Experimental varicocele in the rat: early evaluation of the nitric oxide levels and histological alterations in the testicular tissue.

The relationship between varicocele and male infertility remains to be explained. Oxidative damage because of the testicular venous backflow may represent one of the causes of gonad injury and seems to precede the histological alteration. Therefore measuring the values of spermatic or intratesticular nitric oxide (NO) could be useful in evaluating this oxidative distress. The aim of this study is to assess the role of testicular NO in early detection of the damages induced by an experimental varicocele in the Wistar rat. A left varicocele was induced in 10 animals (group A). A control group of 10 rats was performed (group B). Animals were killed 3 months after the operation. Both testicles were harvested, weighed and sectioned in two equal parts: one for the evaluation of the NO level and the other one for histological examination. All the rats in group A showed a conspicuous dilatation of the left spermatic vein. The histopathological analysis was normal in both the groups. Biochemistry showed a meaningful statistical difference (P < 0.001) in the concentrations of NO among the specimens of the left and right gonads in group A but no difference was found in group B. The increase in NO values and the presence of other oxidant agents represent the first sign of testicular distress and it seems to anticipate histopathological changes. As it is well known that a great difference exist between human and animal sperm, NO could therefore in the future be taken into consideration together with others parameters for the evaluation of patient who is affected by varicocele.

An oncologist-based model of cancer genetic counselling for hereditary breast and ovarian cancer.

BACKGROUND: We describe a multistep model of cancer genetic counselling designed to promote awareness, and disease surveillance and preventive measures for hereditary and familial breast and ovarian cancer. PATIENTS AND METHODS: Step T0 of the model entails information giving; this is followed by pedigree analysis and risk estimation (T1), risk communication and genetic testing (T2), and genetic test result communication (T3). User consent was required to proceed from one step to the next. Surveillance and preventive measures are proposed to at-risk users. Of the 311 subjects who requested cancer genetic counselling, consent data to each counselling step were available for 295: 93 were disease-free, 187 had breast cancer, 12 had ovarian cancer and three had breast plus ovarian cancer. RESULTS: Consent was high at T0 (98.39%), T1 (96.40%) and T2 (99.65%). Consent decreased at the crucial points of counselling: T2 (87.71%) and T3 [genetic test result communication (85.08%), and extension of counselling to and testing of relatives (65.36%)]. CONCLUSIONS: The model fosters the user's knowledge about cancer and favours identification of at-risk subjects. Furthermore, by promoting awareness about genetic testing and surveillance measures, the algorithm enables users to make a fully informed choice of action in case of predisposing or familial cancer risk.

Advanced diagnostics in erectile dysfunction: beyond the concept of hemodynamics.

Axial rigidity is the most important characteristic of a functional erection. Three factors determine axial rigidity: intracavernosal pressure (addressed by hemodynamics), cavernosal tissue mechanical properties ("tissue expandability"), and the ratio between the two dimensions of the penis: length and circumference ("penile geometry"). Intracavernosal pressure only is addressed by hemodynamic diagnostics, dynamic cavernosometry being the only investigation that allows its direct determination. The appreciation of these three rigidity determinants has the implication that there might exist cases of erectile dysfunction for pure geometric reasons, i.e. an excessive erect length/circumference ratio (L/C R). We report our series of 57 consecutive dynamic cavernosometries with concomitant axial rigidity and penile dimensions recording. Six cases of purely "geometric erectile dysfunction (ED)", i.e. patients unable to physiologically develop a rigid erection for a pathologic L/C R were identified. These patients are characteristically young men (mean age: 28 yrs, range 22-33) with life-long ED not responding to oral or intracavernosal treatment. Our L/C R cut-off value for pure geometric ED is 1.31. We also report two surgical strategies that could possibly address pure geometric ED. In conclusion, hemodynamics is not sufficient to assess the potency status, as other factors come to determine penile rigidity. In particular, there are cases of pure geometric ED which, potentially, is surgically curable. These cases should not be erroneously labelled as psychogenic cases.

Hereditary risk of breast cancer: not only BRCA.

