Extramedullary multiple myeloma presenting as a pituitary mass lesion.

INTRODUCTION: A plasmocytoma involving the pituitary gland is an extremely rare entity, with approximately 22 cases of solitary myeloma or multiple myeloma presenting with sellar mass reported in the literature so far. CASE REPORT: Here, we report the case of a 71-year-old female patient affected by an extramedullary IgG-lambda multiple myeloma presenting as a pituitary mass lesion. We summarize the diagnostic approaches that confirmed the diagnosis of multiple myeloma and describe treatment outcome after therapy. DISCUSSION: Intrasellar plasmocytoma though rare, should be considered in the differential diagnosis of a pituitary mass lesion, since associated with different therapeutic and prognostic implications. Physicians should be alert for intrasellar plasma cell tumors in case of well preserved anterior pituitary function in combination with cranial nerve neuropathies and sellar destruction.

Bortezomib retreatment in relapsed multiple myeloma - results from a retrospective multicentre survey in Germany and Switzerland.

OBJECTIVES: This multicenter, retrospective survey evaluated the efficacy and safety of bortezomib retreatment in patients with relapsed multiple myeloma who had responded to initial bortezomib treatment. METHODS: Clinical records of 94 patients receiving bortezomib retreatment in Germany and Switzerland were reviewed. RESULTS: Sixty patients were included according to prespecified criteria. Patients had received a mean 3.7 ± 2.3 therapies prior to initial bortezomib. Overall response rate to bortezomib retreatment was 63.3%; 8 (13.3%), 3 (5.0%) and 27 (45.0%) patients achieved complete response (CR), near-CR and partial response, respectively. Response to retreatment was associated with response to initial treatment (75.0% of patients with CR to initial treatment responded to retreatment) and treatment-free interval (TFI) after initial treatment (76.9 vs. 38.1% overall response rate for patients with TFI >6 vs. ≤ 6 months). After retreatment, median time to progression was 9.3 months. Median TFI was 5.7 months; 31.7, 25.0 and 15.0% of patients experienced a TFI longer than 6, 9 and 12 months, respectively. Reported adverse drug reactions were consistent with the known safety profile of bortezomib and most resolved completely. CONCLUSIONS: These results demonstrate that relapsed multiple myeloma patients who respond to initial bortezomib treatment have a sustained susceptibility to bortezomib and do not experience uncommon toxicity to retreatment.

Helper T cells (CD3 + /CD4 + ) within the autologous peripheral blood stem cell graft positively correlate with event free survival of multiple myeloma patients.

BACKGROUND: The microenvironment in the bone marrow - including lymphocytes - is part of the pathophysiology of multiple myeloma (MM). High dose chemotherapy followed by autologous stem cell transplantation is standard of care for younger patients. AIM: To determine the influence of reinfused lymphocyte subsets on event free survival (EFS) and overall survival (OS). METHODS: In peripheral blood (PB) and aphaeresis products (AP) of 41 MM patients lymphocyte subsets were determined by flow cytometry and were correlated with clinical outcome. RESULTS: PB lymphocyte subsets did not influence EFS or OS. Residual plasma cells in the AP were not correlated with poor outcome, whereas a high percentage of B cells (CD19+) showed a trend towards reduced EFS (P = 0.051). A high amount of CD4 cells and an increased CD4/CD8 ratio were significantly associated with prolonged EFS. In contrast, high percentage of HLA-DR positive lymphocytes showed negative impact on EFS and OS (P = 0.03 and 0.02, respectively). CONCLUSION: Obtained data suggest the non-activated (HLA-DR negative) helper CD4+ T cells in the AP to be tumour protective.

A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells.

CD19 is a B-lineage-specific transmembrane signaling protein participating in the control of proliferation and differentiation. It is present at high surface density on chronic B-lymphocytic leukemia (B-CLL) cells and cells of other B-cell malignancies, and is a prime target for therapy with antibody-derived agents. Many attempts have been made to target malignant cells via CD19, but to date none of these agents have received drug approval. Here we report the design of a monovalent immunotoxin consisting of a CD19-specific single-chain Fv antibody fragment fused to a derivative of Pseudomonas Exotoxin A. This fusion protein induced efficient antigen-restricted apoptosis of several human leukemia- and lymphoma-derived cell lines including Nalm-6, which it eliminated at an effective concentration (EC(50)) of 2.5 nM. The agent displayed synergistic toxicity when used in combination with valproic acid and cyclosporin A in cell-culture assays. It induced apoptosis of primary malignant cells in 12/12 samples from B-CLL patients, including patients responding poorly to fludarabine, and of cells from one pediatric acute lymphoblastic leukemia patient. In NOD/SCID mice transplanted with Nalm-6 cells, the toxin prevented engraftment and significantly prolonged survival of treated mice. Owing to its efficient antigen-restricted antileukemic activity, the agent deserves further development towards clinical testing.

Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.

BACKGROUND/AIMS: Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry. METHODS: A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules. RESULTS: ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders. CONCLUSION: This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.

