Clinicopathological features of cytokeratin 5-positive pulmonary adenocarcinoma.

Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P = 0.012), smoking history (P = 0.001), higher stage (P < 0.001), histological high-grade components (P < 0.001), vascular invasion (P < 0.001), mucinous differentiation (P < 0.001), spread through airspaces (P < 0.001), EGFR wild-type (P < 0.001), KRAS mutations (P < 0.001), ALK rearrangement (P < 0.001) and ROS1 rearrangement (P = 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P = 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P < 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P < 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.

Angiotensin II restoration of reflex adrenal medullary secretion to anephric dogs is physiologically dose dependent.

Acute nephrectomy seriously impairs hypovolemic adrenal epinephrine (E) release in the anesthetized dog. That systemically delivered angiotensin II totally restores E release to acutely anephric dogs is equally clear, but the dose-response relationship of this angiotensin II effect is not known. Adrenal secretion rates and arterial plasma E, norepinephrine (NE), and dopamine levels were studied in nine groups of mongrel dogs (n = 5 in each group) under pentobarbital anesthesia: 1) resting animals; 2) hemorrhage (25 ml/kg); 3) hemorrhage after acute nephrectomy; 4-7) hemorrhage, acute nephrectomy, plus iv angiotensin II at a) 0.01 ng/kg X min, b) 0.10 ng/kg X min, c) 1.00 ng/kg X min, or d) 10.00 ng/kg X min; 8) no hemorrhage, acute nephrectomy, angiotensin II (10.00 ng/kg X min); and 9) hemorrhage, kidneys intact, iv angiotensin II (10.00 ng/kg X min). Arterial and adrenal blood were sampled during a baseline prehemorrhage period and 15, 30, 60, and 90 min after hemorrhage. We confirm blunting of reflex E release by acute nephrectomy in the anesthetized dog and show that angiotensin II restores E (P less than 0.01), NE (P less than 0.01), and dopamine (P less than 0.01) release in acutely anephric dogs. Aortic plasma E and NE were also restored to normal by angiotensin II (P less than 0.01 for each). Dogs with intact kidneys show a blunted hemorrhage response of arterial plasma E (P less than 0.01), NE (P less than 0.01), and DM (P less than 0.05) to our largest angiotensin II infusion rate (10 ng/kg X min). The study demonstrates that in acutely anephric conditions, angiotensin II support of reflex catecholamine release is sensitively dose dependent to physiological infusion rates of systemic angiotensin II and suggests further that this angiotensin II effect is restrained by the kidneys.

Pancreatic alpha- and beta-cell function in pheochromocytoma.

Arginine infusion tests were carried out in seven patients with pheochromocytoma before and after extirpation of the tumors in order to evaluate pancreatic islet alpha- and beta-cell function during the state of endogenous catecholamine excess. Six of the patients had glucose intolerance; one did not. Preoperatively, the pancreatic glucagon response was suppressed, while the insulin response was comparable to that in normal control subjects. Plasma glucose levels decreased rapidly after the beginning of arginine infusion in all patients. Theses changes during the infusion were evident in the one patient without glucose intolerance. Postoperatively, the glucagon response and plasma glucose changes were normalized. In addition to the obvious suppression of pancreatic alpha-cell function in our patients with pheochromocytoma, it seems likely that pancreatic beta-cell function also was suppressed; there was no enhancement of the insulin response to arginine during the period of chronic hyperglycemia, a situation in which a synergistic effect between glucose and arginine might be expected.

Release of gastric inhibitory polypeptide in totally pancreatectomized patients.

The role of insulin in controlling gastric inhibitory polypeptide (GIP) release was assessed in seven totally pancreatectomized patients, in whom inhibitory effects of endogenous pancreatic hormones on GIP secretion were excluded. In these patients, glucose was ingested on two occasions, once alone and once during insulin infusion using an artificial endocrine pancreas to maintain blood glucose at levels similar to those in normal subjects. Plasma levels of GIP, the maximum response of plasma GIP, and the integrated incremental GIP for 180 min were similar. We conclude that insulin does not alter the secretion of GIP in response to oral glucose when the influence of endogenous pancreatic hormones is excluded.

