Successful Antifungal Combination Therapy and Surgical Approach for Aspergillus fumigatus Suppurative Thyroiditis Associated with Thyrotoxicosis and Review of Published Reports.

In immunocompromised patients, Aspergillus infections are important causes of morbidity and mortality. We describe a patient with cryoglobulinemic vasculitis who developed disseminated invasive aspergillosis with thyrotoxicosis caused by Aspergillus fumigatus. The diagnosis was based upon radiological, microbiological and pathological findings. The patient was treated successfully with voriconazole and caspofungin treatment followed by total thyroidectomy. We provide an overview of published reports on Aspergillus thyroiditis with an emphasis on therapeutic approaches.

Interstitial granulomatous dermatitis: a distinct entity with characteristic histological and clinical pattern.

BACKGROUND: Interstitial granulomatous dermatitis (IGD) is a rare disease for which a clinical-pathological correlation is essential to establish diagnosis. OBJECTIVES: To describe the histological and clinical features of patients with IGD seen in our department from 2004 to 2010, and to undertake a literature review and critical analysis of additional cases. METHODS: Twelve adult patients (nine women and three men; mean age 58·5 years; range 32-73 years) with IGD were enrolled. Lesions consisted of asymptomatic erythematous papules and plaques, symmetrically distributed on the trunk and the proximal limbs. Two patients had skin-coloured papules. Six patients had articular involvement (arthralgias, spondyloarthritis, rheumatoid arthritis) and three patients had cancer. RESULTS: All cases showed a predominant CD68-positive macrophage infiltrate distributed between collagen bundles of the mid- and deep dermis. Macrophages were also surrounding degenerated collagen fibres. A few neutrophils and/or eosinophils were also present. No vasculitis or significant mucin deposition was observed. Of the 62 cases of IGD reported since 1993, 53 fulfilled stringent diagnostic criteria. Erythematous papules and plaques on the trunk and proximal limbs were the dominant manifestation. Approximately 10% of patients had cord-like lesions. More than 50% of patients with IGD had arthralgia or arthritis, and less commonly other rheumatic disorders. Disease duration is months to years, but long-term prognosis seems favourable. CONCLUSIONS: IGD is a distinct entity with a typical histological and clinical pattern. The importance and the nature of the association with extracutaneous diseases remains to be clarified. Patients should be screened for rheumatic and autoimmune diseases.

Characterization of innate immune response to Brucella melitensis infection in goats with permissive or restrictive phenotype for Brucella intramacrophagic growth.

Caprine brucellosis is a chronic, world-wide distributed disease which causes reproductive failure in goats and Brucella melitensis, its causative agent, bears a great zoonotic potential. There is evidence suggesting that some cattle and pigs have an innate ability to resist Brucella infection, but this has not yet been investigated in goats. In this study, we compared caprine macrophages that exhibit extreme restriction and permissiveness to B. melitensis' intracellular growth in vitro. Monocyte derived macrophages (MDMs) from 110 female goats were cultured and challenged in vitro with B. melitensis 16 M. After initial screening, 18 donor goats were selected based on their macrophages ability to restrict or allow bacterial intracellular growth and some elements of humoral and cellular immunity were studied in depth. MDMs that were able to restrict the pathogen's intracellular growth showed enhanced bacterial internalization, although there were no differences between groups in the production of reactive oxygen and nitrogen intermediates following 48 h treatment with heat-killed B. melitensis. Moreover, there were no differences between groups in the level of antibodies reacting with keyhole limpet hemocyanin (natural antibodies, NAbs) or with Brucella LPS antigens (cross-reacting antibodies, CrAbs), although a strong positive correlation between individual levels of IgM NAbs and IgM CrAbs was detected. Altogether, these results represent an initial step in understanding innate primary host response to B. melitensis, and deciphering which mechanisms may determine a successful outcome of the infection in goats.

Correction to: AdNut study: effectiveness of a high calorie and protein oral nutritional supplement with ß-hydroxy-ß-methylbutyrate in an older malnourished population in usual clinical practice.

