Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

F-18 fluorodeoxyglucose uptake in leiomyomatous uterus.

Leiomyomas of uterus are common disease in gynecology. It is important to differentiate leiomyoma from leiomyosarcoma at the decision of treatment methods, especially in the case of the conservative treatment for uterine leiomyoma. But the exact diagnosis of benign leiomyoma is often difficult due to the degeneration of myoma by imaging modalities including magnetic resonance imaging. Recently, whole-body positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG) has been used for a diagnosis of malignant tumors. There is a growing body of evidence for the use of FDG in differentiating malignant from benign disease. But optimal utilization in gynecology remains unclear. Our case represents increased uptake of FDG in myomatous uterus, which is pathologically confirmed benign leiomyoma by the hysterectomy. Immunohistochemical analysis of glucose transporter-1 showed positive in endometrial tissue and negative in leiomyoma. Our case indicates that myomatous uterus in premenopausal women shows the potential pitfall of a positive result of FDG-PET.

Whole-body positron emission tomography with F-18 fluorodeoxyglucose for the detection of recurrence in uterine sarcomas.

We evaluated the usefulness of whole-body positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG-PET) for the detection of recurrence in follow-up patients after primary treatment of uterine sarcoma. Eight patients with pathologically proven uterine sarcoma underwent FDG-PET, computed tomography (CT), and ultrasonography (US). Final diagnoses of recurrence were established in five cases (three carcinosarcomas and two leiomyosarcomas). PET revealed recurrent sites in the intraperitoneum, liver, lung, bone, and retroperitoneal lymph nodes. However, the minimum size of the tumor detected by PET depended on the sites of recurrence. CT and US images showed two false-negative cases of intraperitoneal tumors. PET was able to detect a solitary small intraperitoneal tumor, which was very difficult to detect by CT and US. Positive PET findings did not affect the prognosis in three of the five recurrent patients; however, the remaining two patients consequently underwent the combination therapy consisting of surgery and chemotherapy and survived for more than 1 year after the positive FDG-PET results. Application of PET imaging for the early detection of recurrent sites was useful for the decision of treatment strategy for patients with recurrent uterine sarcoma.

Loss of heterozygosity alterations associated with progesterone therapy in endometrial hyperplasia and adenocarcinoma.

Loss of heterozygosity (LOH) was analyzed in four patients with endometrial hyperplasia (EH) with atypia (two patients) and without atypia (two patients) and in five patients with endometrial adenocarcinoma (EAC) to clarify the clinicopathologic relationship between genetic alterations and hormone therapy. Each patient was initially administered high-dose medroxyprogesterone acetate (MPA) as a uterine-sparing treatment. The five microsatellite markers used to analyze LOH were at chromosomal loci 8p22.1, 8p21, 8p21.3, 8p22, and 8p22. DNA was extracted from paraffin-embedded sections before, during, and after MPA therapy using laser capture microdissection. As a result, LOH was more frequently detected after MPA therapy (overall ratios were 16, 17, and 29% before, during, and after MPA therapy, respectively). LOH is more easily detected in EH loci than in EAC loci before MPA. For EAC, initial LOH detection on chromosome 8 may be related to an incomplete response to MPA, but negative LOH does not guarantee a favorable treatment outcome. For EH or atypical endometrial hyperplasia, it is unknown whether LOH alteration associated with MPA therapy is related to atypia of the disease.

Immunohistochemical heterogeneity of type 1 blood group antigen expressions in testicular germ cell tumors.