Correlation of residual leukocyte subsets with neutropenic fever during severe leukopenia after high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND: High-dose chemotherapy with autologous stem cell transplantation is the standard treatment of eligible patients with multiple myeloma. However, this treatment is associated with a substantial risk of infectious complications during leukopenia. The aim of our pilot study was to determine the residual leukocyte subsets during severe cytopenia after high-dose melphalan and to correlate this with the occurrence of neutropenic fever. METHODS: Residual leukocyte subsets in the peripheral blood on days 4-7 following autologous stem cell transplantation were analyzed by three-color flow cytometry in 20 patients with multiple myeloma. In addition, we determined the number of T cells that were transfused with the autografts. RESULTS: Absolute numbers of lymphocytes (mean 25/microL) and monocytes (mean 4/microL) were strongly reduced but rather constant during the period of severe neutropenia. Neutrophil engraftment and duration of neutropenia were very similar in patients with and without neutropenic fever. Low absolute lymphocyte counts and absolute CD4+ T-cell counts on days 4-7 after stem cell transplantation correlated with neutropenic fever. Furthermore, T-cell numbers in the autologous stem cell grafts that the patients received were significantly lower in patients with neutropenic fever. DISCUSSION: These observations suggest that the number of T cells, and in particular CD4+ T cells, in the blood during severe cytopenia is playing a role in defense of infection. T-cell numbers in the graft could provide a predictive factor for the risk of infection in the post-transplant period. However, this needs to be confirmed in a larger study.

Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG).

Patients with CLL responding to initial chemotherapy with fludarabine alone (F) or in combination with cyclophosphamide (FC) were randomized for treatment with alemtuzumab (30 mg i.v. TIW, 12 weeks) or observation. Of 21 evaluable patients, 11 were randomized to alemtuzumab before the study was stopped due to severe infections in seven of 11 patients. These infections (one life-threatening pulmonary aspergillosis IV; four CMV reactivations III requiring i.v. ganciclovir; one pulmonary tuberculosis III; one herpes zoster III) were successfully treated and not associated with cumulative dose of alemtuzumab. In the observation arm, one herpes zoster infection II and one sinusitis I were documented. At 6 months after randomization, two patients in the alemtuzumab arm converted to CR, while three patients in the observation arm progressed. After alemtuzumab treatment, five of six patients achieved a molecular remission in peripheral blood while all patients in the observation arm remained MRD-positive (P=0.048). At 21.4 months median follow-up, patients receiving alemtuzumab showed a significant longer progression-free survival (no progression vs mean 24.7 months; P=0.036). In conclusion, a consolidation therapy with alemtuzumab is able to achieve molecular remissions and longer survival in CLL, but a safe treatment regimen needs to be determined.

Chronic lymphocytic leukaemia: up-dated recommendations on diagnosis and treatment.

Diagnosis and treatment of chronic lymphatic leukaemia (CLL) are currently undergoing great change. New knowledge of prognosis factors and the numerous new therapeutic procedures now available, such as purine analogues, high-dose treatment and monoclonal antibodies are making major contributions to this progress. As a consequence, the options for treatment of CLL are considerably more diverse now than a few years ago, and now include procedures that take into account age and risk. At the same time, it should be emphasized that many important questions regarding the treatment of CLL remain unresolved. It is anticipated that these questions will be answered over the coming few years by including patients in multicentre studies like those being carried out by the German CLL study group.

Blood stem cell collections after mobilization with combination chemotherapy containing ifosfamide followed by G-CSF in multiple myeloma.

High-dose chemotherapy with autologous peripheral blood stem cell transplantation is the standard treatment of patients with multiple myeloma today. In this study we used a combination mobilizing chemotherapy containing ifosfamide with G-CSF before stem cell collection. The chemotherapy regimen consisted of ifosfamide (2,500 mg/m(2) days 1-3), epirubicin (100 mg/m(2) day 1) and etoposide (150 mg/m(2) days 1-3) followed by G-CSF (5 mug/kg from day 5). In 30 younger patients (median age 51 years; range 41-60 years) who received the IEV regimen in 100% dosage, a median of 11.15 x 10(6) CD34(+) cells/kg (range 0-44.60 x 10(6) CD34(+) cells/kg) was collected. In 22 elder patients (median age 64 years; range 59-72 years) similar collection results were obtained with a median of 10.82 x 10(6) CD34(+) cells/kg (range 0.99-42.22 x 10(6) CD34(+) cells/kg) after the IEV regimen in 75% dosage. The pretreatment chemotherapy cycles before mobilization were fewer in elder patients with a median of 0 cycles (range 0-7 cycles) compared with younger patients with a median of 4 cycles (range 0-7 cycles). These collection results were favorable and allowed to support a tandem transplantation procedure in younger and elder patients in 97 and 95%, respectively. In the majority of patients, the hematological toxicity of IEV was of WHO grade 3/4. The extramedullary toxicity was mild to moderate and there were only few cases (5-10%) of relevant nephrotoxicity or neurotoxicity associated with the application of ifosfamide.

Cancer in pregnancy: maternal-fetal conflict.