The BRCA1 and BRCA2 genes are involved in genetic susceptibility to breast cancer (BC). Nevertheless, in a relevant number of families displaying a disease pattern suggesting an inherited susceptibility to BC, mutational analysis fails to detect any defect in the BRCA genes. Therefore, women belonging to such families should be considered eligible for programs aimed at BC control in individuals at hereditary risk. A clinico-mammographic surveillance program for women at high genetic risk, as defined on the basis of pedigree, has been carried out at our centre for ten years, leading to the diagnosis of 19 new BC cases. Only in 13% of the families analysed, the underlying genetic defect was evidenced in BRCA1 or 2. Here we describe two BC prone families where, although no mutations were detected in BRCA genes, follow-up confirmed an increased BC incidence. In three women belonging to these families clinico-mammographic surveillance resulted to be successful in detecting early-stage BC, supporting the usefulness of screening women from high-risk families, irrespective of whether a mutation was found.

The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk.

This report presents the preliminary results of the first phase (21 months) of a multi-centre, non-randomised, prospective study, aimed at evaluating the effectiveness of contrast-enhanced magnetic resonance imaging (MRI), X-ray mammography (XM) and ultrasound (US) in early diagnosis of breast cancer (BC) in subjects at high genetic risk. This Italian national trial (coordinated by the Istituto Superiore di Sanità, Rome) so far recruited 105 women (mean age 46.0 years; median age 51.0; age range 25-77 years), who were either proven BRCA1 or BRCA2 mutation carriers or had a 1 in 2 probability of being carriers (40/105 with a previous personal history of BC). Eight cases of breast carcinomas were detected in the trial (mean age 55.3 years, median age 52.5; age range 35-70 years; five with previous personal history of BC). All trial-detected BC cases (8/8) were identified by MRI, while XM and US correctly classified only one. MRI had one false positive case, XM and US none. Seven "MRI-only" detected cancers (4 invasive, 3 in situ) occurred in both pre- (n = 2) and post-menopausal (n = 5) women. With respect to the current XM screening programmes addressed to women in the age range 50-69 years, the global incidence of BC in the trial (7.6%) was over ten-fold higher. The cost per "MRI-only" detected cancer in this particular category of subjects at high genetic risk was substantially lower than that of an XM-detected cancer in the general women population. These preliminary results confirmed that MRI is a very useful tool to screen subjects at high genetic risk for breast carcinoma, not only in pre-, but also in post-menopausal age, with a low probability of false positive cases.

Usefulness of breast MRI in a patient with genetic risk.

We describe an interesting case-report represented by a patient carrying BRCA1 mutation, recruited for the study "Multicenter evaluation of Magnetic Resonance Imaging (MRI) in early diagnosis and prevention of breast cancer in high risk population", diagnosed with breast cancer on the basis of MRI findings but not with conventional mammography and ultrasound (US). She was already affected at 53 years of age by a multifocal Ductal Infiltrating Carcinoma (DIC) in the left breast; then, she had an axillary and sovraclavear nodal recurrence of the disease, three years after the initial diagnosis. Since other relatives were affected by breast cancer (mother, sister and niece) and two arose at early age (< 40 years), BRCA1 mutational analysis was offered to the patient, identifying a nonsense mutation on the exon 13. Furthermore, this patient was recruited to study contralateral breast and at the second round, two little foci, suspicious of malignancy, were identified only with MRI, but not with mammography and ultrasonography. The final diagnosis was multifocal Ductal Carcinoma in situ (DCIS); the major focus measured 3 mm. In our patient MRI has shown a major sensitivity with respect to conventional radiology and US and has provided a very early diagnosis in this woman at genetic risk.

BRCA1 mutations and clinicopathological features in a sample of Italian women with early-onset breast cancer.

