Focal and non-focal hepatic expression of placental glutathione S-transferase in carcinogen-treated rats

Carcinogenesis develops in stages that have been operationallydefined as initiation, promotion and progression. Although morphologicalend points have been described for detection and quantitationof these stages, to date initiation has been assessed only inthe context of clonal growth in response to certain promotingagents. Initiated cells are morphologicatly indistinguishablefrom surrounding cells and early changes at the cellular levelduring initiation have not been clarified. One commonly usedend point for the detection of preneoplastic hepatic lesionsis their aberrant expression of the placental isozyme of glutathioneS-transferase (PGST). Because single hepato cytes expressingPGST have been detected in aged rats and in those administeredhepatocarcinogens, it has been suggested that such cells constitutea population of putat ively initiated hepatocytes. In orderto further elucidate the characteristics of single PGST-positivehepatocytes, we analyzed the number of these cells 2 and 18weeks after various doses (0–100 mg/kg) of diethylnitrosamine(DEN) and of dimethylbenz[a]anthracene (DMBA). When determined14 days after carcinogen administration, the number of singlehepatocytes expressing PGST was greater after DEN administration(ranging from 0.8±0.3 per cm² transection of liver at1 mg/kg to 33.0±4.7 at 100 mg/kg) than after DMBA administration(ranging from 0.25±0.14 at 10 mg/kg to 3.03±0.5at 100 mg/kg); none were detected in control rats of the sameage. Additional rats were maintained on a basal diet or a basaldiet plus phenobarbital for a further 4 month period. Whereasindividual PGST-positive hepatocytes were only sporadicallydetected in rats treated with DMBA and maintained on a basaldiet for 18 weeks, those rats placed on phenobarbital for 16weeks had an even higher number of such PGST-positive hepatocytes than at 2 weeks after DMBA administration. In contrast,the dose-response curve observed for DEN- treated rats 18 weeksafter carcinogen administration was similar to that observed2 weeks after carcinogen treatment for both phenobarbital- andnon-phenobarbital-treated rats. In addition, the number of singlePGST-positive hepatocytes detected at 2 weeks was directly parallelto the number of altered hepatic foci expressing PGST 18 weeksafter DEN administration. The dose-dependent induction of PGST-positivesingle hepatocytes after treatment with two hepatocarcinogens,the dose-dependent growth of altered hepatic foci (AHF) expressingPGST with phenobarbital administration and the parallel dose-responsecurve of single hepatocytes expressing PGST and later of AHFexpressing PGST argue strongly for a precursor role of singlePGST-positive cells in the development of AHF expressing PGST.     

Type Ia glycogenosis associated with hepatocellular carcinoma.

The predisposition of preexisting cirrhotic metabolic liver disease to the development of hepatocellular carcinoma is well established. However, the association between glycogenoses (a form of noncirrhotic metabolic liver disease) and the formation of benign and malignant liver tumors is less well known. The sixth case of simultaneous occurrence of glycogenosis type Ia and hepatocellular carcinoma, which occurred in a 34-year-old man referred for advice on therapy for his malignant neoplasm, is reported. Cases previously described in the literature are reviewed and management of this entity in light of the current knowledge in the diagnosis and treatment of hepatocellular carcinoma is discussed.     

Focal nodular hyperplasia and hepatic adenoma: a review of eight cases in the pediatric age group

A review of all primary hepatic tumors seen at Children's Hospital, Boston over a 57-year period disclosed six cases of focal nodular hyperplasia (FNH) and two hepatic adenomas (HA). The children with FNH (four females, two males) ranged in age from 6 months to 15 years (average age: 7 years). Three patients had "hepatomegaly" noted on physical examination 2 months to 2 or more years prior to diagnosis. The average diameter of FNH was 7.3 cm (range 2.5-10 cm). The lesion was confined to the right lobe in four cases and showed bilobar involvement in two. The HA's were diagnosed in a newborn male and a 2-year-old girl, both of whom were symptomatic because of large tumor size (10 cm each). There was no maternal history of exposure to exogenous steroids during pregnancy. Three children with FNH underwent hepatic lobectomy and were alive and well 4 to 17 years later. One child who died of acute leukemia had an incidental FNH discovered at autopsy. Two patients were treated conservatively with biopsy only and were alive and symptom-free 13 and 15 years later. Both children with HA underwent hepatic lobectomy. One died postoperatively because of intra-abdominal hemorrhage and the other was alive and well 10 1/2 years later. Complete surgical resection is recommended for most children with HA when technically feasible because of the lingering suspicion of possible (albeit remote) malignant transformation and diagnostic difficulties in distinguishing HA from a well-differentiated hepatocellular carcinoma.     

