Christian Ribas

Prognostic significance of vascular endothelial growth factor immunoexpression in the context of adverse standard prognostic factors in multiple myeloma

Abstract:  Objectives: Vascular endothelial growth factor (VEGF) acts in several steps of multiple myeloma (MM) pathogenesis and it is an important mediator of tumor angiogenesis. The aim of this study was to examine the prognostic significance of VEGF immunoexpression in the context of standard prognostic factors present in a cohort of advanced MM patients. Methods: Fifty untreated MM patients were enrolled from May 2000 to December 2002. Bone marrow sections were subjected to morphologic assessment and immunohistochemical studies with antibodies against CD34 and VEGF. Angiogenesis was measured by microvessel density (MVD) and stratified into high (MVD ≥ 20) and low angiogenesis status (MVD < 20). VEGF immunoreactivity was examined on the basis of intensity and percentage of positive plasma cells (PC). Results: Ninety‐four percent of patients presented advanced disease at diagnosis. Median PC marrow infiltration was 80%. Twelve percent of patients presented plasmablastic morphology. Low angiogenesis was present in 27% of patients, while high angiogenesis was present in 73%. Twenty‐nine percent of patients had VEGF < 10% and 71% had VEGF ≥ 10%. Weak‐intensity VEGF was observed in 34% of cases, while 37% had moderate/strong VEGF intensity. Although VEGF had prognostic impact on overall survival (OS) and event‐free survival (EFS) in univariate analysis, multivariate analysis identified only plasmablastic morphology and elevated serum lactate dehydrogenase (LDH) level as independent prognostic factors to predict OS (P = 0.04 and P = 0.02, respectively). With regard to EFS, although VEGF showed statistical trend to influence survival (P = 0.08), the parameters of independent prognostic value were also plasmablastic morphology (P = 0.01) and elevated LDH level (P = 0.01). Conclusion: Our findings underline the frequent expression of VEGF in advanced‐stage MM and the greater prognostic information of simple and readily available factors, namely plasmablastic morphology and elevated LDH. Moreover, despite the absence of prognostic importance in multivariate analysis, VEGF and its receptors remain promising therapeutic targets in MM.

Analysis of polymorphism at site -174 G/C of interleukin-6 promoter region in multiple myeloma

It is well established that interleukin-6 (IL-6) is an essential growth factor for multiple myeloma (MM) and patients with increased IL-6 levels have a poor prognosis. In healthy subjects, the presence of the C allele at a polymorphic site (-174 G/C) of the IL-6 gene is related to low IL-6 levels. In view of the potential association of this particular polymorphism with IL-6 concentration, and the relevance of IL-6 in MM pathogenesis, the objective of the present study was to investigate the prevalence of IL-6 (-174 G/C) promoter polymorphism and its association with development of MM in Brazilian individuals. We investigated the prevalence of these alleles in 52 patients and 60 healthy subjects (matched by age, sex, and race) of a Brazilian population. Thirty patients were male (42.4%), 24 (46.2%) were white and the median age at diagnosis was 58.5 years (range: 28 to 84 years). To determine the IL-6 (-174 G/C) polymorphism, molecular analysis was performed by polymerase chain reaction followed by endonuclease restriction digestion. The genotype distributions observed in the group of patients were 4% CC, 42% GC and 54% GG. The C allele frequency was 0.25. These results were similar to the control group, suggesting no impact of this polymorphism on the susceptibility to MM.

