Periorbital erythema and swelling as a presenting sign of lupus erythematosus in tertiary referral centers and literature review.

Background Cutaneous lupus erythematosus (CLE) includes a broad range of dermatologic manifestations. Periorbital involvement, however, is a relatively rare clinical presentation of CLE. Objectives This clinical study aimed to investigate the characteristics of this unique presentation of CLE in tertiary medical centers. Methods We enrolled patients with periorbital erythema and swelling as the presenting sign of lupus erythematosus, from January 2003 to November 2017, using the data of 553 pathologically proven CLE cases from the registration database of the Chang Gung Memorial Hospitals in Taiwan. Results We enrolled a total of 25 patients. The mean age was 46.7 years and 68% of the patients were female. Most of the patients (84.0%) presented with unilateral involvement, with the left orbit involved in 15 patients (60%); the upper eyelid was the most frequently involved (72%). Mean duration between the onset of clinical manifestations and the diagnosis of CLE was approximately 59 weeks. Nineteen patients had been previously misdiagnosed. All patients had features compatible with CLE on histopathological examination. In contrast, laboratory analysis of the autoimmune profile often revealed negative results, including those for antinuclear antibodies (25%). Notably, anti-SSA/SSB (45.5%) showed the highest positive rate. During follow-up, six patients developed systemic lupus erythematosus (SLE) and two patients developed Sjögren syndrome. Conclusions The diagnosis of CLE presenting as periorbital erythema and swelling is often delayed because of clinical mimicry and the high proportion of negative results on autoantibody tests. Increased clinical suspicion and prompt histopathological examination are crucial for early diagnosis. Moreover, one-fourth of the patients ultimately developed SLE, which highlights the importance of clinical awareness.

Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS).

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction. However, its histopathological features have not been well defined. OBJECTIVES: To identify the clinicohistopathological findings of DRESS, and analyse the cutaneous histopathological changes observed in DRESS compared with those observed in maculopapular exanthema (MPE). METHODS: In a retrospective study, conducted at Chang Gung Memorial Hospital (Taiwan) between 2001 and 2011, we compared the clinicohistopathological features of 32 patients with probable/definite DRESS (defined by the RegiSCAR scoring system) with those of 17 patients with MPE. RESULTS: The major pathological changes observed in patients with DRESS included dyskeratosis (97%), epidermal spongiosis (78%), interface vacuolization (91%), perivascular lymphocytic infiltration (97%) and eosinophilic infiltration (72%). Many pathological features were common to both MPE and DRESS. However, severe dyskeratosis, epidermal spongiosis and severe interface vacuolization were significantly more prominent in cases of DRESS (P < 0·05). The presence of severe dyskeratosis was significantly associated with the clinical severity of renal impairment (P = 0·01). CONCLUSIONS: The severe dyskeratosis detected in patients with DRESS may correlate with a greater extent of systemic involvement compared with that noted in MPE. However, the histopathological changes associated with DRESS are not entirely specific.

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan.

BACKGROUND: Drug rash with eosinophilia and systemic symptoms (DRESS), a group of non-blistering severe cutaneous adverse drug reactions (SCADRs), is characterized by skin rash and multiorgan involvement. Details of this reaction have not been reported in the literature so far. AIM: We investigate clinical and pathological features and prognosis of DRESS and hope this study will provide data concerning this disorder in Taiwan. METHODS: From January 2001 to June 2006, a total of 30 patients, diagnosed with DRESS, were enrolled and evaluated for demographic characteristics, pathological findings, complications and outcome. RESULTS: Patient ages ranged from 13 to 78, with an equal sex ratio. The most common offending drug was allopurinol followed by carbamazepine. Pathologic changes observed were lichenoid dermatitis, erythema multiforme, pseudolymphoma and vasculitis. Impairment of liver and renal functions and blood dyscrasia were frequent complications. Active infection or reactivation of HHV-6 was observed in 7 of 11 patients studied serologically. Two patients developed type 1 diabetes mellitus. The mortality rate was 10% (3 of 30). CONCLUSIONS: DRESS is a heterogeneous group of life-threatening conditions. The leading drug in DRESS in Taiwan is allopurinol. High eosinophil count and multiple underlying diseases are poor prognostic factors in patients with DRESS.

Shell model description of the 14C dating beta decay with Brown-Rho-scaled NN interactions.