[This corrects the article DOI: 10.1007/s41999-018-0109-4.].

AdNut study: effectiveness of a high calorie and protein oral nutritional supplement with ß-hydroxy-ß-methylbutyrate in an older malnourished population in usual clinical practice.

OBJECTIVE: To evaluate the effectiveness of a high calorie and protein, ß-hydroxy-ß-methylbutyrate containing oral nutritional supplement (HP-HMB-ONS), on nutritional status, activities of daily living and quality of life (QoL) in old malnourished subjects. METHODS: We conducted an observational, prospective, open label, multicenter study. Participants were > 65 years, undernourished or at nutritional risk [Nutrition Risk Score (NRS) ≥ 3] and had been included on an ONS (HP-HMB-ONS twice daily for 12 weeks) per standard of care. Visits at baseline (V1), 6 weeks (V2) and 12 weeks (V3) were performed. The primary endpoints were gain of body weight, change in body mass index (BMI) and NRS 2002 index. Data from QoL (EQ-5D-3L) and activities of daily living (Katz index) were also collected. RESULTS: A total of 235 participants were included in the study. Of these 148 took at least a 75% of the HP-HMB-ONS and were included in the analysis (per protocol); median age was 80.0 (SD:8.3) years, 65.5% (n = 97) were female, 67.6% (n = 100) had 2 or more diseases. At V3, a statistically significant increase in weight (2.1 kg; SD: 3.8) (p < 0.001) and BMI (0.8 kg/m2; SD: 1.45) were found compared to V1, whereas NRS 2002 values decreased by 0.9 (SD: 1.2). A significant (p < 0.001) improvement in Katz index (mean change = 0.3; SD:1.4) and EQ-5D scoring (mean change = 0.5; SD:1.9) compared to V1, were also reported. CONCLUSIONS: The results suggest that administration of a HP-HMB-ONS improve the nutritional status and may led to a significant improvement in patients' activities of daily living and QoL, independent of baseline BMI.

Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma.

Renal epithelial tumors (carcinoma and oncocytoma) have been reported with higher a frequency than expected in patients with the tuberous sclerosis complex. However, the recent identification of a monotypic, epithelioid variant of angiomyolipoma, closely simulating renal cell carcinoma, has cast doubt on the real frequency of carcinoma. Immunohistochemical analysis with a panel of antibodies, including melanogenesis marker HMB45, can discriminate between carcinoma and carcinoma-like angiomyolipoma. We studied five tumors previously reported as carcinoma and found that only one of them showed an immunohistochemical phenotype indicative of an epithelial tumor (Ker+, HMB45-). Three tumors exhibited a phenotype compatible with the monotypic epithelioid variant of angiomyolipoma (HMB45+, Ker-), and two of the three patients died of metastatic disease. The last patient had unusual clinical features, and the tumor was positive both for HMB45 and keratin. It is concluded that (1) renal cell carcinoma is less common in tuberous sclerosis complex than previously believed, (2) some cases called renal cell carcinoma probably represent a monotypic, epithelioid variant of angiomyolipoma, and (3) epithelioid angiomyolipoma is a potentially malignant tumor with invasion and metastases. These findings indicate that all reported renal carcinomas in tuberous sclerosis complex, therefore, must be reevaluated.

Renal angiomyolipoma with epithelioid sarcomatous transformation and metastases: demonstration of the same genetic defects in the primary and metastatic lesions.

Angiomyolipoma (AML) is a benign neoplasm that occurs either sporadically or in patients with tuberous sclerosis complex (TSC) and shows frequent allelic losses at chromosome arm 16p. It has been suggested recently that the melanogenesis marker-positive perivascular epithelioid cell (PEC) has been found consistently in AML. The authors report a 50-year-old woman without evidence of TSC affected by classic renal AML containing an area composed of atypical epithelioid cells with the same morphoimmunophenotypic characters of PEC. After 7 years from surgical removal of the lesion, the patient developed a local recurrence and successive lung and abdominal metastases that showed morphologic and immunohistochemical features overlapping those of the epithelioid area of the previously removed AML. Genetic analysis showed that the classic AML and its epithelioid area as well as the pulmonary and abdominal metastases shared the same allelic loss on chromosome arm 16p. Based on these findings, the authors view this case as evidence of a malignant transformation of a classic AML with morphologic, immunophenotypic, and genetic demonstration of its clonal origin.

