Activity and analysis of costs in a dedicated weaning centre.

AIM: To analyse the diagnosis-related characteristics and the costs of treating patients with difficult/prolonged weaning from mechanical ventilation we have undertaken a retrospective observational study. METHODS: The study has considered all the patients admitted to our weaning unit of a regional Rehabilitation department during 3 consecutive periods since the opening date. Characteristics of the admitted patients and the DRG-related cares delivered have been recorded. A cost analysis has been obtained over time. RESULTS: The number of beds allocated to this unit (from 4 in the 1st period to 6 in the 2nd and 3rd periods) and the number of patients cared for (from 32 to 43 and to 65, respectively) increased over time. In particular, the COPD to non-COPD patient ratio (from 2.2 to 1.3 and to 1.0) and the DRG/patient weight (from 3.0 +/- 0.3 to 3.1 +/- 0.2 and to 3.3 +/- 0.2 point) changed significantly (p < 0.05). The daily reimbursement per patient from the public health care system only slightly increased, whereas the operating margin (reimbursement less costs) per patient significantly improved (from -304, to +17 and +55 Euro/pt/day, respectively, p < 0.05) due to a gradual restriction in the variable costs. Length of stay, mortality rate and weaning rate did not change over time. CONCLUSION: The weaning centre is a hospital area where economic burdens should be carefully evaluated. Given the actual reimbursement received on a national level for these patients, variable costs might be better spread, thus optimising the burdens without losing out on clinical outcomes.

Phase II study of weekly oxaliplatin and high-dose infusional 5-fluorouracil plus leucovorin in pretreated patients with metastatic colorectal cancer.

BACKGROUND: Chemotherapy with oxaliplatin, fluorouracil (5-FU) and leucovorin (LV) has proven efficacy in patients with advanced colorectal carcinoma (CRC), although the optimal dosage and administration schedule are still unclear. This phase II trial investigated the tolerability and activity of weekly oxaliplatin, high-dose infusional 5-FU and LV in pretreated patients with metastatic CRC. MATERIALS AND METHODS: Patients received weekly courses of i.v. oxaliplatin 50 mg/m2 (1-h infusion), LV 100 mg/m2 (1-h infusion) and 5-FU 2100 mg/m2 (24-h infusion) until disease progression or unacceptable toxicity. NCI-CTC criteria were used for assessment of side-effects (at each cycle) and WHO criteria for assessment of tumour response (every 8 cycles). For descriptive purposes, time to progression, overall survival and duration of objective response were also calculated. RESULTS: Forty-four patients were enrolled and received a total of 606 cycles (median 13/patient, range 4-33), and 70% of courses (421/606) were delivered at 100% of the planned dose. The most frequent side-effects were gastrointestinal and neurological and incidence rates were: diarrhoea 66% (grade III: 29%), nausea/vomiting 54%, neurotoxicity 34% (grade III: 2%), fatigue 27%, mucositis 22%, leucopenia 14%. No grade IV toxicity was observed. Objective response rates were: partial response 23% (10 patients), stable disease 59% (26) and progressive disease 11% (5). Median time to progression was 7 months, overall survival 13 months and the duration of partial response and stable disease were 9 and 6 months, respectively. CONCLUSION: The study demonstrated that this regimen has a favourable tolerability profile and is an active combination in the pretreated metastatic CRC patient, deserving further evaluation in phase III trials.

Advanced ovarian cancer in the elderly: results of consecutive trials with cisplatin-based chemotherapy.

From 1982 through 1996, 547 untreated advanced ovarian cancer patients were entered onto Gruppo Oncologico Nord-Ovest (GONO) consecutive randomized trials including cisplatin-based chemotherapy. End points of analysis included the influence of age on prognosis, toxicity, clinical/surgical response rates, progression-free survival and survival. Of the entire study group, 116 patients were 65 years of age or older at diagnosis. WHO main toxicity (any grade) consisted of: emesis (93% of patients), myelotoxicity (leukopenia in 52%, anemia in 51% and thrombocytopenia in 17% of patients), nephrotoxicity in 13% of patients and neurotoxicity in 10% of patients. No significant difference in toxicity was evident between patients > or = or <65 years. Refusal of CT and early (< or =2 courses) interruption of CT due to toxicity were more frequent in elderly patients (3.4 vs. 1.4%; 3.4 vs. 0.7%, respectively). After a median follow-up of 71 months no difference was observed in survival and progression-free survival between younger and older patients. Cox multiple regression analysis of the entire study population demonstrated that age >65 years per se was not a negative prognostic factor.

