Surgical management of insulinoma: Diagnosis of tumor location and high incidence of malignancy

The findings in twenty-two patients with insulinoma were reviewed, as continuous efforts should be made to establish preoperative localization of the tumor. Superselective arteriography and percutaneous, transhepatic portal vein and pancreatic venous catheterization are highly recommended approaches. At the time of surgical intervention, a cautious exploration of the pancreas after thorough mobilization is most important. Recent use of intraoperative ultrasonography increases the likelihood of finding these occult tumors which locate deeply in the head of the pancreas. Apart from the diagnostic problems, we wish to emphasize the high incidence of malignancy (7/22, 31.8 per cent) in our series. Althout patients with malignant isulinoma had a much better prognosis compared to those with a pancreatic ductal malignancy, pancreatic resection with regional lymphnode dissection seems to be a rational procedure. Enucleation can be done when intraoperative findings of the tumor and regional lymphonode indicate no malignant features and no multiple lesions. However, at the first operation, enucleation is still a procedure of choice, even for the malignant insulinoma in the head with a well-defined capsule and no metastatic lesions, the objective being to avoid a duodenopancreatectomy or total pancreatectomy. These data were reported at the 30th Congress of Société Internationale de Chirurgie, Hamburg, Germany, 1983     

Skull metastasis of thyroid papillary carcinoma.

Skull metastasis of thyroid carcinoma is rare. The majority of skull metastases of thyroid carcinoma are of the follicular subtype, rather than thyroid papillary carcinoma. In this report, a 55-year-old woman with skull metastasis from thyroid papillary carcinoma is presented. The metastatic lesion of the skull was hypervascular and osteolytic, and the bleeding was profuse during resection. There have been only four reports of skull metastasis from thyroid papillary carcinoma. The mean period from the initial diagnosis of thyroid carcinoma until the detection of skull metastasis is 23.3 years, whereas in this patient, it was about 2 years. Therefore, in the clinical course of thyroid papillary carcinoma, skull metastasis should be considered, and the patient should be meticulously followed up.     

Glutaminase and glutamine synthetase activities in human cirrhotic liver and hepatocellular carcinoma.

Glutamine synthetase and glutaminase activities in human cirrhotic liver tissues and hepatocellular carcinomas were determined for comparison with normal liver tissues. In hepatocellular carcinoma, glutamine synthetase activity was approximately one-third of that in normal liver, whereas no detectable change in the enzyme activity was observed in cirrhotic liver. Phosphate-dependent and phosphate-independent glutaminase activities were increased approximately 20-fold and 6-fold, respectively, both in the carcinoma and cirrhotic liver compared with those from normal liver, Oxypolarographic tests showed that the rate of glutamine oxidation in the tumor and cirrhotic liver mitochondria was about 5-fold higher than that in the liver mitochondria. The rate of glutamate oxidation in the liver mitochondria was comparable to that in the cirrhotic liver and tumor mitochondria. Glutamine oxidation was inhibited by prior incubation of the mitochondria with 6-diazo-5-oxo-L-norleucine, which inhibited mitochondrial glutaminase. These results indicate that the product of glutamine hydrolysis, glutamate, is catabolized in the tumor and cirrhotic liver mitochondria to supply ATP. In the liver and cirrhotic liver mitochondria, glutamate was oxidized via the routes of transamination and deamination. On the other hand, glutamate oxidation was initiated preferentially via a transamination pathway in the tumor mitochondria.     

Inhibitory effect of anti-platelet prostaglandin on liver metastasis of hamster pancreatic cancer

Coagulation system and platelets play an important role in the stage of lodgement of tumor cells. We examined abilities of human and hamster pancreatic cancer cell lines to aggregate platelets in vitro, and investigated the effect of prostaglandin E1, I2, on artificial liver metastases of pancreatic cancer in Syrian golden hamster. Platelet aggregating activities were found in five out of six human pancreatic cancer cell line and thromboplastin likes activity in five cell lines. Diisopropanolnitrosamine induced hamster pancreatic cancer cells (HPK-1) were able to aggregate platelets both in vitro and in vivo and these activities were inhibited by prostaglandin I2. Hamster was inoculated intraportally with 1 X 10(6) HPK-1 cells. After two weeks autopsy of these hamsters revealed multiple metastatic nodules on liver surface. In this model we administered prostaglandin E1, I2 into the portal vein five minutes before cell inoculation. Number of liver surface nodules were significantly decreased to 33.1 + 7.0, 11.0 + 9.6 in hamster given 100g PGE1 PGI2 before cell inoculation, compared with control group of hamsters (62.0 + 6.6 PH9.3, 66.1 + 13.9 PH7.4). But administration of prostaglandin after cell injection was not effective. In all cases none of extrahepatic metastases were noted. Inhibitory action of PGE1 PGI2 on liver metastasis is suspected to be related to inhibition of platelet aggregation.     

