Low-dose methotrexate - a therapeutical kick in TNF-alpha antagonist treatment for recalcitrant psoriasis vulgaris.

In contrast to the treatment of rheumatoid arthritis, there are few data in psoriasis vulgaris regarding the efficacy of combining tumor necrosis factor (TNF)-alpha inhibitors and methotrexate (MTX). Indeed, combination of MTX with different TNF-alpha inhibitors may enhance the therapeutic effects and reduce side effects because of less dosage of the single agent. The present authors present five cases in which low-dose MTX combined with TNF-alpha inhibitors led to impressive improvement in Psoriasis Area and Severity Index scores. Here, the present authors initiated very low-dose MTX treatment in addition to existing TNF-alpha inhibitor therapy to exhaust current therapy and prevent premature change of the biologic. These observations support the concept of combined treatment in recalcitrant cases of psoriasis, which need a systemically lifelong treatment when both first-line and second-line monotherapies fail to provide sufficient clinical response.

Preoperative characterization of basal cell carcinoma comparing tumour thickness measurement by optical coherence tomography, 20-MHz ultrasound and histopathology.

Optical coherence tomography (OCT) is a new imaging method with promising results for several dermatological indications, including preoperative skin tumour characterization. While high-frequency ultrasound (HFUS) is frequently used for this purpose, overestimation of tumour thickness is a problem, due to subtumoral inflammatory infiltration that cannot be differentiated from tumour tissue. The aim of this single-centre study was to describe OCT features of basal cell carcinoma (BCC) and to determine vertical tumour thickness accurately, including a comparison with HFUS and histopathology. Tumour thickness values of 10 BCCs measured by OCT did not differ significantly from those measured by histopathology (median difference 0.12 mm). By contrast, the difference between HFUS and histopathology was greater (median difference 0.3 mm). A Pearson's correlation coefficient of 0.83 showed a stronger correlation of OCT in measuring tumour thickness compared with HFUS (0.59). Bland-Altman plots revealed a better agreement of OCT and histopathology concerning tumour thickness measurements. On the basis of this explorative study cohort, OCt was more exact than HFUS in preoperative tumour thickness estimation of BCCs compared with histopathological measurements.

Assessment of tumor thickness in melanocytic skin lesions: comparison of optical coherence tomography, 20-MHz ultrasound and histopathology.

BACKGROUND: Accurate assessment of vertical tumor size is important for surgical treatment planning of melanocytic skin lesions. High-frequency ultrasound (HFUS) is frequently used for this purpose, but overestimation of tumor thickness is known as a problem especially in thin melanocytic lesions. Optical coherence tomography (OCT) as a new imaging technique might be a promising alternative. OBJECTIVE: To evaluate the ability of OCT to accurately determine the vertical tumor thickness of melanocytic skin lesions and to compare it with HFUS and histopathology in order to improve surgical planning. METHODS: In this single-center study, 26 melanocytic lesions were imaged by OCT and HFUS. Vertical lesion dimensions of both methods were compared with histopathological measurements. RESULTS: Bland-Altman plots for OCT and histopathology as well as for HFUS and histopathology revealed better agreement for OCT and histopathology concerning tumor thickness measurements. Tumor thickness values for the melanocytic lesions measured by OCT presented a median tumor thickness of 0.31 mm (range 0.10-0.77) compared to a median tumor thickness of 0.25 mm (range 0.06-1.5) measured by histopathology. The median tumor thickness of HFUS was 0.44 mm (range 0.23-1.1). A Spearman correlation procedure including the correlation coefficient (r) showed a stronger relationship between OCT and histopathology (r = 0.734) compared to HFUS and histopathology (r = 0.390). CONCLUSIONS: On the basis of this smaller study cohort, OCT seems to be more exact than HFUS as far as thickness determination of thin melanocytic skin lesions is concerned.

Rational design of a topical androgen receptor antagonist for the suppression of sebum production with properties suitable for follicular delivery.

A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.

H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1.

Methylation of core histones regulates chromatin structure and gene expression. Recent studies have demonstrated that these methylation patterns have prognostic value for some tumors. Therefore, we investigated dimethylation of histone H3 at lysine 4 (H3K4diMe) and H3K4 methylating (Ash2 complex) and demethylating enzymes (LSD1) in carcinomas of the hepatic and gastrointestinal tract. High levels of H3K4diMe were rarely observed in 15.7% of hepatocellular carcinoma (8/51) unlike other carcinomas including, in ascending order, cholangiocellular carcinoma/adenocarcinoma of the extrahepatic biliary tract, gastric carcinoma, pancreatic ductal adenocarcinoma, and neuroendocrine carcinoma (P < .001). Ash2 was expressed in 84.4% of hepatocellular carcinomas (38/45) and correlated directly with H3K4diMe modification (correlation coefficient r = 0.53) and LSD1 expression (r = 0.35). In contrast to other carcinomas, 65.9% (29/44) of hepatocellular carcinomas analyzed showed no LSD1 expression (P < .001). Interestingly, hepatocellular carcinomas without LSD1 expression appeared to be frequently Ash2 and H3K4diMe weak or negative (P = .004). In summary, high H3K4diMe expression is rare in hepatocellular carcinoma compared with other carcinomas (negative predictive value 92.3%), which may aid in the differential diagnosis. Lack of H3K4diMe is possibly due to complex epigenetic regulation involving Ash2 and LSD1.

Stem cell marker expression in small cell lung carcinoma and developing lung tissue.

Histopathologic and clinical findings suggest that small cell lung cancer is derived from a multipotent proximal airway epithelial cell. In order to investigate the histogenetic origin of small cell lung cancer, we compared stem cell marker expression in human fetal lung tissue, human adult bronchial tissue, and a cohort of 64 small cell lung cancers. Supporting derivation of a multipotent precursor cell, 87.5% (56/64) of small cell lung cancers showed a dot-like expression of podocalyxin-like protein 1 (PODXL-1), a marker of embryonic and hematopoetic stem cells. Of small cell lung cancers, 98.4% (63/64) ubiquitously expressed Bmi-1, a key player in self-renewal of stem cells. Oct4 and AP2gamma were not expressed. Although podocalyxin-like protein 1 did not correlate with p53 or Wilms tumor suppressor 1, known regulators of podocalyxin-like protein 1, we could demonstrate demethylated CpG islands in the podocalyxin-like protein 1 promoter in small cell lung cancer, indicating epigenetic regulation. During fetal lung development and within adult bronchial mucosa, Bmi-1 was expressed ubiquitously. In contrast, podocalyxin-like protein 1 was detected in few stromal cells during the pseudoglandular phase (n = 7) and, importantly, in clustered epithelial cells within proximal bronchi and the trachea during the canalicular phase (n = 10). Interestingly, podocalyxin-like protein 1 was not expressed in normal or metaplastic adult bronchial epithelium (n = 36) but was expressed in sparse epithelial cells in half of the cases of normal tumor adjacent bronchial mucosa (20/40). Taken together, we show that small cell lung cancers and clustered epithelial cells in developing proximal bronchi share the expression of stem cell markers, suggesting a possible histogenetic link.

Rational design of 7-arylquinolines as non-competitive metabotropic glutamate receptor subtype 5 antagonists.

Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.

Carboxylate bioisosteres of pregabalin.

Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.