Comparison of Pyrrolobenzodiazepine Dimer Bis-imine versus Mono-imine: DNA Interstrand Cross-linking, Cytotoxicity, Antibody-Drug Conjugate Efficacy and Toxicity.

Antibody-drug conjugates (ADC) delivering pyrrolobenzodiazepine (PBD) DNA cross-linkers are currently being evaluated in clinical trials, with encouraging results in Hodgkin and non-Hodgkin lymphomas. The first example of an ADC delivering a PBD DNA cross-linker (loncastuximab tesirine) has been recently approved by the FDA for the treatment of relapsed and refractory diffuse large B-cell lymphoma. There has also been considerable interest in mono-alkylating PBD analogs. We conducted a head-to-head comparison of a conventional PBD bis-imine and a novel PBD mono-imine. Key Mitsunobu chemistry allowed clean and convenient access to the mono-imine class. Extensive DNA-binding studies revealed that the mono-imine mediated a type of DNA interaction that is described as "pseudo cross-linking," as well as alkylation. The PBD mono-imine ADC demonstrated robust antitumor activity in mice bearing human tumor xenografts at doses 3-fold higher than those that were efficacious for the PBD bis-imine ADC. A single-dose toxicology study in rats demonstrated that the MTD of the PBD mono-alkylator ADC was approximately 3-fold higher than that of the ADC bearing a bis-imine payload, suggesting a comparable therapeutic index for this molecule. However, although both ADCs caused myelosuppression, renal toxicity was observed only for the bis-imine, indicating possible differences in toxicologic profiles that could influence tolerability and therapeutic index. These data show that mono-amine PBDs have physicochemical and pharmacotoxicologic properties distinct from their cross-linking analogs and support their potential utility as a novel class of ADC payload.

Nonmedical use of tramadol among secondary school students in Benin, Africa.

Background: Nonmedical use of tramadol among the young Beninese population is an increasing public health concern. However, there is little research on tramadol use in West Africa.Objectives: This study aimed to assess the prevalence, factors associated with nonmedical use of tramadol and to determine the level of therapeutic intervention needed.Methods: A cross-sectional study design and multi-stage sampling method was used among 384 secondary school students, within the age group of 10-24 years old who gave their consent/assent. An interviewer-administered modified questionnaire based on ASSIST was administered. Urinary toxicological test was performed using NarcoCheck® quick for qualitative detection of tramadol or its metabolites. Logistic regression analysis was performed to identify factors associated with nonmedical use of tramadol.Results: The average age of our respondents was 17 ± 2 SD years old; 58.3% were males and 41.7% females. The lifetime prevalence of nonmedical use of tramadol was 9.6% (95% CI: 6.7-12.6) (13.4% males and 4.4% females) and the average age at onset was 14.8 ± 1.8 years old. Only 1.4% (n = 4) were using tramadol as shown by urine screen. Among users, 45.9% reported a hazardous level of use and required a brief intervention. In a multivariate logistic regression model, tobacco (P < .001), cannabis (p = .023) and amphetamine (p = .037) were significantly associated with nonmedical use of tramadol. The most prevalent motives for nonmedical use of tramadol was experimentation (45.9%) and the leading source for obtaining tramadol was street-level markets (86.5%).Conclusion: These results indicate that nonmedical use of tramadol affects young in Benin and represent a considerable concern among secondary school students.

Successful Clearance of 300 Day SARS-CoV-2 Infection in a Subject with B-Cell Depletion Associated Prolonged (B-DEAP) COVID by REGEN-COV Anti-Spike Monoclonal Antibody Cocktail.

