The purity of tattoo inks, screening substances of high concern.

BACKGROUND: Tattoos have grown in popularity in recent years with over 60 million Europeans having a tattoo nowadays. Currently, there is no harmonized legislation in Europe but from 2022 on, tattoo inks will be regulated through a REACH Amendment implementing compound-specific restrictions. METHODOLOGY: A screening method based on LC-QqQ-MS was developed and validated for screening 40 substances of high concern in tattoo inks. An additional quantification method was validated to quantify 5-nitro toluidine and 4-chloroaniline in tattoo inks with high accuracy. The method was validated according to the total error approach with an acceptance value of ±20% RESULTS: The methodology was applied to 86 samples of which 26 are violating the current Resolution ResAP (2008). 5-nitro toluidine was found in 16 samples, all of them having an unacceptable health risk, with an average concentration of 29 µg/g basic violet 10, basic red 1, 4-chloroaniline, and basic red 9 were detected 8, 7, 4, and 3, times respectively. Counterfeit products with lower quality were observed. CONCLUSION: Our results show that low-quality tattoo inks are easily available to the European consumer. In line with literature, most infringements were observed with red/brown inks which is not surprising since these colors are most often associated with adverse health effects.

Consumer protection provided by the European medical device and cosmetic legislation for condoms and lubricants.

Personal lubricants and lubricants used in condoms contain a number of ingredients which are also present in cosmetic products. These have to comply to the medical device regulation (745/2017) which should provide the same level of consumer protection, if not more, as foreseen in the legal framework of cosmetics (1223/2009). In the current study we developed an analytical method capable of identifying and quantifying 15 ingredients, commonly found in lubricants and cosmetics. Based upon their most important toxicological endpoint, the substances involved were grouped in three toxicological classes provoking either irritation, contact allergic dermatitis or systemic toxicity. The method was applied on 30 condoms and 54 personal lubricants present on the EU market. Their safety was assessed using the same reasoning as commonly applied for cosmetic ingredients. Higher mucosae susceptibility, the main exposed area for lubricants, was taken into account in this assessment. The results show that the majority of the products studied are safe. Nevertheless, for some products the safety could not be confirmed. The results also highlight the fact that there is no consensus for a number of ingredients, used as well in cosmetics as in medical devices. Alignment between both legislations would improve the safety of these products and further raise the general level of consumer protection.

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

BACKGROUND: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. PATIENTS AND METHODS: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101). RESULTS: In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy. CONCLUSION: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.

Paecilomyces variotii Fungemia in a Patient with Lymphoma Needing Liver Transplant.

Paecilomyces sp. are emerging pathogens in immunocompromised patients. We report here a case of Paecilomyces variotii fungemia, cured with amphotericin and anidulafungin, illustrating difficulties of early diagnosis and therapeutic choice in such rare fungal infection.

Exposure to hypomethylating agent, 5-azacytidine, may improve iCasp9 suicide gene therapy for treating GvHD in allografts.

Anti-tumor cellular immunotherapies that implement a suicide gene system can limit potential undesirable effects. In a haplo-identical bone marrow transplant clinical trial, over 90% of iCaspase-9-expressing cells were eradicated after AP1903 exposure, and signs of graft-versus-host disease disappeared. Nevertheless, low numbers of genetically modified T cells survived this treatment. We studied genetically modified cell lines (GMCL) that carried a dual iCaspase-9/ΔCD19 DNA construct (ΔCD19=truncated CD19). With AP1903 exposure, a low percentage of cells (1.47±0.67%; n=5 replications) persisted in vitro. Repeated exposures to increasing AP1903 doses generated low (GMCLLR) and high AP1903-responders (GMCLHR), which expressed different levels of surface ΔCD19 and intracellular iCaspase-9. Compared with GMCLHR, GMCLLR exhibited higher methylation of 5'-long-terminal repeat (LTR) promoters, both in the number of sequences with at least one methylated CpG (16 vs 51.5%, respectively) and in the number of CpG islands (1.2 vs 8.9%, respectively). Four days of 5-azacytidine exposure reduced methylation and increased ΔCD19 and iCaspase-9 expression. Interestingly, LTR demethylation restored GMCLLR sensitivity to AP1903 by 24.3-fold (1.8 vs 43.8%) without affecting GMCLHR. We showed that 5'-LTR-methylation inhibited transgene expression and caused AP1903 hypo-responsiveness. Treating with a hypomethylating agent restored AP1903 sensitivity. This approach can be applied in further clinical trials to improve iCaspase-9 response if low response is detected.