Differentiated thyroid carcinoma with airway invasion: indication for tracheal resection based on the extent of cancer invasion.

OBJECTIVE: Although aggressive approaches to locally invasive differentiated thyroid carcinoma are reported to improve the prognosis, few investigations have provided an indication for airway resection. The present study was undertaken to determine the best indication for airway resection for differentiated thyroid carcinoma invading the trachea. METHODS: One hundred seventeen patients with differentiated thyroid carcinoma invading surrounding structures were retrospectively studied for local failures and prognosis and were divided into five groups mainly on the basis of macroscopic findings: Group 1 consisted of 40 patients who underwent tracheal resection for deep tracheal invasion; group 2 consisted of 14 patients with deep tracheal invasion and no airway resection; group 3 consisted of 13 patients with superficial tracheal invasion and no airway resection; group 4 comprised 48 patients with extrathyroidal invasion other than laryngotracheal structures; and group 5 consisted of two patients who underwent tracheal resection for superficial invasion. RESULTS: Resectional management of the airway for patients with deep tracheal invasion decreased local recurrence and improved postoperative prognosis compared with nonresectional management for the tumor, or shaving off tumor from the trachea for patients with superficial invasion, did not increase postoperative local failures or mortality (group 3 vs groups 4, 5, and 1). CONCLUSION: These results implied that differentiated thyroid carcinomas with superficially limited invasion could be treated successfully by nonresectional management of the trachea and that those with deep invasion should be treated by resection of the invaded trachea.

Overexpression of p53 protein and DNA content are important biologic prognostic factors for thyroid cancer.

BACKGROUND: Many factors gave been reported to be of prognostic importance for thyroid cancer. Biologic aggressiveness may influence postoperative recurrences and the prognosis of thyroid cancer. Immunohistochemical staining for the p53 protein and DNA content are novel factors that suggest biologic aggressiveness. METHODS: Retrospective study of the survival rate after operation of differentiated thyroid cancer was undertaken at Osaka Police Hospital. Age, gender operative method, extent of lymph node dissection, use of radioiodine, primary or recurrent tumor, tumor size and invasion, lymph node involvement, presence of distant metastases, DNA ploidy, percentage of S phase and G2M phase fractions, positive staining for the p53 protein, and histologic type and subtype were evaluated as possible prognostic factors by univariate and multivariate analyses of survival. RESULTS: Positive staining for the p53 protein was related to postoperative local recurrence, and DNA ploidy was related to distant metastatic recurrence. Univariate analysis suggested that age, tumor size and invasion, lymph node involvement, presence of distant metastases, percentage of S phase fraction, histologic subtype, DNA ploidy, and positive staining for the p53 protein were significant prognostic factors. Multivariate analysis suggested that positive staining of the protein and DNA ploidy were independent prognostic factors for overall survival. CONCLUSIONS: Both positive staining for the p53 protein and DNA ploidy, which suggest biologic aggressiveness, are independent prognostic factors for overall survival of patients with thyroid cancer, Examination of these biologic factors may provide new information regarding postoperative recurrences and the prognosis of thyroid cancer.

Beta-adrenergic regulation of gastrin release from gastrinoma cells.