A 59-year-old male with follicular lymphoma treated by anti-CD20-mediated B-cell depletion and ablative chemotherapy was hospitalized with a COVID-19 infection. Although the patient did not develop specific humoral immunity, he had a mild clinical course overall. The failure of all therapeutic options allowed infection to persist nearly 300 days with active accumulation of SARS-CoV-2 virus mutations. As a rescue therapy, an infusion of REGEN-COV (10933 and 10987) anti-spike monoclonal antibodies was performed 270 days from initial diagnosis. Due to partial clearance after the first dose (2.4 g), a consolidation dose (8 g) was infused six weeks later. Complete virus clearance could then be observed over the following month, after he was vaccinated with the Pfizer-BioNTech anti-COVID-19 vaccination. The successful management of this patient required prolonged enhanced quarantine, monitoring of virus mutations, pioneering clinical decisions based upon close consultation, and the coordination of multidisciplinary experts in virology, immunology, pharmacology, input from REGN, the FDA, the IRB, the health care team, the patient, and the patient's family. Current decisions to take revolve around patient's follicular lymphoma management, and monitoring for virus clearance persistence beyond disappearance of REGEN-COV monoclonal antibodies after anti-SARS-CoV-2 vaccination. Overall, specific guidelines for similar cases should be established.

Characteristics and outcome of pediatric renal cell carcinoma patients registered in the International Society of Pediatric Oncology (SIOP) 93-01, 2001 and UK-IMPORT database: A report of the SIOP-Renal Tumor Study Group.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

Preclinical Characterization of an Antibody-Drug Conjugate Targeting CS-1 and the Identification of Uncharacterized Populations of CS-1-Positive Cells.

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.

Prevention of biliary fistula after partial hepatectomy by transcystic biliary drainage: randomized clinical trial.

BACKGROUND: Biliary fistula is one of the most common complications after hepatectomy. This study evaluated the effect of transcystic biliary drainage during hepatectomy on the occurrence of postoperative biliary fistula. METHODS: This multicentre RCT was carried out from 2009 to 2016 in nine centres. Patients were randomized to transcystic biliary drainage or no transcystic drainage (control). Patients underwent hepatectomy (more than 2 segments) of non-cirrhotic livers. The primary endpoint was the occurrence of biliary fistula after surgery. Secondary endpoints were morbidity, postoperative mortality, duration of hospital stay, reoperation, readmission to hospital, and complications caused by catheters. Intention-to-treat and per-protocol analyses were performed. RESULTS: A total of 310 patients were randomized. In intention-to-treat analysis, there were 158 patients in the transcystic group and 149 in the control group. Seven patients were removed from the per-protocol analysis owing to protocol deviations. The biliary fistula rate was 5·9 per cent in intention-to-treat and 6·0 per cent in per-protocol analyses. The rate was similar in the transcystic and control groups (5·7 versus 6·0 per cent; P = 1·000). There were no differences in terms of morbidity (49·4 versus 46·3 per cent; P = 0·731), mortality (2·5 versus 4·7 per cent; P = 0·367) and reoperations (4·4 versus 10·1 per cent; P = 1·000). Median duration of hospital stay was longer in the transcystic group (11 versus 10 days; P = 0·042). The biliary fistula risk was associated with the width and length of the hepatic cut surface. CONCLUSION: This randomized trial did not demonstrate superiority of transcystic drainage during hepatectomy in preventing biliary fistula. The use of transcystic drainage during hepatectomy to prevent postoperative biliary fistula is not recommended. Registration number: NCT01469442 ( http://www.clinicaltrials.gov).

