[Surgical resection of gastrointestinal stromal tumor after treatment with imatinib: clinical case]. / Resezione chirurgica di un tumore stromale gastrointestinale dopo trattamento con imatinib: un caso clinico.

The stromal tumor is the most common mesenchymal tumor of the gastrointestinal tract. Surgical resection is the first-line therapy for operable lesions, however for inoperable imatinib is an effective therapy. In this setting a patient has been operated after a remarkable response to imatinib, used as both neoadjuvant and adjuvant. This approach led to a disease-free condition without toxicity and complications.

Intraperitoneal mitoxantrone: a feasibility and pharmacokinetic study.

Fractionated doses have been advocated to prevent chemoperitonitis after intraperitoneal infusion of mitoxantrone. Patients with peritoneal carcinomatosis of various origin underwent surgery, including intestinal resections, with minimal residual disease. Peritoneal mitoxantrone in 1000 ml/m(2) saline was planned on the first post-operative day in groups of four patients (5 mg/m(2) for 3 and 5 days, 7.5 mg/m(2) for 3 and 4 days, 10 mg/m(2) for 2-4 days, if possible). Due to dose-limiting myelosuppression, only one and three patients received the 7.5-mg 4-day and 10-mg 3-day regimens, respectively. A total of 20 patients were consequently treated. Neither major complications nor severe pain were observed. Pharmacokinetics were completed on the 1st day in five 5-mg and five 10-mg patients, on the 5th day in three 5-mg patients, and on the 3rd day in one 10-mg patient. On the 1st day, mean peritoneal peak concentrations of mitoxantrone resulted 1.45 +/-0.56 (range 0.48-1.9) and 1.9+/-0.85 (range 1.27-3.13) microg/ml in the 5-mg and 10-mg patients, respectively. Mean dialysate/plasma exposure (AUC) ratio was 115. Even in patients with sutures, early post-operative fractionated intraperitoneal mitoxantrone appears feasible and safe, with a high local advantage, for up to 5 days of treatment and a maximum tolerated total dose of 20-25 mg/m(2).

Timing of surgery related to menstrual cycle and prognosis of premenopausal women with breast cancer.

The influence of the timing of surgery in relation to the menstrual cycle on the survival of breast cancer patients has been both advocated and disputed. The records of 165 premenopausal M- breast cancer women consecutively operated from 1977 to 1991 were reviewed. All patients underwent modified radical mastectomies or quadrantectomies plus postoperative radiotherapy. Node-positive patients received adjuvant chemotherapy. Cox regression analysis was used to estimate the relative risk (RR) of death in three models including timing of surgery, age, histology, pT and pN. In each model, patients were divided into two groups according to the criteria proposed by Badwe, Hrushesky, and Senie. Multivariate analysis showed a significant association between pT and pN and survival, whereas no association with survival was observed for the timing of surgery according to either Badwe or Hrushesky or Senie (RR = 1.26, RR = 0.91 and RR = 0.88 respectively). Consensus on the menstrual phase related to the expected best prognosis is still required.

Conventional isolated hyperthermic antiblastic perfusion in the treatment of recurrent limb melanoma.

Hyperthermic Antiblastic Perfusion (HAP) is a widely used method for the treatment of recurrent limb melanoma. In terms of tumor response, locoregional control and survival HAP has led to better results than those achieved with any other treatment. The aim of this report is to analyze our own experience with HAP in locally advanced limb melanoma. Thirty-two patients were submitted to HAP. HAP lasted 60 minutes, with maximal local temperature of 40.5-42 degrees C using melphalan 10 mg/L limb volume as antiblastic agent. Twenty patients had in-transit metastases and 12 local recurrence. Regional nodes were involved in 12 patients. Systemic leakage monitored with 125I or 99Tc ranged between 5-30% (mean 14%). No operative mortality nor major complications occurred. Local toxicity scored Wieberdink grade I in 8 patients, grade II in 17, grade III in 6 and grade IV in 1 case. Response rate (UICC) in the 16 patients treated with unexcised lesions was 94% (56% complete responses). With a median follow-up of 29 months (2-126) 14 patients relapsed after a median time of 10 months, and 17 patients are currently disease free, 3 of these are being reexcised and 3 re-perfused. Actuarial 5 years survival was 64%, with 39% disease free to the first relapse. Our results are consistent with the literature indicating HAP as a safe procedure with a high evidence of clinical responses.

