosis patients seen at one center over a six year period. All patients with definite or probable ocular sarcoidosis were identified. RESULTS: A total of 465 (29%) of the sarcoidosis patients experienced ocular disease. Of these, 365 patients were treated with methotrexate (MTX) for their eye disease with 281 (77% of those started on MTX) still receiving MTX at the end of the study. Methotrexate was the only systemic therapy prescribed in 115 patients while 101 patients also received concurrent prednisone. Other combinations administered include MTX plus azathioprine and/or leflunomide. A total of 25 patients were treated with the monoclonal anti-TNF antibodies infliximab (19 patients) or adalimumab (6 patients). While all patients initially responded to anti-TNF therapy, only ten patients experienced a sustained response with ongoing therapy or complete remission of ocular disease. Recurrent infections, adverse drug events, or financial constraints were responsible for most drug discontinuations. CONCLUSION: Most cases of chronic ocular sarcoidosis respond well to immunosuppressive therapy. However, patients may require combination therapy to achieve and maintain disease control. The use of anti-TNF agents for refractory disease is encouraging but can be accompanied by significant toxicity.

Endpoints for clinical trials of sarcoidosis.

Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life.

Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.

The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis.

Fatigue in sarcoidosis: American versus Dutch patients.

BACKGROUND: Fatigue is a major problem in sarcoidosis. Fatigue has mainly been examined in patients from The Netherlands. OBJECTIVE: The aims of the study were to establish the prevalence of fatigue in US and Dutch patients and to determine whether fatigue was related to the common demographic and clinical parameters. DESIGN: Two patients groups were studied: Dutch outpatients at Maastricht University Medical Center in The Netherlands (n = 121) and US patients at the University of Cincinnati Medical Center in the USA (n = 126). Both groups completed the Fatigue Assessment Scale. Clinical data were gathered from the patients' medical files. RESULTS: The prevalence of fatigue was similar in the US and Dutch patients, but more severe in the latter group. Fatigue was unrelated to demographic and clinical parameters in the total group. However, when examining the US and Dutch patients separately, fatigue was associated with age, extrapulmonary involvement and drug use in the US group. CONCLUSIONS: Dutch patients report more severe fatigue compared with US patients. Interestingly, fatigue was related to clinical and demographical parameters in the US patients, although no such relationships was found in the Dutch patients.

Inhaled iloprost for sarcoidosis associated pulmonary hypertension.

RATIONALE: Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy. OBJECTIVES: To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH. METHODS: Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires. MEASUREMENTS AND MAIN RESULTS: Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease. CONCLUSION: Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.

Inhibitors of tumor necrosis factor (TNF) in sarcoidosis: who, what, and how to use them.

Sarcoidosis patients with chronic disease often require prolonged treatment. Although alternatives to corticosteroids have been frequently administered in this disease, corticosteroids remain the mainstay of treatment. However disabling side effects which accompany prolonged treatment can necessitate the use of alternative, steroid-sparing agents. The tumor necrosis factor (TNF) inhibitors can be useful in treating chronic sarcoidosis. Among the biologic agents which inhibit TNF, infliximab has been studied most extensively in sarcoidosis with fewer reports available for adalimumab and etanercept. This review will summarize the available evidence to identify the best candidate to receive an anti-TNF regimen as well as the relative benefits and side effects of the three anti-TNF biological agents for treating sarcoidosis. A stepwise approach is proposed to increase the likelihood of disease improvement for patients who experience an inadequate response to an anti-TNF agent.

Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

Fungal infections as a complication of therapy for sarcoidosis.

BACKGROUND: Treatment of symptomatic sarcoidosis usually includes systemic immunosuppressive agents. These agents may render the patient more susceptible to opportunistic infections. In addition, the fungal infection may be difficult to distinguish from the underlying sarcoidosis. AIM: To examine the presentation and management of invasive fungal infections in sarcoidosis patients. DESIGN: Retrospective record review. METHODS: We reviewed the notes of all sarcoidosis patients (n = 753) seen at our clinic over an 18-month period. RESULTS: Seven patients (0.9%) with previously diagnosed sarcoidosis developed fungal infections: two each with Histoplasma capsulatum and Blastomyces dermatitidis and three others with Cryptococcus neoformans. No cases of invasive aspergillus or tuberculosis were identified. The diagnosis of fungal infection was made by bronchoscopy (four cases), open-lung biopsy (one case), bone-marrow aspirate (one case), and spinal fluid examination (one case). All patients were receiving corticosteroids at the time of worsening chest X-ray or clinical status. Four patients were also receiving methotrexate prior to infection. No patient with systemic fungal infection was receiving either infliximab or cyclophosphamide. All patients responded to anti-fungal therapy and a reduction in immunosuppression. DISCUSSION: Fungal infections occur rarely in treated patients with sarcoidosis. Deterioration of chest X-ray, especially a localized infiltrate, warrants investigation.