ANTECEDENTES: La fístula biliar es una de las complicaciones más comunes después de la hepatectomía. Este estudio evalúa el efecto del drenaje biliar transcístico durante la hepatectomía en la aparición de una fístula biliar postoperatoria. MÉTODOS: Este ensayo prospectivo aleatorizado y multicéntrico (Clinical Trial NCT01469442) con dos grupos de estudio (grupo transcístico versus grupo control) se llevó a cabo de 2009 a 2016 en 9 centros. Los pacientes fueron sometidos a una hepatectomía (≥ 2 segmentos) en hígados no cirróticos. El resultado principal fue la aparición de una fístula biliar después de la cirugía. Los resultados secundarios fueron la morbilidad, la mortalidad postoperatoria, la duración de la estancia hospitalaria, la reintervención, la necesidad de reingreso y las complicaciones causadas por los catéteres. Se realizaron análisis por intención de tratamiento y por protocolo. RESULTADOS: Un total de 310 pacientes fueron randomizados. Por intención de tratamiento, 158 pacientes fueron aleatorizados al grupo transcístico y 149 al grupo control. Siete pacientes fueron excluidos del análisis por protocolo por desviaciones del protocolo. La tasa de fístula biliar fue del 5,9% en el análisis por intención de tratamiento y del 6,0% en el análisis por protocolo. Esta tasa fue similar para el grupo transcístico y para el grupo control: 5,7% versus 6,0% (P = 1). No hubo diferencias en términos de morbilidad (49,4% versus 46,9%, P = 0,731), mortalidad (2,5% versus 4,7%, P = 0,367) y reintervenciones (4,4% versus 10,1%, P = 1). La mediana de la duración de la estancia hospitalaria fue mayor para el grupo transcístico (11 versus 10 días, P = 0,042). El riesgo de fístula biliar se correlacionó con el grosor y la longitud de la transección hepática. CONCLUSIÓN: Este ensayo aleatorizado no demuestra la superioridad del drenaje transcístico durante la hepatectomía para prevenir la fístula biliar. No se recomienda el uso de drenaje transcístico durante la hepatectomía para prevenir la fístula biliar postoperatoria.

SLC46A3 as a Potential Predictive Biomarker for Antibody-Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads.

PURPOSE: Antibody-drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance. EXPERIMENTAL DESIGN: The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, in vitro. The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft and in vitro models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR. RESULTS: Loss of SLC46A3 expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of SLC46A3, suggesting that expression of SLC46A3 may be more predictive of activity than target antigen levels alone. Interrogation of primary multiple myeloma samples indicated a range of SLC46A3 expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs. CONCLUSIONS: Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.

Efficacy of antenatal corticosteroids in preterm twins: the EPIPAGE-2 cohort study.

OBJECTIVES: To investigate the efficacy of antenatal corticosteroid (ACS) therapy on short-term neonatal outcomes in preterm twins, and further document the influence of the ACS-to-delivery interval. DESIGN: EPIPAGE-2 is a nationwide observational multicentre prospective cohort study of neonates born between 22 and 34 completed weeks of gestation. SETTING: All French maternity units, except in a single administrative region, between March and December 2011. POPULATION: A total of 750 twin neonates born between 24 and 31 weeks of gestation. METHODS: Exposure to ACSs was examined in four groups: single complete course, with an ACS administration-to-delivery interval of ≤7 days; single complete course, with an ACS-to-delivery interval of >7 days; repeated courses; or no ACS treatment. MAIN OUTCOME MEASURES: Neonatal outcomes analysed were severe bronchopulmonary dysplasia, periventricular leukomalacia or intraventricular haemorrhage grade III/IV, in-hospital mortality, and a composite indicator of severe outcomes. RESULTS: Compared with no ACSs, in multivariable analysis, a single course of ACSs with an administration-to-delivery interval of ≤7 days was significantly associated with a reduced rate of periventricular leukomalacia or intraventricular haemorrhage grade III/IV (aOR 0.2; CI 95% 0.1-0.5), in-hospital mortality (0.3; 0.1-0.6), and the composite indicator (0.1; 0.1-0.3), whereas a single course of ACDs with an administration-to-delivery interval of >7 days did not significantly reduce the frequency of in-hospital mortality (0.7; 0.3-1.8). No significant differences in terms of benefit or risk were found when comparing repeated courses with a single complete course. CONCLUSION: In preterm twins, a single complete course of antenatal corticosteroids was associated with an improvement of severe neurological outcome, whereas reduced in-hospital mortality was seen only when the ACS-to-delivery interval was ≤7 days. TWEETABLE ABSTRACT: A single complete course of antenatal steroids reduced severe neurological morbidity in preterm twins (24-31 weeks).

Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin.

A novel pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully conjugated to trastuzumab and the resulting ADC exhibited potent activity against a HER2-expressing human cancer cell line in vitro.

