Bone marrow micrometastases in patients with stage I-II localised prostate cancer.

Prostate cancer commonly metastasises to the bones. Detection of bone marrow micrometastases (BMM) may give important information that helps define treatment strategies. This study was undertaken to analyse BMM in early prostate cancer patients and to determine the accuracy of immunohistochemical (IHC) and morphological methods in detecting cancerous cells. Preoperative core bone marrow biopsy (BMB) was performed in 103 patients with T1-2, N0, M0 prostate cancer after neoadjuvant androgen blockade. BMB were examined by IHC using monoclonal antibodies for cytokeratins (CK) (18, 19, PAN) and by cytomorphology of IHC-positive cells. In 103 patients, BMM were detected in 2 cases (2%) and an additional 3 cases (3%) were classified as suspicious. IHC alone revealed positive cells in 19 patients (18%). Cytomorphology disclosed IHC false-positive staining of some apparently normal bone marrow elements such as plasmocytes. The study shows a rather low rate of BMM in early prostate cancer. It also stresses the importance of cytomorphology as an adjunct to IHC as IHC alone may not be sufficient and appropriate for BMM detection.

Prognostic value of bone marrow biopsy in operable breast cancer patients at the time of initial diagnosis: Results of a 20-year median follow-up.

From May 1975 until May 1980,128 operable breast cancer patients, clinical stage I-II, had a core bone marrow biopsy (BMB) from the posterior iliac crest as a part of the routine diagnostic work-up at the time of initial diagnosis. The mean age of the patients was 56 years, range 26-93. In a previous study on this material, 10 patients (7.8 per cent) were positive for tumor cells and 118 negative by conventional histopathology of BMB [1]. In 1996 we reexamined all BMB separately at two laboratories, using monoclonal antibodies against cytokeratins AE1-AE3, KL1, CAM 5-2 (DOP), and DC10, BA17 (MCI). The number of extrinsic cells in the bone marrow was graded positive for micrometastases when > or = 5 cells or suspicious when 1-4 cells per approximately 2 x 10(6) bone marrow cells were found, using high power field magnification. Micrometastases were detected in 17 patients (13.3 per cent) and another 8 patients were classified as suspicious. The presence of micrometastases was correlated to the axillary lymph node stage and primary tumor location. Median follow-up was 20 years. All 17 micrometastatic patients relapsed and died within 6 years of disease progression with evident osseous metastases. There was one disease-free survivor of the 8 patients with suspicious BMB after 17 years of follow-up. The median overall survival was significantly shorter in tumor-cell positive patients, being 1.9 years compared to 11.7 years in the BMB negative and BMB suspicious groups (p < 0.0001). Immunohistochemical analysis of core BMB taken postoperatively may be useful in predicting the prognosis in patients with breast cancer clinical stage I-II.

Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low-Grade Lymphoma Study Group.

The current study was initiated to compare the anti-lymphoma activity and side-effects of prednimustine/mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) in patients with advanced low-grade non-Hodgkin's lymphomas in way of a prospective randomized multicenter trial. Two hundred and forty-six patients with stage III or IV centroblastic-centrocytic (CB-CC (Kiel-classification)) or follicle center lymphoma (FCL (REAL classification)) and centrocytic (CC) or mantle-cell-lymphoma (MCL) were randomized for therapy with either PmM or COP and are fully evaluable for response and toxicity. PmM consisted of prednimustine 100 mg/m2/day on days 1-5 and mitoxantrone 8 mg/m2 /day days 1 and 2, while COP comprised cyclophosphamide 400 mg/m2/day on days 1-5, vincristine 1.4 mg/m2/day on day 1 and prednisone 100 mg/m2/day on days 1-5. Both regimens were repeated for a total of six cycles followed by an additional two courses for consolidation in responding cases and a subsequent second randomization for interferon alpha maintenance vs observation only. Overall response rates were comparable with 83% complete and partial remissions after COP and 84% remissions after PmM. PmM revealed a significantly higher rate of complete remissions (36 vs 18%, P < 0.006), the majority being achieved after four courses. The more rapid and possibly also more effective reduction of the lymphoma cell mass by PmM resulted in a tendency to a longer event-free interval for patients achieving remissions after PmM as compared to COP with estimated median event-free intervals of 31 vs 14 months, respectively (P=0.04). Separate analysis of lymphoma subtypes showed a tendency to a lower rate of complete remission in CC or MCL as compared to CB-CC or FCL (16 vs 30%, P=0.12, NS) while overall response rates were in a similar range (81 vs 85%). In both subtypes, PmM induced a higher rate of complete remission while overall response rates were comparable after PmM or COP. Treatment associated side-effects comprised predominantly myelosuppression and granulocytopenia in particular which was more frequently observed after PmM than COP (43 vs 31 %, P < 0.0001). This difference was clinically irrelevant, however, since serious infectious complications were encountered in less than 3% of cycles after both regimens. COP therapy was associated with a significantly higher incidence and degree of hair loss and complete alopecia (31 vs 2%) as well as of peripheral neurotoxicity (23 vs 2%). These data show that both PmM and COP reveal a high anti-lymphoma activity in patients with advanced stage non-Hodgkin's lymphoma. PmM appears advantageous with a higher rate of complete remissions and a better tolerability with regard to secondary side-effects. A longer follow-up is needed to assess the long-term effects of initial treatment on disease-free and overall survival and the impact on additional maintenance therapy with interferon alpha.