Can thalidomide be effective to treat plasma cell leptomeningeal infiltration

To the Editor: Dear Sir, In May 2000, a previously healthy, 52-yr-old woman was diagnosed with Salmon-Durie stage IIIA, IgG j multiple myeloma (MM). She was initially treated with six cycles of intravenous (i.v.) vincristine 0.4 mg days 1–4; i.v. doxorubicin 9 mg/m days + 198 1–4; P. O dexamethasone days 1–4, 9–12, 17–20 (VAD) every 4 weeks), the last interrupted because of Staphylococcus aureus endocarditis. At this time, during the infection treatment, she developed radicular symptoms associated with a paravertebral mass identified on computed tomography scan. The biopsy ruled out an abscess and showed a plasmacytoma. The patient underwent lumbar spinal irradiation (4000 cGy) followed by six cycles of i.v. cyclophosphamide 750 mg/m day 1: i.v. doxorubicin 50 mg/m day 1; vincristine 1, 4 mg/m day 1; P. O prednisone 60 mg/m days 1–5 (CHOP), achieving complete clinical response. In December 2000, few days before the harvest of peripheral stem-cell for autologous transplantation, she was confused and hemiparetic on physical examination. A cranial magnetic resonance imaging showed a left parietal mass. Cerebrospinal fluid (CSF) showed 250 cells/ mm, with 100% of plasma cells (Fig. 1). This finding was confirmed by flow cytometry analysis of CSF (CD45–, CD38+, j+). There were no other signs of systemic activity of the disease (no serum or urinary M protein, <5% plasma cells in the bone marrow). She was treated on oral dexamethasone (40 mg on days 1–4, 9–12, 17–20 with interval doses of 16 mg/d) and three doses of weekly intrathecal chemotherapy (methotrexate 12 mg and dexamethasone 2 mg). Despite a brief period of symptomatic relief, there was no CSF cleansing (CSF on 11/30/2001: 640 cells/mm, 100% plasma cell; CSF on 02/14/2002: 80 cells/ mm, 100% plasma cells) and the neurologic symptoms ended up progressing (see Table 1). The patient was then treated with thalidomide (Thal) 800 mg/d for 30 d with simultaneous cranial radiation, achieving total dose of 1000 cGy. Radiotherapy was interrupted because the patient’s focal deficits worsened and her mental status deteriorated, resulting in progression to death 3 months after detection of the central nervous system involvement. In this study, we describe a very unusual complication in MM with 53 cases previously related in the literature. Meningeal myelomatosis, defined as meningeal involvement by plasma cells in the CSF, although might be a presenting feature, has usually been described in the setting of pre-existing MM (1). It tends to occur in stage III disease and is associated with plasma cell leukemia in 20% of patients. Few patients were reported to relapse with meningeal compromising and limited disease outside the central nervous system (CNS) (2). We questioned the role of the paraspinal plasmacytoma as the seeding source of plasma cells into CSF (3). As the meningeal myelomatosis represents a dismal event, with 1– 2 months median survival despite aggressive local treatment, associated or not with systemic therapy (1), we tried to treat this patient with Thal and radiotherapy following intrathecal chemotherapy and high dose glucocorticoid. We were expecting a better outcome than that previously reported, assuming the usefulness of Thal in relapsed/ refractory MM patients (4), the high angiogenesis Fig. 1. Cytospin of CSF sample showing 100% of dysplasic plasmocytes, confirming the diagnosis of leptomenigeal infiltration in our patient, ·1000. Eur J Haematol 2003: 70: 198–199 Printed in UK. All rights reserved Copyright Blackwell Munksgaard 2003

Advances in the Treatment of Multiple Myeloma: The Role of Thalidomide

Multiple myeloma (MM) accounts for 1% of all malignancies and 10% of malignant hematological neoplasms. In spite of high-dose therapy with stem cell rescue, relapse and disease resistance are common events in the course of the disease. Thalidomide (Thal) has been successfully used in such situations and its use has also been expanded to the up-front therapy and as adjuvant to stem cell transplantation. Here, we review the underlying concepts and current clinical data regarding Thal in the treatment of MM.

Response of plasmacytomas to low-dose thalidomide in a patient with refractory multiple myeloma.

To the Editor: The ideal dose of thalidomide (Thal) for multiple myeloma (MM) remains unknown and its actual effect on plasmacytomas is questionable. We report on the case of a patient with refractory MM with several bone and extramedullary plasmacytomas who showed a clinical response with a low-dose Thal schedule. The patient, a 60-year-old male, was diagnosed in January/2002 with Salmon-Durie stage IIIA, IgG kappa MM and simultaneous plasmacytoma in the right jaw and left humerus. The bone marrow (BM) had massive plasmablastic infiltration and high microvessel density (Fig. 1A and 1B). The lytic lesions and the plasmacytomas progressed rapidly during the three cycles of VAD (IV vincristine 0.4 mg D1 /4; IV doxorubicin 9 mg/m D1-4; PO dexamethasone 40 mg D1 /4, 9 /12, 17 /20). The jaw plasmacytoma became very prominent requiring local radiotherapy, given only at a dose of 26 Gy because of severe mucositis and disease progression. Following radiotherapy, systemic treatment was restarted with melphalan and prednisone (PO melphalan 8 mg/m D1 /4; PO prednisone 100 mg D1 /4), but after three cycles the patient’s clinical condition continued to deteriorate (severe bone pain, pathologic fractures, volume increase of the pre-existing plasmacytomas and appearance of another one) (Table 1). The patient was then treated with one cycle of Thal plus dexamethasone (Thal 200 mg/day; PO dexa-