Biovularity and "coalescence of primary follicles" in ovaries with mature teratomas.

Several theories have been postulated regarding the origin of ovarian teratomas, including incomplete twinning, neoplastic proliferation of sequestered totipotent blastomeres or primordial cells, derepression of totipotent genetic information in the nuclei of somatic cells, and parthenogenetic development of germ cells. At present parthenogenetic development of ova is the most widely accepted theory, primarily because of the presence of a 46 XX karyotype in almost all mature teratomas. However, some authors have raised the possibility of fusion of ova in the mechanism of formation of ovarian teratomas. We report the results of a study on ovarian tissue adjacent to 31 teratomas to assess the frequency of biovularity, which could provide evidence favoring the last theory. On the whole we found biovularity in 26 ovaries of young patients (mean age, 27 years) with variable numbers of biovular follicles ranging from 1 in 4 cases to more than 10 in 2 cases; the number of biovular follicles depended on the quantity of ovarian tissue examined as well as on the total number of ova in the tissue. In multiple occasions 2 ova were included within a single follicle; in 24 ovaries the biovularity was correlated with coalescence of primary follicles characterized morphologically by an ovoid or hourglass-like shape that resulted from cohesion of 2 follicles. As control cases, 30 ovaries of patients with an average age of 28 years were examined (12 removed for endometriosis, 8 for serous cystadenoma, 7 for tubal pregnancy, and 3 for acute salpingo-oophoritis). Only 1 ovary with endometriosis contained a single biovular follicle. The results suggest that ovarian teratoma development may result from fusion of ova in ovaries containing biovularity and phenomena of coalescence of primary follicles.

Cutaneous plasmacytoma in a hemodialysis patient.

BACKGROUND: Extramedullary plasma cell dyscrasias are rare. CASE REPORT: We report a case of a 56-year-old male Caucasian hemodialysis patient with cutaneous plasmacytoma. The diagnosis was made a few months after surgical removal of his renal graft due to chronic rejection. Investigations for the presence of an associated myeloma were negative. He underwent local radiotherapy with complete resolution of the skin lesion. CONCLUSIONS: Nephrologists should be aware that the frequency of post-transplant lymphoproliferative disorders is increasing in the dialysis population, especially in those previously or currently treated with immunosuppressive drugs.

[Endometriosis of umbilical cicatrix: a clinical case]. / Endometriosi della cicatrice ombelicale: un caso clinico.

The Authors report a case of umbilical endometriosis in a 46-year-old patient. The woman came in for observation describing acute pain in the vicinity of the umbilical scar. The pain was occasional at first and then became steady and increased at the time of menstruation. Medical examination revealed a left paraumbilical nodule, measuring 1 cm in diameter. The patient underwent surgical treatment: the nodule was excised and the subsequent histological examination was diagnostic for umbilical endometriosis. The surgical excision was effective: at follow-up 3 months later, there was no recurrence and the patient was in good general condition.

Soluble human leukocyte antigen-g and its insertion/deletion polymorphism in papillary thyroid carcinoma: novel potential biomarkers of disease?