Sucralfate in the treatment of chemotherapy-induced stomatitis: a double-blind, placebo-controlled pilot study.

BACKGROUND: The study was a double-blind, placebo-controlled, randomised pilot study to assess the efficacy of sucralfate gel in the treatment of chemotherapy-induced mucositis. PATIENTS AND METHODS: At the onset of stomatitis, forty patients received sucralfate gel (1 gr.) or placebo and were instructed to apply the gel over oral mucosas, 3 times daily. RESULTS: Objective response was observed in 14 patients (11 complete response+3 partial response) and in 15 patients (10 CR+5 PR), in the sucralfate and placebo arms, respectively; (p = NS). Analysis of VAS (visual analogue scale) scoring of pain did not detect any statistical difference between the two groups. No important side-effects were observed. Twelve out 21 patients who obtained a complete resolution of stomatitis (5 out of 11 and 7 out of 10 in the sucralfate and in placebo arms, respectively) received further treatment at the subsequent course of chemotherapy; prevention of mucositis was observed in 4 patients in the sucralfate arm and in 6 patients in the placebo arm, respectively. CONCLUSION: In the present pilot study, sucralfate did not demonstrate a significant advantage in comparison to the placebo in the treatment of chemotherapy-induced stomatitis.

[Jejunal adenocarcinoma: case report and review of the literature]. / Adenocarcinoma isolato del digiuno: considerazioni su un caso e revisione della letteratura.

Adenocarcinoma of the jejunum is a rare tumor. The diagnosis is often difficult and not early. The Authors report a case recently observed in their clinical practice and successfully operated, reporting also what's in the literature about.

Mutations of the HFE gene and the risk of hepatocellular carcinoma.

The discovery of the C282Y and H63D point mutations in the hereditary hemochromatosis-associated HFE gene allows us to study the molecular basis of congenital and acquired iron overload disorders. In hereditary hemochromatosis an increased frequency of the C282Y and, to a lesser extent, of the H63D mutations has been established, but their role in other conditions associated with iron overload and their prevalence in the normal population are still under investigation. We sought to determine the presence of such mutations, and their possible involvement in the multi-step neoplastic transformation of the hepatocytes, in patients diagnosed with hepatocellular carcinoma, a frequent complication of iron-induced liver cirrhosis occurring in untreated hereditary hemochromatosis subjects. The frequency of the C282Y and H63D mutations was determined in DNA from 12 patients with hepatocellular carcinoma and with no clinical signs of hereditary hemochromatosis. The frequency of the mutations was also determined in 130 normal subjects. A germline C282Y mutation was found in none of the hepatocellular carcinoma patients; the frequency of the H63D mutation was not increased, compared to the 130 controls. The allele frequencies of the C282Y and H63D mutations in the normal population were 0.042 and 0.185, respectively. In conclusion, we suggest that the hereditary hemochromatosis-related mutations of the HFE gene do not play a significant role in the pathogenesis of hepatocellular carcinoma.

Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy.

To evaluate toxicity and efficacy of chemotherapy in elderly patients (> or = 65 years of age) with advanced colorectal cancer, data from two consecutive trials conducted between 1984 and 1995 at the National Institute for Cancer Research were analysed comparing the results of treatment in those 65 years of age or older and in those younger than 65 years. Of 215 patients recruited, 82 elderly patients (median age 70 years, median performance status 1) received one of the following regimens based on 5-fluorouracil (5-FU): (1) weekly 5-FU 600 mg/m2 i.v. bolus (30 patients); (2) weekly 5-FU 600 mg/m bolus plus leucovorin (LV) 500 mg/m2 2-h i.v. infusion (28 patients); (3) Weekly 5-FU 2600 mg/m2 24-h continuous i.v. infusion plus LV 100 mg 4-h i.v. infusion and 50 mg orally every 4 h for five doses (24 patients). Overall, 1071 chemotherapy cycles were administered with a median number of 12 courses per patient. The main side effects were diarrhoea, observed in 38% of patients, stomatitis in 24% of patients and hand-foot syndrome in 13% of patients, and haematological toxicity affected only 15% of patients. No patient suffered grade IV toxicity. In three patients chemotherapy was discontinued because of toxicity (two patients suffered grade III diarrhoea, one patient grade III hand-foot syndrome). No significant difference in toxicity was evident between patients older than or younger than 65 years. Analysis of median dose intensity demonstrated no difference between the two groups. Overall objective response was observed in 18% (95% confidence limits 11-29) of elderly patients (15/82) in comparison with 23% (95% CL 17-32) of patients < 65 years of age (31/133 pts). In conclusion, chemotherapy in elderly patients with advanced colorectal cancer is a safe and effective treatment with acceptable toxicity and comparable objective response rates.

