A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study.

BACKGROUND: The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to EC (E 120 mg/m(2), C 600 mg/m(2), arm A) for four cycles or four cycles of D (100 mg/m(2)) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety. RESULTS: There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75-1.31; P = 0.95)], respectively. Grade 3-4 toxicity was more common in arm B. CONCLUSIONS: This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.

Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers.

BACKGROUND: Biliary tract cancers are uncommon tumors with a poor prognosis and most patients present with invasive and inoperable disease at diagnosis. Chemotherapy represents a palliative treatment, with poor response rates and a median survival of less than 6 months. Oxaliplatin and gemcitabine have shown an interesting activity as single agents in this group of patients. PATIENTS AND METHODS: We carried out a multicenter phase II study to evaluate the efficacy and safety of combined oxaliplatin and gemcitabine in locally advanced and metastatic biliary tract carcinoma. The schedule of chemotherapy included oxaliplatin 100 mg/m(2) on day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days. RESULTS: All the 24 patients were evaluable for response and toxicity. According to RECIST criteria we observed one complete response and 11 partial responses for an overall response rate of 50%. Overall survival for all the patients on study was 12 months (range 2-30). According to WHO criteria, three patients (12.5%) suffered grade 3 neutropenia and three patients (12.5%) grade 3 thrombocytopenia. Only two patients (8%) suffered grade 3 neuropathy. CONCLUSIONS: Oxaliplatin and gemcitabine chemotherapy seems to be effective with a favorable safety profile in first-line chemotherapy of advanced biliary tract cancers.

[Clinical guidelines for the management of gastrointestinal stromal tumors]. / Raccomandazioni cliniche per la diagnosi, la terapia ed il follow-up dei tumori stromali gastrointestinali.

Treatment of gastrointestinal stromal tumors (GIST) has been revolutioned by the recently discovered molecular mechanism responsible for the oncogenesis of this disease. In addition, due to the rapid progress at molecular and clinical level observed in the last few years, there is a need to review the current state of the art in order to delineate appropriate guidelines for the optimal management of these tumors. A panel of experts from several specialities, including medical oncology, surgery, pathology, molecular biology and imaging, were invited to participate in a meeting to present and discuss a number of pre-selected questions, and to achieve a consensus according to the categories of the National Comprehensive Cancer Network (NCCN) and the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers. Generally, consensus points were from categories 2A of the NCCN and B2 of the SOR. Conventional histologic examination with immunohistochemistry for CD117, CD34, SMA, S-100 and desmin is considered standard. Molecular analysis for the identification of KIT and PDGFRA mutation may be indicated in CD117-negative GIST. Complete tumor resection with negative margins is the optimal surgical treatment. Adjuvant imatinib should be considered an experimental approach. Neoadjuvant imatinib is also experimental, although its use may be justified in unresectable or marginally resectable GIST. Imatinib should be started in metastatic or recurrent disease, and should be continued until progressive disease or drug intolerance. In these cases, sunitinib can be used. The optimal criteria for the assessment and monitoring of GIST undergoing imatinib therapy are not well known, but they should include reduction in tumor size and disease stabilization, as well as reduction of tumor density on CT scan and metabolic activity on PET scan.

Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies.

Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy.

Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.

Outpatient treatment of deep vein thrombosis (DVT) has become a common practice in uncomplicated patients. Few data are still present in patients with comorbidity (such as cancer) or concomitant symptomatic pulmonary embolism. Cancer patients with DVT are often excluded from home treatment because they have a higher risk of both bleeding and recurrent DVT. We tested the feasibility and safety of the Home Treatment (HT) program for acute DVT a PE in cancer patients. Patients were treated as outpatients unless they required admission for other medical problems, were actively bleeding or had pain that requires parenteral narcotics. Outpatient treatment was with low molecular weight heparin (LMWH) followed by warfarin or with LMWH alone. An educational program for patients was implemented. Two-hundred and seven patients with cancer were evaluated, 36 (17.4%) of whom had metastatic disease. Treatment with LMWH and warfarin was prescribed to 106 (51.2%) and LMWH alone to 102 (48.8%). One hundred and twenty-seven patients (61.3%) were entirely treated at home. There were no differences between patients treated at home and hospitalized patients with regard to gender, mean age, site of cancer, presence of metastases, and treatment. After 6 months, recurrent thrombo-embolism occurred in 8.7% of patients treated at home and in 5.6% of hospitalized patients (P=0.58); major bleeding in 2.0% and 1.5%, respectively (P=0.06). Twenty-seven patients (33%) in the hospitalized, and 33 (26%) in the home-treatment group, died after a follow-up of 6 months. These results indicate that, regarding cancer patients with acute DVT and/or PE, there is no difference between hospitalised and home-treated patients in terms of major outcomes.

FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell'Italia Meridionale (GOIM).

PURPOSE: To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy. PATIENTS AND METHODS: Patients entered in three consecutive trials of the GOIM (protocols no. 9706, 9901, and 2301) were reported in this analysis. A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen: Irinotecan 180 mg/m(2) on day 1 with LV5FU2 regimen (LV at 100 mg/m(2) administered as a 2-hour infusion before FU at 400 mg/m(2) as an intravenous bolus injection, and FU at 600 mg/m(2) as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2); the treatment was repeated every 2 weeks. RESULTS: 287 patients entered in these three trials, and 264 (92%) were evaluable for response. The overall response rate was 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was 37% (95% CI: 31% to 43%). Median time to progression, median duration of response and survival were 7 months, 10.5 months and 14 months, respectively. All but three patients were evaluable for toxicity which was globally mild; grade 3-4 toxicity was uncommon, and gastrointestinal disturbances were the most common. CONCLUSIONS: FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer. Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy.

Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study.

BACKGROUND: Although Ki-ras and TP53 mutations have probably been the genetic abnormalities most exhaustively implicated and studied in colorectal cancer (CRC) progression, their significance in terms of disease relapse and overall survival has not yet clearly been established. PATIENTS AND METHODS: A prospective study was carried out on paired tumor and normal colon tissue samples from a consecutive series of 160 previously-untreated patients, undergoing resective surgery for primary operable sporadic CRC. Mutations within the TP53 (exons 5-8) and Ki-ras (exon 2) genes were detected by PCR-SSCP analyses following sequencing. RESULTS: Mutation analyses of exons 5 to 8 of the TP53 gene showed mutations in 43% (68/160) of the cases, while mutation analyses of exon 2 of the Ki-ras gene showed mutations in 46% (74/160) of the cases. Multivariate analyses showed that clinical outcome were strongly associated with the presence of specific TP53 mutations in L3 domain alone (only in DFS) or in combination with specific Ki-ras mutations at codon 13. CONCLUSION: Specific TP53 mutations in L3 domain alone (only in DFS) or in combination with specific Ki-ras mutations at codon 13 are associated with a worse prognosis in sporadic CRC.

Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma.

A consecutive series of 63 untreated patients undergoing surgical resection for stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome. All of the patients taking part in this study were followed up for a median of 73 months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of these (4/45) showed multiclonality. Both DNA ploidy and SPF were associated with tumor-node-metastasis (TNM) stage and node status, whereas only DNA ploidy was related to depth of invasion. CB, CL, uPA, but not CD, levels were significantly higher in GC as compared to paired normal mucosa, whereas stefin A levels were lower in tumor tissues. CB levels were significantly associated with TNM stage, nodal status, histological grade, and DNA ploidy. At univariate analysis, only node involvement, advanced TNM stage, DNA aneuploidy, and high SPF proved to be significantly related to quicker relapse and to shorter overall survival, whereas depth of invasion was related only to survival. With multivariate analysis, only high SPF (>15.2%) was related to risk of relapse (RR = 8.50), whereas high SPF and DNA aneuploidy were independently related to risk of death (RR = 1.88 and 2.09, respectively). Our preliminary prospective study has identified SPF and DNA ploidy as important biological indicators for predicting the outcome of patients with GC.

The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers.

Zoledronic acid is a bisphosphonate that is effective in the treatment of complications of metastatic bone disease. We have carried out a perspective study on 24 consecutive patients with prostate cancer metastatic to bone to verify the effect of zoledronic acid on analgesic response and a possible relationship with the levels of bone metabolism biomarkers. Eligibility for this study required prostate cancer patients with metastatic bone disease and pain not controlled by analgesics. Patients were excluded from the study if they were receiving cytotoxic chemotherapy or radiation therapy within three months. Eighteen patients (75%) were considered responder to acid zoledronic, only 6 patients did not respond. Before starting treatment (T0) mean Visual Analogue Scale was 7.8 (SE +/- 0.29), after 1 month therapy (T1) was 3.6 (SE +/- 0.3) and after three months (T2) was 3.1 (SE +/- 0.4) with a significant difference between T0 and T1 (p<0.0005) and between T0 and T2 (p<0.0005). Visual Analogue Scale improvement was positively correlated with decrease of C-telopeptide and bone phosphatase alkaline (p<0.05) serum levels.