INTRODUCTION: Human leukocyte antigen-G (HLA-G), a nonclassical major histocompatibility complex class I antigen, plays a pivotal role in immune tolerance and a paradoxical role in cancers. AIMS: Our aims were to evaluate plasma soluble HLA-G (sHLA-G) concentrations and the 14-bp insertion/deletion polymorphism of the HLA-G gene in patients with papillary thyroid carcinoma (PTC) or Hashimoto's thyroiditis (HT) and to assess the possible association of these parameters with PTC aggressiveness. METHODS: Samples for the analysis of sHLA-G and +14/-14-bp HLA-G polymorphism were obtained from 121 patients with HT and 183 with PTC; 245 gender- and age-matched healthy subjects served as controls. PTC histopathological aggressiveness was defined according to the last American Thyroid Association guidelines. RESULTS: Positive serum antithyroid antibody titers were observed in 22% of PTC patients and lymphocyte infiltration of thyroid parenchyma at histological examination in 21%, whereas both circulating and histological autoimmunity was detectable in 12% of PTC patients. No differences in the +14/-14-bp polymorphism frequencies were observed between the study groups. The prevalence of detectable sHLA-G was lower in healthy controls (52%) as compared with both HT (57%) and PTC (62%) patients. By stratifying the study groups according to sHLA-G level of positive subjects, significantly higher plasma sHLA-G values in PTC (42.9 ± 3.3 ng/ml; P = 0.002) and HT patients (49.1 ± 2.6 ng/ml; P < 0.002) as compared with healthy controls (8.5 ± 1.8 ng/ml) were obtained. Moreover, PTC patients with detectable plasma sHLA-G levels showed a higher aggressive behavior (P < 0.04) than those without. CONCLUSIONS: Although confirming the frequent association between PTC and chronic autoimmune thyroiditis, these data suggest that elevated circulating sHLA-G levels, besides an important signal of alterations of immune homeostasis, may be considered a potential, novel marker of PTC histopathological aggressiveness at diagnosis. Additional studies are needed to confirm the actual role and clinical relevance of the HLA-G complex in PTC development and progression.

Radioiodine ablation: when and how.

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy with the highest mortality although with appropriate treatment has a good long-term prognosis and cure rate. Over the last 30 years there is a worldwide trend showing an increasing incidence of thyroid cancer. In DTC patients, total thyroidectomy has been for many decades routinely followed by the administration of radioiodine (131I) activity to destroy remnant thyroid tissue. Several reasons are in favour to routine ablation of postoperative thyroid remnants. The combination of both surgery and radioiodine has proven as a safe and effective treatment, resulting in improved life expectation and reduced recurrence rate for DTC patients. Recently, however, 131I ablation is not uniformly recommended for cancers smaller than 10 mm, and its use is debated for papillary tumours with diameter between 10 and 20 mm. Indeed, the decision about subsequent 131I thyroid remnant ablation is recommended as "individualized and selective". Even if new evidence has emerged that provides additional support for performing 131I treatment, the possible presence of radioiodine-associated side effects should be not overlooked. Moreover, a lot of discussion has taken place as to whether, and to what extent, 131I may cause secondary malignancies. Blood-based dosimetry is important to avoid surplus bone marrow toxicity while treating DTC patients. In this regard, the availability of a genetically engineered version of recombinant human TSH (rhTSH) provides an alternative tool to enhance serum TSH levels without inducing hypothyroidism. The administration of rhTSH to thyroid cancer patients still on LT4 therapy promotes radioiodine uptake and thyroglobulin production by thyroid cells to an extent comparable with hypothyroidism, preserving patients' quality of life, increasing the renal clearance of 131I and decreasing both the whole body and the blood dose. In this review the authors will discuss the pros and cons of postoperative radioiodine-induced thyroid remnant ablation.

Clinical relevance of highly sensitive Tg assay in monitoring patients treated for differentiated thyroid cancer.