The Monte Carlo validation framework for the discriminant partial least squares model extended with variable selection methods applied to authenticity studies of Viagra® based on chromatographic impurity profiles.

The aim of this work was to develop a general framework for the validation of discriminant models based on the Monte Carlo approach that is used in the context of authenticity studies based on chromatographic impurity profiles. The performance of the validation approach was applied to evaluate the usefulness of the diagnostic logic rule obtained from the partial least squares discriminant model (PLS-DA) that was built to discriminate authentic Viagra® samples from counterfeits (a two-class problem). The major advantage of the proposed validation framework stems from the possibility of obtaining distributions for different figures of merit that describe the PLS-DA model such as, e.g., sensitivity, specificity, correct classification rate and area under the curve in a function of model complexity. Therefore, one can quickly evaluate their uncertainty estimates. Moreover, the Monte Carlo model validation allows balanced sets of training samples to be designed, which is required at the stage of the construction of PLS-DA and is recommended in order to obtain fair estimates that are based on an independent set of samples. In this study, as an illustrative example, 46 authentic Viagra® samples and 97 counterfeit samples were analyzed and described by their impurity profiles that were determined using high performance liquid chromatography with photodiode array detection and further discriminated using the PLS-DA approach. In addition, we demonstrated how to extend the Monte Carlo validation framework with four different variable selection schemes: the elimination of uninformative variables, the importance of a variable in projections, selectivity ratio and significance multivariate correlation. The best PLS-DA model was based on a subset of variables that were selected using the variable importance in the projection approach. For an independent test set, average estimates with the corresponding standard deviation (based on 1000 Monte Carlo runs) of the correct classification rate, sensitivity, specificity and area under the curve were equal to 96.42% ± 2.04, 98.69% ± 1.38, 94.16% ± 3.52 and 0.982 ± 0.017, respectively.

Overview of skin whitening agents with an insight into the illegal cosmetic market in Europe.

Lightening skin tone is an ancient and well-documented practice, and remains common practice among many cultures. Whitening agents such as corticosteroids, tretinoin and hydroquinone are medically applied to effectively lighten the skin tone of hyperpigmented lesions. However, when these agents are used cosmetically, they are associated with a variety of side-effect. Alternative agents, such as arbutin and its derivatives kojic acid and nicotinamide have been subsequently developed for cosmetic purposes. Unfortunately, some cosmetics contain whitening agents that are banned for use in cosmetic products. This article provides an overview of the mode of action and potential side-effects of cosmetic legal and illegal whitening agents, and the pattern of use of these types of products. Finally, an EU analysis of the health problems due to the presence of illegal products on the market is summarized.

Combining Aspergillus mitochondrial and ribosomal QPCR, in addition to galactomannan assay, for early diagnosis of invasive aspergillosis in hematology patients.

The combination of two quantitative Aspergillus PCR assays, targeting a mitochondrial and a ribosomal target (AfQPCR), has proved effective for diagnosing invasive aspergillosis (IA) in hematology patients with risk factors and a positive galactomannan antigen (GM). The aim of the present study was to assess the performance of systematic AfQPCR for IA screening in at risk patients in a hematology intensive care unit (ICU). The study was performed in the hematology ICU at Besançon University Hospital from March 2012 to December 2013. GM detection (Platelia Aspergillus, Biorad, France) and AfQPCR were performed on the same serum sample, twice a week, in all patients with risk factors for IA. Risk factors and clinical, radiological, and biological data were prospectively recorded using the information sheet from the French network for the surveillance of Invasive Fungal Infection. Thirty-two patients were diagnosed with proven, probable, or possible IA according to the 2008 EORTC/MSG criteria. Sixteen patients had a positive AfQPCR: 9/16 had a positive GM at the same time (GM index >0.5), 4/16 had a positive GM before the AfQPCR and 3/16 had a negative GM at the time of the positive AfQPCR. Screening at risk patients using both AfQPCR and GM on the same serum sample is very feasible in a routine clinical setting. Our results confirm the usefulness of combining biomarkers for an early IA diagnosis.

[Mucositis after allogeneic stem cell transplantation: Risk factors, clinical consequences and prophylaxis]. / La mucite post-allogreffe de cellules souches hématopoïétiques: facteurs de risque, conséquences cliniques et prévention.