We present shell model calculations for the beta decay of 14C to the 14N ground state, treating the states of the A=14 multiplet as two 0p holes in an 16O core. We employ low-momentum nucleon-nucleon (NN) interactions derived from the realistic Bonn-B potential and find that the Gamow-Teller (GT) matrix element is too large to describe the known lifetime. By using a modified version of this potential that incorporates the effects of Brown-Rho scaling medium modifications, we find that the GT matrix element vanishes for a nuclear density around 85% that of nuclear matter. We find that the splitting between the (J(pi),T)=(1(+),0) and (J(pi),T)=(0(+),1) states in 14N is improved using the medium-modified Bonn-B potential and that the transition strengths from excited states of 14C to the 14N ground state are compatible with recent experiments.

Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy.

BACKGROUND: Hand-foot skin reaction is a distinctive cutaneous side-effect of antineoplastic kinase inhibitor-targeted therapy. Severe hand-foot skin reaction requires postponement of treatment or dose reduction. Histopathological studies of skin toxicity associated with kinase inhibitors are currently unavailable. OBJECTIVES: To report the clinical and histopathological findings of hand-foot skin reaction produced by the multikinase inhibitor sorafenib. METHODS: Nine patients with metastatic carcinoma-seven with renal cell carcinoma (RCC), one with melanoma and one with hepatocellular carcinoma (HCC)-received continuous, oral sorafenib 400 mg twice daily. Hand-foot skin reaction was defined and graded according to National Cancer Institute Common Toxicity Criteria 3.0. Biopsies from lesions of erythematous scaly or blistering skin were obtained from five cases (four RCC and one HCC). RESULTS: Seven of the nine (78%) patients developed hand-foot skin reaction characterized by well-demarcated, tender, erythematous papules and plaques with greyish blisters or hyperkeratotic, callus-like formations on palmoplantar surfaces and distal phalanges. Skin biopsy of hand-foot skin reaction lesions revealed epidermal acanthosis, papillomatosis, parakeratosis, dispersed dyskeratotic cells and keratinocyte vacuolar degeneration. Other skin toxicities included angular cheilitis, seborrhoeic dermatitis and perianal dermatitis. CONCLUSIONS: The clinical manifestations and histopathological features of sorafenib-induced skin reactions are unique. The most relevant histopathological findings of hand-foot skin reaction include keratinocyte vacuolar degeneration, the presence of intracytoplasmic eosinophilic bodies, and intraepidermal blisters in the stratum malpighii. Further studies are warranted to elucidate the mechanisms of this novel multitargeted kinase inhibitor-associated skin reaction.

Granulomatous variant of chronic pigmented purpuric dermatoses: report of four new cases and an association with hyperlipidaemia.

Four patients presenting with chronic pigmented purpuric dermatosis (CPPD) on the limbs were found to have granulomatous inflammation superimposed on the pathological changes of CPPD. Three of the four patients had hyperlipidaemia. Therefore, the granulomatous reaction observed could be associated with hyperlipidaemia. Whether it occurs only in Asian people or not needs further observation.

Disseminated xanthogranulomas associated with adult T-cell leukaemia/lymphoma: a case report and review the association of haematologic malignancies.

Xanthogranuloma (XG) is rarely observed in adults and has been reported to be associated with chronic myelogenous leukaemia (CML) and/or neurofibromatosis type 1 (NF1). A 68-year-old woman with adult T-cell leukaemia/lymphoma (ATLL) gradually developed disseminated XGs over the 3 years since disease onset. Histopathological examination of a skin biopsy revealed the presence of histiocytes in the dermis with a few Touton giant cells admixed with lymphoid cells. The lesions of XGs persisted despite chemotherapy with prednisolone and chlorambucil for her ATLL. This is the first report of disseminated XGs associated with ATLL. The association of disseminated XGs with haematologic malignancies was reviewed and the possible pathogenesis of this association will be discussed.

Identification of mixed-symmetry states in an odd-mass nearly spherical nucleus.

The low-spin structure of 93Nb has been studied using the (n,n'gamma) reaction at neutron energies ranging from 1.5 to 3 MeV and the 94Zr(p,2ngamma)93Nb reaction at bombarding energies from 11.5 to 19 MeV. States at 1779.7 and 1840.6 keV, respectively, are proposed as mixed-symmetry states associated with the pi2p(1/2)-1x(2(1),MS+,94Mo) coupling. These assignments are derived from the observed M1 and E2 transition strengths to the 2p(1/2)-1x(2(1)+,94Mo) symmetric one-phonon states, energy systematics, spins and parities, and comparison with shell model calculations.