Infliximab in chronic ocular inflammation.

OBJECTIVE: Infliximab is a chimeric antibody which binds tumor necrosis factor (TNF). It is effective in several chronic inflammatory conditions, including sarcoidosis. METHODS: We report our experience with infliximab in chronic ocular inflammation as part of a retrospective review of all patients treated for chronic inflammatory ocular conditions seen over a 2-year period at our institution. RESULTS: 14 patients with various underlying ocular conditions were treated during the previous two years including patients with sarcoidosis (7), Crohn's disease (2), birdshot choroiditis (2), idiopathic disease (2), Volt-Koyanagi-Harada (1) and Behçet's disease (1). All patients had persistent inflammation despite systemic immunosuppressive agents and all but one patient experienced marked improvement in ocular inflammation with infliximab. One patient was non-compliant and non-evaluable; four patients, who had previously received etanercept with either no response (3 patients) or subsequent relapse (1 patient), responded to infliximab. CONCLUSION: Infliximab is an effective therapy in chronic inflammatory eye disease, especially when related to sarcoidosis.

Breast disease in sarcoidosis.

BACKGROUND: Breast disease in sarcoidosis can be classified as sarcoidosis patients with breast granulomas, sarcoidosis patients with breast cancer, and breast cancer patients displaying sarcoidosis-like breast reactions. METHODS: We reviewed the medical records of 629 women with sarcoidosis followed in the Interstitial Lung Disease Clinic at the University of Cincinnati for findings associated with breast disease. In addition, three women with breast cancer who had granulomas in proximity to their tumors were also examined. RESULTS: Abnormal breast examinations or mammograms were reported in 15 patients with sarcoidosis (2% of women with sarcoidosis). Breast biopsy revealed granulomas consistent with sarcoidosis in six. One of them developed breast cancer five years later. Breast cancer was identified in twelve further patients, therefore a total of thirteen patients with breast cancer were identified. Ten were diagnosed with breast cancer plus sarcoidosis: sarcoidosis preceded breast cancer in three, followed breast cancer in five, the two diseases appeared simultaneously in two. Three additional women with breast cancer were also evaluated and classified as patients with sarcoid-like reaction. Review of the mammographic and physical findings could not distinguish between sarcoidosis in the breast and breast cancer. CONCLUSION: Sarcoidosis patients develop breast cancer at the expected frequency. The breast cancer diagnosis may precede or follow that of sarcoidosis. There is no relationship between stage of sarcoidosis or treatment and the development of cancer. Because physical examination and mammography findings are unable to distinguish between sarcoidosis and malignancy, biopsy of all suspicious lesions in sarcoidosis is recommended.

Combination therapy for sarcoidosis.

Combination therapy has proved useful in infectious, rheumatologic, and oncologic diseases. The role of combination therapy in sarcoidosis is less defined. A stepwise approach to therapy in sarcoidosis treatment includes multiple agents, such as topical and systemic corticosteroids. The introduction of cytotoxic agents has led to the combination of these drugs with lowered doses of corticosteroids. Recently, the combination of cytotoxic and immune modifiers has been used for some cases of refractory sarcoidosis. The rationale use of combination therapy may enhance efficacy with reduced toxicity.

Infliximab for refractory sarcoidosis.

BACKGROUND AND AIM OF WORK: Tumor necrosis factor-alpha (TNF-alpha) appears to be an important cytokine in the inflammation of sarcoidosis. Infliximab is a chimeric monoclonal antibody which specifically inhibits TNF-alpha. We investigated the efficacy of infliximab for the therapy of chronic, resistant sarcoidosis. METHODS: Patients with persistent symptomatic sarcoidosis despite corticosteroids and immunosuppressive agents were selected for treatment with infliximab. Patients were treated initially and at 2, 4, and 12 weeks with 5 mg/kg of infliximab at each treatment. Index lesions, which had progressed despite corticosteroid therapy, were reevaluated at 16 weeks. RESULTS: Three patients were treated. In two patients, the index lesion was lupus pernio, which significantly improved with infliximab. The third patient had restrictive lung disease. At week 16, there was a 26% improvement in the vital capacity from pretreatment values. All patients tolerated the treatments well. CONCLUSIONS: Infliximab was associated with significant improvement in chronic sarcoidosis.