AIM: Oral mucositis is a very common complication of allograft. However, preventive treatments are still limited. The objective of this study is to identify risk factors for onset of oral mucositis in patients undergoing allogeneic hematopoietic stem cells transplantation (HSCT), to measure clinical consequences and to study their evolution according to type of prevention. PATIENTS AND METHODS: All patients undergoing HSCT in hematology unit of CHU Besançon between January 2009 and August 2010 were included, and received according to their choice, either the standard protocol: solution of sodium bicarbonate 1.4% associated with chlorhexidine-chlorobutanol (Eludril(®)) (n=49), or the experimental treatment by the ionic solution, Caphosol(®) (n=42). RESULTS: The overall incidence of severe mucositis and mucositis is respectively 69% and 36%. In multivariate analysis, a myeloablative conditioning (OR=11.1) and prevention of GVHD (graft-versus-host disease) including methotrexate (OR=7.5) appear such as the two significant mucositis risk factors. The presence of mucositis resulting in a significant increase in the incidence of febrile aplasia (P=0.008) and the use of opioid analgesics and parenteral nutrition (P<10(-3)). The risk of acute gastrointestinal GVHD is also increased in severe mucositis (P=0.01). The duration of post-transplant hospitalization is not changed. The type of prevention does not influence the incidence of mucositis (P=0.11). CONCLUSION: The consequences of mucositis are significant and the risk factors identified. The interest of the ionic solution Caphosol(®) seems limited, the incidence of mucositis is not decreased by this prevention.

Evaluation of invasive aspergillosis risk of immunocompromised patients alternatively hospitalized in hematology intensive care unit and at home.

UNLABELLED: Contrary to hospital exposure, little is known about the indoor fungal exposure of hematology patients at home. The aim of our study was to investigate the mold exposure of hematology patients both at home and at hospital to assess their invasive aspergillosis (IA) risk. Fungal exposure was assessed by quantifying opportunistic molds at hospital during hospitalization and in homes of 53 hematology patients. IA was diagnosed in 13 of 53 patients and invasive fungal infection (IFI) in one patient. In hospital, no opportunistic species, or low levels of opportunistic species, were found in 98% of weekly controls. Only 2% of hematology intensive care unit (ICU) controls showed a high level of Aspergillus fumigatus spores in corridor air. Five patients IA were hospitalized during these periods. Seven dwellings of 53 (5/14 dwellings of patients with IA/IFI and 2/39 dwellings of non-IA patients) had a percentage of A. fumigatus and Aspergillus flavus to total mold (significant predictor variable of IA/IFI in our study, general linear model, P-value = 0.02) as high as 15%. Maintaining a 'zero Aspergillus' goal at hospital is essential, and establishing specific and individually opportunistic mold monitoring at home could help to further reduce the IA risk through continuous surveillance. PRACTICAL IMPLICATIONS: This study emphasizes the fact that preventive measures should not be aimed only at the hospital setting: among patients diagnosed with invasive aspergillosis/invasive fungal infection (IA/IFI), 5 of 14 (36%) were exposed to opportunistic fungal species at home exclusively. Moreover, four of these five patients were living in homes having the highest percentage of Aspergillus fumigatus and Aspergillus flavus (>15%), one of which had 48% of A. fumigatus. Therefore, our work supports the need for a counselor to carry out an environmental survey in patients' homes.

Incidence and risk-factors of CHOP/R-CHOP-related cardiotoxicity in patients with aggressive non-Hodgkin's lymphoma.

WHAT IS KNOWN AND OBJECTIVE: The CHOP regimen with rituximab (R-CHOP) remains the standard for chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). The cardiotoxicity of doxorubicin appears to be a key problem in clinical practice. We studied the cardiotoxicity of CHOP/R-CHOP regimen in a retrospective series. The prognostic factors of congestive heart failure (CHF) were investigated, including the impact of empirical cardioprotection by dexrazoxane. METHODS: Patients with an aggressive NHL between 1994 and 2005 were included. Cardiac events were defined as either a decline in resting left ventricular ejection fraction (LVEF) <50%, a decline in LVEF of ≥20% from baseline or as clinical evidence of CHF. The risk of cardiotoxicity was explored by the Kaplan-Meier method. RESULTS: The study included 180 consecutive patients. During the second period of the survey, cardioprotective therapy by dexrazoxane was administered to 45% of patients. The 5-year cumulative risks of cardiac events (29% vs. 8%) and clinical CHF (17% vs. 1·5%) varied significantly between the two periods of study (1994-2000 vs. 2001-2005). In multivariate analysis, use of dexrazoxane (HR = 0·1 [0·01-0·75], P = 0·02) and age  < 60 years (HR = 0·4 [0·17-0·9], P = 0·03) appeared as protective factors of cardiac events. WHAT IS NEW AND CONCLUSION: Our study confirmed the weight of cardiac toxic effect of CHOP ± R regimen. Even if the use of dexrazoxane is highly debatable in curative situations, it may be an effective prevention of cardiotoxicity in aggressive NHL patients.