Palliative chemoembolization of hepatocellular carcinoma with mitoxantrone, Lipiodol, and Gelfoam. A phase II study.

Transcatheter chemoembolization, in conjunction with various drugs, has been widely used for palliative treatment of hepatocellular carcinoma. A phase II study was carried out on mitoxantrone chemoembolization. High risk cirrhotic patients were excluded from this study. Fourteen mg/m2 mitoxantrone and up to 20 ml Lipiodol were injected, followed by Gelfoam embolization as indicated. Thirty-seven patients (33 with cirrhosis) were treated. Sixty-nine cycles were delivered, with mean (+/-SD) Lipiodol and emulsified mitoxantrone doses of 11.3+/-3.8 ml and 11.8+/-5.2 mg, respectively. Thirteen, 16, and 8 patients received one, two, and three cycles, respectively, with time intervals of 123+/-60 days. Thirty patients received Gelfoam embolization at the first cycle, 9 at the second and 4 at the third. No treatment-related deaths occurred. Complications were mild and transient, including nausea/vomiting in most cases, fever over 38 degrees C 67%, pain 74%, ascites 8%, jaundice 3%, bleeding 3%, pancreatitis 3%, myelosuppression 44%, diarrhea 5%. Treatment response rate was 49% (including 16% minor responses) with 16% early progressions. With a median follow-up of 12 months, the 12-month response duration and survival rates were 56% and 79% respectively. Transcatheter chemoembolization with mitoxantrone appears to be a promising method for the palliation of advanced hepatocellular carcinoma, and deserves to be evaluated in well controlled randomized studies.

Pharmacological control of intimal hyperplasia in small diameter polytetrafluoroethylene grafts. An experimental study.

OBJECTIVE: The efficacy of a postoperative treatment with Low molecular weight heparin (LMWH) vs Ticlopidine in controlling early thrombosis, intimal hyperplasia and growth of true endothelial cells in small prosthetic expanded polytetrafluoroethylene (ePTFE) grafts (4 mm) interposed in the carotid artery of sheep has been evaluated. EXPERIMENTAL DESIGN: Thirty animals were randomized into three different groups: control group (CTRL); ticlopidine hydrochloride (TICL) 250 mg/b.d. by month for 4 weeks from day 1; LMWH 3,085 IU AXa s.c. preoperatively and once a day for the same period. RESULTS: Complete thrombosis of the graft occurred in 7 sheep in the CTRL group and 5 in the TICL group while 2 partial thrombosis were observed in the LMWH group (n.s.). In all the evaluable cases, hyperplasia was observed in both anastomotic areas and did not involve the middle portion of the graft. The mean +/- SD intimal thickness was 603 +/- 20 micron in the CTRL group, 356 +/- 10 in the TICL group and 152 +/- 17 in the LMWH group (p < 0.001) compared to the 60 +/- 12 of the normal intima. True endothlial cells were found mainly in the LMWH group close to the arterial anastomosis. CONCLUSIONS: The postoperative use of LMWH seems to inhibit intimal hyperplasia, with interesting results also on patency and cellular coverage. Further studies are necessary to support this promising trend.

Effect of hyaluronidase on the pharmacokinetics of free and total platinum species after intra-arterial Cisplatin in refractory patients with colorectal liver metastases.