Activity of high dose 24 hour 5-fluorouracil infusion plus L-leucovorin in advanced colorectal cancer.

BACKGROUND: Modulation of 5-fluorouracil (5-FU) by leucovorin (L-LV) in patients (pts) with advanced colorectal cancer has been demonstrated to produce a highly significant benefit over single-agent 5-FU in terms of tumor response rate, but this advantage does not translate into an evident improvement of overall survival. To improve the clinical efficacy of the 5-FU plus L-LV regimen a phase II study of weekly 24-hour high-dose 5-FU infusion with L-LV was undertaken. PATIENTS AND METHODS: Seventy advanced colorectal patients were enrolled and treated by a weekly outpatient combination regimen according to the following schedule: L-LV 100 mg/sqm by 4 hours i.v. infusion followed by 5-FU 2600 mg/sqm over a 24 hours infusion combined with a fixed dose of oral L-LV (50 mg) every 4 hours for 5 times. Forty-four pts did not receive any previous CT and 26 pts were pretreated with fluoropyrimidines. RESULTS: The overall objective response rate (OR) was 35.3%; 7 CR and 11 PR (42.8% OR) were observed in the group of untreated pts, and 6 PR (23% OR) were reported among previously treated pts. Major side effects were represented by diarrhoea (grade III: 26%, grade IV: 1%), hand-foot syndrome (grade III: 4%, grade IV: 1%) and mucositis (grade III: 4%); however, this did not significantly influence the therapeutic programme. Median 5-FU dose intensity was 100% and 80% at 4 weeks, 87% and 75% at 8 weeks in untreated and pretreated pts, respectively. CONCLUSIONS: L-Leucovorin modulation of weekly short-term continuous infusion of high-dose 5-fluorouracil appeared a well-tolerated outpatient regimen; it demonstrated a high activity in advanced colorectal cancer, both in untreated pts and in pts resistant to 5-FU-based chemotherapy.

Hand-foot syndrome induced by high-dose, short-term, continuous 5-fluorouracil infusion.

The aim of this study was to examine in detail the incidence and severity of hand-foot syndrome in advanced colorectal cancer patients receiving 5-fluorouracil (5-FU) and leucovorin (L-LV) chemotherapy. 70 advanced colorectal cancer patients (pts) were given weekly 24 h continuous 5-FU (2600 mg/m2) infusion plus L-LV (100 mg/m2 i.v., 50 mg orally). The toxicity, in particular HFS, was analysed, correlated to the main pts characteristics and compared to the other observed side-effects. HFS occurred in 36/70 pts (51%): grade 1 in 16 pts, grade 2 in 16 pts, grade 3 in 3 pts and grade 4 in 1 pt. It occurred after a median number of nine courses. In one case, chemotherapy was interrupted for this toxicity, and in another 5 pts drug reduction and/or treatment delay were undertaken. Changes in the therapeutic programme because of diarrhoea or mucositis were more frequent, even though these toxicities were generally mild in our series of pts. HFS was significantly correlated to previous exposure to chemotherapy (P = 0.00003). HFS was a frequent side-effect of high-dose, short-term continuous 5-FU infusion, but the impact on quality of life of pts and on the correct delivery of the planned chemotherapy was limited.

Treatment of metastatic colorectal carcinoma with lymphoblastoid interferon and 5-fluorouracil: data of a phase II study.

Many clinical trials have tested the combination of 5-fluorouracil and recombinant alpha-interferons in metastatic colorectal carcinoma. The efficacy of 5-fluorouracil and lymphoblastoid interferon was evaluated in a phase II study in which 31 patients with advanced colorectal carcinoma were enrolled. 5-Fluorouracil was administered at the dose of 600 mg/sqm bolus weekly and lymphoblastoid interferon was given intramuscularly at 3 million units every two days. All patients were evaluable for toxicity. Thirty patients were available for response: no complete response was recorded, three patients reached a partial response (10%), three a minor response (10%) and 18 progressed (59.4%). Overall median survival was 8 months. No grade IV toxicity was observed: in 2 patients grade III occurred and in 8 patients grade III fever and fatigue attributable to interferon developed. It appears that this combination does not yield better results than 5-fluorouracil alone.