Focal myositis

Focal myositis is a rare, benign focal inflammation of muscle. The lesion often presents as a mass that may be mistaken for a soft tissue sarcoma. This report describes the MRI and histopathological features of a case and illustrates how the diagnosis may be suspected on the basis of the MR findings.     

Focal intestinal heating with regional abdominal hyperthermia

The effect of regional abdominal heating on the small and large bowel was evaluated in three female research pigs. The BSD Annular Phased Array was used for heating. Blind-end catheters and a free peritoneal probe were surgically attached to small bowel, large bowel, liver, and kidney. Each pig underwent 4-8 heating sessions and was subsequently autopsied. There was no histologic evidence of acute bowel, liver, or kidney damage. There were significant differences in temperatures at the various sites. The average small bowel temperature was significantly higher than predicated by the free peritoneal probe or than seen in the liver or kidney. The large bowel temperatures averaged higher than the free peritoneal probe temperatures, but the difference was not significant. Liver and kidney temperatures approximate whole body temperature due to extensive vascular network. Although the elevated small bowel temperatures may be due in part to different position in relation to isotherms, the frequent occurrence of a large temperature difference suggests focal heating of fluid pockets in the small bowel.     

胃粘膜灶性异型增生的形态研究

３９６例活检胃粘膜炎症性病变中１９．９％找见异型增生灶，其由单个至１０多个细胞构成，可向管腔内或外突起。其检出率为糜烂性胃炎的８．０％，浅表性胃炎的１０．９％，萎缩性胃炎的３８．４％，慢性溃疡的１８．９％。灶性异型增生细胞ＰＣＮＡ阳性表达６１．３％；ＡｇＮＯＲ计数３．８１～８．７２个，提示ＰＣＮＡ和ＡｇＮＯＲ检测可帮助判断胃粘膜灶性异型增生。     

Focal acinar cell dysplasia in human pancreas

A series of 108 prospectively collected human pancreata were evaluated histologically for the presence of acinar cell and ductal lesions. Foci of dysplastic acinar cells were present in 44% of the series. Some of the focal acinar cell abnormalities were similar to atypical acinar cell nodules which have been described in carcinogen-treated experimental animals. The incidence of nodules was higher among patients with a history of heavy cigarette smoking than among nonsmokers, and among patients with a history of alcohol abuse than among abstainers. The presence of dysplastic acinar cell nodules in a pancreas seemed unrelated to the presence of cancer in other sites, or diabetes. Ductal epithelial abnormalities were more frequent than focal acinar cell dysplasia.     

Focal salabrasion for removal of linear tattoos

The use of a power-driven, cotton-tipped, wooden applicator permits precision salabrasion of small or linear tattoos. Such focal salabrasion is facilitated by prior removal of the overlying epidermis by means of a rotating dental burr.     

肝动脉栓塞化疗和经皮肝穿刺冷冻联合治疗肝癌

目的 研究肝动脉栓塞化疗（TACE）和经皮肝穿刺冷冻（PHCT）联合治疗肝癌的近期疗效和安全性。方法 30例不能手术切除的肝癌病人行1－3个周期TACE的,予PHCT治疗。结果 综合治疗后1个月复查,综合治疗的肿瘤,缩小≥50％为36．4％（12／33）,单纯TACE的肿瘤,缩小≥50％为25．0％（2／8）。术后血AFP和CEA水平均有不同程度下降。术后不良反应轻。结论 TACE和PHCT联合治疗肝癌为一种较好的综合治疗方法。     

