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.

Vinblastine, bleomycin, and methotrexate chemotherapy plus extended-field radiotherapy in early, favorably presenting, clinically staged Hodgkin's patients: the Gruppo Italiano per lo Studio dei Linfomi Experience.

PURPOSE: To ascertain whether vinblastine, bleomycin, and methotrexate (VBM) (CT) combined with extended-field radiotherapy (EF RT) is effective enough to spare laparotomy in early, favorably presenting Hodgkin's disease (HD) patients. PATIENTS AND METHODS: Fifty patients with clinical stage IA or IIA HD with favorable histology and no bulky masses entered a prospective multicenter study started in January 1988. The median follow-up time was 38 months. RESULTS: All patients achieved a complete remission (CR). Five relapsed after 3 to 40 months and underwent successful salvage therapy. The actuarial remission rate was 0.89% at 3 years and 0.82% at 5 years. Two patients died in CR: one of severe pulmonary toxicity, the other of a second neoplasia (adenocarcinoma of the lung), 2 and 43 months after the end of therapy, respectively. The hematologic toxicity recorded during VBM CT was mild on the whole. Major toxicity was represented by pulmonary side effects and neurologic symptoms. Multiple regression analysis demonstrated that pulmonary toxicity was significantly related only to the amount of RT delivered to the mediastinum and not to the relative dose of bleomycin, to the dose-intensities of the three drugs in the regimen, or to patient age or sex. The same statistical technique showed that the only clinical factor related to grade of neurotoxicity was vinblastine dosage. CONCLUSION: VBM CT combined with EF RT is an effective treatment for early, clinically staged, favorable HD patients. However, the toxicity of this combination suggests that certain modifications should be evaluated.

Double-blind, multicenter, randomized trial to compare the effect of two doses of adrenocorticotropic hormone versus placebo in controlling delayed emesis after high-dose cisplatin in adult patients with cancer.

PURPOSE: To compare, in a double-blind, placebo-controlled, randomized trial, the efficacy of two different doses of the depot formulation of adrenocorticotropic hormone (ACTH) in controlling delayed emesis after cisplatin. PATIENTS AND METHODS: One hundred fifty-two patients were enrolled onto the study. On day 1, all patients received cisplatin (60 to 120 mg/m2) and a combination of dexamethasone 20 mg plus ondansetron or metoclopramide to prevent acute emesis. On day 2 (24 hours after cisplatin administration), patients were randomized to receive placebo, or ACTH 1 mg intramuscularly (I.M.), or ACTH 2 mg I.M. plus one additional dose of 1 mg on day 4. Details of vomiting, nausea, and adverse effects were recorded daily for every 24-hour period from day 2 to day 6. In a subset of patients, serum cortisol levels were measured between 20 and 72 hours after cisplatin administration. RESULTS: One hundred fifty patients were assessable. Over the 5 days of the study, delayed vomiting occurred less frequently in the patients treated with ACTH 2 mg plus 1 mg than in those treated with ACTH 1 mg or placebo (28%, 38%, and 65%, respectively; P = .001). The greatest observed differences were seen on days 2 (24 to 48 hours; P = .01) and 3 (48 to 72 hours; P = .01). On days 4, 5, and 6 (96 to 144 hours), no significant differences were observed among the three arms. The severity of delayed emesis expressed as the mean number of emetic episodes per day was 0.48, 0.70, and 0.80, respectively (P = .002). Patients treated with the higher dose of ACTH had the least nausea on day 3 (P = .02) and day 4 (P = .03). Adrenal cortisol secretion rapidly increased after ACTH injection, but was suppressed for approximately 44 hours in the placebo group. Toxicity was mild and transient in all groups. CONCLUSION: ACTH reduces the incidence and severity of delayed vomiting and nausea after cisplatin. A dose of 2 mg 24 hours after cisplatin is better than one of 1 mg. Whether the activity of ACTH is mediated only by adrenal corticosteroids needs to be verified.

Recovery from aplastic anemia after treatment with antilymphocyte globulin.

