Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group.

OBJECTIVE: The study was conducted to determine whether the performance of an extended lymphadenectomy and retroperitoneal soft-tissue clearance in association with a pancreatoduodenal resection improves the long-term survival of patients with a potentially curable adenocarcinoma of the head of the pancreas. SUMMARY BACKGROUND DATA: The usefulness of performing an extended lymphadenectomy and retroperitoneal soft-tissue clearance in conjunction with a pancreatoduodenal resection in the treatment of ductal adenocarcinoma of the head of the pancreas is still unknown. Published studies suggest a benefit for the procedure in terms of better long-term survival rates; however, these studies were retrospective or did not prospectively evaluate large series of patients. MATERIALS AND METHODS: Eighty-one patients undergoing a pancreatoduodenal resection for a potentially curable ductal adenocarcinoma of the head of the pancreas were randomized to a standard (n = 40) or extended (n = 41) lymphadenectomy and retroperitoneal soft-tissue clearance in a prospective, multicentric study. The standard lymphadenectomy included removal of the anterior and posterior pancreatoduodenal, pyloric, and biliary duct, superior and inferior pancreatic head, and body lymph node stations. In addition to the above, the extended lymphadenectomy included removal of lymph nodes from the hepatic hilum and along the aorta from the diaphragmatic hiatus to the inferior mesenteric artery and laterally to both renal hila, with circumferential clearance of the origin of the celiac trunk and superior mesenteric artery. Patients did not receive any postoperative adjuvant therapy. RESULTS: Demographic (age, gender) and histopathologic (tumor size, stage, differentiation, oncologic clearance) characteristics were similar in the two patient groups. Performance of the extended lymphadenectomy added time to the procedure, although the difference did not reach statistical significance (397 +/- 50 minutes vs. 372 +/- 50 minutes, p > 0.05). Transfusion requirements, postoperative morbidity and mortality rates, and overall survival did not differ between the two groups. When subgroups of patients were analyzed, using an a posteriori analysis that was not planned at the time of study design, there was a significantly (p < 0.05) longer survival rate in node positive patients after an extended rather than a standard lymphadenectomy. The survival curve of node positive patients after an extended lymphadenectomy could be superimposed onto the curves of node negative patients. Survival curves in node negative patients did not differ according to the magnitude of the lymphadenectomy. Multivariate analysis of all patients showed that long-term survival was affected by tumor differentiation (well vs. moderately vs. poorly differentiated, p > 0.001), diameter (< or = 2.0 cm. vs. > 2.0 cm., p < 0.01), lymph node metastasis (absent vs. present, p < 0.01) and need for 4 or more units of transfused blood (< 4 vs. > or = 4, p <0.01). CONCLUSIONS: The addition of an extended lymphadenectomy and retroperitoneal soft-tissue clearance to a pancreatoduodenal resection does not significantly increase morbidity and mortality rates. Although the overall survival rate does not differ in the two groups, there appears to be a trend toward longer survival in node positive patients treated with an extended rather than a standard lymphadenectomy.

Pancreatic cancer resection in elderly patients.

BACKGROUND: Pancreatic cancer resection is considered a high-risk procedure in patients aged 70 years or older. METHODS: Some 398 patients with pancreatic adenocarcinoma, observed between 1990 and 1995, were reviewed. Operative outcome and survival of 33 patients aged 70 years or more were compared with findings in 85 younger patients who underwent resection. RESULTS: Resectability was not significantly different between the elderly and younger patients; neither were mortality or overall morbidity. However, patients aged 70 years or more had more relaparotomies (P < 0.01) and more haemorrhagic complications (P < 0.001). Nutritional recovery after resection was satisfying even for elderly patients (body-weight gain and increase in serum albumin concentrations, P < 0.05). Univariate analysis showed a moderately poorer survival in the elderly (P = 0.09). Multivariate analysis demonstrated that tumour diameter, grading and Union Internacional Contra la Cancrum stage were independent prognostic factors, whereas age was not. CONCLUSION: Patients aged 70 years or more can benefit from pancreatic cancer resection similarly to younger patients.

The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats.

Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin (ET-1) levels and with selective enhancement of ET-1 peptide and messenger RNA (mRNA) and endothelin-A (ET-A) receptor mRNA in rat lung. Our study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, can prevent hypoxia-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with A-127722 (3, 10, and 30 mg/kg/day in drinking water for 2 days) caused dose-dependent inhibition of the pulmonary vasoconstrictor response to short-term hypoxia (10% O2, 90 min). Long-term A-127722 treatment (10 mg/kg/day in drinking water for 2 weeks) instituted 48 h before hypoxic exposure attenuated the subsequent development of pulmonary hypertension, the associated right atrial hypertrophy, and pulmonary vascular remodeling. Institution of A-127722 treatment (10 mg/kg/day in drinking water for 4 weeks) after 2 weeks of hypoxia retarded the progression of established hypoxia-induced pulmonary hypertension and right atrial hypertrophy and reversed the pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that ET-A receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.

Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats.