Genital porokeratosis: a series of 10 patients and review of the literature.

BACKGROUND: Porokeratosis (PK) is an uncommon disorder of epidermal keratinization with a unique clinical appearance, unknown aetiology, and an unpredictable outcome. Genital PK (defined as localized PK confined to the genital area in this study) is extremely rare and is not well documented. OBJECTIVES: To evaluate the clinical manifestations, histopathology, clinical course and treatment response for genital PK. METHODS: We reviewed the clinicohistological data from 10 patients with genital PK seen at Chang Gung Memorial Hospital from 1990 to 2005. RESULTS: Seven patients had lesions only in the genital area, and three patients had genital and adjacent areas involved. All patients were male and the mean age at initial diagnosis was 46.0 years (range 36-59). All but one patient presented with pruritic lesions. Three patients (30%) had diabetes mellitus. No malignant transformation was observed. Surgical excision was the most effective treatment if it could be performed. CONCLUSIONS: Genital PK appeared more frequently in the Asian population than in reports from western countries. Genital PK presented mostly as pruritic lesions in Taiwan, with a wide age distribution. Long-term follow-up might be needed.

Corpuscular thymoma: entity or variant of organotypical thymomas WHO B2/B3?

Hassall's corpuscles are regular structures in the medulla of the normal thymus and in non-neoplastic thymic conditions, e.g. in multilocular thymic cysts. In thymomas, however, they are inconsistently found, and are believed to indicate medullary differentiation of WHO type B1-3 thymomas. We present five organotypical thymomas resembling WHO type B2 and B3 thymomas, but with an abundance of Hassall's corpuscles. We wonder whether this exceedingly rare observation might herald a distinct entity. Four tumors were asymptomatic, incidental findings and of low Masaoka stage (I or II) [20] . One patient suffered from myasthenia gravis which disappeared upon surgical removal of the thymus, while all other patients had no concomitant autoimmune disease. Two patients had a relapse-free follow-up of 12 and 2 years, respectively, upon curative surgery, and another tumor was an autopsy finding; follow-up data of two more recent cases was not yet available. The neoplastic epithelium other than Hassall's corpuscles was arranged either in a cortical type B2 pattern or in type B3 solid cords. In all examples, there was cyst formation, inflammatory reaction and repair, indicative of a long-standing condition. Immature T cells were present in all instances. "Corpuscular thymomas" morphologically resemble WHO type B2 and B3 thymomas, but appear biologically indolent and are rarely associated with myasthenia gravis. Whether they qualify for a separate entity has to be proven by larger series, including genetic studies.

Primary aleukemic myeloid leukemia cutis treated successfully with combination chemotherapy: report of a case and review of the literature.

Aleukemic myeloid leukemia cutis is extremely rare and is usually associated with early marrow relapse and poor treatment outcome. We report a 39-year-old man presenting with generalized cutaneous nodules. The initial diagnosis was cutaneous malignant lymphoma. New skin lesions and a nasopharyngeal mass developed during phototherapy. Biopsy of the cutaneous and nasopharyngeal lesions revealed monotonous blast cell infiltration. Cytochemical stain and immunophenotypic analysis of the fresh cell suspension made from another skin biopsy specimen identified that the neoplastic cells belonged to the monocytic lineage. A diagnosis of primary aleukemic leukemia cutis was established. The leukemic cells expressed CD56 but did not carry AML-1/ETO, CBFbeta/MYH11, or common MLL fusion transcripts. He received standard induction therapy for acute myeloid leukemia, followed by high-dose postremission chemotherapy and has been disease-free for more than 30 months. To the best of our knowledge, the current case has the longest disease-free survival among those reported.

Pigmented spindle cell carcinoid tumour of the thymus with ectopic adrenocorticotropic hormone secretion: report of a rare variant and differential diagnosis of mediastinal spindle cell neoplasms.

