Contribution of vascular endothelial growth factor to the Nottingham prognostic index in node-negative breast cancer.

The prognostic contribution of intratumour VEGF, the most important factor in tumour-induced angiogenesis, to NPI was evaluated by using flexible modelling in a series of 226 N-primary breast cancer patients in which steroid receptors and cell proliferation were also accounted for. VEGF provided an additional prognostic contribution to NPI mainly within ER-poor tumours.

Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis.

OBJECTIVE: To evaluate the impact of breast carcinoma (T1-2N0) surgery without axillary dissection on axillary and distant relapses, and to evaluate the usefulness of a panel of pathobiologic parameters determined from the primary tumor, independent of axillary nodal status, in planning adjuvant treatment. METHODS: In a prospective nonrandomized pilot study, 401 breast cancer patients who underwent breast surgery without axillary dissection were accrued from January 1986 to June 1994. At surgery, all patients were clinically node-negative and lacked evidence of distant metastases after clinical or radiologic examination. A precise 4-month clinical and radiologic follow-up was performed to detect axillary or distant metastases. Patients with clinical evidence of axillary nodal relapse were considered for surgery as salvage treatment. Biologic characteristics of primary carcinomas were investigated by immunohistochemistry, and four pathologic and biologic parameters (size, grading, laminin receptor, and c-erbB-2 receptor) were analyzed to determine a prognostic score. RESULTS: The 5-year follow-up of these patients revealed a low rate of nodal relapses (6.7%), particularly for T1a and T1b patients (2% and 1.7%, respectively), whereas T1c and T2 patients showed a 10% and 18% relapse rate, respectively. Surgery was a safe and feasible salvage treatment without technical problems in all 19 cases of progressive disease at the axillary level. The low rate of distant metastases in T1a and T1b groups (<6%) increased to 15% in T1c and 34% in T2 patients. Analyzing the primary tumor with respect to the panel of pathologic and biologic parameters was predictive of metastatic spread and therefore can replace nodal status information for planning adjuvant treatment. CONCLUSIONS: Middle-term follow-up shows that the rate of axillary relapse in this patient population is lower than expected, suggesting that only a minimal number of microembolic nodal metastases become clinically evident. Avoidance of axillary dissection has a negligible effect on the outcome of T1 patients, particularly in T1a and T1b tumors with no palpable nodes, because the rate of axillary node relapse is very low for both. In T1 breast carcinoma, postsurgical therapy should be considered on the basis of biologic characteristics rather than nodal involvement. The authors' prognostic score based on the primary tumor identified patients who required postsurgical treatment, providing a practical alternative to axillary status for deciding on adjuvant treatment. Conversely, in the T2 group, the high rate of salvage surgery for axillary relapses, which is expected in tumors larger than 2.5 cm or 3.0 cm, represents a limit for avoiding axillary dissection. Preoperative evaluation of axillary nodes for modification of surgical dissection in this subgroup would be more useful more than in T1 breast cancer because of the high risk. Complete dissection is feasible without technical problems if precise follow-up detects progressive axillary disease.

The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients.

UNLABELLED: There has been growing interest in determining the possible immune consequences of opioid administration for the management of postoperative pain. We studied the effects of morphine and tramadol on pain and immune function during the postoperative period in 30 patients undergoing abdominal surgery for uterine carcinoma. Phytohemoagglutinin-induced T lymphocyte proliferation and natural killer cell activity were evaluated immediately before and after surgery, and 2 h after the acute administration of either 10 mg of morphine IM or 100 mg tramadol IM for pain. In all patients, phytohemagglutinin-induced lymphoproliferation was significantly depressed by surgical stress. However, in the morphine-treated group, proliferative values remained lower than basal levels for 2 h after treatment, whereas in tramadol-administered patients proliferative values returned to basal levels. Natural killer cell activity was not significantly affected by surgery nor by morphine administration, whereas tramadol significantly enhanced the activity of natural killer cells. Both drugs produced a comparable reduction in postoperative pain. We conclude that, as previously observed in the experimental animal, tramadol and morphine, when administered in analgesic doses, induce different immune effects. IMPLICATIONS: Recent studies suggest that opioids can have an adverse impact on the immune system. Because surgical stress also induces immune dysfunction, the search for analgesic drugs devoid of immunosuppressive effects is of import. This study compared the effects on immune responses of morphine and of the atypical opioid analgesic, tramadol, given for postoperative pain to gynecological cancer patients. Tramadol and morphine showed comparable analgesic activity; however, tramadol, in contrast to morphine, induced an improvement of postoperative immunosuppression and, therefore, may be preferred to morphine for the treatment of postoperative pain.

Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.

BACKGROUND: The role of orthotopic liver transplantation in the treatment of patients with cirrhosis and hepatocellular carcinoma is controversial, and determining which patients are likely to have a good outcome after liver transplantation is difficult. METHODS: We studied 48 patients with cirrhosis who had small, unresectable hepatocellular carcinomas and who underwent liver transplantation. In 94 percent of the patients, the cirrhosis was related to infection with hepatitis B virus, hepatitis C virus, or both. The presence of tumor was confirmed by biopsy or serum alpha-fetoprotein assay. The criteria for eligibility for transplantation were the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors. Thirty-three patients with sufficient hepatic function underwent treatment for the tumor, mainly chemoembolization, before transplantation. After liver transplantation, the patients were followed prospectively for a median of 26 months (range, 9 to 54). No anticancer treatment was given after transplantation. RESULTS: The overall mortality rate was 17 percent. After four years, the actuarial survival rate was 75 percent and the rate of recurrence-free survival was 83 percent. Hepatocellular carcinoma recurred in four patients (8 percent). The overall and recurrence-free survival rates at four years among the 35 patients (73 percent of the total) who met the predetermined criteria for the selection of small hepatocellular carcinomas at pathological review of small hepatocellular carcinomas at pathological review of the explanted liver wer 85 percent and 92 percent, respectively, whereas the rates in the 13 patients (27 percent) whose tumors exceeded these limits were 50 percent and 59 percent, respectively (P=0.01 for overall survival; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum alphafetoprotein concentration, treatment received before transplantation, and 10 other variables were not significantly correlated with survival. CONCLUSIONS: Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.

[Hemodynamic changes in orthotopic transplantation of the liver]. / Modificazioni emodinamiche durante trapianto ortotopico di fegato.

OBJECTIVE: To evaluate the hemodynamic changes during orthotopic liver transplantation (OLT). DESIGN: Retrospective analysis of the hemodynamic data during OLT. SETTING: National Cancer Hospital. PATIENTS: Thirty-two patients with hepatic neoplasia and various degrees of cyrrhosis classified according to Child-Pugh. INTERVENTIONS: Orthotopic liver transplantation. MEASUREMENTS AND MAIN RESULTS: For each of the six phases of the operation a complete hemodynamic profile was reported as general mean and as mean of each Child class. The catecholamins given were also reported. At baseline the Child C showed a cardiac index (CI) and heart rate higher than others. At the end of first phase the blood pressure (BP) of the Child C lowered more than the others'. The anhepatic phase was stable. At reperfusion CI increased, the systemic resistances and BP decreased in all the classes. The Child C needed more catecholamins at this time. In the last profile all tended to return to baseline values. CONCLUSIONS: The baseline hemodynamic was the more hyperdynamic the more sever was the cyrrhosis. The Child C, despite a meticolous fluid therapy, were prone to hypotension in response to even minimal decreases of filling pressures. At reperfusion an hemodynamic disturbance featured by systemic vasodilation occurred. It was more severe in the hyperdynamic patients and it was time limited. The causes of this disturbances have not yet been fully elucidated.

Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan.

BACKGROUND: Utilization of alpha-tumor necrosis factor (alpha-TNF) in clinical practice is limited by severe general side effects. Very promising results with low toxicity were reported with administration of alpha-TNF by isolation perfusion in extracorporeal circulation. METHODS: From December 1991 to November 1992, 14 patients underwent perfusion with alpha-TNF (2-4 mg, total dose), gamma-interferon (1.5 x 10(6) IU), and melphalan (10 mg/l/perfused limb). Twelve patients presented in-transit metastases of the limbs, one patient, a clear cell sarcoma of the hand, and one patient, a wide spindle cell carcinoma of the thigh. Perfusion lasted 90 minutes and was conducted in mild hyperthermia (38-40.5 degrees C, muscle temperature). RESULTS: Nine complete regressions and four stable diseases were recorded. In one case, a reliable evaluation of response was not possible for diffused tissue necrosis. Five patients relapsed or progressed locally from 3 to 4 months after surgery, five presented distant localizations from 2 to 7 months after surgery, and one died of disease 6 months after perfusion. Twelve patients are alive, seven without evidence of disease. A septic-like shock syndrome was observed in all patients and required administration of dopamine, dobutamine, or noradrenaline. One patient died 30 days after perfusion from a multiorgan-failure syndrome, likely due to alpha-TNF. The follow-up time ranges from 4 to 15 months (median, 6). CONCLUSIONS: The preliminary, impressive results reported in other series were not completely confirmed in this study adopting the same treatment scheme. Further clinical experience and biologic data are needed to state the real efficacy of the approach and to reduce the severe general toxicity consistently associated with this type of treatment.