A 16-year-old boy with aplastic anemia that was resistant to treatment with androgens and prednisone and that had a high transfusion requirement was treated with antilymphocyte globulin. A complete normalization of the hematologic values was obtained. The result supports the theory of immune pathogenesis in some cases of aplastic anemia.

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.

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.

ProMECE-CytaBOM vs MACOP-B in advanced aggressive non-Hodgkin's lymphoma: long term results of a multicenter study of the Italian Lymphoma Study Group (GISL).

A randomized trial was designed in order to compare the efficacy and feasibility of ProMECE-CytaBOM (P-C) and MACOP-B (M-B) in patients with advanced, aggressive non Hodgkin's lymphoma (NHL). P-C and M-B were chosen due to their association with a very high complete remission rate when compared to other published protocols. The study was conducted on 210 patients with intermediate or high-grade NHL in stage I bulky, or stages II-IV, randomized to receive either 6 courses of P-C delivered every 28 days (106 patients), or 12 weeks of M-B chemotherapy (104 patients). In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin (i.e. 30 mg/m2 of the analog). At the end of induction therapy patients could receive additional radiotherapy to residual masses or to sites of previous bulky disease. The two groups of patients were compared for response rates, number and severity of therapy related side effects, overall survival, disease-free survival, and time to treatment failure. Sixty-five patients (62%) treated with P-C and 69 patients (67%) treated with M-B achieved a complete remission, with no significant differences between the two treatment arms (P = 0.13). The overall objective response rate (complete + partial remission) was 74% for patients treated with P-C, and 81% for patients treated with M-B, respectively. The 4-year relapse-free survival rate was 59% for P-C and 69% for M-B, respectively (P = 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)

Hairy cell leukemia: a clinical review based on 725 cases of the Italian Cooperative Group (ICGHCL). Italian Cooperative Group for Hairy Cell Leukemia.

The Italian Registry for hairy cell leukemia (HCL) has recorded 725 patients with HCL diagnosed over 25 years. We analysed this large series of patients with the aim of providing an evaluation of changes in clinical presentation, impact of initial therapy and modifications in prognostic factors over the period of two decades. Over time, a progressive down-staging of the disease at the onset, along with a reduction of patients with severe anemia and marked splenomegaly, has been observed. A second malignancy was found in 3.7% of patients, mostly detected several years after the onset of HCL. A striking improvement of survival rates has been observed, from 58.9% survival at five years for patients diagnosed before 1985 to 87.5% at five years for patients diagnosed after 1985 (p < 0.0001). Before 1985 hemoglobin alone provided prognostic information, whereas after 1985, clinical stage and the number of leukocytes correlated better with patient outcome. Survivals at 5 and 10 years were 34.4% and 29.6% respectively for untreated patients, 58.8% and 44.1% for patients receiving chemotherapy, steroids or other drugs, 64.1% and 56.1% for splenectomized patients and 88.9% (at 5 years) for alpha interferon (IFN)-treated patients (p < 0.0001). Our findings suggest that IFN has improved the prognosis of HCL, and that it must be considered a good initial treatment for patients with HCL.

Effects of thymostimulin with combination chemotherapy in patients with aggressive non-Hodgkin's lymphoma. A report from the Italian Lymphoma Study Group (GISL).