Breast cancer in young women is uncommon and often presents with unfavourable biopathological features. Although early age at onset could suggest a genetic susceptibility to cancer, the appropriateness of BRCA1 testing for women with early-onset breast cancer and modest family history (FH) is controversial. 40 Women diagnosed with breast cancer at the age of 35 years or less, unselected for FH, were screened for germ line BRCA1 mutations by automated sequencing of exons 2, 5, 6, 11, 13 and 20. Overall, deleterious mutations were evidenced in 6 (15%) patients. With regard to FH, mutations were detected in 14%, 11% and 29% of women with none, weak and strong FH, respectively. Large tumour size, grade 3, lack of oestrogen receptors and high proliferation rate were significantly more common in mutation carriers (MC). Our data support both the appropriateness of testing young breast cancer patients and the frequency of unfavourable features in BRCA1-related breast cancer. It is hypothesised that BRCA1 mutations partially justify the high rate of aggressive breast cancer in young patients and that combining age and breast cancer phenotype could help to identify probable MC.

Adhesion to 90K (Mac-2 BP) as a mechanism for lymphoma drug resistance in vivo.

A cell-adhesive protein of the human serum, 90K binds galactin-3, beta1-integrins, collagens, and fibronectin, and it is of importance in cell-cell and cell-extracellular matrix adhesion. Serum 90K levels in 137 patients with lymphoma were measured by enzyme-linked immunosorbent assay. Compared with healthy controls, pretreatment serum 90K levels in patients with lymphoma were elevated (P <.001). Of 97 patients who showed objective response to treatment, 20 (21%) had pretreatment 90K levels above the normal cutoff compared with 17 (53%) of 32 patients who did not respond (P =.002). When used as a plastic-immobilized substrate, 90K caused a significant reduction in chemotherapy-induced apoptosis of Jurkat T lymphoma cells. This finding could explain the lack of response in lymphoma patients with high 90K serum levels.

Audiovisual sexual stimulation by virtual glasses is effective in inducing complete cavernosal smooth muscle relaxation: a pharmacocavernosometric study.

Audiovisual sexual stimulation (AVSS) is frequently employed to promote cavernosal smooth muscle relaxation (SMR) in hemodynamic diagnostic settings for erectile dysfunction. Our aim has been to adapt conventional AVSS to the particular test conditions of pharmacocavernosometry and pharmacocavernosography (DICC), by the use of virtual glasses. Thirty-seven consecutive patients undergoing DICC were randomized in two groups: no-AVSS and AVSS through commercially available virtual glasses (VG-AVSS) with tri-dimensional capabilities and stereophonic headphones. Such device partially excludes the patient from the surrounding environment. In both groups a standard dose of vasoactive agents was intracavernosally administered, and possibly repeated (re-dosing), until complete SMR was obtained (3 doses/patient maximum). Psychometric tests (State Trait Anxiety Inventory and ad hoc visual analogue scales for embarrassment, stress and pain) were administered before and after DICC. The no-AVSS group consisted of 18 patients, the AVSS group of 19. Number of needed vasoactive agent doses: in the no-AVSS group 6 patients needed 1 dose, 3 patients 2, 9 patients 3 (mean dose number: 2.17); in the AVSS group 15 patients needed 1 dose, 1 patient 2, 3 patients 3 (mean dose number: 1.37). The difference in the number of doses used in the two groups was statistically significant (Student's t-test P = 0.007). Complete SMR, regardless of the number of used doses: in the no-AVSS group 9 patients (50%) achieved complete SMR, in the AVSS group 16 patients (84.2%). The difference in the two groups was statistically significant (chi-square P = 0.026). From evaluated psychometric measures no statistically significant difference between the two groups was detected. VG-AVSS significantly promotes complete SMR without increasing test related stress or anxiety. Its induced arousal suggests the possibility of performing dynamic evaluations of the erectile function with the oral agent sildenafil in place of intracavernosally administered vasoactive agents. VG-AVSS furthermore constitutes a promising tool for the investigation of normal physiology and pathophysiology of female sexual function.

Detection of circulating tumor cells by reverse transcriptase polymerase chain reaction of maspin in patients with breast cancer undergoing conventional-dose chemotherapy.