The effect of epinephrine on the plasma gastrin level was investigated in three patients with Zollinger-Ellison syndrome (ZES) and in 14 normal subjects. Two ZES patients had undergone total gastrectomy, and the third had undergone subtotal gastrectomy before our study. A significant increase in plasma gastrin, from 23 +/- 5 pg/ml to 53 +/- 20 pg/ml, in response to intravenous epinephrine (40 ng/kg.min), was observed in the normal subjects. This response was completely abolished by beta-blockade. In the ZES patients, epinephrine (40 ng/kg.min) also resulted in an increase in the plasma concentration of gastrin. The basal and maximum concentrations of gastrin were 580 and 1680 pg/ml in patient 1, 145000 and 320000 pg/ml in patient 2, and 200 and 1800 pg/ml in patient 3, respectively. beta-Adrenergic blockade suppressed the epinephrine-stimulated gastrin release in these patients as well. Graded intravenous doses of epinephrine given to the ZES patients resulted in elevation of the plasma gastrin in a dose-dependent manner. Insulin hypoglycemia caused an increase in both plasma epinephrine and plasma gastrin in ZES patients and normal subjects. A significant correlation between plasma gastrin and epinephrine during insulin hypoglycemia was observed in both groups. Exercise, with use of a bicycle ergometer, resulted in an increase in plasma epinephrine. An increase in plasma gastrin with exercise was observed in the ZES patients, and this was also suppressed by beta-blockade. The results suggest that gastrinoma cells, like normal G cells, are equipped with beta-adrenergic receptors that regulate gastrin release.

Role of gastric inhibitory polypeptide in altered glucose metabolism after removal of the jejunum in dogs.

To investigate the role of gastric inhibitory polypeptide (GIP) in the abnormal glucose metabolism occurring after resection of the small intestine, we performed a serial observation on secretion of GIP in dogs before and after removal of the jejunum. After removal of the jejunum, glucose intolerance was observed when glucose was administered intraduodenally but not intravenously. Significant decreases were simultaneously observed in the responses of both insulin and GIP 1, 3, and 6 months after the surgery compared with the preoperative controls. The insulin response to intravenous glucose was not altered by removal of the jejunum. The response of GIP to intraduodenal lipid also remained decreased for 6 months after the operation. These results indicate that the GIP deficiency caused by removal of the jejunum may play a role in the poor insulin response to luminal stimuli, which contributes to glucose intolerance.

Removal of mesenteric gastrinoma: a case report.

A 37-year-old man with a primary mesenteric gastrinoma is reported. A parathyroid adenoma had been removed 13 years ago. Six years earlier the patient underwent an emergency distal gastrectomy because of massive bleeding from a duodenal ulcer. Two months later stomal ulcers developed associated with hypergastrinemia. No gastrinoma was detected and total gastrectomy was performed. The fasting plasma level of gastrin was stable in the range from 580 to 920 pg/ml for the following 5 years. However, the level was found to abruptly increase to 4125 pg/ml. The level increased progressively to 11383 pg/ml within 1 year. A gastrinoma was identified in the jejunal mesenterium, and it was completely removed. After surgery the plasma level of gastrin decreased below the limit of the assay, and the paradoxical response to secretin was no longer observed.

An electron microscopic study on VIP-, BOM- and CCK-like immunoreactive terminals in the celiac-superior mesenteric ganglion complex of the guinea pig.

The distribution and fine structure were studied of the following 3 peptide-containing fibers of enteric origin, vasoactive intestinal polypeptide (VIP), bombesin (BOM) and cholecystokinin (CCK)-like immunoreactive peptide in the celiac-superior mesenteric ganglion complex (CMG) of the guinea pig. These peptides, especially VIP, were distributed more densely on the mesenteric side than on the celiac side of the CMG, and their distribution shared a similar mosaic pattern. Immunoelectron microscopic analysis revealed that the fibers formed synaptic contacts with the proximal dendrites of the principal ganglion cells, however, the profiles of these synaptic junctions differed between fibers. Those containing VIP or CCK formed symmetrical synapses, while those containing BOM formed assymetrical ones. This suggests that there are some functional differences between these enterofugal fibers in the CMG.

Projections of bombesin-like immunoreactive fibers from the rat stomach to the celiac ganglion revealed by a double-labeling technique.