The purpose of this study was to test the efficacy and safety of thymostimulin (TS) administered in addition to conventional chemotherapy in patients with intermediate- and high-grade non-Hodgkin's lymphoma (IG, HG-NHL). A total of 150 patients with newly diagnosed IG- or HG-NHL were entered in a multicenter trial to compare the effectiveness of two different third-generation regimens (MACOP-B versus ProMACE-CytaBOM) and were randomized to receive chemotherapy (CT) alone or CT + TS. In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin. TS was administered i.m. at a dose of 1 mg/kg daily on days 22-28 of each drug course to patients treated with ProMACE-CytaBOM, and on days 22-29, 50-57, and 77-85 to patients treated with MACOP-B. There were 134 fully evaluable patients: 68 treated with CT alone and 66 treated with CT + TS. Patients treated with CT + TS had a higher complete remission (CR) rate compared to patients given CT alone (59.1% vs 42.4%; P = .05). CR were significantly higher for patients treated with CT + TS in the groups with IG-NHL (P = .01), in those aged less than 60 years (P = .05), with good performance status (P = .05), and normal hemoglobin levels (P = .05). Four-year survival rates are 64.5% for patients treated with CT + TS and 43.0% for those treated with CT alone (P = .30). No difference between the two treatment arms have been observed as regards drug-related toxicity and the number and severity of infectious episodes. The use of TS during the 7 days before chemotherapy has been associated with a significantly superior CR rate. The advantage of CT + TS was mostly obtained in patients with IG-NHL, and those with good performance status or normal hemoglobin levels. In these patients TS may have potentiated the host reactions against the tumor, leading to an increase in NK activity and the production of cytokines. This postulated increase in the effectiveness of chemotherapy after TS might also explain the absence of the expected myeloprotective action.

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.

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.

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.

Detection of bone marrow involvement in patients with cancer.

Current methods for the study of bone marrow to evaluate possible primary or metastatic cancers are reviewed. Bone marrow biopsy, radionuclide scan, computed tomography and magnetic resonance imaging (MRI) are analyzed with regard to their clinical usefulness at the time of diagnosis and during the course of the disease. Bone marrow biopsy is still the examination of choice not only in hematologic malignancies but also for tumors that metastasize into the marrow. Radionuclide scans are indicated for screening for skeletal metastases, except for those from thyroid carcinoma and multiple myeloma. Computed tomography is useful for cortical bone evaluation. MRI shows a high sensitivity in finding occult sites of disease in the marrow but its use has been restricted by high cost and limited availability. However, the future of MRI in bone marrow evaluation seems assured. MRI is already the method of choice for diagnosis of multiple myeloma, when radiography is negative, and for quantitative evaluation of lymphoma when a crucial therapeutic decision (i.e. bone marrow transplantation) must be made. Finally, methods are being developed that will enhance the sensitivity and specificity of MRI studies of bone marrow.

A report of seven long survivors for evidence of prognostic factors in hairy cell leukemia.

The clinical hematologic and pathologic findings of 30 patients with hairy cell leukemia observed between 1966 and 1979 were studied. Twelve patients had long-lasting course of the disease. Seven of them displayed a survival greater than or equal to 120 months, whereas 18 patients died within 36 months of the diagnosis. Their clinical and laboratory characteristics (age of onset, sex, ESR, hemoglobin, WBC, neutrophils, monocytes, platelets, spleen and liver size) were analyzed to ascertain possible prognostic features. Multivariate discriminant analysis, performed both with a direct method and with a stepwise method (Wilks' method), provided a discriminant function able to correctly predict the prognosis of the disease in 83.3% of the examined cases. Spleen size, neutrophil count, age of onset, ESR and liver size turned out to be the most important prognostic factors; in contrast, splenectomy did not significantly affect the prognosis in our cases.

Prevention of cisplatin-induced vomiting in patients with cancer. A pilot study with a multiagent protocol.

Forty patients receiving a total of 102 courses of cisplatin (CDDP)-based treatment were observed in the present study. The patients received an antiemetic prophylaxis with metoclopramide (6 mg/kg), dexamethasone (12 mg/m2), lorazepam (2.5 mg), promethazine (50 mg), and diazepam (10 mg). Complete protection from acute vomiting was obtained in 77.5% of patients during the first course, and partial protection (1 to 3 episodes of vomiting) was observed in 10.1% additional cases. Complete protection was achieved in 84.6% of males vs 57.1% of females. Patients at their first course of chemotherapy had 80% complete protection compared to 66.7% in those who received prior chemotherapy. No differences in the response rate between patients treated with high versus patients receiving low doses of CDDP were noted. The same pattern of response was observed in subsequent courses of therapy. Side effects were minimal (mild sedation in almost all the cases and hiccups in a few cases). No major extrapyramidal reaction was observed. The regimen used in the study showed good efficacy in preventing acute CDDP-induced nausea and vomiting. Moreover, the very low incidence of major side effects makes this protocol safe and recommendable in patients undergoing CDDP chemotherapy.