Plasmablastic multiple myeloma is associated with increased vascular endothelial growth factor immunoexpression

The biologic basis of the negative prognosis of plasmablastic myeloma is not fully understood. To determine whether histologically aggressive multiple myeloma (MM) is associated with a more angiogenic marrow environment, bone marrow samples from 50 recently diagnosed MM patients were evaluated. Twelve percent (6/50) of patients presented plasmablastic MM, and this feature correlated with moderate/strong intensity of vascular endothelial growth factor staining of plasma cells (P = 0.036). Although plasmablastic MM was not associated with increasing of microvessel density, this new evidence of increased expression of vascular endothelial growth factor on plasmablasts suggests that the adverse prognosis conferred by plasmablastic disease may be due, at least in part, to secretion of this angiogenic cytokine, also suggesting that the subset of MM patients with plasmablastic features may derive particular benefit from antiangiogenic therapies.

Individualized Chemotherapy for Metastatic Gastric Cancer: Retrospective Data from a University Hospital in Brazil.

BACKGROUND Despite the decreased incidence, gastric cancer is still a frequent cause of cancer related death. The 1st line 2 or 3 drugs regimen is still a debatable issue. HER2 targeted therapy has emerged as the standard of care, but it is unavailable in the Brazilian Public Health System. The end-point of this trial was overall survival (OS) in patients with metastatic gastric cancer treated in a public university hospital in Brazil. The secondary end-points were efficacy and safety of regimens with 2 (F+P) or 3 (EOX) drugs to develop an institutional guideline to facilitate optimal treatments. MATERIALS AND METHODS In this retrospective study, 1st line regimens were evaluated for OS and PFS stratified by age and ECOG using Cox regression. RESULTS 47 patients were treated over the last 3 years. In 1st line, 29 were treated with F+P (mean 59.3 years, 34.5% ECOG 2 and a mean of 5.69 cycles) and 16 with EOX (mean 47 years, 18.8% ECOG 2 and a mean of 5.44 cycles). The median OS was 13.8 months (95%CI 10.7-16.9). Response was evaluated in 40 cases and was 64.3% for EOX and 37.5% for F+P (p=0.25). The median PFS was 9.5 months for EOX and 5.6 months for F+P (HR 0.85, 95%CI 0.41-1.74). However, among patients with ECOG 2 mPFS was 3.70 vs 5.40 months, respectively (p=0.86). Regimens showed similar manageable adverse events. A total of 34 patients suffered progression and 14 received 2nd line therapy. Diffuse histology (HR 1.89, 95%CI 1.22-2.88), achieving 2nd line (HR: 0.25, 95%CI 0.11-0.58) and treatment response (HR 0.23, 95%CI 0.12-0.47) were OS prognostic factors. CONCLUSIONS Patients treated in our hospital had outcomes compatible with the literature. The regimen choice should be related to patient features. Second line treatment should be considered.

Elevada incidência de anormalidades cromossômicas numéricas detectadas por FISH multicentromérico em pacientes com mieloma múltiplo

This study aimed to characterize genetic alterations by interphase multicentromeric FISH focusing on chromosomal numerical abnormalities and using some locus specific probes for the most frequent aberrations found in the disease, in a homogeneous cohort of 34 advanced stage, but recently diagnosed MM patients; 97% had numerical chromosomal abnormalities detected by FISH, being 75% hyperdiploid, 18% hypodiploid and 3% tri/tetraploid. Using locus specific probes, we found 13q deletion in 30% and IGH rearrangement in 25% of cases. Grouping hypodiploid patients together with del13q (unfavorable group) and comparing them to the remaining cases (non unfavorable group) we found a trend towards younger patients presenting more unfavorable abnormalities (p = 0.06) and significant lower hemoglobin level (Hb < 8.5 mg/dl, p = 0.03).