Bulky centroblastic non-Hodgkin's lymphoma of the cranium vault mimicking brain involvement managed with chemotherapy: a case report.

BACKGROUND: Patients with central nervous system (CNS) involvement by high grade non-Hodgkin's lymphoma (NHL) have a poor prognosis. The roles of computed tomography, radiotherapy, and intrathecal and systemic chemotherapy still need to be defined. METHODS: A patient with bulky cranial lymphoma mimicking brain involvement is reported. A 62-year-old man was admitted with a huge scalp lump, headache, fatigue, and focal and generalized neurologic symptoms. Computed tomography showed an abnormal mass in the frontoparietal region involving the subcutaneous scalp, osteolytic destruction of the cranial vault, and a bulky mass that was interpreted to be intracranial. A systemic survey also revealed bulky retroperitoneal involvement and focal involvement of the spleen. Biopsy revealed a B-cell NHL of centroblastic type according to the Kiel classification. RESULTS: The patient was treated with a modified combination of cyclophosphamide plus mitoxantrone plus vincristine plus prednisone (CNOP) and intrathecal methotrexate. The patient responded with complete remission, including partial bone restoration of the cranium. At the time of this writing, his relapse free survival lasted 5 years. CONCLUSIONS: The initial interpretation of this case indicated that systemic chemotherapy with modified CNOP plus intrathecal methotrexate would be useful in the management of NHL with CNS involvement. The clinical outcome with rapid neurologic repair and also bone restoration of the cranial vault within 5 years suggests that the lymphoma probably never penetrated the dura and a successful treatment was achieved with combination chemotherapy only.

Mitoxantrone in combination with prednimustine in treatment of unfavorable non-Hodgkin lymphoma.

Mitoxantrone (Novantrone) and prednimustine (Sterecyt) are both active as single agents in the treatment of unfavorable non-Hodgkin lymphoma (UNHL). The efficacy and toxicity of the combination of these agents (NOSTE) was evaluated in 28 patients with advanced histopathologically proven UNHL who were not eligible for aggressive conventional chemotherapy. The median age was 68, range 45-84. Sixteen patients were previously untreated. Eleven patients had received doxorubicin or epidoxorubicin containing regimens and 1 patient had received CVP as first line therapy. MUGA scan was used in monitoring cardiac function in patients with cardiac risk. Novantrone was administered at a dose of 8 mg/m2 IV on days 1 and 2 and Sterecyt as an absolute dose 100 mg/less than or equal to 1.6 m2-150 mg/greater than 1.6 m2 on days 1 through 5. The regimen was repeated every 4th week. The number of courses per patient ranged from 2 to 10. Objective response was obtained in 22 (78%) patients (20 CR and 2 PR). No response occurred in 6 patients (4 SD, 2 PD). Decreased left ventricular ejection fraction was recorded in 1 patient who suffered from asthma and ischemic heart disease. Hematological toxicity was tolerable. Gastrointestinal toxicity was rare. No hair loss was observed. After a median follow-up of 28 months the crude survival was 46%. Twelve of twenty complete responders are still in remission, the median duration of remission is 28.3 months, range 15-37. NOSTE in this pilot study showed a high response rate, good tolerance and mild toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitoxantrone in the treatment of patients with non-Hodgkin's Lymphoma.

Thirty-five patients with non-Hodgkin's lymphoma, who had relapsed from or failed prior cytotoxic regimens including doxorubicin, received mitoxantrone at a dose of 14 mg/m2 iv every 3 weeks. According to the working formulation, 18, 15, and two patients had low-, intermediate-, and high-grade malignancy, respectively. Thirty-four patients were evaluable for response and all were evaluable for drug toxicity. Three patients achieved complete response, 12 achieved partial response, eight had stable disease, and 11 had progressive disease. The overall objective response rate was 43% (95% confidence limits, 25%-61%) for all patients. The response durations ranged from 7 to 11+ months. Time to treatment failure was 4.5 months (range, 1-10+). The response achieved were clustered in patients with low-grade malignancy. There was a partial response in a patient who had relapsed from prior anthracyclines. A total of 155 cycles of mitoxantrone therapy were given. The median number of courses per patient was four (range, one to ten). Myelosuppression was the dose-limiting factor. Most nonhematologic toxic effects were mild. The data indicate that mitoxantrone is effective in the treatment of non-Hodgkin's lymphoma with acceptable toxicity.

Mitoxantrone as a first-line treatment of advanced breast cancer.