[Current role of chemotherapy in musculo-invasive transitional carcinoma of the bladder]. / Ruolo attuale della chemioterapia nel carcinoma transizionale della vescica muscolo-invasivo.

The results obtained with chemotherapy (CT) in the management of muscle-infiltrating transitional cell bladder carcinoma (TCBC) are compared with those of radiotherapy (RT) and surgery (S). Cisplatin and methotrexate are the most effective agents, with an overall response rate ranging from 20 to 45% when administered singly. Other chemotherapeutic drugs which proved of some antitumor activity in TCBC are doxorubicin and vinblastine, with an overall response rate of approximately 15% (range 4.28%). With each drug used singly, however, complete response (CR) is uncommon. Combination CT regimens (cisplatin + methotrexate, cisplatin + methotrexate + vinblastine, methotrexate + vinblastine + doxorubicin + cisplatin) are inducing a higher number of CR with an overall response rate between 40 and 70%. CT, previously used as adjuvant or salvage therapy in advanced TCBC, is now given in neo-adjuvant fashion in order to achieve tumor size reduction and control of micrometastases. With these multiagent regimens a significant down-staging can be obtained without major toxicity in over 50% of patients with muscle-infiltrating TCBC, thus increasing the number of patients which can be cured by surgery. These neo-adjuvant programs suggests potential benefit, yet randomized studies and prolonged observations are required to provide definitive results.

[Malignant histiocytosis. Histiocytic medullary reticulosis]. / Istiocitosi maligna. Histiocytic medullary reticulosis.

The Authors report a case of malignant histiocytosis apparently localized only in the spleen. The diagnosis of the disease, characterized at the onset by moderate leukopenia and thrombocytopenia, was made possible by the histopathologic examination of the spleen following splenectomy. The disease shows a chronic course. The Authors discuss the clinical and histological features of the case.

[Anergic miliary tuberculosis, with principally splenic localization simulating hemolymphopathy. Report of 4 cases]. / Tubercolosi miliare anergica a principale localizzazione splenica simulante una emolinfopatia. Descrizione di 4 casi.

Four cases of disseminated tuberculosis with prevailing spleen involvement and lack of tuberculin reactivity are described. The atypical clinical picture justified, at the beginning of the disease, the suspect of a lymphoreticular disorder (malignant lymphoma in 3 cases) or of a pulmonary hemosiderosis (in 1 case). The splenectomy and the following anti-tubercular chemotherapy were fully successful in all 4 patients and the skin reactivity was restored. The Authors discuss the pathogenesis of the observed features and the differential diagnosis of the cases of tuberculosis with only extrapulmonary involvement. These cases represent today about 1/6 of the patients with postprimary tuberculosis.

[Clinico-immunological study of 6 cases of Behçet's disease]. / Studio clinico-immunologico di sei casi di morbo di Behçet.

6 cases of Behçet's disease are reported. Diagnosis was particularly arduous because the typical triad of symptoms (oral aphthae, genital ulcers, uveitis) was masked by secondary disturbances in other organs and systems. Immunology confirmed the presence in these patients of changes in various in vivo and in vitro tests and particularly interesting was the aspecific cutaneous hypersensitivity seen in 5 cases and enhanced lymphocyte blastic transformation. This was seen spontaneously and following PHA. On the basis of the outcome of the studies carried out and the literature data, the possibility that Behçet's disease may contain immunological changes and changes in the mechanisms that regulate quinine, complement and clotting activation is suggested. Therapeutically, confirmation was obtained of the effectiveness, at least temporarily, of corticosteroid treatment and antilymphocyte globulin was experimented for the first time in these patients. This might be used to replace the immune depressant antiblastic substances already successfully employed in patients with Behçet's disease.