AIMS: A variety of histological variants of thymic carcinoid tumour have been described. A rare case of pigmented spindle cell carcinoid tumour of the thymus is documented and compared with the reported cases of thymic pigmented carcinoid tumour in the literature, with a discussion of the differential diagnosis of spindle cell tumours of the mediastinum. METHODS AND RESULTS: A thymic tumour with ectopic adrenocorticotropic hormone (ACTH) secretion was resected from a 24-year-old man suffering from Cushing's syndrome. Histological, immunohistochemical, and ultrastructural studies revealed an ACTH-producing spindle cell carcinoid tumour harbouring pigmented melanocytes. Among four thymic pigmented carcinoid tumours reported before, only one was similar to the present case by being also an ACTH-secreting pigmented spindle cell thymic carcinoid tumour. The clinicopathological features of this tumour distinguish it from a spindle cell thymoma, spindle cell thymic carcinoma, and other mediastinal spindle cell tumours. CONCLUSIONS: This case illustrates an extremely rare variant of thymic carcinoid tumour exhibiting a spindle cell morphology and harbouring pigmented melanocytes. Awareness of this histological variant is important in the differential diagnosis of spindle cell tumours of the mediastinum.

Intraductal papillary neoplasia of the liver associated with hepatolithiasis.

Intraductal papillary growth of neoplastic biliary epithelia with a fine fibrovascular stalk (intraductal papillary neoplasia of liver [IPN-L]) resembling intraductal papillary mucinous neoplasm of pancreas is occasionally associated with hepatolithiasis. In this study, 136 cases of hepatolithiasis in Taiwan, between January 1998 and March 2000, and an additional 21 cases of IPN-L before December 1998, were examined histologically. IPN-L was found in 41 of 136 hepatolithiasis cases (30.1%). Sixty-two IPN-L cases (42 women and 20 men; age range, 59.8 +/- 10 years) were divided into 4 types (type 1, IPN-L with low-grade dysplasia, 23 cases; type 2, IPN-L with high grade dysplasia, 11 cases; type 3, IPN-L with in situ and microinvasive carcinoma, 13 cases; and type 4, IPN-L of types 2 and 3 with distinct invasive carcinoma, 15 cases). Intraductal spreading and glandular involvement were commonly observed in all types. About half of types 3 and 4 cases had mucobilia, and mucinous carcinoma was variably found in two thirds of group 4 patients. IPN-L frequently showed variable gastroenteric differentiation such as goblet cells and foveolar and colon-like metaplasia. IPN-L with goblet cells and colon-like metaplasia was frequently associated with overproduction of mucin and mucobilia (P <.01). In Japan, IPN-L was not frequent in hepatolithiasis (12 of 135 cases). In conclusion, IPN-L forms a spectrum of biliary neoplasm in hepatolithiasis. It often displays variable gastroenteric metaplasia and significant intraductal spread. IPN-L tends to progress to mucinous carcinoma. Formerly reported "mucin-producing intrahepatic cholangiocarcinoma" with a favorable prognosis is included in IPN-L.

Specificity of the histopathological triad for the diagnosis of toxoplasmic lymphadenitis: polymerase chain reaction study.

Toxoplasmosis is a common cause of lymphadenopathy, but toxoplasmic cysts are not usually found in histological sections used for establishing diagnosis, except on extremely rare occasions. The histopathological triad of florid reactive follicular hyperplasia, clusters of epithelioid histiocytes, and focal sinusoidal distention by monocytoid B cells has been considered to be diagnostic of toxoplasmic lymphadenitis, but the validity of the histopathological triad is based indirectly on serological correlation only. The demonstration of Toxoplasma gondii DNA in lymph nodes displaying the histopathological triad will indicate the validity of the histopathological triad as the criterion for the histopathological diagnosis of toxoplasmic lymphadenitis. We used frozen tissues of 12 lymph nodes with the histopathological triad and tissues of 27 lymph nodes from patients with various other conditions (including 13 cases of follicular lymphoid hyperplasia, FLH; three cases of dermatopathic lymphadenopathy, DPL; two cases of plasmacytosis; two cases of Castleman's disease; two cases of metastatic adenocarcinoma; and five cases of lymphoma) to detect T. gondii DNA by polymerase chain reaction. Ten out of 12 lymph nodes with the triad and six out of 27 lymph nodes without the triad were positive for T. gondii DNA. Thus, the sensitivity of the triad was 62.5% (10/16) and the specificity was 91.3% (21/23). The predictive value of positive tests was 83.3% (10/12) and the predictive value of negative tests was 77.7% (21/27). The six cases positive for T. gondii DNA without the triad were four cases of FLH, one case of DPL, and one case of plasmacytosis. None of the neoplastic diseases was positive. The false positive and negative cases could be due to sampling problems or past T. gondii infection. The results confirm that the histopathological triad is highly specific for the diagnosis of toxoplasmic lymphadenitis and can be used confidently.