Bilateral synchronous breast cancer: mode of detection and comparison of histologic features between the 2 breasts.

BACKGROUND: Bilateral synchronous breast cancer is uncommon (accounting for 1.0%-2.6% of all patients with breast cancer), and most physicians do not accumulate a large personal experience of patients with this disease. We reviewed our experience with patients with bilateral synchronous breast cancer, focusing on the mode of detection and histologic features in the 2 breasts. METHODS: The charts of patients who were treated at this institution for bilateral synchronous breast cancer during the 15-year period of 1984 through 1999 were reviewed. Information regarding age, mode of detection, histopathologic features, treatment, and overall survival were analyzed. RESULTS: During the study period, 51 patients (all women) were treated at our institution for bilateral synchronous breast cancer. This comprised 2.1% of all patients (n = 2382 patients) treated for breast cancer during the same period of time. The first cancer was detected by palpation in 81% and by mammography in 14%. The corresponding figures for the contralateral cancer were 24% and 54%, respectively. The histologic type of cancer was identical in the 2 breasts in 29 patients (57%) and was different between the 2 breasts in 22 patients (43%). The overall 10-year survival rate was 63%. CONCLUSIONS: Bilateral synchronous breast cancer is often detected by mammography and is frequently of the same histologic type as the index cancer. A better awareness of the risk for this disease may help detect bilateral breast cancer earlier.

Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.

BACKGROUND AND AIM OF THE WORK: Methotrexate has been steroid sparing for some patients with chronic sarcoidosis. We wished to determine whether methotrexate can be steroid sparing in the first year of corticosteroid therapy in sarcoidosis. METHODS: Patients with new onset, symptomatic disease within four weeks of starting on prednisone were randomized to receive either methotrexate or placebo for the next year. They were seen monthly and prednisone dosage was tapered following a pre-determined schedule. RESULTS: Of 24 patients enrolled, only 15 received at least six months of therapy. Since methotrexate appears to take six months to be effective, only patients who completed six or more months of therapy were evaluated. The amount of prednisone per day decreased for both groups: methotrexate (First 6 months: Median 26 (Range 15-37) mg/day); Second 6 months 8 (1-22) mg/day, p < 0.01) and placebo (First 6 Months 28 (24-33) mg/day; Second 6 months 16 (11-22) mg/day, p < 0.02), with less prednisone used for the methotrexate patients versus placebo in the last six months (p < 0.01). There was also less weight gain for those patients receiving methotrexate. There was no difference in toxicity between methotrexate and placebo. The difference between methotrexate versus placebo was not seen when all patients (including the dropouts) were analyzed. CONCLUSIONS: Methotrexate can be a steroid sparing agent in acute sarcoidosis.

Cyclin D1, retinoblastoma, p53, and Her2/neu protein expression in preinvasive breast pathologies: correlation with vascularity.

OBJECTIVES: Preinvasive breast pathologies show a degree of vascularization that correlates with risk of invasion. Recently, numerous oncogenes and tumor suppressor genes have been shown to regulate neovascularization. Therefore, we examined archival tissues of preinvasive breast pathologies by immunohistochemistry for alterations in the expression of four proteins, cyclin D1, retinoblastoma (Rb), p53, and Her2/neu, known to be important in breast tumorgenesis, and correlated these data with tissue vascularity. METHODS: Vascularity was determined by immunologic detection of von Willebrand factor. For carcinoma in situ (CIS) both stromal vascularity (MVD) and vascular cuffing (MCD) were determined. RESULTS: We found that cyclin D1 expression was increased in usual hyperplasia (11% of cases). Atypical hyperplasia, noncomedo CIS and comedo CIS were positive in 43, 49, and 57% of cases, respectively. Changes in Rb and p53 were rare in hyperplasia but occurred in 8 and 10% of CIS, respectively. Her2/neu protein was identified rarely in atypical hyperplasia and in both noncomedo and comedo ductal CIS. Neither Rb nor Her2/neu expression correlated with vascularity. p53 immunoreactivity correlated positively with both MCD and MVD. Cyclin D1 was negatively associated with MVD. CONCLUSION: These data suggest that p53 and cyclin D1 proteins may regulate the microvessel density of preinvasive breast pathologies.