A pharmacokinetic study was carried out in patients with unresectable colorectal liver metastases who had primarily been included in a phase II trial of intra-arterial cisplatin (DDP) plus intravenous fluorouracil. Ten patients of those accrued for the clinical study underwent the pharmacokinetic investigation upon liver progression of the disease. Four patients were treated with DDP (24 mg/m(2)) through short intra-arterial infusion (baseline study) and 4 patients received intra-arterial hyaluronidase (HY, 100 000IU) 2 minutes before DDP infusion. Two additional patients were treated with both DDP alone and DDP + HY. Plasma concentrations of total and free platinum (Pt) were consistently lower than baseline in the presence of HY. HY administration resulted in a longer terminal half-life (2.1 ± 0.7 vs 1.0 ± 0.2 days, p < 0.05), a reduced area under the plasma concentration-time curve from 0 to 2 hours (AUC0-2h) [0.08 ± 0.009 vs 0.12 ± 0.017 g/L•min, p < 0.01], and an increased volume of distribution, both initially (11.7 ± 3.4 vs 6.6 ± 2.1L, p < 0.05) and at steady-state (43.0 ± 10.8 vs 22.1 ± 8.8L, p < 0.05), for total Pt. However, significant HY-related effects on the overall plasma exposure (AUC0-∞) to total Pt or on the total body clearance were not observed. HY treatment was also associated with a lower plasma concentration at time zero (C0) [p < 0.01 ] and AUC0-2h (p < 0.02), and a higher plasma clearance (p < 0.02) and apparent volume of distribution (p < 0.05), for free Pt. Renal clearance (CLR) and cumulative urinary excretion of Pt were significantly increased (p < 0.01) by HY, while fluid output was not significantly affected. The increase in both CLR and the extent of Pt distribution was not due to a protein binding drug interaction nor to a reaction between DDP and HY in the plasma. Combined treatment with HY yielded a clinically acceptable toxicity.

Screening for abdominal aortic aneurysms and associated risk factors in a general population.

OBJECTIVES: To evaluate the prevalence of abdominal aortic aneurysms (AAA) in a general population and to compare the results with those of similar studies in other countries. DESIGN: Ultrasound screening study and collection of clinical and biochemical data. SETTING: An urban Health Service District in Genoa, Italy. MATERIALS: A general population, aged 65-75 years, invited by personal letter between 1991-1994. RESULTS: 1601 subjects (741 males and 860 females) out of 2734 invited (58.5%) were evaluated. According to the ultrasound findings, 27 patients (1.7%) had an aortic dilatation of 26-29 mm; an AAA of 30-39 mm was found in 37 (2.3%) and an AAA > or = 40 mm in 33 (2.1%). The overall prevalence for AAA was 4.4% (8.8% in males and 0.6% in females respectively). The prevalence of smoking, alcohol consumption, coronary heart disease, chronic obstructive pulmonary disease and arterial disease were significantly higher in patients with AAA (p < 0.01). CONCLUSIONS: Ultrasound screening for AAA is a reliable and useful method and should be focused on men, regardless of concurrent disease.

[Screening for abdominal aortic aneurysms in the general population. Preliminary results]. / Screening per gli aneurismi dell'aorta addominale nella popolazione generale. Risultati preliminari.

Between March 1991 and April 1993, 1188 subjects aged 65-75 years, out of 2734 invited, underwent abdominal ultrasound for screening of asymptomatic abdominal aortic aneurysms (AAA). For each patient the maximal anteroposterior and transverse diameters of the suprarenal and infrarenal aorta were measured. According to the literature data an AAA is defined as an aortic dilatation > 29 mm. AAA < 40 mm are followed by ultrasound every 6 months and the AAA > 39 mm are considered for surgical repair after complete clinical work-up. In addition any aortic dilatation ranging 26-29 mm is followed too, using the same criteria. The aorta was normal in 1112 patients (95.12%), an infrarenal aortic dilatation was found in 21 patients (1.79%), an AAA < 40 mm in 15 patients (1.28%) and an AAA > 39 mm in 21 patients (1.79%). The global prevalence of AAA > 29 mm was 3.07% (0.3% for the females and 6.8% for the males), similar to that reported by other authors. The statistically significant (p < 0.01) risk factors were: smoking, alcohol consumption, coronary disease and chronic lung obstruction. Hypertension and dyslipidaemia were not significant (but HDL-cholesterol and Apo-B), according to a different etiology of the aneurysms. In addition 38.5% of the patients had total cholesterol > 240 mg/dl but only 34.9% of these was under medical treatment and/or on a diet. Our preliminary data confirm the results of similar studies in other countries: screening for AAA is worthwhile on the general population and, looking to a better cost-benefit rate, it might be focused only on males.

