Meletios-Athanassios Dimopoulos

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-κB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf‐1 (DKK‐1), soluble receptor activator of nuclear factor‐κB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C‐telopeptide of type‐I collagen (CTX) and tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b); bone‐alkaline phosphatase and osteocalcin were reduced. Serum DKK‐1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK‐1, sRANKL, CTX, and TRACP‐5b after four cycles, and dramatically increased bone‐alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK‐1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.

Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor–κB ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton

The role of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) system, and osteopontin (OPN) was studied in patients with solid tumors metastatic to the bone in relation to the type of malignancy and the neoplastic burden to the skeleton. Levels of soluble RANKL (sRANKL), OPG and OPN were assessed in 61 patients with breast, lung and prostate cancer with newly-diagnosed metastasis to the bone, in parallel with bone resorption [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase-5b (TRACP-5b)] and bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)]. Patients had elevated serum levels of sRANKL, OPG, OPN, TRACP-5b, and bALP, and reduced OC levels compared to controls. OPG correlated with the extent of metastatic bone burden. Patients with breast and lung cancer shared increased levels of sRANKL, OPG, and OPN whereas prostate cancer patients had elevated values of OPG and bALP only. These results suggest that patients with solid tumors metastatic to the bone have severe disruption of the sRANKL/OPG axis. Breast and lung cancer seem to exert their osteolytic action through upregulation of the sRANKL/OPG system and OPN, whereas prostate cancer seems to provoke profound elevation of OPG levels only, thus leading to increased osteoblastic activity.

Endothelial vascular toxicity from chemotherapeutic agents: Preclinical evidence and clinical implications

In cancer biology angiogenesis plays a vital role in tumour growth and its subsequent metastatic potential. By targeting the angiogenic process, a new treatment strategy was added in the clinicians therapeutic armamentarium. On the other hand, numerous classic cytotoxic agents are currently considered as potential angiogenesis inhibitors, although they were not originally developed as such, representing the so-called accidental anti-angiogenic drugs. The discovery of these new properties of classic cytotoxic agents led to the re-evaluation of their effect on vascular cells, rendering thus the endothelium an appealing target for therapeutic intervention, either with chemotherapy alone or with combination of cytotoxics with molecular angiogenesis inhibitors. Moreover, current evidence supports that chemotherapy-induced endothelial dysfunction constitutes an integrating predictive marker of future cardiovascular events and correlates well with traditional cardiovascular risk factors. It has therefore been suggested that evaluation of endothelial function may be useful in identifying asymptomatic subjects at high risk for cardiovascular events as well as for risk stratification of patients with established cardiovascular disease. Integration of the assessment of endothelial function in the clinical setting will thus enable effective intervention strategies to prevent or minimize the impact of these late adverse effects and design accurate follow-up protocols focused on cardiovascular complications. In the current review we provide a comprehensive overview of the effects of cytotoxic chemotherapeutic agents on endothelial function and the clinical implications of chemotherapy-associated endothelial toxicity in patients with cancer.

Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis

Leptomeningeal carcinomatosis (MC) represents an uncommon, but devasting manifestation of metastatic breast cancer. This is the first systematic review/pooled analysis to synthesize all available data evaluating the efficacy and safety of intrathecal (IT) administration of trastuzumab for the treatment of MC in HER2-positive breast cancer patients. This study was performed in accordance with the PRISMA guidelines. A total of 13 articles (17 patients) were eligible. The mean age of patients at IT trastuzumab administration was 48.2xa0years (SD 8.4, range 38–66). The mean total dose was 399.8xa0mg (SD 325.4, range 35–1,110xa0mg). IT trastuzumab alone or as part of combination therapies seemed to be safe; no serious adverse events were reported in 88.2xa0% of cases. In 68.8xa0% of cases, a significant clinical improvement was observed, while stabilization or progression of the disease was noticed in 31.2xa0% of cases. Cerebrospinal fluid (CSF) response was noted in 66.7xa0% of cases. The median overall survival was 13.5xa0months, whereas the median central nervous system progression-free survival (CNS-PFS) was 7.5xa0months. In 23.5xa0% of cases, IT trastuzumab was administered beyond CNS progression with a response noticed in 75xa0% of cases and a CNS-PFS of 9.4xa0months. The cumulative dose of IT trastuzumab given was 1,040xa0mg (SD 697.9, median 1,215, range 55–1,675). The protective effect of prior radio- or neurosurgery upon CNS-PFS was sizeable but did not reach formal statistical significance (HR 0.28, 95xa0% CI 0.06–1.37). Clinical improvement (HR 0.14, 95xa0% CI 0.02–0.91) and CSF response (HR 0.09, 95xa0% CI 0.01–0.89) were associated with longer CNS-PFS. IT trastuzumab administration seems to represent a safe and in some cases effective option for the treatment of HER2-positive breast cancer patients with leptomeningeal involvement. However, clinical trials are urgently needed to establish the definite role of IT trastuzumab in HER2-positive metastatic breast cancer patients with MC.

High-dose chemotherapy followed by stem cell transplantation in patients with resistant Waldenstrom's macroglobulinemia

Preliminary evidence suggests that high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation may be effective in some patients with resistant Waldenstroms macroglobulinemia. During the last 10 years, seven patients with Waldenstroms macroglobulinemia have received transplants at the MD Anderson Cancer Center, four with autologous and three with allogeneic stem cells. Four patients achieved partial remission, and three patients have remained alive for at least 2 years. Our data confirm the feasibility of high-dose therapy in patients with macroglobulinemia and support the need for prospective studies of this modality in patients with chemosensitive disease. Bone Marrow Transplantation (2001) 27, 1027–1029.