The occurrence of malignancies during pregnancy has increased over the last decades. They complicate approximately 1 per 1000 pregnancies. The most common malignancies associated with pregnancy include malignant melanoma, malignant lymphomas and leukemia, and cancer of the cervix, breast, ovary, colon and thyroid. Since it is impossible for prospective randomized clinical trials to be conducted in this field, relevant data have been generated from case reports and matched historical cohort studies in order to evaluate the treatment outcomes and the issues complicating the management of malignancy in the pregnant patient. There is almost always a conflict between optimal maternal therapy and fetal well-being. The maternal interest is for an immediate treatment of the recently diagnosed tumor. However, the optimal therapy, be it chemotherapy, radiotherapy or surgery, may impose great risks on the fetus. Consequently, either maternal or fetal health, or both, will be compromised. Therefore, both the pregnant patient and her physician are often in a dilemma as to the optimal course. On the basis of the medical facts, we discuss the issues raising potential ethical conflicts and present a practical ethical approach which may help to increase clarity in maternal-fetal conflicts. We review the available data informing the incidence and impact of the most common malignancies during pregnancy and their treatment on both the pregnant woman and her fetus. The optimal therapy for the tragic diagnosis of cancer in pregnancy requires a collaborative and interdisciplinary approach between gynecologists, oncologists, obstetricians, surgeons, neonatologists, psychologists, nursing staff and other disciplines. The purpose of this article is not to answer specific questions or to construct management schemes for specific tumors but to provide a framework for approaching some of these complex issues.

Lymphadenopathy detected by ultrasound examination as first diagnostic hint of chronic lymphocytic leukaemia in a patient with melanoma.

Recent reports indicate that patients with malignant melanoma might be at higher risk for developing a non-cutaneous unrelated second malignancy. We describe the case of a 46-year-old woman who had a malignant melanoma on her right shoulder that was treated in 1998 by surgical excision combined with axillary lymph node dissection. In 1999, ultrasound examination of peripheral lymph nodes revealed one suspicious echopoor structure in the woman's right axilla that was not palpable. Diagnostic excision and histopathological examination revealed a small B-cell lymphocytic lymphoma, and further investigations led to a diagnosis of chronic lymphocytic B-cell leukaemia (B-CLL). We would like to point out the value of high-resolution ultrasound examination in the follow-up of patients with malignant melanoma; this examination can detect early metastasis as well as other unrelated malignancies.

Ulcerative colitis in a patient with Wiskott-Aldrich syndrome.

A 30-year-old man with underlying Wiskott-Aldrich syndrome, which is a rare X-linked congenital immunodeficiency syndrome characterized by recurrent infections, thrombopenia, eczema and hematopoietic malignancies, presented with bloody diarrhea. Endoscopic and histological evaluation was compatible with ulcerative colitis. Congenital immune defects are paralleled by enterocolitis mimicking inflammatory bowel disease in a substantial number of patients. Despite therapy with prednisolone and 5-ASA compounds, the patient described here experienced a relapse of the colitis twice. Subsequently a JC virus infection of the central nervous system was diagnosed, and he died due to progressive multifocal leukencephalopathy.

Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.

Inhibition of bcl-2 expression by antisense oligodeoxynucleotides (ODN) might render bcl-2 overexpressing malignant B cells more susceptible to chemotherapy. ODN containing unmethylated CG dinucleotides (CpG) are known to activate B cells. We studied the effects of two bcl-2 antisense ODN, with (G3139) or without CG dinucleotides (NOV 2009) within the sequence, and the effects of a nonantisense, CpG-containing ODN (ODN 2006) on activation and apoptosis of malignant B cell lines and primary B-CLL cells. Without cationic lipids, no antisense-mediated inhibition of bcl-2 synthesis was achieved with G3139 and NOV 2009. Instead, G3139, but not NOV 2009, induced similar changes as ODN 2006 in proliferation, expression of costimulatory and antigen-presenting molecules, as well as in bcl-2 and bcl-xL levels of primary B-CLL cells. G3139 and ODN 2006 inhibited in vitro, spontaneous apoptosis in B-CLL cells of patients with high serum thymidine kinase activity (s-TK, marker for proliferative activity of malignant B cells), whereas in patients with low s-TK activity, apoptosis was induced. In conclusion, our results suggest that modulation of malignant B cell apoptosis by G3139 depends on its immunostimulatory properties rather than on antisense-mediated reduction of bcl-2 expression. Immunostimulatory CpG ODN may have a therapeutic potential in patients with B-CLL, especially those with low s-TK activity.

Physical principles of ultrasonic dissection and clinical application of BERCHTOLD SONO-CUT reusable ultrasonic scissors.

Technical principles and physical action mechanisms of ultrasonic dissection are introduced. We list various indications for using the BERCHTOLD SONO-CUT scissors and describe early clinical experiences, e.g. in pediatric laparoscopic surgery.

Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis.

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.

Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d. Twenty-one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute-sponsored Working Group, were recorded in 29 out of 32 assessable patients (90.6%). Twenty-four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69.4%, 16.7% and 16.7%) respectively. Other side-effects were uncommon. No treatment-related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side-effect. These results warrant further study on the FC combination in randomized trials.

Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.