Pyrrolobenzodiazepine Antibody-Drug Conjugates Designed for Stable Thiol Conjugation.

Thiosuccinimide-linked antibody-drug conjugates (ADCs) are susceptible to drug loss over time due to a retro-Michael reaction, which can be prevented by selecting stable conjugation positions or hydrolysis of the thiosuccinimide. Here, we investigate pyrrolobenzodiazepine (PBD) ADC drug-linkers equipped with N-phenyl maleimide functionality for stable thiol conjugation via thiosuccinimide hydrolysis. Two PBD drug-linker formats (enzyme-cleavable and non-cleavable) were evaluated following site-specific conjugation to an engineered cysteine incorporated at position T289, which is known to be unstable for N-alkyl maleimide conjugates. N-phenyl maleimide PBDs conjugated to antibodies with similar efficiencies as N-alkyl maleimide PBDs and enhanced thiosuccinimide hydrolysis for N-phenyl maleimide PBDs was confirmed by mass spectrometry, capillary isoelectric focusing, and a SYPRO Orange dye binding assay. All of the PBD ADCs were highly potent in vitro regardless of maleimide- or linker-type, exhibiting low pM EC50 values. Thiol conjugation to N-phenyl maleimide PBD minimized the retro-Michael reaction in both rat and mouse serum. However, cleavage of the valine-alanine dipeptide in mouse serum for ADCs containing cleavable drug-linker led to drug loss regardless of maleimide type, which impacted ADC potency in tumor growth inhibition studies that were conducted in mouse models. Therapeutic improvement in mouse tumor models was realized for ADCs prepared with non-cleavable PBD drug-linkers that were conjugated through N-phenyl maleimide, where a stronger tumor growth inhibition (TGI) response was achieved when compared to the analogous N-alkyl maleimide drug-linker ADC. Altogether, our findings highlight the stability and efficacy benefits of N-phenyl maleimide functionality for ADCs that are produced with thiol-maleimide conjugation chemistry.

[Delayed umbilical cord clamping in preterm infants born before 37 weeks of gestation: A prospective observational study]. / Clampage tardif du cordon ombilical chez les enfants prématurés nés avant 37 semaines d'aménorrhée : étude observationnelle prospective.

INTRODUCTION AND OBJECTIVES: Many international studies have demonstrated that delayed umbilical cord clamping reduces neonatal morbidity. However, in France, delayed umbilical cord clamping is still not performed in many neonatal units. The aims of this study were to evaluate the feasibility of developing a protocol of delayed umbilical cord clamping in the maternity ward of the Toulouse university hospital and to evaluate the impact of this new protocol on neonatal mortality. METHODS: We conducted a prospective observational study including 123 preterm infants born before 37 weeks of gestation between June 2012 and June 2013 and hospitalized at birth. Delayed cord clamping was performed for at least 30s after birth; otherwise, it was evaluated as early cord clamping. We excluded twin-to-twin transfusion syndrome, congenital abnormalities, alloimmunization, and perinatal asphyxia. We analyzed the reasons why delayed umbilical cord clamping was not performed and then neonatal morbidity in our population. RESULTS: Delayed umbilical cord clamping was performed on 79 infants and 44 infants had early umbilical cord clamping. The two groups had similar baseline characteristics. Preterm infants in the delayed cord-clamping group had a higher level of hemoglobin during the first 24h of life (17.9g/dL versus 16.6g/dL, P=0.005), fewer of them required transfusion (14% versus 35%, P=0.03), and fewer presented late-onset sepsis (8% versus 26%, P=0.02) or bronchopulmonary dysplasia (9% versus 26%, P=0.03). There was no statistically significant increase of hyperbilirubinemia requiring phototherapy. DISCUSSION AND CONCLUSION: Implanting a new protocol of delayed umbilical cord clamping in our maternity ward proved to be possible without difficulty. The advantages of delayed umbilical cord clamping were observed in this prospective study. Today, delayed cord clamping has become a common practice in our maternity unit.

Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload.

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.

