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.

[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.

CD4- and TCRalphabeta-positive T lymphocytes predominantly infiltrated into well-moderately differentiated colon adenocarcinoma tissues.

Intraepithelial T lymphocytes have been reported as being functional in the growth of epithelial cells and also in the discrimination of aberrant cells, whereas their function against colon adenocarcinoma cells is obscure. The phenotype of colon intraepithelial T lymphocytes has been found in patients with inflammatory bowel diseases but not in patients with colon adenocarcinoma. In this study, we investigated cell surface markers of tumor-infiltrating T lymphocytes of adenocarcinoma of the colon and rectum at various grades of differentiation and intraepithelial T lymphocytes of adjacent normal colon by enzyme immunostaining. Among intraepithelial T lymphocytes of the normal colon, CD8-and TCRgammadelta-positive T lymphocytes were predominant as described. In contrast, tumor-infiltrating T lymphocytes of well-moderately differentiated adenocarcinoma of the colon and rectum were predominantly CD4- and TCRalphabeta-positive. The decrease of TCRgammadelta-positive T lymphocytes and the increase of CD4 and TCRalphabeta-positive T lymphocytes in adenocarcinoma tissues of the colon and rectum suggests that an alteration of the local immune system participates in the formation of adenoma and/or adenocarcinoma of the colon and rectum, resulting in infiltration of CD4-positive T lymphocytes that have certain activity against transformed cells.

Preservation of recurrent laryngeal nerve invaded by differentiated thyroid cancer.

OBJECTIVE: This study was undertaken to determine whether the recurrent laryngeal nerve involved in differentiated thyroid carcinoma could be preserved. SUMMARY BACKGROUND DATA: Few investigations have provided definitive results concerning preservation of the recurrent laryngeal nerve involved in thyroid cancer. Complete excision with resection of the recurrent laryngeal nerve reportedly did not improve survival over incomplete excision in differentiated thyroid carcinoma. METHODS: A retrospective study was performed with the medical records of 50 patients with differentiated carcinoma and preoperative normal vocal cord function to investigate outcomes of recurrent laryngeal nerve preservation including local recurrence, prognosis, and postoperative vocal cord function. The recurrent laryngeal nerves on 1 or both sides were preserved in 23 patients (the preserved group), whereas the involved recurrent laryngeal nerve of the other 27 patients was resected (the resected group). RESULTS: Backgrounds of patients were similar between the resected and preserved groups. The number of patients with recurrences in each group was similar, and incidence of local, regional, and distant metastatic recurrences were not different between the groups. Postoperative overall survival of the preserved group was similar to that of the resected group (p = 0.1208). More than 60% of patients or of nerve at risk in the preserved group restored normal vocal cord function within 6 months. Some functional vocal cord movement was recognized in 80% of patients or of nerve at risk. All patients in the resected group including patients with nerve anastomosis showed permanent paralysis of the ipsilateral vocal cord. CONCLUSIONS: These results suggested that the recurrent laryngeal nerve, even if infiltrated by differentiated thyroid cancer, is worthwhile to preserve for maintenance of postoperative vocal cord function without affecting the incidence of local recurrence or prognosis.

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.

Prognostic significance of proliferative cell nuclear antigen in carcinoma of the extrahepatic bile duct.

Bile duct cancers are still difficult to cure, and even if curatively resected locoregional recurrences are frequent. Biologic proliferative activity of the cancer may influence postoperative recurrence and the prognosis. A retrospective study was performed with the medical records of 44 consecutive patients who underwent surgery for histologically extrahepatic bile duct cancer (stage 3 or 4) at Osaka Police Hospital during the period 1980 to 1992. Univariate analysis suggested that the stage according to the UICC classification, curability, DNA ploidy, proliferating cell nuclear antigen (PCNA), S-phase and G2M-phase fractions, and histologic differentiation were significant prognostic factors. The Cox's proportional hazard model indicated that PCNA and histologic differentiation were independent prognostic factors for crude and cause-specific survival. When PCNA was omitted from the analysis, DNA ploidy and histologic differentiation were independent prognostic factors for both crude and cause-specific survival. These results suggested that proliferative activity influenced the postoperative prognosis of extrahepatic bile duct cancer.

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.

[Usefulness of expandable metallic stent to bronchial stenosis caused by an advanced lung cancer--a case report].

We used Expandable Metallic Stent (EMS) to bilateral bronchial stenosis due to invasion of lung cancer. A 75-year-old man was admitted to our hospital because of dyspnea and a fainting fit on October 19, 1991. He had been suffered from squamous cell carcinoma of right lung with bilateral bronchial invasion (T4N2M0), which has no indication for surgery. As the stenosis of bilateral main bronchus and the respiratory distress progressed, we applied EMS to the patient and inserted it into the left main bronchus on December 19, 1991. The procedure promptly relieved the respiratory distress and improved his quality of life. Bronchial endoscopy, performed on the 20th postoperative day, revealed the left bronchus patency. Thus, EMS applied to the bronchial stenosis caused by advanced lung cancer may be a choice of palliative therapy and can improve the quality of patient's life.

Gastric varices formation due to pancreatic tumor: a case of successful resection of cystadenocarcinoma.

We report a 70-year-old woman with gastric varices due to splenic vein obstruction by a cystadenocarcinoma of the caudal pancreas. Most of the pancreatic cancer had already extensively progressed and was unresectable when an obstruction of the splenic vein was also discovered. Two contributing factors are thought to have enabled us to perform a curative resection in this case: (1) the gastric varices were detected by chance in a mass survey, (2) the cancer was not so advanced as to be unresectable.

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.

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.

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.

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.

Impaired adrenal vascular response to hemorrhagic hypotension by an adreno-femoral venous shunt.

We studied the influence of an adreno-femoral venous shunt on the regional blood flow in the dog adrenal gland during hemorrhagic hypotension. An adreno-femoral venous shunt was placed transperitoneally in the left adrenal gland while the animal was under pentobarbital anesthesia. The right adrenal gland was left intact. Hemorrhagic hypotension was induced at 50 mm Hg mean arterial blood pressure for 1 hr in six dogs and the other six dogs served as normotensive controls. Nonradioactive microspheres (2 X 10(6), 15 +/- 2 micron) were injected into the ventricle. The adrenal cortical and medullary blood flows were estimated by microscopic counting of the microspheres in the serially sectioned adrenal gland. The total adrenal blood flow (sum of the cortical and medullary blood flows) of two methods was compared; the microsphere method vs timed venous sampling through the shunt. In the intact right adrenal gland, the cortical blood flow was significantly decreased, but the medullary blood flow remained unchanged during hemorrhagic hypotension. Subsequently the total adrenal blood flow was not significantly decreased. In the cannulated left adrenal gland, both the cortical and medullary blood flows were significantly decreased and adrenal vascular autoregulation was inhibited. The total adrenal blood flow calculated by the microsphere method showed a significant correlation with that by timed venous sampling through the shunt. These results indicate that the adrenal medullary vasculature autoregulates during hemorrhagic hypotension and that an adreno-femoral venous shunt abolishes this vascular response.

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.

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.

Segmental auto-transplantation of the pancreas.

A total pancreatectomy was performed in a 39-year-old man diabetic with diffuse calcification of the whole pancreas, a pseudocyst and intrapancreatic bile duct obstruction. The body of the excised pancreas was immediately transplanted into the left groin. The postoperative responses of plasma glucagon and insulin were not impaired compared with their preoperative responses. The patient was relieved of unremitting pain and is doing well six months after this operation.