Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma.

BACKGROUND: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.

Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial.

BACKGROUND: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. PATIENTS AND METHODS: An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection. RESULTS: Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia. CONCLUSIONS: The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.

Prognostic utility of intact immunoglobulin Ig'κ/Ig'λ ratios in multiple myeloma patients.

To determine whether isotype matched immunoglobulin (Ig; Ig'κ/Ig'λ) ratios had prognostic significance in patients with intact Ig multiple myeloma (MM). Novel immunoassays measuring serum concentrations of the Ig heavy chain/light chain (HLC) subsets IgGκ, IgGλ, IgAκ and IgAλ were compared with monoclonal protein ('M-spike') quantification by serum protein electrophoresis, ß(2)-microglobulin (ß(2)-M), albumin, serum free light chain (FLC) and cytogenetic markers in relation to outcome in 339 MM patients. Abnormal IgGκ/IgGλ and IgAκ/IgAλ ratios present in the respective tumor isotypes at clinical presentation were predictive of shorter progression-free survival (PFS) (hazard ratio (HR) 1.9; P=0.0002), predominantly due to the suppression of the uninvolved (polyclonal) Ig of the same isotype as the tumor (HR 1.8; P=0.002). No significant associations were observed between PFS and M-spike concentrations, suppression of non-tumor Igs of different isotypes or FLC κ/λ ratios. ß(2)-M and HLC ratios were independently prognostic (P=0.045 and P=0.001). A staging system using ß(2)-M and extreme HLC ratios (<0.01 or >200) had greater prognostic value than the widely used ISS staging system (HR 1.7; P=0.00002 vs HR 1.3; P=0.017). These results suggest that HLC ratios may have a role in clinical management of MM.

High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients.

BACKGROUND: Circulating tumor cells (CTCs) are a prognostic marker in metastatic breast cancer, but comparisons with serum tumor markers (CA 15-3, carcinoembryonic antigen and lactate dehydrogenase) variations are needed. PATIENTS AND METHODS: CTCs were counted with CellSearch® at baseline, before cycle 2 (C2) and cycle 3 or 4 (C3/4) in 267 metastatic breast cancer patients on first-line chemotherapy with/without targeted therapy. RESULTS: Baseline CTC detection rate was 65% with ≥1 CTC/7.5 ml threshold and 44% with ≥5 CTC/7.5 ml and was independent of subtypes (luminal, triple negative, human epithelial growth factor receptor 2 (HER2)+). CTCs were associated with tumor markers, bone/liver involvement, tumor burden and performance status. CTC detection ≥1 CTC/7.5 ml was a strong prognostic factor for progression-free survival (PFS), P < 0.0001. Threshold of CTC ≥5 was statistically significant for PFS and overall survival (OS), P = 0.03 on multivariate analysis. Among patients with ≥5 CTC/7.5 ml at baseline, 50% had <5 CTC/7.5 ml at C2. Changes were correlated with both PFS and OS (P < 0.0001). All patients receiving anti-HER2 therapy had <5 CTC/7.5 ml after three cycles of treatment. CONCLUSION: This is the largest prospective series validating the prognostic value of CTC independently from serum tumor marker. Elevated CTCs before C2 are an early predictive marker of poor PFS and OS, which could be used to monitor treatment benefit. CTC decrease under treatment seems stronger with targeted therapy.

Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy.

BACKGROUND: We investigated whether circulating tumor cells (CTCs) and circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy combined with bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: In a French substudy of the MO19391 trial, CTC and CEC counts (CellSearch system) at baseline and changes after two cycles of treatment were correlated with time to progression (TtP). RESULTS: CTC and CEC levels were not correlated in the 67 patients included. At baseline, CTC positivity was a significant prognostic marker for TtP at a threshold of 3 CTC/7.5 ml (P < 0.05) but not at 5 CTC/7.5 ml (P = 0.09). Baseline CEC levels (median 17 CEC/4 ml, range 1-769) were associated with age > or =45 years (P = 0.01), elevated lactate dehydrogenase (P < 0.01) and not with TtP at any threshold. Changes of CTC count during treatment were not a surrogate of TtP, with any of the model tested (threshold based or relative decrease in percent). However, increase in CEC count was associated with improved TtP, at the threshold of 20 CEC/4 ml (P < 0.01). CONCLUSION: Bevacizumab combined with first-line chemotherapy may modify the predictive value of CTC during treatment possibly due to impaired tumor cells intravasation through vessels endothelium. Variations in CEC levels appear to be a promising early surrogate marker of TtP under antiangiogenic treatment.

Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer.