Trastuzumab administration during pregnancy: a systematic review and meta-analysis

Landmark studies have established trastuzumab in the treatment of HER2-positive breast cancer. The present systematic review and meta-analysis aims to synthesize all available data, so as to evaluate the safety of trastuzumab during pregnancy. This study was performed in accordance with the PRISMA guidelines. All studies that examined the safety of trastuzumab administered during pregnancy, regardless of sample size, were considered eligible. Overall, 17 studies (18 pregnancies; 19 newborns) were included. In 55.6xa0% of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration was 14.8xa0weeks. Occurrence of oligohydramnios/anhydramnios (O/A) was the most common (61.1xa0%) adverse event. 73.3xa0% of pregnancies exposed to trastuzumab during the second/third trimester were complicated with O/A; the respective rate of pregnancies exposed to trastuzumab exclusively during the first trimester was 0xa0% (Pxa0=xa00.043). The mean GA at delivery was 33.8xa0weeks, and the mean weight of babies at delivery was 2,261 gr. In 52.6xa0% of cases, a healthy neonate was born. At the long-term evaluation, all children without problems at birth were healthy with a median follow-up of 9xa0months, while four out of nine children facing troubles at birth were dead within an interval ranging between birth and 5.25xa0months. All children exposed to trastuzumab in utero exclusively in the first trimester were completely healthy at birth. Trastuzumab should not be administered during pregnancy. However, for women who become accidentally pregnant during trastuzumab administration and wish to continue pregnancy, trastuzumab should be stopped and pregnancy could be allowed to continue.

Novel anti-myeloma agents and angiogenesis

During the last decade several novel agents have been used in the management of patients with multiple myeloma. Immunomodulatory drugs and proteasome inhibitors exert their efficacy both directly by inducing apoptosis of myeloma cells and indirectly through the interruption of the interactions between myeloma and stromal cells in the bone marrow (BM) microenvironment. These interactions are crucial for myeloma cell growth and survival. The adherence of myeloma cells to BM stromal cells leads to the overproduction of several cytokines with angiogenic properties that enhance the survival and growth of myeloma cells through paracrine and autocrine loops. The correlation of these molecules with clinical features and survival of myeloma patients supports the importance of angiogenesis in the pathogenesis of the disease and reveals these cytokines as suitable targets for the development of novel anti-myeloma therapies. This review summarises all available preclinical and clinical data for the effect of novel agents that are used in myeloma therapy, such as thalidomide, lenalidomide, bortezomib and VEGF inhibitors, on angiogenesis, which is at least partially responsible for their remarkable anti-myeloma efficacy.

Hsp90 inhibitors in breast cancer: A systematic review

PURPOSEnPharmacological inhibition of Hsp90 shows great promise in breast cancer treatment. This is the first systematic review to synthesize all available data and to evaluate the efficacy and safety of Hsp90 inhibitors in breast cancer.nnnMETHODSnThis study was performed in accordance with the PRISMA guidelines. Eligible articles were identified by a search of MEDLINE and ClinicalTrials.gov databases, using a predefined combination of the terms breast, cancer, Hsp90, inhibitors.nnnRESULTSnOverall, 19 articles (190 patients) were eligible. The greatest clinical activity has been observed on the field of HER2-positive metastatic breast cancer. However, accumulating data suggest that Hsp90 inhibitors may play a significant role in the treatment of triple negative and aromatase inhibitor-resistant breast cancer.nnnCONCLUSIONnIn the last decade, the development of Hsp90 inhibitors has moved forward rapidly; however, no phase III trials have been conducted and none agent has been approved for use in the clinical practice.

Genetic predisposition for the development of ONJ

In this issue of Blood , Sarasquete and colleagues report that the rs1934951 polymorphism mapped within the cytochrome P450-2C polypeptide 8 gene ( CYP2C8 ) is associated with increased risk for the development of ONJ in myeloma patients who receive intravenous BPs.nnOsteonecrosis of the jaw (ONJ)

Clinical implications of chromosomal abnormalities in multiple myeloma

The adverse prognostic role of cytogenetic abnormalities has recently been established in plasma cell dyscrasias. Modern techniques such as fluorescence in situ hybridization and comparative genomic hybridization have revealed a higher incidence of cytogenetic abnormalities in patients with multiple myeloma (MM) compared to conventional cytogenetics. Hypodiploidy and chromosome 13 abnormalities are found in more than 50% of myeloma patients, representing well known factors with adverse prognosis. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at 14q32 with various partner genes represent the most common structural abnormalities, having an incidence of 70% in MM. Structural abnormalities of chromosomes 17 and 8 involving the p53 and c-myc genes are considered to be less frequent events, but carry a poor prognosis. New therapeutic approaches such as non-myeloablative allotransplantation and modern therapeutic agents (thalidomide, lenalidomide, and bortezomib) and their combinations give promise for an improved therapeutic management of patients with MM. The detection of t(4;14), t(14;16), deletion of chromosome 13 on metaphase analysis, or deletion of p53 by FISH will define high-risk prognostic groups that are not generally controlled with high-dose melphalan and autologous stem cell transplantation (ASCT), and should therefore be treated with more investigational therapies. Alternatively, eligible patients who do not have these poor risk factors are more likely to benefit from a high-dose, melphalan-based, regimen followed by ASCT.