The immunohistochemical expression of type 1 blood group antigens (type 1 BGAs) was analyzed for 30 cases of testicular germ cell tumors (TGCTs), using monoclonal antibodies against DU-PAN-2, CA19-9, Lewis(a) (Le(a)), and Lewis(b) (Le(b)). DU-PAN-2 was expressed very frequently in all of the embryonal carcinomas (ECs). CA19-9 expression was demonstrated in 53% of ECs, but the number of positive cells was generally smaller than that for DU-PAN-2. CA19-9-negative ECs tended to show a higher number of DU-PAN-2-positive cells compared to CA19-9-positive ECs, and ECs in which DU-PAN-2 was more strongly expressed showed a relatively frequent expression of CA19-9. In 36% of seminomas and 56% of yolk sac tumors (YSTs), DU-PAN-2 was weakly expressed, and the positive cells were few in number. Little or no expression of CA19-9 was demonstrated in seminomas and YSTs. Regarding Le(a) and Le(b), the expressions were found to be limited to teratomas at a frequency of 57% and 86%, respectively, with the exception of one EC positive for Lea and one YST positive for Leb. Eighty-six percent of teratomas showed expressions of DU-PAN-2 and CA19-9. DU-PAN-2 was also seen in some intratubular malignant germ cells. The antibodies used were all negative for choriocarcinomas, syncytiotrophoblastic giant cells, and normal testicular tissues. The antigen expressions were predominantly observed on the surface of tumor cells developing luminal structures. In conclusion, although CA19-9 was relatively specific for ECs, it should be emphasized that ECs were rather characteristic of extensive DU-PAN-2 expression. Particularly in CA19-9-negative ECs, a combined analysis of DU-PAN-2 and CA19-9 would be helpful in confirming the histopathologic diagnosis of TGCTs. The clinical significance of DU-PAN-2 in ECs as a tumor marker remains to be clarified. Le(a) and Le(b) expressions were thought to be related to the differentiation or maturation rather than to the malignant transformation in TGCTs.

An immunohistochemical study of metaplastic endocrine cells in human gallbladder cancer.

BACKGROUND/PURPOSE: In order to better understand the genesis of gallbladder cancer, we investigated the metaplastic changes and the presence of endocrine cells in mucosal tissue in the tissues of 100 patients with cholecystitis and 50 patients with gallbladder cancer. METHODS: All the tissue samples were submitted to Hematoxylin-eosin and Alcian blue-periodic acid-Schiff stain. To identify endocrine cells, we utilized Grimelius or Fontana-Masson stain. To detect intestinal hormones, we used streptavidin-biotin staining. If a given tissue sample presented with goblet cells or pseudopyloric cells, we determined that it was undergoing metaplasia. To locate a focus of endocrine cells, we used the presence of argyrophil cells and argentaffin cells. RESULTS: Metaplastic changes and endocrine cells were observed in 50% or more of the studied tissues that had been sampled from the lesions of chronic cholecystitis, and from the tumor and nontumor sites of gallbladder cancer. The tissues sampled from chronic cholecystitis patients showed endocrine cells releasing gut hormones, and the incidence of tissue presenting with such hormone-secreting cells tended to increase with the degree of metaplasia. The tissues sampled from the gallbladder cancer patients also showed endocrine cells, but the incidence in these tissues was not significantly correlated with the degree of metaplasia. In the tissue sampled from gallbladder cancer patients, the degree of metaplasia and the incidence of the tissues presenting with endocrine cells was not significantly different from the corresponding results obtained from chronic cholecystitis tissues. However, tissues presenting with endocrine cells occurred more frequently in samples from nontumor sites than in samples from chronic cholecystitis sites. The incidence of metaplastic cells and of endocrine cells correlated closely with the genesis of highly differentiated cancers. Lysozyme, a nonspecific defensive factor against infections, was frequently observed in the tissues sampled from patients with chronic cholecystitis as well as those with gallbladder cancer. CONCLUSIONS: Although metaplastic changes and endocrine cells were observed in the tissues of chronic cholecystitis as well as gallbladder cancer, these markers were most frequently observed in nontumor sites close to the tumors themselves, suggesting that these markers are closely involved in the genesis of gallbladder cancer.

Acidosis or inorganic phosphate enhances the length dependence of tension in rat skinned cardiac muscle.