Anterior interosseous nerve palsy after reduction and percutaneous pinning of open fractures of the radius and ulna.

We report a case of an anterior interosseous nerve palsy after closed reduction and percutaneous pinning of open fractures of the radius and ulna in an adult. Operative findings showed that the anterior interosseous nerve was trapped between the distal and proximal part of the fractured radius. Treatment by neurorrhaphy gave a satisfactory result.     

The value and limitation of resting 201Tl reinjection after stress-redistribution imaging for the assessment of myocardial viability: comparison with wall motion improvement by revascularization]

Clinical value and limitation of resting reinjection of small dose of thallium (37 MBq) for the assessment of myocardial viability were evaluated. The results were compared with the degree of wall motion improvement by revascularization to infarcted myocardium supplied by chronic total vessels in 12 patients with old myocardial infarction. Thallium uptake was visually scored and judged as normal, reversible defect (Group 1), new fill in after reinjection (Group 2A), and no fill in even after reinjection (Group 2B). Among 53 segments with initial perfusion abnormality, 21 segments reverted to almost normal, while 32 segments remained abnormal on redistribution images. New fill in after reinjection was observed in 11 segments of 32 segments showing persisting defect on stress and delayed image (37%). Wall motion score index of Group 2A improved significantly higher than Group 2B (p less than 0.01) and almost equal to Group 1, suggesting the utility of reinjection for the assessment of tissue viability which may be underestimated by conventional imaging. But significant wall motion improvement (greater than or equal to 0.6 mean SD/chords) was observed in 6 segments (29%) of 21 segments showing neither redistribution nor fill in after reinjection. These data indicate that small dose of thallium reinjection may enhance detection of viable but jeopardized myocardium, although some underestimation of viability remained to be resolved.     

Frequent co-localization of Cox-2 and laminin-5 gamma2 chain at the invasive front of early-stage lung adenocarcinomas

Laminin-5 is an extracellular matrix protein that plays a key role in cell migration and tumor invasion. Cox-2 is an induced isoform of cyclooxygenases that plays an important role in carcinogenesis, suppression of apoptosis, angiogenesis, and metastasis of colon cancer. We report frequent co-expression of cox-2 and laminin-5 at the invasive front of early-stage lung adenocarcinomas. We investigated the expression of cox-2 and laminin-5 immunohistochemically in 102 cases of small-sized lung adenocarcinoma (maximum dimension, 2 cm or less). Cox-2 and laminin-5 were expressed in 97 (95.1%) and 82 (80.4%) cases, respectively. Both were preferentially localized in cancer cells at the cancer-stroma interface, although cox-2 tended to show a diffuse staining pattern in some cases. A comparison of their staining patterns revealed a striking similarity in their distribution in 24 cases, and a partial overlap between their localization in another 20 cases. Moreover, an overall correlation was found between the expression levels of cox-2 and laminin-5 (P = 0.018). To gain insight into the mechanisms that regulate the expression of these proteins, we additionally studied their expression in 58 cases of stage I lung adenocarcinoma, in which p53 status was determined by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism analysis, and direct sequencing. The results showed that tumors with mutant p53 tended to express more cox-2 than those with wild-type p53 (P = 0.080). Also, tumors that overexpressed p53 had higher levels of cox-2 and laminin-5 than those without p53 overexpression (P = 0.032 and 0.047, respectively). Further immunohistochemical analysis showed that tumors that overexpressed both epidermal growth factor receptor (EGFR) and erbB-2 had higher levels of cox-2 and laminin-5 than those without concomitant overexpression of these proteins (P = 0.014 and P = 0.018, respectively). To see whether EGFR signaling is involved in cox-2 and laminin-5 expression, we further conducted in vitro analyses using six lung adenocarcinoma cell lines (A549, HLC-1, ABC-1, LC-2/ad, VMRC-LCD, and L27). Western blot analyses showed that cox-2 mRNA levels, and to a lesser extent laminin-5 gamma2 mRNA levels, correlated with the expression levels of erbB-2 and the phosphorylated form of MAPK/ERK-1/2 protein. The addition of transforming growth factor-alpha increased both cox-2 and laminin-5 gamma2 mRNA levels in A549, ABC-1, and L27 with different kinetics; the induction of cox-2 occurred earlier than that of laminin-5 gamma2. Finally, the migration of ABC-1 cells was inhibited by MAP kinase kinase inhibitor PD98059 and a selective cox-2 inhibitor NS-398. In contrast, the migration of A549 cells was inhibited by PD98059, but much less effectively by NS-398. These results suggest that co-stimulatory mechanisms may exist that increase the expression of cox-2 and laminin-5 at the invasive front of lung adenocarcinomas and that EGFR signaling could be one of the mechanisms. Further investigations are warranted concerning the role of cox-2 and laminin-5 in cancer cell invasion and the significance of p53 and EGFR signaling in the regulation of cox-2 and laminin-5 expression.     

Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer

We previously found frequent loss of heterozygosity at 12q21 and 12q22-q23.1 in primary pancreatic cancers, and the DUSP6/MKP-3 gene residing in this region at 12q22 lost its expression in the great majority of pancreatic cancer cell lines. The DUSP6/MKP-3 protein is a dual-specificity phosphatase that dephosphorylates the active form of ERK, making a feedback loop to control ERK activity. Gain-of-function mutations of KRAS2 occur in the great majority of pancreatic cancer cells, and loss of expression of DUSP6/MKP-3 may synergistically promote constitutive activation of ERK and uncontrolled cell growth. To study loss of the feedback pathway and its impact on pancreatic cancer cell growth, we first investigated the expression of DUSP6/MKP-3 in primary pancreatic cancer tissues immunohistochemically; we found up-regulation in mildly as well as severely dysplastic/in situ carcinoma cells and down-regulation in invasive carcinoma, especially in the poorly differentiated type. Adenovirus-mediated reintroduction of DUSP6/MKP-3 into cultured pancreatic cancer cells induced strong expression of recombinant DUSP6/MKP-3 and reduction of phosphorylated ERK in a dose-dependent manner based on the multiplicity of infection and resulted in suppression of cell growth. Moreover, analyses by flow cytometry and immunocytochemistry revealed that the exogenous expression of DUSP6/MKP-3 induced apoptosis. These results show that DUSP6 exerts apparent tumor-suppressive effects in vitro and suggest that DUSP6 is a strong candidate tumor suppressor gene at 12q22 locus.     

Expression of vascular endothelial growth factor receptor 3 in blood and lymphatic vessels of lung adenocarcinoma

Vascular endothelial growth factor receptor 3 (VEGFR-3) has been proposed as a marker for lymphatic endothelial cells. This study investigated the expression of VEGFR-3 in the tumour vessels of lung adenocarcinoma and evaluated whether VEGFR-3 staining was useful for identifying lymphatic vessels within the tumour stroma. It also explored whether active growth of lymphatic vessels occurred in lung adenocarcinoma. Formalin-fixed, paraffin-embedded specimens obtained from 60 cases of lung adenocarcinoma, including five cases of pure bronchiolo-alveolar carcinoma (BAC) without stromal, vascular, and pleural invasion, were examined. No VEGFR-3-positive vessels were observed in pure BAC, but varying numbers of VEGFR-3-positive vessels were found in 39 of 55 (70.9%) invasive adenocarcinomas. A comparison of serial sections stained for VEGFR-3, CD31, and laminin-1 showed that most of the VEGFR-3-positive vessels appeared to be blood vessels (CD31-positive, laminin-1-positive), but some had the characteristics of lymphatic vessels (variable staining for CD31, little or no staining for laminin-1). VEGFR-3 staining highlighted lymphatic invasion by cancer cells; this invasion could not be detected by CD31 or haematoxylin and eosin (H&E) staining. Active growth of lymphatic vessels (as indicated by nuclear Ki-67 labelling of the endothelium) was observed in five tumours, four of which showed a high level of lymphatic invasion by cancer cells. It was concluded that VEGFR-3 immunostaining did not discriminate clearly between vascular and lymphatic endothelial cells, since expression of VEGFR-3 can be up-regulated in tumour blood vessels. However, VEGFR-3 staining combined with laminin-1 and CD31 staining would be useful for identifying lymphatic vessels and their invasion by tumour cells in a more objective way. Finally, proliferation of lymphatic endothelial cells may occur in association with lymphatic invasion by cancer cells.