Reappraisal of the role of liver transplantation in the treatment of hepatocellular carcinoma arising in cirrhosis.

Several retrospective analyses have recently shown the advantage of liver transplantation (OLT) for patients with hepatocellular carcinoma (HCC) at early tumor stages. Preliminary results of a prospective series of OLT for unresectable small HCC arising in cirrhosis are reported. Eighteen out of 22 patients (82%) are alive without evidence of HCC recurrence after a median follow-up of 11 months.

Treatment of recurrent in transit metastases from cutaneous melanoma by isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study.

Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by isolation perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.

Comparison of glucose vs. Glucose fat solutions in cancer patients: A controlled crossover study.

The purpose of this investigation was to evaluate in a randomised crossover study the effects on nutritional status of two isonitrogenous-isocaloric regimens of total parenteral nutrition (TPN) in 12 severely cachectic cancer patients. The regimens consisted of (1) G: 50 kcal of glucose.kg(-1).day(-1) + 2g amino-acids.kg(-1).day(-1) (2) GL: 30 kcal glucose and 20 kcal lipids.kg(-1) + 2g amino-acids.kg(-1).day(-1). Regimens G and GL were delivered sequentially for a period of 10 days each. Six patients (Group A) were randomised to receive regimen G first and regimen GL subsequently. In Group B patients the regimens alternated in the opposite way. The following nutritional variables were measured before TPN, after regimen G and after regimen GL: weight, arm circumference, arm muscle circumference, triceps skin fold, serum proteins, serum albumin, cholinesterase, transferrin, pre-albumin, retinol-binding protein, peripheral lymphocytes, cumulative nitrogen balance and mean urinary excretion of creatinine and 3-methylhistidine. The data showed that body weight and retinol-binding protein significantly increased with both G and GL regimens. No difference was found in the remaining variables, not even when comparing regimen G to GL. Increase in retinol-binding protein and in nitrogen balance were significantly better in the first period of treatment than in the second. These results show that the two regimens had a similar impact on the nutritional status of the cachectic cancer patients and choice between a glucose or a glucose-fat TPN should depend mainly on tolerance of the patients, duration and cost of therapy.

Impact of hospitalization on the nutritional status of cancer patients.

This study was undertaken to examine the influence of hospitalization on the nutritional status of cancer patients. We examined 126 patients consecutively admitted to the Istituto Nazionale Tumori of Milan. At admission, all patients underwent standard evaluations, including actual weight, percentage weight loss, arm circumference, triceps skinfold, serum proteins, serum albumin, total iron binding capacity, cholinesterase and peripheral lymphocytes. Finally, from all patients a 24-h dietary recall was obtained, in order to calculate calorie and protein intake. All the patients underwent another evaluation after 1 week of hospitalization; after 2 weeks only 37 of them were evaluated again, since some were operated, some were treated with radio-chemotherapy, some were discharged or had died. Results showed that after one week of hospitalization some variables were significantly altered, such as arm circumference in male patients, serum proteins, cholinesterase, total iron binding capacity, peripheral lymphocytes, calorie and protein intake. A significant weight loss was seen after 2 weeks. The reduced calorie and protein assumption was correlated with depletion of some of the nutritional variables (body weight, arm circumference in males, total iron binding capacity, serum albumin, cholinesterase, lymphocytes). Our data show that hospitalization plays an important role in deterioration of nutritional status in our patient population, and this problem is generally overlooked by the clinicians primarily involved in the care of cancer patients.

Total parenteral nutrition prevents further nutritional deterioration in patients with cancer cachexia.

The effects of total parenteral nutrition (TPN) on some nutritional variables were prospectively investigated in 12 severely cachectic patients with advanced cancer. The following variables were determined before and at 5-day intervals during the 20-day administration of TPN: anthropometric indices (body weight, arm circumference, triceps skinfold, arm muscle circumference, arm muscle area, arm fat area, total body muscle mass); biochemical indices (total protein, albumin, cholinesterase, total iron binding capacity, thyroxin-binding prealbumin, retinol binding protein, urinary 3-methylhistidine and creatinine excretion, nitrogen balance); and peripheral lymphocyte count. TPN was delivered at 49.5 nonprotein kcal/kg-1/day-1 (80% as dextrose and 20% as fat) and amino acids 1.9 g/kg-1/day-1. A significant increase was obtained in body weight, triceps skinfold, arm fat area, and retinol binding protein. All remaining anthropometric and biochemical parameters did not show any significant positive or negative change, although nitrogen balance remained positive. No significant liver toxicity was apparent after the TPN period. It was concluded that although TPN is unable to completely reverse some nutrition-related variables in cachectic patients with cancer, most patients were kept within a normal range and some improved. Therefore, further deterioration of the nutritional state, which is characteristic of this phase of disease, was at least prevented.

