Non-exophytic Lambl excrescences of aortic valves: a morphological study.

AIMS: To elucidate the histopathological findings of classical Lambl excrescences (LEs) and non-exophytic LEs (non-ex LEs) without excrescent papillary features. METHODS AND RESULTS: We examined 126 aortic valves (AVs) and revealed LEs (non-ex and/or classical), non-ex LEs and classical LEs in 106, 78 and 88 AVs, respectively. The detection of non-ex LEs was challenging, but elastica van Gieson stain highlighted their presence. Non-ex and classical LEs chiefly involved the ventricular regions, favoured posterior cusps and coexisted in the same areas of 31 AVs. A possible transformation of classical LEs into non-ex LEs was suggested histologically in 39 AVs. Non-ex LEs were associated with age of >70 years (P < 0.001) and marked deformity (P = 0.007). Classical LEs were associated inversely with marked deformity (P < 0.001), but not with age of >70 years. Compared with age- and sex-matched control AVs, non-ex LEs and marked deformity in dysfunctional AVs were more common (P = 0.037 and P < 0.001, respectively), but classical LEs were less common (P = 0.021). CONCLUSIONS: Non-ex LEs have subtle features but are a common form of LEs, and seem to develop from classical LEs. AV dysfunction-related marked deformity can promote non-ex LEs.

Simvastatin-romidepsin combination kills bladder cancer cells synergistically.

The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining simvastatin with the histone deacetylase (HDAC) inhibitor romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs, thus further promoting histone acetylation. This AMPK activation was essential for the combination's action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination's ability to induce apoptosis. We also found that the combination increased the expression of peroxisome proliferator-activated receptor (PPAR) γ, leading to reactive oxygen species production. Furthermore, the combination induced endoplasmic reticulum (ER) stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation, thus playing an important role in the combination's action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression.

Co-expression of mesothelin and CA125/MUC16 is a prognostic factor for breast cancer, especially in luminal-type breast cancer patients.

The expression of mesothelin correlates with a poor prognosis in patients with breast cancer. Since mesothelin plays a role in cancer metastasis in association with CA125, we herein examined the expression of mesothelin and CA125, and the clinicopathological meaning and prognosis of the co-expression of mesothelin and CA125 in breast cancer. Our results showed that among 478 patients, mesothelin and CA125 were co-expressed in 48 (10 %), mesothelin only in 75 (16 %), CA125 only in 217 (45 %), and neither in 234 (49 %). A high correlation was observed between the expression of mesothelin and CA125 (P =0.0004). The co-expression of mesothelin and CA125 correlated with poor patient relapse-free survival (RFS) (P = 0.0001) and was identified as an independent predictor of RFS by Cox's multivariate analysis. In conclusion, this is the first to report the prognostic significance of the co-expression of mesothelin and CA125 in breast cancer. The co-expression of mesothelin and CA125 may be clinically useful for prognostication after surgical therapy in patients with breast cancer.

Numerous osteoclast-like giant cells in metastases from lung adenocarcinoma, but absent from primary tumor.

We report a rare case of lung adenocarcinoma in a 54-year-old man, in whom osteoclast-like giant cells (OCGCs) were found only in metastases. Autopsy revealed that metastases involving the tongue, gallbladder, stomach, intestines, right adrenal gland, and bones contained numerous OCGCs. Some metastases to the lungs and liver also contained OCGCs, but the primary tumor and metastases to the right atrium, spleen, left adrenal gland, and lymph nodes did not. Primary lung carcinoma cells were positive for cytokeratin 7 (CK7), epithelial membrane antigen (EMA), thyroid transcription factor 1 (TTF-1), and Napsin A, but were negative for vimentin and CD68. Frequently poorly cohesive metastatic carcinoma cells admixtured with OCGCs showed weak CK7/EMA positivity, no TTF-1/Napsin A staining, and newly expressed vimentin. OCGCs were positive only for CD68 and vimentin, implying reactive cells. OCGCs can develop only in metastatic lesions, possibly associated with their anaplastic changes or epithelial mesenchymal transition.

Non-sarcomatous spindle cell morphology in conventional lung adenocarcinoma: a clinicopathological study.

Non-sarcomatous spindle cell foci (N-SSCF) without aggressive invasiveness, also called morule-like lesions, occur occasionally in conventional lung adenocarcinoma, but their characteristics remain poorly understood. We identified N-SSCF in 7 (4.0 %) of 173 lung adenocarcinomas and examined their clinicopathological features. The patients were six men and one woman with a mean age of 57.0 years (range, 43-76 years). All tumors were papillary-predominant adenocarcinomas, ranging in size from 1 to 4.5 cm (mean, 2.7 cm). N-SSCF occupied 10-30 % of the tumors, and in all cases, there were focal or multifocal transitions between the two morphotypes. Most N-SSCF were plug-like nodules filling the spaces of cancerous alveoli/tubules or patchy insular nests. N-SSCF frequently contained mucin + lumina and were positive for cytokeratin 7, thyroid transcription factor 1, and Napsin A, but negative for cytokeratin 5/6 and vimentin, similar to the adenocarcinoma cells of the same tumor. Five cases (71 %) were at stage I or II, suggesting that N-SSCF can occur in an early phase of lung cancer. In an age-, sex-, and stage-matched control study, N-SSCF were not associated with prognosis (P = 0.471). We consider tumors with N-SSCF a distinct structural variant of adenocarcinoma without prognostic significance. They should be distinguished from true sarcomatous spindle cells and micropapillary components, which are associated with aggressive behavior.