Gastrofugal bombesin (BOM)-like immunoreactive (BOMI) structures in the rat were studied by immunocytochemistry combined with retrograde labeling. Transection of the mesenteric nerve peripheral to the celiac ganglion resulted in the complete disappearance of BOMI nerve terminals, whereas transection of the splanchnic nerves did not alter the immunoreactivity. Injection of biotinylated wheat germ agglutinin into the celiac ganglion labeled several neurons in the myenteric ganglion of the stomach. Simultaneous staining with antiserum against BOM showed that some of them are BOMI-positive. These findings demonstrate that BOMI neurons in the myenteric ganglion of the rat stomach project to the celiac ganglion.

Distribution of peptidergic terminals of enteric origin in the rat celiac ganglion.

We examined the distribution of enterofugal nerve terminals of bombesin-, cholecystokinin- and vasoactive intestinal polypeptide-like immunoreactivity in the rat celiac-superior mesenteric ganglion complex. The majority of these nerve terminals were concentrated in the mesenteric side of the ganglion. The present findings suggest that some functional specialization occurs in the celiac ganglion of the rat.

Reconstruction of portal vein with an autograft of splenic vein.

To re-establish the portal circulation following extensive resection of the portal vein, we interposed an autograft of the splenic vein between the portal and superior mesenteric veins during total pancreatectomy in three patients with cancer of the pancreas. The postoperative course in two patients was uneventful, and patency of the graft was demonstrated angiographically on the 41st and 78th postoperative days, respectively. In the remaining patient an episode of postoperative peritonitis occurred with leakage of the gastrointestinal anastomosis. The patient died on the 78th postoperative day from a massive metastasis to the liver. Autopsy revealed a narrowing of the graft due to technical failure and inflammatory changes, but there was no evidence of cancer invasion. Thus, the autograft of the splenic vein proved useful to bridge the portal vein system.

[A preliminary study on dihydropyrimidine dehydrogenase activity in breast cancer].

We studied dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS), key enzymes in regulating the pharmacokinetics and chemosensitivity to 5-FU, in 36 breast cancer patients as a control group and 18 patients as a 5-FU group, in which 5-FU was given orally for 2 weeks before surgery at a dose of 200 mg/day. Cancer tissues with adjacent normal tissue were sampled and stored until the assay. The DPD activity and TS amount were determined according to the radio-enzymatic assay and radiobinding assay, respectively. The DPD activity was significantly higher in breast cancer than in the adjacent breast tissue. This finding was observed in T1 and T2, node negative and ER positive breast cancers in the control group as well as in the 5-FU group. The DPD activity in T3 was significantly lower than in T1, and that of the adjacent breast tissue in T3 was significantly higher than in T1; therefore, the tumoral/non-tumoral ratio of DPD activity was significantly lower in T3 than T1. TS was significantly elevated in both groups, without significant differences. The clinical implication of elevated DPD activity in T1, T2, node negative or ER positive breast cancer compared to the respective normal breast tissue activity remains to be studied, because it is still unclear whether or not the tumoral DPD activity regulates the local concentration of 5-FU within the tumor. The amount of TS and DPD activity was not influenced by the oral administration of 5-FU for 2 weeks at the dose of 200 mg/day.

[Thermo-chemotherapy using low-dose CPT-11 in a patient with local recurrence of rectal cancer].

We report a case of pelvic recurrence of advanced rectal carcinoma, presenting a favorable response with a low dose (25 mg/m2) of CPT-11 (Irinotecan) combined with topical hyperthermia for relapse after treatment with 4 cycles of high-dose (100 mg/m2) CPT-11 chemotherapy alone. This combination therapy was safely carried out on an outpatient basis. The degrees of recovery of the left lower limb pain and edema, and of serum CEA reduction were comparable to those in high-dose chemotherapy alone. No significant adverse effects were encountered in the thermo-chemotherapy attempted. Since hyperthermic treatment enhances the cytotoxic effects of CPT-11 in vitro, topical hyperthermia with low-dose CPT-11 therapy may produce a response comparable to that in high-dose CPT-11 chemotherapy alone. However, an optimal dose and comparative study with other chemotherapeutic agents would be needed. This regimen may be advantageous in the maintenance of quality of life for the palliation of postoperative pelvic recurrence since this treatment can be performed on an outpatient basis.