"Nutritional" markers as prognostic indicators of postoperative sepsis in cancer patients.

A study was undertaken to identify the nutritional parameters associated with a high risk of postoperative sepsis. The nutritional status of 162 cancer patients subjected to clean or clean-contaminated elective surgery was preoperatively evaluated according to the following parameters: percentage weight loss, arm circumference, triceps skinfold, arm muscle circumference, creatinine-height index, total serum protein, serum albumin, total iron-binding capacity, cholinesterase, peripheral lymphocytes, complement C3-C4 components, and skin tests. Patients were followed postoperatively according to a precise protocol to classify them as infected or noninfected. Postoperative sepsis was present in 40 patients who had significantly different mean values for four nutritional parameters from those of 114 patients with no complications, ie, total serum protein, 6.60 vs 6.99 g/dl, p = 0.008; serum albumin, 3.39 vs 3.66 g/dl, p = 0.001; total iron-binding capacity 301.32 vs 337.17 mmg/dl, p = 0.006; and cholinesterase, 2389.77 vs 2770.10 mU/ml, p = 0.005. Moreover, the relative risk and the attributable risk for these variables were evaluated and the significance was tested by the chi 2 test. By using multiple logistic analysis it appeared that only total serum protein and total iron-binding capacity gave an independent contribution to the risk of postoperative sepsis, while serum albumin disappeared and cholinesterase became non significant when the contribution of the first two variables was accounted for. It was also possible to identify, in a small number of patients, combinations of two variables that were associated with a very high risk of postoperative sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional perfusion at high temperature in treatment of stage IIIA-IIIAB melanoma patients.

The results obtained with isolation perfusions in stage IIIA-IIIAB melanoma patients, performed at 42.5-43 degrees C for 2.5 h, are reported. These temperatures and perfusion times were chosen on the basis of experimental data in animal models and in vitro. The clinical results were impressive, but the high percentage of complications and the high cost from a social and human point of view make this experience negative with regard to its clinical applicability, at least with such a high temperature and long perfusion time.

Subclavian venous thrombosis due to indwelling catheters: a prospective study on 52 patients.

Clinical occurrence of subclavian venous thrombosis due to indwelling catheters is rare, but there is some evidence that subclinical thrombosis frequently occurs. It is purpose of this study to report the results of a prospective investigation in patients with subclavian vein catheters. Fifty-two patients admitted to the Istituto Nazionale Tumori of Milan and candidate to infraclavicular percutaneous catheterization of the subclavian vein were evaluated. There were 26 polyvinyl chloride and 26 rubber silicone catheters, which were correctly positioned in the superior vena cava-atrium. Average duration of the intravenous stay was 12.8 days. Asymptomatic thrombosis was venographically demonstrated in 46.1% of the polyvinyl chloride catheters and in 11.5% of the silicone ones (p = 0.005). The average age of catheters with or without thrombosis was 10.8 and 13.8 days, respectively. Addition of heparin to the infusate (1 U/ml) did not reduce the thrombosis rate in polyvinyl chloride or in silicone catheters, but risk of thrombosis was significantly higher (p = 0.03) in polyvinyl chloride catheters without heparin in comparison to the silicone ones. Osmolarity of the infusional fluid, manipulation during the cannulation, colonization of the catheter tip, and duration of the intravenous stay of the catheter apparently did not influence the rate of thrombosis. Since the natural history of the thrombotic subclavian veins is not known, some caution must be paid to repeat the percutaneous cannulation of the same vein and the change the catheter over a guidewire.

Prevention and treatment of central venous catheter sepsis by exchange via a guidewire. A prospective controlled trial.