Randomised comparison of weekly bolus 5-fluorouracil with or without leucovorin in metastatic colorectal carcinoma.

148 patients with advanced untreated colorectal cancer were randomised to receive a weekly bolus of 5-fluorouracil (5-FU) 600 mg/m2 alone, with or without leucovorin (LV) 500 mg/m2. 5-FU plus LV produced a higher response rate than 5-FU alone: 23% (5 complete response, 11 partial response) vs. 8% (2 complete response, 4 partial response) (P = 0.03) out of 70 and 72 evaluable patients, respectively. Median survival was 11 months in both groups and median time to progression was not significantly different (P = 0.08). The combined regimen was more toxic than 5-FU alone, as evidenced by (a) a higher percentage of grade 3-4 diarrhoea, 19.5% vs. 8.5% (P = 0.045) and conjunctivitis, 26.5% vs. 5.6% (P = 0.0025); (b) the recording of one toxic death in the combined arm; and (c) the reduction of the median dose intensity of 5-FU actually delivered during the first 2 months of treatment. We conclude that 5-FU plus LV at a price of a higher toxicity is more active than 5-FU alone without improving survival and progression-free survival.

Phase II study of 5-fluorouracil plus leucovorin and interferon alpha 2b in advanced colorectal cancer.

15 untreated patients with advanced measurable colorectal cancer along with other 29 patients in progression after failing first line chemotherapy with fluoropyrimidines received 5-fluorouracil (5FU) 500 mg/m2 given as a weekly bolus at mid-infusion of leucovorin (LV), 500 mg/m2 administered intravenously over 2 h and interferon alpha 2b (IFN) 3 x 10(6) U given intramuscularly every other day. All patients had their previous chemotherapy at least 4 weeks prior to 5FU-LV-IFN. 5 patients discontinued the three drug regimen due to toxicity (intense weakness, fever and influenza-like symptoms in 4 patients; diarrhoea in 1 patient) however no grade IV toxicity was observed. IFN administration was reduced to twice/weekly in 5 patients due to influenza-like symptoms. 1 complete response and 5 partial responses were observed (13.6% response rate); the complete response was obtained in a patient resistant to 5FU: the response rate was only twice as much in untreated patients (3/15 patients, 20%) compared with that in patients previously treated with fluoropyrimidines (3/29 patients, 10.3%). Therefore, modulation of 5FU with LV plus IFN at the doses and schedules employed in this study may rarely overcome clinical resistance to the fluoropyrimidine and the addition of IFN does not appear to enhance the activity of 5FU plus LV.

A phase I study of recombinant interleukin-2 intraperitoneal infusion in patients with neoplastic ascites: toxic effects and immunologic results.

A phase I study to evaluate the use of i.p. infusion of recombinant interleukin-2 (rIL-2) was planned. The following dose levels were calculated: 0.1, 0.3, 1.0, 3.0 and 10 mg/m2/day for 14 days, but only the second levels were reached. In this trial the acute toxic effects at this dosage included cardiac ischemia, transient liver impairment and septic peritonitis. The maximum tolerated dose (MTD) was 0.3 mg/m2/day for 14 days. In addition, two patients developed peritoneal fibrosis. No objective responses were observed. Therefore, in order to explore the biological activity of low (nontoxic) doses, three patients (one untreated and two previously treated with rIL-2) were infused with 0.01 and 0.03 mg/m2/day for 7 days. Potentiation of cytolytic activities in peritoneal lymphocytes and activation of a lymphokine cascade in the ascitic fluid were observed at doses ranging from 0.03 mg/m2/day to 0.3 mg/m2/day. These findings in association with the toxic effects observed at the MTD suggest the use of the minimum effective dose for future locoregional immunotherapeutic protocols.

Intrahepatic epidoxorubicin in metastatic and primary liver tumours: a phase II study.

Primary and metastatic gastrointestinal tumours in the liver have been treated by intrahepatic artery infusion of chemotherapeutic drugs in an attempt to increase the efficacy of the administered agents. Among the several active agents, 4' epidoxorubicin, an anthracycline analogue, was selected for this study because of the therapeutic level reached in the liver by this drug. Seven patients with primary hepatic carcinoma and twenty with metastatic adenocarcinoma of the colon to the liver received intraarterial hepatic infusion of epidoxorubicin at the dosage of 30 mg weekly. No haematological or gastrointestinal grade 3-4 toxicity was recorded, only one patient experienced transient cardiac toxicity. No objective response was observed in primary hepatic carcinoma and six objective responses, 1 complete and 5 partial (30%), were achieved in metastatic colorectal cancer patients. This results is not far from those reported with FUDR, but does not justify epidoxorubicin in colorectal cancer patients as first line intraarterial treatment.

