Thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation: an autopsy study.

BACKGROUND: Posttransplantation thrombotic microangiopathy (PTMA) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT). However, limited autopsy data are available, and it remains unclear whether PTMA is a discrete clinical and pathologic entity. The aims of this autopsy study were to determine the correlation between clinical and pathologic diagnosis of PTMA, to define the precise morphologic spectrum of PTMA, and to seek for potential etiologic factors. METHODS: The study included 20 consecutive patients with HSCT autopsied at the University of Oklahoma, between 1994 and 2005. Applying strict clinical-laboratory criteria, 6 patients were diagnosed clinically with PTMA and treated with plasma exchange. Clinical variables, including underlying disease, conditioning regimen, stem cell donor status, duration and serum level of cyclosporine, infections, and acute graft versus host disease were compared statistically in patients with histologic signs of PTMA (n=8) with those without PTMA (n=12). RESULTS: PTMA was verified histologically in all 6 patients with a clinical diagnosis of PTMA but only 2 of the 14 patients who were not clinically diagnosed had histologic evidence of PTMA (P<0.0001). Kidneys were affected in all 8 patients with PTMA, and limited extrarenal involvement by PTMA was observed in 3 of these 8 patients. No statistically significant differences in relevant clinical and morphologic variables were identified between the PTMA and non-PTMA groups. CONCLUSIONS: This study documents a strong correlation between the clinical and morphologic diagnosis of PTMA. The kidney is the primary target of PTMA, with dominant glomerular and arteriolar involvement. The etiology is likely to be multifactorial.

Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas.

Thyroid transcription factor-1 (TTF-1) is widely used in the diagnosis of lung and thyroid carcinomas. Although there have been reports of TTF-1 immunoreactivity in tumors other than those originating in the lung or thyroid, endocervical and endometrial adenocarcinomas have not been studied in large numbers. Our study provides data regarding the incidence and distribution of TTF-1 expression in these tumors. Twenty-eight endocervical (9 well, 12 moderately, and 7 poorly differentiated), 32 endometrioid endometrial adenocarcinomas (11 grade I, 8 grade II, and 13 grade III), and 13 uterine serous carcinomas were retrieved and stained with TTF-1. None of the tumors had a neuroendocrine component. The hematoxylin and eosin and anti-TTF-1 antibody stained sections were reviewed, and the presence and distribution of TTF-1 nuclear positivity was recorded. A semiquantitative grading system used to evaluate the distribution of TTF-1 staining (0 = negative, 1+ = <5%, 2+ = 5% to 25%, 3+ = 26% to 50%, 4+ = 51% to 75%, and 5+ = >75%). TTF-1 expression was seen in 1 of 28 (4%) of the endocervical adenocarcinomas and this was 4+ in distribution. The positive endocervical carcinoma was poorly differentiated. TTF-1 expression was present in 6 of 32 (19%) of the endometrioid adenocarcinomas (1 grade I, 2 grade II, and 3 grade III) and varied from 1+ to 4+ in distribution. Only 2 of 32 (6%) of the endometrioid adenocarcinomas stained diffusely (4+). There was no apparent correlation between the degree of differentiation and TTF-1 positivity in the adenocarcinomas. Three of 13 (23%) serous carcinomas were also positive (1 case 5+ and 2 cases 1+). Although TTF-1 is generally considered to be a relatively specific marker for lung and thyroid neoplasms, the occasional expression of endometrial and endocervical carcinomas should be kept in mind when evaluating neoplasms of uncertain origin. It should also be taken into consideration in the evaluation of adenocarcinomas involving the lung in patients with a history of a gynecologic malignancy.

Maturation enhances fluid shear-induced activation of eNOS in perfused ovine carotid arteries.

The present study tests the hypothesis that age-dependent increases in endothelial vasodilator capacity are due to maturational increases in endothelial nitric oxide (NO) synthesis and release. Intact 4-cm carotid artery segments taken from term fetal lambs and nonpregnant adult sheep were perfused by using a closed system that enabled independent control of flow and inflow pressure and facilitated complete recovery of all NO released. Fluid shear stress induced a graded release of NO (in nmol NO x min x cm(-2) of luminal surface area) that was significantly greater in adult (890 +/- 140) than in fetal (300 +/- 40) carotid arteries at corresponding values of shear stress (5.9 +/- 0.3 dyn/cm2) but was independent of inflow pressure in both age groups. These age-related differences in NO release were not attributable to corresponding differences in endothelial NO synthase (eNOS) abundance, as eNOS protein levels (in ng of eNOS/cm2 of luminal surface area) were similar in adult (14 +/- 2) and fetal (12 +/- 1) arteries. Adult (80 +/- 15) and fetal (89 +/- 32) levels of eNOS mRNA (in 10(6) copies/cm2 of luminal surface area) were also similar. However, when NO release was normalized relative to the associated mass of eNOS protein to estimate eNOS-specific activity in situ, this value (in nmol NO x microg of eNOS(-1) x min(-1)) was significantly greater in adult (177 +/- 44) than in fetal (97 +/- 36) arteries when the endothelium was maximally activated by A-23187. Similarly, the slope of the relation between fluid shear stress and estimated eNOS-specific activity (in nmol NO x microg of eNOS(-1) x min(-1) per dyn/cm2) was also significantly greater in adult (6.8 +/- 0.1) than in fetal (2.9 +/- 0.1) arteries, which suggests that eNOS may be more sensitive to or more efficiently coupled to activating stimuli in adult compared with fetal arteries. We conclude that maturational increases in endothelial vasodilator capacity are attributable to age-dependent increases in NO release secondary to elevated eNOS-specific activity and involve more efficient coupling between endothelial activation and enhancement of eNOS activity in adult compared with fetal arteries.