1. We investigated the effect of acidosis on the sarcomere length (SL) dependence of tension generation, in comparison with the effect of inorganic phosphate (P(i)), in rat skinned ventricular trabeculae. The shift of the mid-point of the pCa-tension relationship associated with an increase in SL from 1.9 to 2.3 microm (DeltapCa(50)) was studied. 2. Decreasing pH from 7.0 to 6.2 lowered maximal and submaximal Ca(2+)-activated tension and increased DeltapCa(50) in a pH-dependent manner (from 0.21 +/- 0.01 to 0.30 +/- 0.01 pCa units). The addition of P(i) (20 mM) decreased maximal tension and enhanced the SL dependence, both to a similar degree as observed when decreasing pH to 6.2 (DeltapCa(50) increased from 0.20 +/- 0.01 to 0.29 +/- 0.01 pCa units). 3. Further experiments were performed using 6 % (w/v) Dextran T-500 (molecular weight approximately 500 000) to osmotically reduce interfilament lattice spacing (SL, 1.9 microm). Compared with that at pH 7.0, in the absence of P(i) the increase in the Ca(2+) sensitivity of tension induced by osmotic compression was enhanced at pH 6.2 (0.18 +/- 0.01 vs. 0.25 +/- 0.01 pCa units) or in the presence of 20 mM P(i) (0.17 +/- 0.01 vs. 0.24 +/- 0.01 pCa units). 4. H(+), as well as P(i), has been reported to decrease the number of strongly binding cross-bridges, which reduces the co-operative activation of the thin filament and increases the pool of detached cross-bridges available for interaction with actin. It is therefore considered that during acidosis, the degree of increase in the number of force-generating cross-bridges upon reduction of interfilament lattice spacing is enhanced, resulting in greater SL dependence of tension generation. 5. Our results suggest that the Frank-Starling mechanism may be enhanced when tension development is suppressed due to increased H(+) and/or P(i) under conditions of myocardial ischaemia or hypoxia.

Fate of Legionella pneumophila in macrophages of C57BL/6 chronic granulomatous disease mice.

We compared the intracellular survival and growth of Legionella pneumophila Philadelphia-1 in peritoneal macrophages obtained from A/J, C57BL/6, and X-linked chronic granulomatous disease (CGD) mice produced from C57BL/6 strain. The initial killing was observed in A/J and C57BL/6 macrophages at 2, 4 and 6 hr after in vitro phagocytosis, but not in the CGD macrophages. Thereafter, there was a 10-fold increase of CFU in A/J macrophages. The bacteria, however, did not proliferate in C57BL/6 and CGD macrophages at 24 or 48 hr after in vitro phagocytosis. These results suggest that effector molecules for the initial killing are a superoxide anion and its metabolites, and Lgn1 gene product inhibits the intracellular growth of L. pneumophila independently of NADPH oxidase.

Bilirubin calculi crushing by laser irradiation at a molecular oscillating region wavelength based on infrared absorption spectrum analysis using a free-electron laser: an experimental study.

We investigated a new laser technique of crushing bilirubin calculi, our aim being to crush calculi in isolation using a minimally invasive procedure. Infrared absorption spectrum analysis of the bilirubin calculi was conducted, revealing maximum absorption spectrum at a wavelength of the C=O stretching vibration of ester binding that exists within the molecular structure of bilirubin calcium. As an experiment to crush calculi using the free-electron laser, we set the laser at the effective irradiation wavelength of ester binding, and conducted noncontact irradiation of the bilirubin calculi. The calculi began to slowly ablate until the irradiated site had been completely obliterated after 20s of irradiation. Moreover, absorption spectrum analysis of the irradiated site, from a comparison of absorption peak ratios, revealed that absorption peak intensities decreased over time at the absorption wavelength of ester binding. These findings suggest that irradiation of molecular oscillating region wavelengths peculiar to calculi based on infrared absorption spectrum analysis results in the gradual crushing of calculi in isolation by breaking down their molecular structure.

Omental cyst: report of a case.

We report the case of an omental cyst, a rare type of abdominal cystic lesion that is difficult to diagnose preoperatively. A 43-year-old man with no clinical symptoms was admitted to our hospital for investigation of an abdominal cyst detected by ultrasonography (US). We performed diagnostic examinations including US, computed tomography, and magnetic resonance imaging. An omental cyst was diagnosed because of its position and connection to the surrounding tissues. Pathological examination of the surgical specimen revealed endothelial cells on its internal wall and colonies of lymphocytes, confirming a diagnosis of lymphangioma, which is the most common type of omental cyst.

Delayed onset of systemic bacterial dissemination and subsequent death in mice injected intramuscularly with Streptococcus pyogenes strains.