End-to-end arteriovenous fistula for chronic haemodialysis: 11 years' experience.

Between January 1979 and December 1989, an end-to-end arteriovenous fistula for chronic haemodialysis was performed at the anatomical snuffbox in 140 patients with a mean age of 51 (range 14-81) years and at the wrist in 248 with a mean age of 53 (range 19-83) years. The choice of site depended on the characteristics of the vessels and on the arterial blood pressure. No operative mortality, major complications or side effects occurred. The primary median patency for the arteriovenous fistula at the anatomical snuffbox was 36 months with a patency rate of 77.3% at 1 year, 36.3% at 5 years and 18.9% at 10 years. For the arteriovenous fistula at the wrist the median patency was 64 months and the patency rate 75.5% at 1 year, 54.5% at 5 years and 30.7% at 10 years. The higher incidence of thromboses in the patients with a fistula in the snuffbox may reflect an excessive enthusiasm for this technique because of initially promising results.

Pelvic perfusion in the adjuvant therapy of locally advanced rectal cancer. Feasibility trial and initial clinical experience.

PURPOSE: The increased risk of pelvic recurrence in patients with locally advanced rectal cancer seems to justify a more aggressive regional therapeutic approach. In this attempt a feasibility study has been recently activated on hyperthermochemotherapeutic pelvic wash in patients with resectable, locally advanced, cancer of the distal rectum. METHODS: Two alternative methods of hyperthermochemotherapeutic pelvic wash have been used in sequence. In the first method 3000 ml of warm (45 degrees C) saline solution containing 30 mg of mitomycin C were injected into the pelvis both intraoperatively and in the immediate postoperative period. In the second method a 60-minute perfusion of the pelvic space with 2000 ml of heated (45 degrees C) saline solution with 40 mg of mitomycin C was provided intraoperatively using an extracorporeal circuit. RESULTS: Four patients submitted to abdominoperineal amputation with pelvic lymph node dissection have been treated following one of the two methods. No complications related to the treatment occurred. Either the first or the second hyperthermochemotherapeutic pelvic wash method showed a high regional pharmacokinetic advantage with a perfusate/blood "AUCs" ratio of 576 and 374, respectively. CONCLUSIONS: The potential role of hyperthermochemotherapeutic pelvic wash as an additional regional treatment in locally advanced rectal cancer and the differences between the two methods, in our limited experience, are discussed.

[Clinical use of a totally implantable and programmable pump for the infusion of drugs]. / Impiego clinico di una pompa totalmente impiantabile e programmabile per l'infusione di farmaci.

Totally implantable programmable systems allow preordained complex continuous infusion of drugs. Sixteen totally programmable implantable pumps (Medtronic DAD) have been implanted in fifteen advanced colorectal and renal cancer patients for continuous ia and iv sinusoidal Fudr infusion. Median duration of pump function was 125 days (range 46-468), there was observed only one case of malfunction device which required the implant of a new device, and three complications of pump pocket (seroma, hematoma and infection) without interrumption of chemotherapy for clinical causes. The use of totally implantable programmable systems provides and important clinical improvement in controlled long-term drugs administration improving quality of life and duration of chemotherapy.

[Continuous sinusoid systemic Fudr infusion in advanced colorectal carcinoma. Preliminary experience]. / Infusione sistemica continua sinusoidale di Fudr nel carcinoma colorettale avanzato. Esperienza preliminare.