The current study examined the effects of bosentan, an orally active antagonist of endothelin-A and -B receptors, on the development and maintenance of hypoxia (10% O2)-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with bosentan (100 mg.kg-1.day-1, 1 gavage/day for 2 days) completely blocked the pulmonary vasoconstrictor response to acute hypoxia. Chronic bosentan treatment (100 mg.kg-1.day-1 po in the food) instituted 48 h before hypoxic exposure prevented the subsequent development of pulmonary hypertension, attenuated the associated right heart hypertrophy, and prevented the remodeling of small (50-100 microns) pulmonary arteries without altering systemic arterial pressure. Institution of bosentan treatment (for 4 wk) after 2 wk of hypoxia produced a significant reversal of established hypoxia-induced pulmonary hypertension (from 36 +/- 1 to 25 +/- 1 mmHg), right heart hypertrophy, and pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous endothelin-1 plays a major role in hypoxic pulmonary vasoconstriction and/or hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that endothelin-receptor blockade may be useful in the treatment of hypoxic pulmonary hypertension humans.

ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat.

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

Medullary-thyroid carcinoma - clinical-evaluation of 19 cases.

Medullary thyroid carcinoma (MTC) accounts for 5-10% of thyroid malignancies and occurs either as a sporadic or as a familial form. The familial form is inherited in an autosomal dominant pattern, and it is clinically expressed as multiple endocrine neoplasia (MEN), types IIa and IIb or as familial MTC alone. It is possible to make an early diagnosis in patients who have the familial form of the disease as well as to perform an organ specific localisation regarding possible spread of the disease. Calcitonin is a major product of MTC cells and represent the most used tumour marker for diagnosis and evaluation of prognosis. The purpose of this investigation is to analyse our experience with patients treated for MTC in the period 1980-1993.

Paradoxical release of insulin by adult pig islets in vitro. Recovery after culture in a defined tissue culture medium.

In this study, in vitro responsiveness to glucose of fresh and cultured islets from adult pigs was tested under both static (incubation) and dynamic (perifusion) conditions. Islets were isolated by an automated method from pancreases of 24-month-old animals and cultured overnight in CMRL 1066 and 10% FCS plus antibiotics; islets, perifused immediately after the overnight culture, showed a paradoxical decrease in insulin release when exposed to an acute glucose stimulus (16.7 mmol/L), and a normal response to acute glucose when isobutylmethylxanthine (IBMX) was added to the perifusing buffer. In addition, an acute reduction of glucose concentration in the perifusate elicited a paradoxical insulin release. At the microscope, islets appeared loose and irregularly shaped after the overnight culture; immunohistochemistry showed loss of peripheral A and other mantle cells. After the overnight culture, islets were divided into 5 groups and were cultured for a further 48 hr in different tissue culture media: CMRL 1066; RPMI 1640 (without glucose); RPMI 1640 (plus 11.1 mmol/L glucose); Ham's F12; and medium 199 (all media were supplemented with 10% FCS and antibiotics). During this period, insulin release was 11.4 +/- 1.1 pg/islet/min in islets cultured in CMRL 1066, 16.2 +/- 2.4 in islets cultured in RPMI 1640 (11.1 mmol/L glucose), 1.8 +/- 0.2 (P < 0.001 vs. all the other groups), and 9.0 +/- 0.6 and 8.4 +/- 0.9 pg/islet/min in islets cultured in RPMI 1640 (without glucose), Ham's F12, and medium 199, respectively. After the 48-hr culture in different media, the islets' responsiveness to an acute glucose stimulus (16.7 mmol/L; static incubation) was evaluated: islets cultured in CMRL 1066 and in RPMI 1640 (with and without glucose) showed no insulin response to the acute glucose stimulus; in contrast, insulin release rose from 0.42 +/- 0.06 to 0.60 +/- 0.12 pg/islet/min (NS) in islets cultured in Ham's F12, and from 0.24 +/- 0.06 to 0.48 +/- 0.06 pg/islet/min (P < 0.001) in islets cultured in medium 199. During perifusions, the paradoxical insulin release in response to an acute fall in glucose concentration disappeared, but a significant increase in response to high (16.7 mmol/L) glucose was observed only in islets previously cultured in medium 199. To assess the possible role of glucagon and of cAMP, additional perifusions were done in islets cultured for 48 hr in CMRL 1066 in the presence of glucagon (10 mumol/L) and IBMX (10 mumol/L); glucagon and IBMX were unable to modify the insulin response to 16.7 mmol/L glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Prognostic ability of nutritional assessment methods in surgical cancer patients.

To identify patients at high-risk for post-operative infections, several methods have been proposed, including prognostic nutritional index (PNI), instant nutritional assessment (INA) and nutritional assessment (NA). Weight loss (WL) has also been related to post-operative morbidity. We have evaluated the prognostic ability of PNI, INA, NA and WL in a prospective study carried out in 94 patients affected by gastro-intestinal malignancy, who underwent major surgery. Post-operative infections occurred in 26 (27.7%) patients. PNI, INA and NA identified classes of patients with a progressive risk of septic complications. To determine the prognostic ability of PNI, INA, NA and WL, sensitivity, specificity, Youden index and predictive values were evaluated. All methods had a Youden index greater than one, with a positive predictive value ranging from 0.33 to 0.36. Since all the methods studied showed a similar predictive ability, it seems reasonable to identify the high-risk surgical patient by using weight loss in association with those nutritional parameters derived from routine hospital laboratory tests.