Resistance to 5-fluorouracil and 5-fluoro-2'-deoxyuridine mechanisms and clinical implications.

Preliminary to studies on biopsy specimens from colorectal carcinomas, we have investigated the mechanisms of resistance to 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) on a human colon carcinoma cell line, HCT-8 in vitro. After obtaining a high level of resistance, extracts were made from sensitive and resistant HCT-8 cells and the enzymes responsible for the activation or catabolism of fluoropyrimidines were assayed using a thin-layer chromatographic method. The activity of thymidine-kinase, thymidine phosphorylase, uridine-kinase, uridine phosphorylase, orotate phosphoribosyl transferase as well as the activity of the target enzyme thymidylate synthase were not significantly different in sensitive, FUra resistant or FdUrd resistant cells. The activities of these enzymes in sensitive HCT-8 cells were respectively 15.6, 3.4, 40.8, 2.1, 6.9 and 30.2 nmol/mg protein/h. Direct evidence that impaired transport was the mechanism of resistance to FdUrd was obtained using a short term "oil stop" technique, whereas indirect evidence suggests that reduced inhibition of thymidylate synthase is likely to be the mechanism of resistance to FUra. Cells seven hundred-fold resistant to FdUrd were in fact still sensitive to FUra (ED50 value after continuous exposure 2.1 microM) while FUra resistant cells were fully cross-resistant to FdUrd (ED50 value after continuous exposure 0.003 microM). The clinical relevance of these data is discussed in the light of the extensive literature about the potentiation of fluoropyrimidines by leucovorin.

Disodium clodronate in the treatment of pain due to bone metastases.

Disodium clodronate (dichloromethylene bisphosphonate) a drug belonging to the class of bisphosphonates, inhibits osteoclastic bone resorption and therefore it may be used in the palliative treatment of patients affected by osteolytic bone metastases. The authors have evaluated the activity and tolerability of disodium clodronate in providing pain relief and improving the quality of life in patients with bone metastases, who were not improved by radiotherapy or chemotherapy. Out of 37 patients, 32 could be evaluated for pain relief. Of these, 62.5% had their pains improved by disodium clodronate administration without regard to the type of ongoing analgesic therapy, which had no implications on the outcome of the treatment.

A preliminary clinical study of cyclophosphamide with reduced glutathione as uroprotector.

Reduced glutathione (GSH) has been reported to be an effective protector against cyclophosphamide-induced urotoxicity in experimental models, providing protection comparable to that of mesna. This paper describes our preliminary results of the clinical use of GSH in combination with cyclophosphamide. GSH was administered i.v. in two divided doses of 2.5 g, 15 min before and 30 min after escalating doses of cyclophosphamide ranging from 1.2 up to 1.6 g/m2 (1-h infusion). GSH was well tolerated and did not produce unexpected toxicity. The lack of bladder damage, including microscopic hematuria, supports the protective role of this thiol compound.

Regional pharmacokinetic selectivity of intraperitoneal cisplatin in ovarian cancer.

Five patients with intraabdominal ovarian cancer, 4 of whom with concomitant ascites, refractory to cisplatin-containing combination chemotherapy were treated with intraperitoneal cisplatin. Cisplatin, 90 mg/m2, was administered intraperitoneally in 2 liters of warm 0.9% NaCl with a 4-hour dwelling time on day 1 q 21 days. Platinum concentrations in plasma, ascites, ultrafiltrates of plasma and ascites, and urine were assayed by flameless atomic absorption spectrophotometry and determinations were verified by neutron activation analysis. Peak total and ultrafiltrable plasma platinum levels were 1.63 +/- 0.6 and 0.76 +/- 0.3 microgram/ml, respectively. Peritoneal clearance of total platinum (PA) was 21 ml/min whereas body clearance of total platinum was on the average 13.8 times PA, varying from 171 to 429 ml/min; the mean AUC (peritoneum) to AUC (plasma) ratio was 11 +/- 3. In 2 patients control of ascites was obtained, in 1 of these patients prior positive cytology became negative after her first intraperitoneal course. No nephrotoxicity was observed and gastrointestinal toxicity was mild. No catheter-related infections were observed. Intraperitoneal cisplatin therapy is well tolerated, pharmacokinetically rational and may be useful in managing ovarian cancer patients with malignant ascites or minimal residual disease at second-look laparotomy.