PURPOSE: To establish, in patients with breast cancer subjected to primary conventional chemotherapy and enrolled in a prospective study, the mobilizing effect of therapy on potentially neoplastic cells by means of a reverse transcriptase polymerase chain reaction (RT-PCR) assay for mRNA of maspin, a protein related to the serpin family of protease inhibitors. PATIENTS AND METHODS: Peripheral-blood samples were collected from 30 patients with histologically proven breast cancer before and 4 and 8 days after conventional chemotherapy for three consecutive courses. A total of 216 samples were screened for the presence of maspin mRNA by RT-PCR. RESULTS: Before therapy, all samples but one were negative. After chemotherapy, 11 patients (38%) had positive samples. No difference in the rate of positivity was observed between groups defined according to initial stage, type of chemotherapy, Ki-67-related proliferative activity, or CA 15.3 expression. CONCLUSION: Our results confirm that RT-PCR for maspin mRNA is a sensitive assay for the study of circulating potentially neoplastic mammary cells in patients with breast cancer. Moreover, our findings indicate a marked effect of conventional-dose chemotherapy on the mobilization of these cells in breast tumors. In our series of patients, this phenomenon does not seem to be associated with other known risk factors. Finally, the data suggest, without proving, an association between the presence of circulating maspin positive cells and a higher risk of disease progression. If this association could be confirmed, then the assay could have prognostic significance. However, larger confirmatory studies are necessary.

A variant of ProMACE-CytaBOM chemotherapy for non-Hodgkin's lymphoma with threefold higher drug dose size but identical cumulative dose intensity. A pilot study of the Italian lymphoma study group (GISL).

BACKGROUND AND OBJECTIVE: The positive results of high-dose chemotherapy followed by rescue with bone marrow progenitor cell transplantation are generally ascribed to the high dose size (DS) of the drugs given. However, a concomitant marked increase in dose intensity (DI) is always involved. With the aim of comparing the role of DS and DI in non-Hodgkin's lymphomas, a variant of Fisher's ProMACE-CytaBOM regimen was designed in which the projected cumulative drug DIs remained the same as in the original schedule but the DSs were tripled. DESIGN AND METHODS: Dosages in mg/m(2), route and days of administration were the following: cyclophosphamide 1,950 i.v. on days 1, 64; methotrexate 360 i.v. days 15, 78; vincristine 1.4 iv days 15, 78, 43, 106; etoposide 360 i.v. days 29, 92; epirubicin 120 i.v. days 29, 92; bleomycin 15 i.v. days 43, 106; cytarabine 900 i.v. days 50, 113. Thirty-six outpatients with intermediate- and high-grade non-Hodgkin's lymphomas entered the pilot study; 29 were untreated and 7 had relapse disease. Clinical stage was I in 1 patient, II in 7, III in 5 and IV in 23; 10 had B symptoms; the IPI score was 0-2 in 29 cases and > or =3 in the remaining 7. RESULTS: Of the 29 previously untreated patients, 16 achieved complete remission, 8 partial remission, 4 developed progressive disease and 1 was withdrawn early from the study because of acute viral hepatitis; subsequently 4 relapsed and 3 died (2 of disease progression, 1 of causes unrelated to the disease). In the pre-treated group 3 patients obtained complete remission, 2 partial remission and in 1 patient the disease progressed; 3 of these pre-treated patients died (1 of progressive disease, 1 of a new relapse, 1 of myocardial infarction during therapy). With a 20-month median follow-up, the 30-month overall and relapse-free survival were 0.58 and 0.70, respectively. G-CSF was administered to all but 2 patients, with median delivery throughout the whole regimen of 8, 400 microg per patient. Actual cumulative DI was 0.82+/-0.11. Grade 3-4 hematologic toxicity consisted of anemia in 3 cases, of leukopenia in 8 and of thrombocytopenia in 2; the same grade of non-hematologic toxicity involved the liver in 2 cases, the heart in 1 (the above mentioned death), the digestive mucosa in 2 and the peripheral nerves in 1 patient. INTERPRETATION AND CONCLUSIONS: The iso-DI sequential variant of the ProMACE-CytaBOM regimen can be considered feasibile, relatively non-toxic, and can be given on an out-patient basis. Limited use of G-CSF is required (about 3 vials after each drug administration). Thus, a randomized trial with the original ProMACE-CytaBOM regimen can be designed.