OBJECTIVE: Serum thyroglobulin (Tg) represents a highly specific biomarker for detecting residual thyroid tissue/recurrence/metastases after treatment for differentiated thyroid cancer (DTC). We evaluated the clinical impact of a highly sensitive Tg assay during routine follow-up of DTC patients. DESIGN: Tg values were measured by a highly sensitive Tg assay during L-T4 suppressive therapy and after recombinant human thyrotropin (rh-TSH) stimulation and were compared with those obtained by using a routinely employed Tg assay. PATIENTS: One hundred and sixty consecutive DTC-treated patients (papillary carcinoma n = 124, follicular carcinoma n = 36) were studied. MEASUREMENTS: Measured variables included neck ultrasonography, (131)I whole body scanning, and Tg assayed by Immulite (Diagnostic Products Corporation, Los Angeles, CA) and by the highly sensitive Access assay (Beckman Coulter, Brea, CA). RESULTS: During L-T4 therapy, measurable Tg was found in only two patients (1% of total) by Immulite and in 23 patients (14% of total) by Access assay. Using the institutional cut-off of 2 microg/l after rh-TSH, a negative response was associated with undetectable Immulite Tg during L-T4 therapy in all patients (negative predictive value, NPV, 100%) and in 137 out of 152 patients with Access assay (NPV 90%). Measurable Tg during L-T4 therapy was found in 17% of positive patients with Immulite and in 100% of patients with Access, respectively. CONCLUSIONS: The use of a highly sensitive Tg assay may represent a useful diagnostic tool for improving the interpretation of Tg results during monitoring of DTC-treated patients for the early detection of recurrence and for optimizing the use of the more expensive rh-TSH test.

Specific microRNAs are downregulated in human thyroid anaplastic carcinomas.

Thyroid carcinomas comprise a broad spectrum of tumors with different clinical behaviors. On the one side, there are occult papillary carcinomas (PTC), slow growing and clinically silent, and on the other side, rapidly growing anaplastic carcinomas (ATC), which are among the most lethal human neoplasms. We have analysed the microRNA (miR) profile of ATC in comparison to the normal thyroid using a microarray (miRNACHIP microarray). By this approach, we found an aberrant miR expression profile that clearly differentiates ATC from normal thyroid tissues and from PTC analysed in previous studies. In particular, a significant decrease in miR-30d, miR-125b, miR-26a and miR-30a-5p was detected in ATC in comparison to normal thyroid tissue. These results were further confirmed by northern blots, quantitative reverse transcription-PCR analyses and in situ hybridization. The overexpression of these four miRs in two human ATC-derived cell lines suggests a critical role of miR-125b and miR-26a downregulation in thyroid carcinogenesis, since a cell growth inhibition was achieved. Conversely, no effect on cell growth was observed after the overexpression of miR-30d and miR-30a-5p in the same cells. In conclusion, these data indicate a miR signature associated with ATC and suggest the miR deregulation as an important event in thyroid cell transformation.

Long-term quiescence of ectopic Cushing's syndrome caused by pulmonary neuroendocrine tumor (typical carcinoid) and tumorlets: spontaneous remission or therapeutic effect of bromocriptine?

In 1990, a 55-yr-old woman was admitted to the Medical Department of our hospital for severe hypercortisolism complicated by secondary diabetes mellitus and serious hypokalemia. Although inferior petrosal sinus sampling did not show any significant difference between central and peripheral ACTH concentration, suggesting an ectopic source of ACTH secretion, diagnostic imaging was negative and Cushing's disease due to hyperplasia of the pituitary intermediate lobe was suspected. Medical treatment with bromocriptine and cyproheptadine led to a rapid and stabile normalization of adrenal function, so that after two months cyproheptadine was stopped and bromocriptine was tapered to a smaller dose. An attempt to discontinue medical treatment, carried out 3 yr later, was followed by a quick increase of ACTH and cortisol levels, which were normalized by the resumption of the bromocriptine. Adrenal function remained normal until 1994 when hypercortisolism relapsed despite the treatment. Chest radiography and computed tomography (CT) scan detected a 6 mm nodule in the middle lobe of the lung which proved to be a neuroendocrine tumor, with immunohistochemical positivity for ACTH. Nests of neuroendocrine cells (tumorlets) were also demonstrated in the surrounding lung tissue. After the lobectomy, the patient recovered completely from Cushing's syndrome and no symptoms and/or signs of recurrence have been observed over the subsequent follow-up period. Although cyclical spontaneous Cushing's syndrome could not be excluded, there was strong evidence that medical treatment with bromocriptine might have played a key role in long-lasting remission. To our knowledge, this is the second case described in literature of Cushing's syndrome caused by neuroendocrine lung tumor responsive to bromocriptine.