BACKGROUND: Circulation of cancer cells in the blood is a mandatory step for metastasis, but circulating tumor cells (CTC) have a low metastatic efficiency in preclinical animal models. In this prospective study, we reported the clinical outcome of nonmetastatic breast cancer patients according to CTC detection. PATIENTS AND METHODS: In 115 nonmetastatic patients diagnosed with large operable or locally advanced breast cancer, we prospectively detected CTC using the CellSearch system before and after neoadjuvant chemotherapy in a phase II trial (REMAGUS02). RESULTS: At baseline, 23% of patients were CTC positive, but only 10% had >1 CTC/7.5 ml of blood. After a median follow-up of 36 months, CTC detection before chemotherapy was an independent prognostic factor for both distant metastasis-free survival [DMFS; P = 0.01, relative risk (RR) = 5.0, 95% confidence interval (CI) 1.4-17] and overall survival (OS; P = 0.007, RR = 9, 95% CI 1.8-45). CTC detection after chemotherapy was of less significance (P = 0.07 and 0.09, respectively). Moreover, CTC detection showed interesting characteristics as an individual predictive test for metastatic relapses (sensibility 55%, specificity 81%, and global accuracy 77%). CONCLUSIONS: Detection of > or =1 CTC/7.5 ml before neoadjuvant chemotherapy can accurately predict OS. Our findings may change the clinical management of nonmetastatic breast cancer and indicate that the metastatic efficiency of CTC could be higher than previously reported.

[Circulating tumor cells and breast cancer: detection techniques and clinical results]. / Cellules tumorales circulantes et cancer du sein : méthodes de détection et résultats cliniques.

Due to recent technological progresses, Circulating Tumor Cells (CTC) are currently extensively studied in order to define their diagnostic, prognostic and predictive value. We review here the different detection techniques and their clinical results in breast cancer patients.

Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells.

BACKGROUND: At metastatic relapse, detection of circulating tumor cells (CTC) in peripheral blood is predictive of poor survival of breast cancer patients. Detection of disseminated tumor cells (DTC) in bone marrow (BM) is an independent prognostic factor in early breast cancer. We evaluated the prognostic value of DTC detection in the BM of metastatic breast cancer patients. MATERIALS AND METHODS: BM aspirates from 138 patients were screened for DTC with the pancytokeratin mAb A45-B/B3, according to the ISHAGE classification. One hundred and ten patients (80%) were enrolled before first-line treatment. Thirty-seven patients were simultaneously screened for CTC in the blood. RESULTS: DTC detection rate in the BM was 59%. DTC were associated with bone metastasis (P = 0.0001), but not with a poorer overall survival. Adverse significant prognostic factors were hormone receptor negativity (P = 0.0004) and more than one line of chemotherapy (P = 0.002). CTC detection in the subgroup of 37 metastatic patients was associated with shorter survival (P = 0.01). CONCLUSIONS: Detection of CTC but not BM DTC had a prognostic significance in stage IV breast cancer patients. CTC in blood are a more reliable and a less invasive tool to evaluate prognostic and monitor tumor response in this metastatic setting.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)). We identified a subgroup of patients presenting at diagnosis with both low beta(2)-microglobulin <4 mg/l and high hemoglobin (Hb) >/=10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high beta(2)-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.

Mosquito vectors of the 1998-1999 outbreak of Rift Valley Fever and other arboviruses (Bagaza, Sanar, Wesselsbron and West Nile) in Mauritania and Senegal.

Following an outbreak of Rift Valley fever (RVF) in south-eastern Mauritania during 1998, entomological investigations were conducted for 2 years in the affected parts of Senegal and Mauritania, spanning the Sénégal River basin. A total of 92 787 mosquitoes (Diptera: Culicidae), belonging to 10 genera and 41 species, were captured in light traps. In Senegal, Culex poicilipes (41%) and Mansonia uniformis (39%) were the most abundant species caught, whereas Aedes vexans (77%) and Cx. poicilipes (15%) predominated in Mauritania. RVF virus was isolated from 63 pools of Cx. poicilipes: 36 from Senegal in 1998 and 27 from Mauritania in 1999. These results are the first field evidence of Cx. poicilipes naturally infected with RVFV, and the first isolations of this virus from mosquitoes in Mauritania - the main West African epidemic and epizootic area. Additional arbovirus isolates comprised 25 strains of Bagaza (BAG) from Aedes fowleri, Culex neavei and Cx. poicilipes; 67 Sanar (ArD 66707) from Cx. poicilipes; 51 Wesselsbron (WSL) from Ae. vexans and 30 strains of West Nile (WN) from Ma. uniformis, showing differential specific virus-vector associations in the circulation activity of these five arboviruses.

Peripheral blood stem cell collection in 24 low-weight infants: experience of a single centre.