Validation of the international prognostic index in working formulation group A low-grade non-Hodgkin's lymphoma: retrospective analysis of 137 patients from the Gruppo Italiano per lo Studio dei Linfomi registry.

BACKGROUND AND OBJECTIVE: The subset of non-follicular non-Hodgkin's lymphoma (NHL) includes patients with varied prognoses, thus suitable for different therapeutic approaches. The International Prognostic Index (IPI), originally proposed for aggressive NHL, has been demonstrated to be of prognostic relevance also in follicular NHL. The main aim of the study was to validate the IPI in this histologic category; in addition, the specific prognostic classification, currently employed in the Gruppo Italiano per lo Studio dei Linfomi (GISL) prospective therapeutic trials and based on different features, more similar to those applied to chronic lymphocytic leukemia, was analyzed. DESIGN AND METHODS: The present series consists of 137 evaluable patients affected by Working Formulation group A NHL out of 256 cases referred to the GISL Registry. The retrospective prognostic study included the evaluation by both univariate and multivariate analyses of overall survival, response to therapy and response duration. The IPI was applied as originally proposed. The GISL definition of indolent and aggressive disease at diagnosis was based on the presence of B symptoms, bulky disease, anemia and thrombocytopenia. RESULTS: The distribution of patients in IPI risk groups was rather unbalanced with 18%, 47%, 28% and 7% of cases classified as low (L), intermediate-low (IL), intermediate-high (IH) and high (H) risk, respectively. The median overall survival was not reached in either L or IL risk groups, and was 84.1 and 7.4 months for IH and H risk groups, respectively (p=0. 0005). A simplified IPI model was designed merging patients in both intermediate risk groups and the statistical difference of survival retained its significance. GISL prognostic stratification was demonstrated to have a significant association with survival, with a median survival of 71.3 months in aggressive disease and a median survival not reached at 152 months in indolent disease. Both the simplified IPI model and the GISL risk definition retained their significance in multivariate analysis for overall survival, while for response to therapy only the simplified IPI model resulted to be of statistical significance. In addition, the GISL prognostic stratification identified patients with different outcomes within the IPI intermediate risk group, with a median survival of 70.2 months for patients with aggressive disease wheras the median survival for those with indolent disease was not reached. Finally, a prognostic score resulting from the integration of the simplified IPI and the GISL system was statistically validated. INTERPRETATION AND CONCLUSIONS: The retrospective analysis of this series demonstrates the validity of the IPI in non-follicular indolent NHL and the usefulness of integrating the IPI parameters with disease specific prognostic variables.

High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients.

Thirty-seven colorectal cancer patients with grade 1-4 diarrhea (NCICTC) caused by chemotherapy with 5-FU-containing regimens, received oral loperamide at the initial dose of 4 mg followed by 4 mg every 8 h (total dose 16 mg/24 h). Twenty-five patients (69%) were diarrhea-free and were considered to be treatment responders. Eight-four percent of the patients with grade 1 or 2 diarrhea achieved a response, but only 52% of those with grade 3-4 diarrhea. These data seem to suggest that high-dose loperamide is effective in patients with moderate diarrhea and can be regarded as the treatment of choice. The patients with more severe diarrhea did not respond so well, and should, perhaps, be given first-line treatment with more effective drugs, such as somatostatin analogues (e.g., octreotide).

Comparison between genotype and phenotype identifies a high-risk population carrying BRCA1 mutations.