Focal dystonia after chemotherapy: a case series

Dystonia is a rare neurologic disorder of thebasal ganglia presenting with involuntary twisting or turningspasm of muscles. Movements localized to the face,eyes, or neck generally present during late adulthood.Cranial dystonia is usually idiopathic but may becaused by trauma or medications. Of 148 patientswith focal dystonia referred to Indiana University overfour years, four women had the onset offace and neck symptoms eight days to 34months after completing treatment with chemotherapy alone orcombined with radiation therapy. Two patients were treatedwith 5-FU, one received doxorubicin and one wastreated with both. Both drugs have been associatedwith transient parkinsonism, but no chemotherapeutic medications havebeen reported to cause dystonia. Three patients remainfree of demonstrable malignancy. A possible association ofchemotherapy and focal dystonia has not been previouslydescribed.     

Focal adhesion kinase promotes the aggressive melanoma phenotype

Malignant melanoma continues to remain a significant health threat, with death often occurring as a result of metastasis. The metastatic phenotype typically is characterized by augmented tumor cell invasion and migration in addition to tumor cell plasticity as shown by vasculogenic mimicry. Therefore, understanding the molecular mechanisms that promote an aggressive phenotype is essential to predicting the likelihood of metastasis at a stage when intervention may be possible. This study focuses on the role of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase important for many cellular processes, including cell survival, invasion, and migration. We found FAK to be phosphorylated on its key tyrosine residues, Tyr397 and Tyr576, in only aggressive uveal and cutaneous melanoma cells, which correlates with their increased invasion, migration, and vasculogenic mimicry plasticity. Additionally, we confirmed the presence of FAK phosphorylated on Tyr397 and Tyr576 in both cutaneous and uveal melanoma tumors in situ. Examination of a functional role for FAK in aggressive melanoma revealed that disruption of FAK-mediated signal transduction pathways, through the expression of FAK-related nonkinase (FRNK), results in a decrease in melanoma cell invasion, migration, and inhibition of vasculogenic mimicry. Moreover, we found that FRNK expression resulted in a down-regulation of Erk1/2 phosphorylation resulting in a decrease in urokinase activity. Collectively, these data suggest a new mechanism involved in promoting the aggressive melanoma phenotype through FAK-mediated signal transduction pathways, thus providing new insights into possible therapeutic intervention strategies.     

肝脏局灶性结节性增生的诊断和处理

为了探讨对肝脏局灶性结节性增生诊治的合理方案,回顾性研究１９８４年～１９９８年经手术切除且经病理证实的６例肝局灶性结节性增生,并结合近期文献报道进行分析和探讨。６例肝局灶性结节性增生病人均无类固醇激素应用史,其中３例有临床症状,术前均未明确诊断而行手术切除,无手术死亡及术后并发症。肝局灶性结节性增生的准确诊断十分困难,但合理地联合应用多种影像学检查手段,可以提高诊断水平,对于无症状的确诊病例,可以采取密切随访及保守疗法;对于有症状的或生长迅速的或诊断不明确的病例应行外科手术切除     

Focal paraneoplastic limbic encephalitis presenting as orgasmic epilepsy

Purpose: To report orgasmic epilepsy as a manifestation of paraneoplastic limbic encephalitis in a patient with small cell lung cancer.Case report: A 57 years-old woman presented with 2 month history of daily spells that consisted of a sudden pleasure provoking feeling described ‘like an orgasm’ lasting for 30 s to 1 min. She was a heavy smoker and had noted recent weight loss. Bronchial biopsy, following the finding of a right lung mass, confirmed the diagnosis of small cell lung cancer (SCLC). Spells subsided after starting carbamazepine. The lung cancer was treated with chemotherapy and chest radiation therapy resulting in a complete radiologic response.Results: Brain magnetic resonance imaging (MRI) revealed left temporal lobe area of increased signal on T2 and FLAIR sequence. T1-weighted images after contrast administration demonstrated a circumscribed area of enhancement in the left anterior medial temporal lobe. Electroencephalogram (EEG) showed focal left mid-temporal sharp waves and intermittent slowing. Anti-Hu antibodies were detected in her serum supporting a diagnosis of paraneoplastic limbic encephalitis as the cause of her orgasmic epilepsy. The patient has been followed for 2 years after treatment without tumor recurrence or neurological deterioration.Conclusion: Orgasmic epilepsy is another mode of presentation of paraneoplastic limbic encephalitis leading to the diagnosis of an occult SCLC. EEG and MRI findings suggest that in this case the seizures originated from the left hemisphere. It is possible that early recognition and treatment of the SCLC will improve the prognosis of this neurologic entity.     