Peripheral blood stem cells (PBSC) harvest may be difficult in young children. Extracorporeal separator line priming by red blood cells is usually required to improve haemodynamic tolerance and efficacy of collection. We present our experience with 24 children weighing less than 15 kg treated between January 1997 and September 1999, in whom we tried to avoid systematic blood priming. The median age and weight at the time of apheresis were 2.4 years and 12 kg, respectively. A total of 48 PBSC were performed. When haemoglobin was less than 12 g/dl, packed red cells were transfused before collection (40% of aphereses). The median cell yield per apheresis was 7.1 (2.2-30.6)x10(6)/kg CD34(+) cells and 16.0 (3.3-44.3)x10(5) CFU-GM/kg. Initial collection failed in three cases. Four children required an additional haematopoietic progenitor mobilization. This procedure allowed PBSC collection without transfusion in 37.5% of children, and was safe (two serious and five mild transient side effects) and effective (median CD34(+) cells collected per child: 7.1 x 10(6)/kg (4.6-30.6) and CFU-GM: 15.1 x 10(5)/kg (4.7-44.3)). Despite their low weight, insertion of a femoral catheter was avoided in 43% of children.

Use of reverse transcriptase PCR in early diagnosis of Rift Valley fever.

Reverse transcriptase PCR (RT-PCR) for diagnosis of Rift Valley fever (RVF) was evaluated by using 293 human and animal sera sampled during an RVF outbreak in Mauritania in 1998. Results of the RT-PCR diagnostic method were compared with those of virus isolation (VI) and detection of immunoglobulin M (IgM) antibodies. Our results showed that RT-PCR is a specific, sensitive tool for RVF diagnosis in the early phase of the disease and that its results do not differ significantly from those obtained by VI. Moreover, the combined results of RT-PCR and IgM antibody detection were in 100% concordance with the results of VI.

Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons.

Besides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMPs) play critical roles in angiogenesis, tumor invasion and metastasis. Increased angiogenesis is observed in chronic B lymphocytic leukemia (B-CLL) and published data reported VEGF and bFGF production in this disease. The purpose of this study was to investigate MMP expression in early stage B-CLL. Elevated MMP-9 concentrations were detected by ELISA in the sera of B-CLL patients (median level 250 ng/ml) compared with healthy donors (67 ng/ml) (P < 0.0001), and immunostaining with antibodies against MMP-9 and B cell antigens (CD19, CD23) substantiated the presence of MMP-9 in tumoral B lymphocytes. By using RT-PCR, ELISA and zymography experiments, we confirmed that B-CLL cells expressed and released the pro-form of MMP-9 with Mr 92 kDa (158-1300 pg/ml/10(6) cells/48 h), p-aminophenylmercuric acetate generating a 82 kDa active form. In contrast, the production of MMP-9 by normal counterpart B cells was significantly low (28-169 pg/ml/10(6)cells/48 h). Moreover, B-CLL culture supernatants contained bFGF (median levels 17 pg/ml/10(6) cells/48 h), VEGF (1.4 pg/ml/10(6) cells/48 h) and TNF-alpha (0.2 pg/ml/10(6) cells/48 h). TNF-alpha and VEGF antibodies blocked MMP-9 at the mRNA and protein levels. Interferons (IFNs) type I or type II repressed MMP-9 gelatinolytic activity in a dose and time dependency, and this was reflected by a parallel inhibition of MMP-9 mRNA and protein. IFNs however did not affect the production of bFGF, VEGF and TNF-alpha. Together, our data show that B-CLL lymphocytes synthesize MMP-9 and emphasize the specific inhibitory actions of IFNs on its expression.

Multicenter study of street foods in 13 towns on four continents by the food and environmental hygiene study group of the international network of pasteur and associated institutes.

An international multicenter study of ready-to-eat foods, sandwiches, and ice creams or sorbets sold in the streets and their vendors was carried out to assess the microbiological quality of these foods and to identify characteristics of the vendors possibly associated with pathogens. Thirteen towns in Africa, America, Asia, and Oceania were involved in the study. A single protocol was used in all 13 centers: representative sampling was by random selection of vendors and a sample of foods bought from each of these vendors at a time and date selected at random. Microbiological analyses were carried out using standardized Association Française de Normalisation methods, and the use of a standardized questionnaire to collect data concerning the characteristics of the vendors. Fifteen surveys were carried out, with 3,003 food samples from 1,268 vendors. The proportion of unsatisfactory food samples was between 12.7 and 82.9% for ice creams and sorbets and between 11.3 and 92% for sandwiches. For ice creams and sorbets, the sale of a large number of units (>80 per day) increased the risk of unsatisfactory food by a factor of 2.8 (95% confidence interval [CI]: 1.5 to 5.1), lack of training in food hygiene by 6.6 (95% CI: 1.1 to 50). and by a factor of 2.8 (95% CI: 1.4 to 5.4) for mobile vendors. These risk factors were not identified for sandwiches, this difference may be due to the presence of a cooking step in their preparation. These results show that the poor microbiological quality of these street foods constitutes a potential hazard to public health, that the extent of this hazard varies between the cities studied, and that vendors' health education in food safety is a crucial factor in the prevention of foodborne infections.