Cathepsin-d activity levels in colorectal-cancer - correlation with cathepsin-B and cathepsin-L and other biological and clinical-parameters.

Cathepsin D, B and L activity levels were determined in colorectal cancer and correlated with a number of biological and clinical parameters. Our studies have evidenced significant higher activity levels of these lysosomal enzymes in tumor cytosol compared to paired normal mucosa as well as an evident increase of tumor specific cathepsin D activity in Dukes' stage A tumors compared to later stages (B, C and D). Furthermore, significant higher cathepsin B and L activity levels were observed in Dukes' stage A compared to Dukes' stage D tumors while significant higher cathepsin B activity levels were observed in tumors less than or equal to 5 cm than in those >5 cm as well as in moderately differentiated tumors (G2) than in well differentiated (G1) ones. No further correlation between tumor specific cathepsin B activity levels and other parameters examined i.e., anatomical site, nodal status, DNA ploidy, and proliferation rate (S-phase fraction) or between tumor specific cathepsin D and L and all these parameters were observed. These results indicate that cathepsin D, B and L may be involved in colorectal tumor progression by acting, probably, at different levels of this process and suggest that the altered tumor specific activity of these proteinases may be of interest as independent, prognostic factor of malignant progression of this neoplastic disease.

Subcutaneous recombinant-human-erythropoietin prevents chemotherapy-related anemia in patients with advanced cancer.

Nineteen patients with advanced cancer were randomly allocated to receive: (i) rhEpo 150 UI/kg subcutanously three times/week starting 24 hours after the completion of cisplatin- or carboplatin-based chemotherapy; or (ii) normal saline. There were 17 patients with advanced head and neck carcinoma and 2 patients with small cell lung cancer. Patients were monitored for hemoglobin level, hematocrit, WBC, PLT and reticulocytes. Patients who received rhEpo overall showed a 7.2 +/- 6.3% mean increase in Hb level over their pretreatment values, while control patients had a 26.4 +/- 12% decrease. This difference was statistically significant (p<0.001). No patients in the rhEpo group required transfusion, while 4 patients in the control group received packed red cell transfusion. No significant side-effects attributable to rhEpo were recorded, but 1 patient showed a transitory increase in PLT count. In conclusion, subcutaneous rhEpo may be safely administered to patients with advanced cancer and effectively prevents cisplatin- or carboplatin-related anemia.

Elf regimen in advanced gastrointestinal malignancies - an analysis of its clinical effectiveness and toxicity.

A multi-institutional phase 11 study of the combination of levofolinic acid 100 mg/m2, VP16 120 mg/m2 and 5-fluorouracil 500 mg/m2 for 3 consecutive days was carried out on a series of 73 evaluable patients with low performance status affected by locally advanced and/or metastatic gastrointestinal carcinomas. Site of primary tumor were: stomach 26, large bowel 20, pancreas 16, gall-bladder 5, and liver 6. Among patients with gastric carcinoma, 2 patients (8%) had a complete response with a mean duration of 6.8+ months, and 9 (35%) had a partial response with a mean duration of 5.8+ months, for an overall response rate of 43%. Overall response rate was largely unsatisfactory in colorectal carcinoma (20%), pancreatic (12%), gall-bladder and liver carcinomas. The treatment was very well tolerated with no grade 4 toxicity over a total of 267 cycles administered. Grade 3 leukopenia was seen in 25% of cases, and grade 2 thrombocytopenia in 18%. Vomiting never exceeded grade 2. Thus, the ELF regimen is quite active in advanced gastric carcinoma, and may be recommended as palliative treatment of patients who cannot receive intensive chemotherapy. On the other hand, it cannot be considered active in colorectal, pancreatic, gall-bladder and liver carcinomas, and its use should be discouraged in these neoplasms.

Weekly docetaxel as II line therapy in non-small cell lung cancer: an interim analysis of a phase II study.