A new approach for preventing and treating sepsis due to central venous catheter (CVC) has been devised at the Istituto Nazionale Tumori of Milan. A prospective protocol has been developed that includes the weekly exchange of the CVC via a guidewire as well as its exchange when a CVC-related sepsis is suspected. Growth of microorganisms on the tip of the CVC is defined as contamination if peripheral blood culture is negative and as sepsis if it is positive for the same microorganism. Colonization simply means growth of microorganism independently of the results of peripheral blood culture. Two hundred seven CVCs (64 polyvinyl chloride and 143 rubber silicone) were evaluated in 62 patients, for a total of 170 exchanges. The incidence of colonization and sepsis was 33.8% and 4.8%, respectively, a rate which is not significantly different from the values found in 81 historical controls (30.8% and 11.1%). However, it is noteworthy that the sepsis rate was reduced strongly during the first month of observation (0% vs. 11.9%; p = 0.01), whereas in the second month, it was similar in both groups (15% vs. 7.1%). Moreover, it should be noted that three-fourths of the colonized CVCs became negative after the first exchange, and virtually all were negative at the fourth exchange. All of the episodes of sepsis resolved spontaneously with the CVC exchange. The study, therefore, concludes that this procedure: 1) is without risk for CVC cross contamination, 2) is effective in the treatment of contaminated CVCs and of septic patients without any interruption of total parenteral nutrition, and 3) can reduce the incidence of CVC sepsis during the first month of total parenteral nutrition. One must be cautious about the possible onset of pulmonary embolism in patients with subclavian venous thrombosis, since a transient pulmonary embolism occurred in one of the patients. With the use of silastic CVCs, which are less thrombogenic than polyvinyl ones, the rate of pulmonary embolism due to blind exchange (without previous venography) is estimated to be 0.1% to 0.2%.

Management of lymphatic fistulas by total parenteral nutrition.

Lymphatic fistula is a rare surgical complication, which mainly occurs after cervical or retroperitoneal lymph node dissection and which frequently requires a surgical repair. A small series of nine postoperative lymphatic fistulas treated conservatively with total parenteral nutrition (TPN) is reported. All the patients were malnourished at the beginning of the TPN, and all exhibited an objective improvement of their nutritional status after completion of the treatment. Due to the interruption of the enteral alimentation or to the nutritional repletion, spontaneous closure of the fistula was achieved in eight of nine patients treated with TPN longer than 1 week. The authors conclude that whenever the immediate surgical repair is not recommended, or it is not successful, a 2- to 3-week course of TPN may be used with the chance of spontaneous healing. In any case, patients conservatively treated by TPN can undergo a delayed operation with minimal risk because of the improved nutritional status.

Impact of cancer, type, site, stage and treatment on the nutritional status of patients.

This study analyzed the nutritional status of cancer patients in relation to type and site of origin of the tumor, stage of disease, and previous chemical or radiation therapy. The analysis was performed on 321 patients (280 with cancer and 41 controls). The nutritional parameters included per cent of weight loss, anthropometric indices (arm circumference, triceps skinfold, arm muscle circumference), creatinine-height index, serum protein, albumin, total iron binding capacity and cholinesterase, C3 and C4 components of complement, total peripheral lymphocytes, and skin tests. The statistical comparison between patients with different tumors and controls, between patients with different stages of the same tumor, and between patients treated with or without previous chemical or radiation therapy led to the following conclusions: 1) malnutrition is mainly related to the type and site of origin of the tumor and, in the early stages of disease, is more pronounced in patients with cancer of the esophagus and stomach; 2) except in patients with breast and cervix cancer, malnutrition gets more severe as the disease becomes advanced; 3) chemical or radiation therapy has a variable impact on the nutritional status, but in selected patients it causes a drop in body weight, arm circumference, arm muscle circumference, and peripheral lymphocytes; 4) body weight, cutaneous delayed hypersensitivity and serum albumin are the most commonly altered parameters.

Effect of supportive intravenous hyperalimentation on the nutritional status of cancer patients.

The effect of intravenous hyperalimentation on the nutritional status of 84 cancer patients treated at the Istituto Nazionale Tumori, Milan, has been evaluated. The body weight increased in 78% of patients, mid upper arm circumferance in 93%, triceps skinfold in 73%, mid upper arm-muscle circumference in 73%, creatinine/height index in 30%, serum albumin in 32%, transferrin in 35%, total peripheral lymphocytes in 38%. Lymphocyte blastogenesis increased in 74% of the patients examined and skin tests were converted from negative to positive in about 20% of patients. In addition 8 our of 18 patients responsive to IVH benefited from chemotherapy and/or radiotherapy indicating that the nutritional repletion of the host did not significantly affect the growth of the tumor. These findings support the opinion that neoplastic cachexia may depend partially on malnutrition and can be often reversed by IVH. Moreover, IVH might have an adjunctive role as potentiator of chemotherapy which however must be confirmed by clinical trials.