Hereditary breast carcinomas constitute about 10% of all malignant mammary tumors, but the selection criteria to identify a high-risk population carrying BRCA1 mutations are not yet well-defined. We have collected 51 pedigrees of familial breast cancer, 16 pedigrees of familial breast and ovarian cancer, and 30 cases of early-onset breast cancer (<35 years of age) without any family history of breast cancer. The index cases of the 97 selected families were further subdivided into three groups based on histopathological parameters: group A (n = 19) was characterized by tumor grade III, negative estrogen and progesterone receptors, and high proliferative rate; group B (n = 20) was characterized by grade I-II tumors, positive hormonal receptors, and low proliferative rate; and group C (n = 58) was not homogeneous for the histopathological criteria. The aim of our study was to evaluate, in patients with a family history of breast cancer or with early diagnosis of breast cancer, the incidence of BRCA1 mutation on the basis of tumor phenotype. We found the highest rate of BRCA1 mutations in group A (53%), and low frequencies in groups B (5%) and C (0%). Our data strongly indicate that an aggressive tumor phenotype in patients with a positive family history or early diagnosis identifies a population with high probability of carrying BRCA1 mutations. Genes Chromosomes Cancer 27:130-135, 2000.

Identification of families with hereditary breast and ovarian cancer for clinical and mammographic surveillance: the Modena Study Group proposal.

Hereditary factors play a fundamental role in the pathogenesis of breast cancer (BC). Approximately 15-20% of all BCs have been reported to show familial clustering. In spite of the recent demonstration and chromosomal localization of BC predisposing genes, clinical clues and careful inspection of pedigree still remain major instruments in HBC diagnosis. The aim of the present study was to develop minimum operational criteria for the selection of family groups at high risk of developing BC. Following a stepwise procedure, families were stratified into four clusters with increasing probability of genetic involvement. So far, 317 BC-prone families have been identified and distributed in the four groups, and 151 high risk women underwent our clinical and mammographic surveillance program. Among these, after a mean follow-up of 24 months, six BCs and one OC were diagnosed (one BC and one OC occurred in the same woman) and one 'interval' BC was observed. Since the prevalence rate so far detected is dramatically higher than that seen at the first round of Italian population-screening programs, our preliminary data support the usefulness of the proposed procedure in selecting high risk individuals.

Clinical characteristics, treatment outcome and survival of 36 adult patients with primary anaplastic large cell lymphoma. Gruppo Italiano per lo Studio dei Linfomi (GISL).

BACKGROUND AND OBJECTIVE: Although in recent years anaplastic large-cell lymphoma (ALCL) has emerged as a distinct clinico-pathological entity, a gold standard for treatment has still not been defined. Goals of our histologic, phenotypic and clinical study were to present clinical findings, treatment outcome and survival rates of a small, but highly homogeneously treated, series of patients. DESIGN AND METHODS: From April 1991, 36 newly diagnosed adult patients with systemic ALCL CD30+, entered a prospective non-randomized trial in one of the institutions participating in a GISL (Gruppo Italiano per lo studio dei Linfomi) study and were treated with a MOPP/EBV/CAD hybrid scheme. Chemotherapy (CHT) was administered every 28 days, for a total of 6 cycles. After CHT, 19 patients received radiation therapy (RT) to the site of previously involved fields. Kaplan and Meier and log-rank tests were used for statistical analysis. RESULTS: The overall complete remission rate was 78%, the partial remission rate was 6%. The overall survival rate at 74 months was 69%. No statistically significant differences in response or survival rates were noted comparing ALCL-HL and -CT subgroups, T+ Null- and B- subtypes, or ALCL-HL and -CT, with different phenotypes. In the analysis of patients with T+ Null phenotype treated with CHT+RT in comparison with B-ALCL patients who had the same treatment, we observed statistically significant differences in the survival rate (p=0.048). No prognostic factors predictive of response or survival were identified. INTERPRETATION AND CONCLUSIONS: Our results show that using MOPP/ABV/CAD the results, in terms of remission rate and survival, are similar to those obtained with 3rd generation CHT regimens. The diagnosis of T and Null ALCL is the most important prognostic factor, because it is associated with a very good survival, even in patients with a high prognostic index. Finally, we believe that longer follow-ups are needed to evaluate long-term survival and toxicity with different treatments.

Retrospective analysis of mantle cell lymphoma: experience of the "Gruppo Italiano per lo Studio dei Linfomi" (GISL).