Forty-two women with measurable or evaluable advanced breast cancer who had received neither prior chemotherapy for advanced disease nor any anthracycline-containing regimen as adjuvant were entered in a phase II study of mitoxantrone (Novantrone; dihydroxyanthracenedione). Patients were aged from 36 to 80 years, performance status was from 0 to 2. All patients had normal hematological status and normal renal and liver function tests. Cardiac scintigraphy and sonography techniques were used to monitor cardiac function. Mitoxantrone was administered at a dose of 14 mg/m2 in 100 ml 5% dextrose solution over 30 minutes, repeated every three weeks. The number of courses per patient ranged from 2 to 12. Of 42 eligible patients 39 were fully evaluable for response and all for drug toxicity. Responses to treatment were: complete response four patients, partial response 10 patients, stable disease 18 patients and progressive disease seven patients. The overall response rate was 36% (95% confidence limits 20-52%). Three patients showed decreased left ventricular ejection fraction but no patient developed signs of overt left ventricular failure during the treatment period. Hematological and gastrointestinal toxicities were mild. Hair loss was minimal. The data indicate that mitoxantrone is an effective agent for the treatment of advanced breast cancer with mild side-effects, especially with respect to nausea/vomiting, hair loss and cardiotoxicity.

Prognostic value of bone marrow biopsy in breast cancer.

Bone marrow biopsies (BMB) were performed on 622 women with a history of primary or metastatic breast cancer. In 332 of the patients bone scintigraphy (BSC) was also carried out at the time of initial diagnosis or during follow-up. The BMB revealed metastases in 22/88 patients (25%) in Stage I--III with positive BSC and in 39/111 patients (35%) in Stage IV with positive BSC, a total of 61/199 patients (31%). Moreover, the BMB was positive in 6/73 patients in Stage I--III with negative BSC, and in 5/37 patients in Stage IV with negative BSC, a total of 11/110 patients (10%). Statistical evaluation showed that the patients with BMB revealing tumor had a significantly higher death risk (P less than 0.0000001) than patients with BMB revealing tumor had a significantly higher death risk (P less than 0.0000001) than patients with negative BMB. No significant correlation was found in patients with positive or negative BSC. Similar results were also found for a subgroup of 207 patients who underwent BSC and BMB within five months. BMB may therefore be indicated for verification of metastases and prediction of prognosis in all patients with positive BSC and in BSC-negative patients Stage II--IV.

A new trephine for closed bone marrow biopsy.

Our experience with a new trephine, called the LM-trephine, for carrying out bone marrow biopsy is reported. This trephine is larger and stronger than most previously described instruments. Two main problems in bone marrow biopsy, namely compression and difficulty in obtaining specimens from osteoblastic (or sclerotic) metastases are overcome by the special design of the LM-trephine tip. 310 out-patients with different tumour diseases were examined, and no complications were observed.

Incidence and histopathology of metastases of mammary carcinoma in biopsies from the posterior iliac crest.

Bone marrow biopsies were taken from the posterior iliac crest in 532 women with unilateral breast cancer. Metastatic tumors were found in 10% of the biopsies. In a group with negative radiological examinations of the skeleton, the incidence of positive bone marrow biopsies was 1.6%. In a group with radiologically detectable metastases in the skeleton 28% of the biopsies were positive. In the latter group 43 out of 45 individuals with positive biopsies had negative x-rays of the pelvis. Histopathologically, 19% of the metastatic tumors were osteolytic, 65% were osteoblastic and 16% did not influence the bone structure. The fibrous reaction in and around the bone marrow tumors was similar to that found in the primary tumor. In 74% the morphological pattern was consistent throughout the biopsy, whereas in 26% the morphology was different in different parts of the biopsy. No specific histopathology was observed in the individuals with negative radiological examinations of the skeleton. Bone marrow biopsy of the posterior iliac crest does not seem to be helpful as a routine method in the initial staging of mammary carcinoma but may contribute to establish the degree of tumor spread in individuals with positive or suspicious x-ray of the skeleton.

CVP-remission-maintenance in stage I or II non-Hodgkin's lymphomas: preliminary results of a randomized study.

The effect of adjuvant combination chemotherapy when given to non-laparotomized patients in remission after radiotherapy in stage I or II non-Hodgkin's lymphoma was studied in a prospective randomized multicenter study. Locally extended field radiotherapy was given to a target absorbed dose of 40 Gy in 20 fractions. Fifty-five patients who were in complete remission 6 weeks after conclusion of radiotherapy were randomized to either no further therapy or to 9 cycles of CVP (cyclophosphamide + vincristine + prednisolone). The relapse-free survival at 30 months was 41% for patients without and 86% for patients with adjuvant chemotherapy (p = 0.02). The survival was the same for both treatment arms, being 90% at 30 months. Fifteen patients have relapsed, 14 of them with extensions and 1 with a recurrence within the radiation target volume. Analysis of subgroups showed that adjuvant chemotherapy in the present series significantly prolonged the relapse-free survival in diffuse histiocytic lymphoma.

Bone marrow biopsy of the posterior iliac crest with Gidlund's instrument in malignant diseases.

The bone marrow was examined on material obtained with the Gidlund trephine and with conventional cytologic bone marrow aspiration in 225 patients with malignant disease, 144 of whom had malignant lymphoma, and in 5 patients with haematological, non-malignant disease. With Gidlund's instrument, the malignant disease to 7 cases with needle biopsy. No complications were met with either technique. Bone marrow biopsy was routinely performed in the out-patient department.