Diagnosis and management of nocardiosis after bone marrow stem cell transplantation in adults: lack of lymphocyte recovery as a major contributing factor.

Hematopoietic cell transplantation (HCT) is a curative treatment for hematological malignancies. This therapeutic approach is associated with a profound immune deficiency and an increased rate of opportunistic infections. Nocardiosis is a rare bacterial infection occurring mainly in patients with deficient cell-mediated immunity, such as AIDS patients or transplant recipients. Diagnosis of nocardiosis can be challenging, as signs and symptoms are non-specific. Routine prophylaxis with trimethoprin/sulfamethoxazole (TMP/SMZ) does not prevent the risk of infection. Between May 2001 and December 2009, five cases of nocardiosis were diagnosed from the 366 allogeneic HCT recipients in our centre. Four patients developed a disseminated nocardiosis within the first year after HCT. The fifth patient presented a localized cutaneous nocardiosis. In disseminated cases, median total CD4+ T-cells were below 100 cells/µL. Naive CD4+ CD45RA+/RO- T-cells were almost undetectable. CD8(+) T-cells and NK cells were below the normal range and CD19+ B-cell reconstitution was completely deficient. In a localized case, we observed a lack of naive thymic emigrants CD4+ CD45RA+/RO- T-cells.

A strategy for the identification of plants in illegal pharmaceutical preparations and food supplements using chromatographic fingerprints.

The detection of regulated and forbidden herbs in pharmaceutical preparations and nutritional supplements is a growing problem for laboratories charged with the analysis of illegal pharmaceutical preparations and counterfeit medicines. This article presents a feasibility study of the use of chromatographic fingerprints for the detection of plants in pharmaceutical preparations. Fingerprints were developed for three non-regulated common herbal products--Rhamnus purshiana, Passiflora incarnata L. and Crataegus monogyna--and this was done by combining three different types of detection: diode-array detection, evaporative light scattering detection and mass spectrometry. It is shown that these plants could be detected in respective triturations of the dry extracts with lactose and three different herbal matrices as well as in commercial preparations purchased on the open market.

[How I manage respiratory syncytial virus, human herpesvirus 6 and adenovirus reactivation or infection after allogeneic stem cell transplantation: a report of the SFGM-TC]. / Conduite à tenir devant une réactivation ou une infection à virus respiratoire syncytial, herpèsvirus 6 et adénovirus après allogreffe de cellules souches hématopoïétiques.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of virus respiratory syncytial virus (RSV), human herpes virus 6 (HHV6) or adenovirus allogeneic Stem Cell Transplantation.

Clustering of Tadalafil API Samples According to their Manufacturer in the Context of API Falsification Detection.

This paper reports the results of the active pharmaceutical ingredient (API) fingerprint study, organised by the General European Official Medicines Control Laboratory Network (GEON), on tadalafil. A classical market surveillance study, evaluating compliance to the European Pharmacopoeia, was combined with a fingerprint study, the latter to obtain characteristic data for the different manufacturers, allowing the network laboratories to conduct authenticity tests for future samples, as well as to detect substandard and falsified samples. In total, 46 tadalafil API samples from 13 different manufacturers were collected. For all samples fingerprint data was collected through analysis of impurities and residual solvents, mass spectrometric screening, X-ray powder diffraction and proton nuclear magnetic resonance (1H-NMR). Chemometric analysis revealed that all manufacturers could be characterised based on the impurity, residual solvent and 1H-NMR data. Future suspicious samples in the network will therefore be analysed with these techniques in order to attribute the sample to one of the manufacturers. If the sample cannot be attributed, a more profound investigation will be necessary to reveal the origin of the sample. In cases where the suspect sample is claimed to be from one of the manufacturers included in this study, analysis can be limited to the test distinguishing that manufacturer.

Double reduced-intensity allogeneic hematopoietic stem cell transplantation: a retrospective study from the SFGM-TC.