To evaluate the efficacy and toxicity of weekly docetaxel (D) as II line treatment in non-small cell lung cancer (NSCLC), in November 1999, we started a phase II study on advanced (stages IIIB-IV) NSCLC patients pre-treated with at least one platinum-based chemotherapy regimen with or without radiotherapy. The schedule consisted of D 40 mg/m(2), weekly for 6 weeks, followed by a rest period of 2 weeks, for three cycles or until progression. Eligibility criteria were: histopathologic diagnosis of NSCLC; age

Cis-diamminodichloroplatinum plus a 5-day continuous infusion of 5-fluorouracil in the treatment of locally recurrent and metastatic head and neck cancer patients.

A group of 23 consecutive patients with biopsy-proven advanced or metastatic head and neck cancer were treated with cisplatinum, 100 mg/m2 i.v., on day 1 plus 5-fluorouracil, 1000 mg/m2, in continuous infusion for 5 days. Most patients (87%) had recurrent or metastatic cancer and were previously treated (78%). Out of 21 evaluable patients we obtained a 42% overall response rate (complete + partial responses) with a mean duration of more than 8 months and a 14% minimal response rate. A stabilization of disease was achieved in 28% of cases, while 14% of patients progressed. This response rate, as well as the duration of response, seems to be similar to those obtained in other series comprising previously treated patients with advanced or metastatic head and neck carcinoma. The toxicity was generally acceptable, with few cases of grade 3 (WHO criteria) toxicity. However most patients required hospitalization because of the length of treatment. In conclusion the response rate and the duration of responses obtained with cisplatinum plus a 5-day infusion of 5-FU in advanced or metastatic pretreated patients is, at present, unsatisfactory, even if the impact on survival is still not entirely clear.

Combination chemotherapy with mitomycin C, vindesine and melphalan for refractory metastatic breast cancer.

A combination of mitomycin C, vindesine and melphalan was administered to 33 patients with heavily pretreated refractory breast cancer. The overall response rate was 27% with a mean duration of more than 10.2 months. A stabilization with a mean duration of 5.1 months was seen in 56% of cases, while 20% of patients progressed. Gastrointestinal toxicity, mostly grade 1 or 2 nausea/vomiting was seen in 85% of cases, grade 1 or 2 leukopenia in 60% of patients, and grade 1 or 2 thrombocytopenia in 42%. Considering the good compliance of this regimen and the poor prognosis of patients with refractory advanced breast cancer, this combination can be useful as a palliative treatment of breast carcinoma.

High-dose folinic acid and 5-fluorouracil plus cisplatin on a weekly schedule in the treatment of advanced cancer of the head and neck.

A group of 60 patients with advanced head/neck cancer were treated with high-dose folinic acid (500 mg/m-2/week-1) plus 5-fluorouracil (400 mg/m-2/week-1 on day 1, and cisplatin (20 mg/m-2/week-1) 24 h after folinic acid infusion was completed. Out of 55 evaluable patients, 10 patients (18%) experienced a complete response with a mean duration of 11.4+ months, 25 patients had a partial response (45%) of 6.7+ months, 6 patients (11%) showed a stabilization of 4.8+ months, and 14 (25%) progressed. The overall response rate was 63.6% (95% confidence limits 56.5%-69.5%). Patients pretreated with radiotherapy had a 67% overall response rate, while those pretreated with chemotherapy showed a 54% overall response rate. All patients with cancer of the oropharynx had a major response, while patients with cancer of the oral cavity had the lowest response rate. The mean survival of patients who attained a complete response was 14.5+ months. Partial responders had a mean survival of 10.6+ months, while patients who progresses survived a mean of 3.6+ months. The treatment has been very well tolerated with few cases of grade 3 gastrointestinal toxicity. Grade 1-2 leukopenia was recorded in 64% of cases, grade 1-2 nausea/vomiting in 85%. In one case therapy was stopped because of persistent diarrhoea.

5-Fluorouracil plus interferon alpha-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: a multicentric randomized study.

Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were aged 75 years or less, had a Karnofsky index of at least 60 and had good bone marrow, renal, liver and cardiac functions. No previous chemo-immunotherapy was allowed. The treatment was 750 mg/m2 5FU (4 h i.v. infusion) on days 1 5 and then i.v. bolus weekly, starting from day 12, with or without IFNalpha-2a given s.c. three times weekly (starting dose 3 x 10(6) IU rising to 9 x 10(6) IU, if tolerated). Patients were treated until progression or, if responsive, for a maximum of 48 weeks and then observed for a period of 2 years. The primary end-point of the study was objective clinical response (OR); secondary parameters were time to progression, overall survival, and time to death after progression. WHO criteria were used for both clinical response and toxicity measurements. Dose reduction was planned a priori in the event of significant toxicity due to 5FU, IFNalpha-2a or both. Association between primary and secondary end-points and treatment was studied by univariate and multivariate analysis. Altogether, 47 patients achieved a documented response. A 25% OR was observed in the combination arm while a 21% OR was seen in the 5FU arm; this difference is not statistically significant (P = 0.6). Patients with a small tumour burden (below 5 cm2) showed a higher probability of response in both arms. Patients in the experimental arm had a higher but not statistically significant cumulative progression-free probability. Median survival was 47.1 weeks overall, while it was 43.7 and 48.5 weeks in the control and experimental arms, respectively. The combination was clearly more toxic than 5FU alone, leukopenia being the most frequent side-effect in the experimental arm and nausea and vomiting in the control arm. In conclusion these results are quite disappointing and 5FU + IFNalpha-2a can not be considered a standard treatment for advanced colon cancer.

DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict outcome in colorectal cancer patients. Result of a 5-year prospective study.

PURPOSE: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. METHODS: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. RESULTS: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P<0.05) and DNA aneuploid tumors (P<0.05) tumors. DNA-aneuploidy was associated with distal tumors (P<0.01), histological grade (G3) (P<0.05), advanced Dukes' stage (C and D) (P<0.01), lymph node metastases (P<0.01) and high SPF (>18.3%) (P<0.01). The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA-aneuploidy, and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. CONCLUSIONS: Our results indicate that DNA aneuploidy and high SPF are associated in CRC with a poor clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23-H1 expression is still to be clarified.

Lysosomal alterations in heart and liver of mice treated with doxorubicin.

This study was carried out to evaluate the influence of long-term treatment with doxorubicin (DXR) (4 mg/kg IV for 5 weeks) on heart and liver lysosomes of mice. We evaluated the variations in both total and "sedimentable" enzyme activity of cathepsin D, which is the major endopeptidase of myocites and probably involved in physiologic and pathologic degradation of actomyosin and mitochondria, and that of acid phosphatase, which is more prominent in interstitial cells. Our results show that marked changes occur in both total and sedimentable enzyme activity of cathepsin D in the heart of treated animals and to a lesser extent in the liver. In contrast, no modification of either total or sedimentable acid phosphatase was seen in either organ. The effects we observed are much more marked for cardiac cathepsin D; this is in good agreement with the cardiac specificity of DXR-induced cardiotoxicity with long-term administration and suggests that lysosomes could play a role in the pathogenesis of this phenomenon.

Lysosomal aspartic and cysteine proteinases serum levels in patients with pancreatic cancer or pancreatitis.

Lysosomal cathepsins D (CD), B (CB), and L (CL) serum levels were determined by immunoassays in patients with chronic (CHP) or acute (AP) pancreatitis and in patients with ductal pancreatic carcinoma (DPC) and correlated with some biological and clinical parameters of this tumor. CB serum concentrations significantly higher than those measured in healthy subjects (NS) were observed in CHP, AP, and DPC patients (p < 0.01). However, no significant difference was noted among these groups. Increased CL serum levels were evident only in cancer patients compared to NS, AP, or CHP groups (p < 0.05), while no difference was observed among these groups. Elevated CD serum values were observed in CHP and AP patients compared to healthy subjects or cancer patients (p < 0.01). In cancer patients no correlation between CD, CB, and CL and clinical stage or tumor size was found. However, significant correlations were observed only between serum CD and CA50 (p < 0.02) and between CD and CL (p < 0.05). No further relationship among the biochemical parameters examined was observed. The present data suggest that the different serum patterns of CD, CB, and CL in patients with pancreatitis and pancreatic cancer may be of clinical interest as additional biochemical parameters for the differential diagnosis of these diseases. However, further prospective clinical studies are needed to assess better their potential value as prognostic parameters to identify patients with pancreatitis at increased risk to develop pancreatic cancer.