Prognostic role of preoperative nutritional and immunological assessment in the surgical patient.

The utilization of delayed hypersensitivity response (DHR) for the identification of high-risk patients with regard to postoperative septic complications is still discussed. The aim of this study was to clarify how much DHR may improve the prognostic capacity of nutritional assessment (NA). Nutritional and immunological evaluations were performed at admission on 405 patients undergoing elective general surgical procedures. Subjects with serum albumin less than or equal to 3.0 g/dl or total iron-binding capacity less than or equal to 220 micrograms/dl or weight loss greater than or equal to 10% with respect to usual body weight were classified as malnourished. DHR was assessed by performing skin tests with four recall antigens: PPD, candida, trichophyton, sk-sd. The incidence of postoperative complications resulted higher among the 187 malnourished patients (31.0%) than in the 218 well-nourished ones (14.2%) (p less than 0.001), and among the 213 anergic patients (29.6%) than in the 192 normal responders (13.5%) (p less than 0.001). To determine how much skin tests may improve the prognostic ability of NA, the relationship between DHR and postoperative complications was also studied in the malnourished and in the well-nourished patients, separately. In the malnourished group, the patients with an impairment of DHR had a higher incidence of postoperative infections than normal responders (p less than 0.05). In the well-nourished group, no significant differences were found between anergic patients and normal responders. In our study, DHR slightly improved the prognostic capacity of NA. Therefore, the first approach to identify the high-risk patients seems to be the unexpensive, quick and available determination of nutritional status.

Causes of anergy in the surgical patient and its relationship to postoperative sepsis.

Between June 1981 and June 1983 the delayed hypersensitivity response (DHR) was studied in 401 patients considered for major surgical procedure: 320 of these patients underwent surgery. The incidence of sepsis and postoperative mortality was higher in anergic and relative anergic patients than in normal responders (p<0.001). To evaluate whether DHR depression in cancer patients was due to the direct effect of cancer or to tumour-linked malnutrition, the 401 patients were divided into 4 groups: 1) 140 malnourished cancer patients, 2) 51 malnourished non-cancer patients, 3) 120 well-nourished cancer patients and 4) 90 well-nourished non-cancer patients. The mean age was not significantly different for the 4 groups. The results showed a relationship between DHR and nutritional status (p<0.001). The tumour-related DHR impairment disappeared when the cancer and non-cancer patient groups were homogeneous with regard to their nutritional status. Therefore, the tumour was able to determine the DHR depression because of the cancer-linked malnutrition. We did not observe any relationship between local extension of the tumour and lymph node involvement and DHR depression. In 90 well-nourished non-cancer patients the relation between DHR and age was investigated. The incidence of anergy and relative anergy was higher in patients over 59 years than in patients under 60 years (p<0.001).

Liver biopsy and percutaneous cholangiography using a posterior approach. 500 needle biopsies and 121 cholangiographies.

A technique of posterior percutaneous liver biopsy and cholangiography was used in 500 liver biopsies and 121 cholangiographic examinations of the biliary tract. It provided a successful liver biopsy in 98.6 percent of cases and was associated with a less than 2 percent complication rate. Successful cholangiography was possible in all patients with dilated ducts and in 87 percent of patients with normal undilated ducts. Percutaneous cholangiography was associated with a 5 percent complication rate. The advantages of this technique are that it can be performed by relatively inexperienced physicians with minimal risk of hemo- or choleperitoneum. It has a low failure rate and can be performed in obese patients or patients with coagulation defects. The route of entry eliminates the risk of injury to the gallbladder or colon. Due to the posterior position, this technique can be used in relatively uncooperative patients.

The role of cardiovascular hemodynamics and liver histology in evaluating bleeding cirrhotic patients.

Preoperative cardiovascular hemodynamics and percutaneous liver biopsies were used to evaluate the pathophysiologic factors determining the operative prognosis of patients with cirrhotic liver disease and bleeding esophageal varices. These studies confirm the observations of Siegel that the greater the magnitude of the peripheral abnormalities in vascular tone and oxygen consumption the better must be the capability of the ventricular function, if the cirrhotic is to survive emergency or urgent portal decompressive surgery. These studies also show that the cardiovascular hemodynamics are directly correllated with the nature and degree of the abnormalities in the liver biopsy, and that pathologic and physiologic features of this disease which impact on surgical prognosis can be expressed through the easily obtained Survival Index. Bleeding cirrhotic patients with poor quality hemodynamics and poor histologic characteristics should be treated non operatively, since the operative mortality appears greater than that produced by a strategy of medical supportive therapy and delayed surgery if stabilization occurs.