BACKGROUND AND OBJECTIVE: Mantle cell lymphoma is a recently recognized histologic entity with specific biological and clinical features. Clinically, the reported unfavorable outcome of these patients has focused attention on this category of non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: The slide specimens of 69 NHL patients, originally classified as Working Formulation (WF) group B and E, were reviewed. The clinical features at presentation, response to therapy, response duration and survival were analyzed in cases reclassified as MCL. The correlation between clinical and histologic characteristics and the final outcome was evaluated. RESULTS: Out of 69 cases, 34 specimens were reclassified as MCL; in 6 patients, previously classified as WF group B, the nodular pattern was confirmed; in 2 instances the blastoid form was recognized. After a median follow-up of 35.7 months, the entire series displayed a median overall survival of 41.2 months; a significantly longer survival was associated with the nodular histologic pattern, IPI score < 2, response achievement, and a higher Hb level. The vast majority of patients received anthracycline-containing combination chemotherapy. Complete remission rate was 38.8% and overall response rate was 67.6%; response achievement was significantly influenced only by Hb level. Median response duration was 23.3 months. INTERPRETATION AND CONCLUSIONS: The present study confirms the unfavorable clinical course of MCL and the possible need for an alternative therapeutic strategy for this NHL category. Therefore, the correct identification of MCL at diagnosis appears of relevance.

Efficacy of two different ProMACE-CytaBOM derived regimens in advanced aggressive non-Hodgkin's lymphoma. Final report of a multicenter trial conducted by GISL.

BACKGROUND AND OBJECTIVE: To compare the efficacy of ProME(Epidoxorubicin)CE-CytaBOM (PE-C) and ProMI(Idarubicin)CE-CytaBOM (PI-C) in the treatment of adult patients with aggressive non Hodgkin's lymphoma in a multicenter randomized controlled trial performed by 18 centers of the Italian Lymphoma Study Group (GISL). DESIGN AND METHODS: One hundred and twenty-eight and 122 patients were randomly assigned to receive either 6 courses of PE-C or PI-C, respectively. Some patients achieving complete remission with induction therapy participated in another randomized study comparing no further therapy versus maintenance therapy consisting of four blocks of two drugs. RESULTS: The rate of CRs was 62% and 64% for patients treated with PE-C and PI-C, respectively (p = 0.51). The 5-year relapse-free survival was 60% for PE-C and 53% for PI-C (p = 0.29). The estimated relapse-free disease survival rates at 4 years were 75% for patients in the consolidation group and 57% for those in the observation group (p = 0.11). Patients alive in first complete remission 4 years after study entry were estimated to be 39% in the PE-C arm and 38% in the PI-C arm (p = 0.90). The 3-year and 5-year estimated survival rates were 61% and 55% for the PE-C group and 56% and 47% for the PI-C group (p = 0.26). Fatal toxicities occurred in 7 patients (2.9%) with active disease and in 4 patients (1.7%) in complete remission. Stage (p = 0.04), bulky disease (p = 0.02), serum LDH (p = 0.0006), serum albumin (p = 0.0051), hemoglobin (p = 0.0011), performance status (p = 0.0001), International prognostic index (p < 0.0001) and the index proposed by the French group G.E.L.A. (p < 0.0001) were of prognostic value. In a multivariate analysis (Cox regression model) alternatively IPI alone or G.E.L.A. index plus performance status emerged as independent prognostic factors. INTERPRETATION AND CONCLUSIONS: The present study indicates that epirubicin and idarubicin in a combined chemotherapy regimen, have similar activities. The toxic profile also indicates the safety of both anthracyclines at the dosages employed, suggesting their possible dose escalation in a combined chemotherapy setting. PE-C and PI-C were both effective and feasible regimens in an outpatient setting, with acceptable cardiovascular toxicity. The trend toward a better outcome in patients undergoing consolidation therapy after the achievement of a complete remission, warrants further investigation.

Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease.

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow-up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin's disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin's disease, is needed.