Streptococcus pyogenes causes severe invasive diseases in humans, including necrotizing fasciitis, sepsis, and streptococcal toxic shock syndrome (STSS). We found that mice infected intramuscularly (i.m.) with S. pyogenes strains developed bacteremia and subsequent sudden death after at least 10 days of a convalescent period. Mostly, it occurred more than 21 days after muscle infection. We provisionally designate this phenomenon as "delayed death." Just after muscle infection, all the mice lost weight and activity, but recovered completely within 3 days. They had kept good activity and a fine coat of fur till one or two days before their death. Some of the dead mice were found to have soft-tissue necrosis. There was no correlation between the virulence leading to the delayed death and the severity of diseases from which strains were isolated. It was also found that the production of neither streptococcal pyrogenic exotoxin (SPE) A nor B correlated to the virulence leading to delayed death. The bacteria obtained from the organs of the mice with delayed death expressed capsule. We suggest that the mice with delayed onset of systemic bacterial dissemination and subsequent death after muscle infection with S. pyogenes are the animal models of STSS, because the pathophysiology is extremely similar to that of human STSS.

Contribution of sodium channel and sodium/hydrogen exchanger to sodium accumulation in the ischemic myocardium.

Contribution of sodium channels and sodium/hydrogen exchangers (NHEs) to sodium accumulation during ischemia in the ischemic/reperfused heart was examined. Ischemia increased the myocardial sodium. Reperfusion elicited a further increase in the myocardial sodium, which was associated with little recovery of the left ventricular developed pressure (LVDP) of the perfused heart. Treatment with tetrodotoxin or dimethylamirolide (DMA) dose-dependently attenuated the ischemia- and reperfusion-induced increase in myocardial sodium and enhanced the post-ischemic recovery of the LVDP. There was an inverse relationship between the increase in myocardial sodium during ischemia and the post-ischemic recovery of the LVDP.The myocardial sodium accumulation during ischemia is mainly attributed to sodium influx through sodium channels and NHEs.

[Photodynamic diagnosis and photodynamic therapy for experimental hepatoma with ME 2906].

We studied the effects of photodynamic diagnosis (PDD) and photodynamic therapy (PDT) in confirming the existence of hepatoma, using the new photosensitizer mono-L-aspartyl chlorine 6. Japanese white rabbits were selected for abdominal incision under intravenous anesthesia, and VX 2 tumor cells were transplanted into the left liver lobe to create a hepatoma model. In the experiment, hepatoma of 1 cm in diameter (at one week after transplantation) was radiated with a semiconducter laser (664 nm, 200 J/cm2) for treatment.

Immunohistochemical study of type-1 blood antigen expressions in thyroid tumors: the significance for papillary carcinomas.

Immunohistochemical expressions of type 1 blood group antigens were studied for 95 cases of thyroid tumors, including 29 follicular adenomas, 23 follicular carcinomas, and 43 papillary carcinomas, applying monoclonal antibodies against DU-PAN-2, CA19-9, Lewis(a) (Le(a)), and Lewis(b) (Le(b)). Normal thyroid tissue invariably failed to express all four antigens. In follicular adenomas, DU-PAN-2 and CA19-9 were focally expressed in 7% and 21% of cases, and in follicular carcinomas, CA19-9 expression was limited to one case (4%); all cases were negative for DU-PAN-2. No or little expression of Le(a) or Le(b) was observed in these follicular tumors. In contrast, DU-PAN-2, CA19-9, Le(a), and Le(b) were expressed in 98%, 84%, 33%, and 49% of 43 papillary carcinomas, respectively. The positive stainings were observed mainly on the luminal surface of the tumor cells. The number of tumor cells that expressed DU-PAN-2 generally was greater than that of tumor cells that expressed CA19-9, Le(a), or Le(b). There was no significant difference in antigen expressions in female papillary carcinomas between subjects who were younger and older than 50 years old. The results suggest that DU-PAN-2 would be a useful immunohistochemical marker for distinguishing papillary carcinomas from follicular tumors. These immunohistochemical profiles imply the following: the activity of alpha2-3 sialyltransferase, a specific glycosyltransferase, would be more strongly enhanced in papillary carcinomas than in follicular tumors; the antigen expressions in papillary carcinomas may not be related to the alteration of the female sex hormone environment.

Effect of troponin I phosphorylation by protein kinase A on length-dependence of tension activation in skinned cardiac muscle fibers.