The purpose of this paper is to describe the outcome of patients who underwent double allogeneic hematopoietic stem cell transplantation (AHSCT) with reduced-intensity conditioning regimens (RIC). Forty-five patients who received double RIC-AHSCT between 1997 and 2006 were retrospectively studied. The predominant diagnosis was acute myeloid leukemia (AML) (n = 17). Other diagnoses were aplasic anemia (AA) (n = 5), myelodysplasic disorder (n = 5), acute lymphoblastic leukemia (ALL) (n = 4), chronic myelomonocytic leukemia (CML) (n = 3), myeloma (n = 3), non-Hodgkin lymphoma (NHL) (n = 3), chronic lymphocytic leukemia (CLL) (n = 2), Hodgkin's disease (HD) (n = 2), and chronic myelomonocytic leukemia (n = 1). Main indications for RIC-AHSCT 2 were relapse (n = 25, 56%) and early (n = 8, 18%) or late (n = 12, 26%) graft failure. Median delays to reach a neutrophil count of 0.5 × 10(9)/L and platelet counts of 50 × 10(9)/L were significantly smaller after the second AHSCT. Among 25 patients who relapsed after RIC-AHSCT 1, 14 patients (56%) presented a response improvement after RIC-AHSCT 2. In this group, 9 patients sustained a complete response and 5 patients a partial response. Moreover, among the 20 patients who had early or late graft failure following RIC-AHSCT 1, 9 (45%) finally reached an engraftment. Disease-free survival (DFS) was significantly improved after RIC-AHSCT 2. Thirteen patients (28%) died of transplant-related mortality (TRM) at a median delay of 69 days (range: 0-451) after RIC-AHSCT 2. Double RIC-AHSCT is a feasible procedure that allows a response or engraftment not observed after RIC-AHSCT 1. The main indication is relapse. However, TRM remains high.

A 4-weekly course of rituximab is safe and improves tumor control for patients with minimal residual disease persisting 3 months after autologous hematopoietic stem-cell transplantation: results of a prospective multicenter phase II study in patients with follicular lymphoma.

BACKGROUND: This study explored the efficacy and safety of rituximab as treatment of clinical or molecular residual disease after autologous stem-cell transplantation (ASCT) in follicular lymphoma (FL). PATIENTS AND METHODS: Forty patients with CD20+ FL and clinically (group A, n = 14) or clono-specific PCR-detectable (group B, n = 25) residual disease persisting 3 months after ASCT received rituximab 375 mg/m² once weekly for 4 weeks. RESULTS: Response rate at day 50 was 36% [90% confidence interval (CI) 15-61] in group A (World Health Organization criteria) and 52% (90% CI 34-70) in group B (conversion PCR-undetectable status to undetectable status). The best response rate was 71% [nine complete responses (CRs) and one partial response] in group A and 76% in group B. At 36 months, all 10 responses persisted in group A, whereas 46% of patients in group B still had PCR-undetectable disease. Furthermore, 68% of patients in group B were still in clinical CR. Rituximab after ASCT was safe with few grade 3-4 toxic effects (15% patients), mainly acute reactions and infections. CONCLUSION: Rituximab induced a high rate of durable CRs in patients with clinically detectable disease, as well as durable eradication of PCR-detectable disease in patients with FL after ASCT. Continued molecular responses assessed with a highly sensitive and clono-specific PCR technique were correlated with an excellent disease control.

Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up.

BACKGROUND: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). PATIENTS AND METHODS: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m(2)), 46 have been followed with a long-term analysis of clinical and molecular responses. RESULTS: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed. CONCLUSION: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients.

GEONs API fingerprint project: Selection of analytical techniques for clustering of sildenafil citrate API samples.

Through its Active Pharmaceutical Ingredient Working Group (API-WG) the General European Official Medicines Control Laboratory (OMCL) Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), regularly organises market surveillance studies for specific APIs for conformity to their monograph in the European Pharmacopoeia. During the past years some studies were combined with a fingerprint study of the APIs. The idea is to obtain a fingerprint for each manufacturer of the API under investigation, allowing the OMCL network to identify future samples as well as to detect substandard and falsified APIs. This paper reports the results of the latest fingerprint study, organised on sildenafil citrate API samples. Seventy-nine samples from 14 different manufacturers were collected throughout the Network. Fingerprint data was collected through Mid-Infrared spectroscopy, Raman spectroscopy, liquid chromatography for related substances, gas chromatography for residual solvents, X-ray diffraction and Nuclear Magnetic Resonance (NMR) spectroscopy. Chemometrics applied to the collected data showed that all manufacturers could be discriminated based on the data of only three of these tests, i.e. gas chromatography for residual solvents, X-ray diffraction and proton NMR. Suspicious API samples for sildenafil citrate will therefore be analysed in the future with the selected techniques in order to link the sample to a manufacturer or demonstrate the absence of such link. If the sample cannot be attributed to one of the manufacturers, further analysis and research on provenance and identity will be required. Of course, if the suspected sample claims to originate from one of the manufacturers included in the study, analysis can be limited to the test distinguishing this manufacturer.