Characterization of a Saccharomyces cerevisiae mutant with oversecretion phenotype.

An oversecreting mutant of Saccharomyces cerevisiae was obtained from about 400 meiotic segregants derived from thediploid cells made by crossing the HBsAg-induced mutant NI-C with the wild-type strain Sey6211. When transformed with a plasmid containing mouse alpha-amylase cDNA, the mutant (NI-C-D4) exhibited an increased capacity (up to 13-fold) for the secretion of mouse alpha-amylase, higher than the parental strains and other standard wild-type strains. It was also shown that alpha-amylase secreted by the oversecreting mutant had a higher activity and contained more of the non-glycosylated form than the glycosylated form. This isolated oversecreting, low-glycosylation mutant may prove to be a potential S. cerevisiae host for the production of foreign proteins. Further genetic analysis suggested that the mutation responsible for the mutant's oversecretion was partially dominant and that both the oversecretion and low-glycosylation phenotypes were governed by a single chromosome mutation. These pleiotrophic phenotypes may be attributed to a defect in the synthesis of an ER-resident chaperone.

Induction of a mitosis delay and cell lysis by high-level secretion of mouse alpha-amylase from Saccharomyces cerevisiae.

Some foreign proteins are produced in yeast in a cell cycle-dependent manner, but the cause of the cell cycle dependency is unknown. In this study, we found that Saccharomyces cerevisiae cells secreting high levels of mouse alpha-amylase have elongated buds and are delayed in cell cycle completion in mitosis. The delayed cell mitosis suggests that critical events during exit from mitosis might be disturbed. We found that the activities of PP2A (protein phosphatase 2A) and MPF (maturation-promoting factor) were reduced in alpha-amylase-oversecreting cells and that these cells showed a reduced level of assembly checkpoint protein Cdc55, compared to the accumulation in wild-type cells. MPF inactivation is due to inhibitory phosphorylation on Cdc28, as a cdc28 mutant which lacks an inhibitory phosphorylation site on Cdc28 prevents MPF inactivation and prevents the defective bud morphology induced by overproduction of alpha-amylase. Our data also suggest that high levels of alpha-amylase may downregulate PPH22, leading to cell lysis. In conclusion, overproduction of heterologous alpha-amylase in S. cerevisiae results in a negative regulation of PP2A, which causes mitotic delay and leads to cell lysis.

Granulomatous variant of chronic pigmented purpuric dermatosis: report of two cases.

Two patients presenting with chronic pigmented purpuric dermatosis (CPPD) on the dorsum of both feet were found to show granulomatous inflammation superimposed on the pathological changes of CPPD. Two similar cases have been reported from Japan. The unique clinicopathological features of this group of patients suggest that they have a rare granulomatous variant of CPPD.

Presence of Epstein-Barr virus latent membrane protein 1 gene in the nasopharyngeal swabs from patients with nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy in southeastern China and Taiwan. Early detection of the local disease followed immediately by proper treatment is essential to increase the cure and survival rates. Because every NPC tumor cell carries Epstein-Barr Virus (EBV) genomes, detection of EBV genomic DNA such as latent membrane protein 1 gene (LMP1) might indicate the presence of NPC. We developed a simple and noninvasive technique of nasopharyngeal swabbing to acquire nasopharyngeal cells for detecting the presence of EBV genome. The aim of this study was to investigate the feasibility and reliability of this technique. METHODS: We collected nasopharyngeal cells by means of a nasopharyngeal swabbing technique and detected the presence of EBV LMP1 with polymerase chain reaction (PCR). Thirty-eight swab specimens were obtained from patients with NPC who were newly diagnosed or were just beginning radiotherapy. Two groups of control subjects were recruited, including 20 patients with other head and neck cancers and eight family members of the NPC patients. An additional group of 65 NPC patients were enrolled in the course of regular follow-up after definitive radiotherapy. RESULTS: All of the samples yielded sufficient DNA for PCR amplification. Thirty-six of 38 NPC swab samples were positive for EBV LMP1, and all the control subjects had swab sample results negative for EBV. All five patients with suspected local recurrence exhibited positive EBV test results. CONCLUSIONS: Demonstration of EBV LMP1 in the nasopharyngeal swab specimens detected NPC with a sensitivity of 94.7% and specificity of 100%. This study confirms the reliability and feasibility of nasopharyngeal swab in the predicting and screening of NPC.