We examined the effect of troponin I (TnI) phosphorylation by cAMP-dependent protein kinase (PKA) on the length-dependent tension activation in skinned rat cardiac trabeculae. Increasing sarcomere length shifted the pCa (-log[Ca2+])-tension relation to the left. Treatment with PKA decreased the Ca2+ sensitivity of the myofilament and also decreased the length-dependent shift of the pCa-tension relation. Replacement of endogenous TnI with phosphorylated TnI directly demonstrated that TnI phosphorylation is responsible for the decreased length-dependence. When MgATP concentration was lowered in the absence of Ca2+, tension was elicited through rigorous cross-bridge-induced thin filament activation. Increasing sarcomere length shifted the pMgATP (-log[MgATP])-tension relation to the right, and either TnI phosphorylation or partial extraction of troponin C (TnC) abolished this length-dependent shift. We conclude that TnI phosphorylation by PKA attenuates the length-dependence of tension activation in cardiac muscle by decreasing the cross-bridge-dependent thin filament activation through a reduction of the interaction between TnI and TnC.

The effects of a novel cyclohexane dicarboximide derivative, ST-6, on hypoxia/reoxygenation injury in perfused rat heart.

The present study was undertaken to test if some cyclohexane dicarboximide derivatives may have a cardioprotective effect against hypoxia/reoxygenation injury. Isolated rat hearts were subjected to 20-min of hypoxia followed by 45-min reoxygenation, and their recovery of post-hypoxic cardiac contractile function was examined. Treatment with agents was carried out from 3 min after the onset of hypoxia to the end of hypoxia (17 min during hypoxia). Among the 17 compounds, 2-[4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-i soindol-1,3(2H)-dione (ST-6) showed a significant enhancement of post-hypoxic contractile force. This was associated with attenuation of the releases of creatine kinase and purine nucleosides and bases from the perfused heart. Hypoxia-induced increase in myocardial sodium and decrease in potassium ion content was suppressed by ST-6 treatment. The results suggest that ST-6 is capable of protecting the heart against hypoxia/reoxygenation injury possibly through a mechanism by which sodium overload during hypoxia is suppressed.

Effects of MgADP on length dependence of tension generation in skinned rat cardiac muscle.

The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 microm decreased the muscle width by approximately 11% and shifted the midpoint of the pCa-tension relationship (pCa(50)) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca(2+)-activated tension and concomitantly diminished the SL-dependent shift of pCa(50) in a concentration-dependent manner. In contrast, pimobendan, a Ca(2+) sensitizer, which promotes Ca(2+) binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa(50), suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1. 9 microm, osmotic compression, produced by 5% wt/vol dextran (molecular weight approximately 464 000), reduced the muscle width by approximately 13% and shifted pCa(50) leftward to a similar degree as that observed when increasing SL to 2.3 microm. This favors the idea that a decrease in the interfilament lattice spacing is the primary mechanism for SL-dependent tension generation. MgADP (5 mmol/L) markedly attenuated the dextran-induced shift of pCa(50), and the degree of attenuation was similar to that observed in a study of varying SL. The actomyosin-ADP complex (AM.ADP) induced by exogenous MgADP has been reported to cooperatively promote myosin attachment to the thin filament. We hereby conclude that the increase in the number of force-generating crossbridges on a decrease in the lattice spacing is masked by the cooperative effect of AM.ADP, resulting in depressed SL-dependent tension generation.

Clinicopathological studies of esophageal carcinoma in achalasia: analyses of carcinogenesis using histological and immunohistochemical procedures.

Achalasia of the esophagus is a benign disease caused by dyskinesia of the lower esophagus and cardia and is presumed to be a premalignant lesion leading to an increased risk of squamous cell carcinoma. We analyzed six surgically or endoscopically resected carcinomas among 54 cases of esophageal achalasia using histological and immunohistochemical procedures. The mean interval between the diagnosis of achalasia and carcinoma was 21.5 years. Four of the six cases were superficial early-stage cancers whilst the other two were advanced cancers invading the adventitia. Histological mapping of the resected esophageal specimens demonstrated marked hyperplastic changes of stratified squamous epithelium and multiple foci of dysplastic changes. The squamous cell carcinomas showed well-differentiated type with low-grade atypia, closely associated with dysplastic foci. Immunohistochemical staining for p53, p21, p16 and epidermal growth factor receptor suggested that the dysplastic epithelium was a borderline lesion between hyperplasia and in situ carcinoma. Our observations suggested that esophageal food stasis induces chronic hyperplastic esophagitis and eventually malignant transformation of esophageal epithelial cells, associated with dysplasia-carcinoma sequence.