肝局灶性结节样增生的临床病理学研究

目的：探讨肝局灶性结节样增生（FNH）的病理学形态学特点。方法：分析7例FNH患者的临床资料。采用HE染色，结合免疫组织化学方法观察其形态特点，并利用流式细胞仪进行DNA倍体分析。结果：男性4例，女性3例，年龄18－44岁，肝功能、血清AFP均正常，结节直径为2．7－8．0cm，大体检查；5例有特征性中央星状瘢痕，由致密的纤维结缔组织、畸形的脉管和增生的胆管构成，伴有淋巴细胞浸润。免疫组化；AFP及c-erbB-2均阴性。5例DNA倍体分析；4例为二倍体，1例为异倍体。7例随访6个月－11年，未见复发及恶性病变。结论：FNH是1种肝细胞对局部血管异常的反应性增生。     

Focal adhesion kinase inhibitors are potent anti-angiogenic agents

Focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase and scaffold protein localized to focal adhesions, is uniquely positioned at the convergence point of integrin and receptor tyrosine kinase signal transduction pathways. FAK is overexpressed in many tumor cells, hence various inhibitors targeting its activity have been tested for anti-tumor activity. However, the direct effects of these pharmacologic agents on the endothelial cells of the vasculature have not been examined. Using primary human umbilical vein endothelial cells (HUVEC), we characterized the effects of two FAK inhibitors, PF-573,228 and FAK Inhibitor 14 on essential processes for angiogenesis, such as migration, proliferation, viability and endothelial cell tube formation. We observed that treatment with either FAK Inhibitor 14 or PF-573,228 resulted in reduced HUVEC viability, migration and tube formation in response to vascular endothelial growth factor (VEGF). Furthermore, we found that PF-573,228 had the added ability to induce apoptosis of endothelial cells within 36 h post-drug administration even in the continued presence of VEGF stimulation. FAK inhibitors also resulted in modification of the actin cytoskeleton within HUVEC, with observed increased stress fiber formation in the presence of drug. Given that endothelial cells were sensitive to FAK inhibitors at concentrations well below those reported to inhibit tumor cell migration, we confirmed their ability to inhibit endothelial-derived FAK autophosphorylation and FAK-mediated phosphorylation of recombinant paxillin at these doses. Taken together, our data indicate that small molecule inhibitors of FAK are potent anti-angiogenic agents and suggest their utility in combinatorial therapeutic approaches targeting tumor angiogenesis.     

Oral Contraceptive-Induced Hepatic Adenoma and Focal Nodular Hyperplasia

These hepatic “tumours” occur with long-term contraceptive usage. Hepatic adenomas are more common than focal nodular hyperplasia. There is a high incidence of recurrent haemorrhage in hepatic adenomas, hence the need for resection. Focal nodular hyperplasia has no increased incidence of malignant transformation or haemorrhage. It may be multiple and show a characteristic angiographic appearance. One-third of these lesions will show sulphur colloid isotope uptake due to the presence of Kupffer cells. Hepatic adenomas show no isotope activity as these lesions lack Kupffer cells. The differentiation between focal nodular hyperplasia, hepatic adenomas, hepatomas and solitary metastases may be difficult as they may all be ultrasonographically echoic and, apart from some cases of focal nodular hyperplasia, show as defects on nuclear scanning. Usually hepatomas are less echoic than the normal liver substance, whereas metastases show at least some area of increased reflectivity especially if mucin producing. Angiography may indicate focal nodular hyperplasia, but the separation of the other three is often not possible short of tissue biopsy.