Sinusoidal circadian continuous infusion with a maximal flow rate in the afternoon (3-9 pm) reduces Fudr toxicity. In order to estimate if the reported lower toxicity is merely due to the quasi-intermittence of the daily dose or to the circadian rhythm of infusion. Ten patients with widespread cancer (9 colorectal and 1 renal) underwent sinusoidal continuous iv Fudr infusion with the peak level in antiphase (ie 68% of the dose from 3 to 9 am) as compared with the Römeling shape. An initial dose of 0.15 mg/kg/d for 14 days monthly has been given, escalating it every cycle by 0.025 mg/kg/d increments until toxicity. Mean (+/- SD) number of cycles has been 4.1 +/- 2.1 (range 2-8), maximal dose given has been 0.2 mg/kg/die in 5 patient and mean dose intensity of 0.570 +/- 0.04. Gastrointestinal toxicity consisted of nausea/vomiting WHO grade 1 in one patient and diarrhoea grade 1 in two, grade 2 and 3 in one and one case. Toxicity and dose intensity of both sinusoidal infusion seem to be similar and allow higher dose of Fudr than continuous constant infusion. Some other studies have to be done to include pharmacokinetics evaluation in order to estimate chronobiologic implication in continuous Fudr infusion.

[Modification of the in situ saphenous vein technique as vascular access for chronic hemodialysis treatment. Technical note]. / Modificazione della tecnica della safena "in situ" come accesso vascolare per il trattamento emodialitico cronico. Nota tecnica.

A modification of the "in situ" saphenous vein graft above the knee is used to perform vascular access for maintenance haemodialysis when the upper arms are no more suitable. This technique is easy to perform with only one vascular anastomosis and the above knee saphenous vein is entirely available for venipuncture. The possible use of the Fogarty catheter form both sides and the convenient cost-benefit rate make this method indeed interesting.

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases.

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with an without coadministration of 600 mg degradable starch microspheres (DSM). Mean (+/- standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 +/- 0.69 micrograms/ml) than after DDP alone (2.13 +/- 0.43 micrograms/ml, P less than 0.05), with the area under the curve (AUC0-30 min) values of 15.8 +/- 5.5 and 25.1 +/- 3.8 micrograms x min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 +/- 1.60 micrograms/g) than after DDP alone (0.67 +/- 0.49 micrograms/ml, P less than 0.05). Liver concentrations and tumor-liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole-liver extraction of the drug and a redistribution of blood flow and flow-dependent tissue uptake of platinum.

[Hyperthermic-antiblastic isolation perfusion for advanced melanoma of the limbs. The technic, immediate results and a review of the literature]. / La perfusione isolata ipertermico-antiblastica per il melanoma avanzato degli arti. Tecnica, risultati immediati e revisione della letteratura.

Hyperthermic antiblastic isolated perfusion is a method largely used for the treatment of locally advanced limb melanoma. The method requires vascular isolation and hyperthermic perfusion of the limb using an extracorporeal circuit and administering the melphalan as antiblastic drug. Twenty-six patients with primary or recurrent melanoma of the limbs have undergone this treatment at our Institute. There were no cases of operative mortality and systemic toxicity was negligible. The local complications were transitory and no patient showed symptoms of nervous toxicity or permanent functional damage. Two cases of deep thrombophlebitis and two of lymphocele were documented a few months after treatment. Four clinically complete responses, 3 partial and 2 cases of stable disease were observed in the 9 patients treated with unexcised lesions. Our data like the totality of the present experience points to the safety of this method in the therapy of locally advanced limb melanoma. Nevertheless further controlled studies are required to define its role in order to improve survival.

Changes in vascularity of liver tumours after hepatic arterial embolization with degradable starch microspheres.

The role of vascularity as a prognostic factor was investigated in 35 patients undergoing arterial chemotherapy for liver tumours. Compared with parenchyma, tumour vascularity was classified as hot (18 cases), cold (12 cases), and mixed (12 cases) using 99mTc-macroaggregated albumin (MAA) hepatic arterial scans. The proportion of patients showing complete and partial responses to treatment was higher in the hot group (56 per cent) than in the combined cold and mixed group (12 per cent). In 15 cases (six hot, six cold and three mixed lesions), additional MAA scans were performed immediately after arterial embolization with degradable starch microspheres (DSMs). Either complete or partial reversal of tumour vascularity was observed after DSM-embolization in five and seven cases respectively, two and two of them respectively showing native cold lesions. As tumour vascularity appears to be a prominent prognostic factor, DSM-embolization should improve the efficacy of treatment by improving liver extraction of drugs and causing flow redistribution towards hypovascular areas.