A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology.

A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody-drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity.

The pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, SG2000) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are eliminated, the imine moieties can bind covalently in the DNA minor groove, forming an interstrand cross-link. The mean in vitro cytotoxic potency of SG2285 against human tumor cell lines is GI(50) 20 pmol/L. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was primarily dependent on ERCC1 and homologous recombination repair. In primary B-cell chronic lymphocytic leukemia samples, the mean LD(50) was significantly lower than in normal age-matched B and T lymphocytes. Antitumor activity was shown in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic, and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced-stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development.

Use of emergency contraceptive pill by 15-year-old girls: results from the international Health Behaviour in School-aged Children (HBSC) study.

OBJECTIVE: To describe emergency contraceptive pill (ECP) use and variation across countries/regions; and to explore personal and contextual factors associated with ECP use and differences across countries/regions. DESIGN: Data were obtained from 11 countries/regions in the 2006 Health Behaviour in School-aged Children cross-sectional study. SETTING Data were collected by self-report questionnaire in school classrooms. POPULATION: The analysis is based on 2118 sexually active 15-year-old girls. METHODS: Contraceptive behaviours were compared across countries/regions by chi-square tests. Individual factors related to ECP use were investigated with separate logistic regression models. Multilevel random-intercept models allowed the investigation of individual and contextual effects, by partitioning the variance into student, school and country/region levels. MAIN OUTCOME MEASURES: ECP use at last sexual intercourse. RESULTS: ECP use rate varied significantly across countries/regions. Poor communication with at least one adult (odds ratio [OR] 1.62 [1.12-2.36], P = 0.011) and daily smoking (OR 1.46 [1.00-2.11], P = 0.048) were independently associated with ECP use in comparison with condom and/or birth-control pill use. Sexual initiation at 14 years or later (OR 2.02 [1.04-3.93], P = 0.039), good perceived academic achievement (OR 1.69 [1.04-2.75], P = 0.035) and daily smoking (OR 1.63 [1.01-2.64], P = 0.045) were associated with higher levels of ECP use in comparison with unprotected girls. The country-level variance remained significant in both comparisons. CONCLUSIONS: These data document the large heterogeneity in rates of ECP use between countries/regions. These differences could not be explained by individual or contextual factors, and raise further questions in relation to ECP access for adolescents and their education in its appropriate use.

Ocular graft-versus-host disease after allogeneic stem cell transplantation.

PURPOSE: To determine the prevalence and manifestations of ocular graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (allo-SCT). METHODS: Prospective study of 101 consecutive patients who received allo-SCT from 2004 to 2007. All patients received ophthalmologic examination for 3 months after allo-SCT, and those with ocular complaints were evaluated at 12 and 24 months thereafter. We registered ophthalmologic and hematological data, including the indication for allo-SCT, occurrence of systemic and ocular GvHDs, ocular manifestations, and various ocular treatments. RESULTS: Over time, ocular GvHD developed in 54% of patients and consisted mainly of dry eyes and conjunctivitis, which increased in severity during follow-up; blepharitis and uveitis were less often encountered. Acute systemic GvHD, especially the involvement of mouth and skin, was strongly associated with ocular GvHD at 3 months (P = 0.000). Chronic GvHD was associated with the occurrence of ocular GvHD (P = 0.000), especially with the development of the dry eye. Although eye symptoms affecting activities of daily living were reported in 24 of 54 patients (44%) and 16 of 54 patients (30%) experienced temporary loss of visual acuity of more than 2 Snellen lines, only 1 developed permanent unilateral loss (counting fingers) because of ischemic vasculopathy. Cataract development was not encountered, and only 1 eye developed intraocular infection. CONCLUSION: Ocular GvHD develops in a substantial part of patients after allo-SCT and decreases the activities of daily living.

Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents.

A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.

Synthesis of a novel C2/C2'-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate.

A prodrug form (17) of a novel C2/C2'-aryl-substituted pyrrolobenzodiazepine (PBD) dimer (16) has been synthesized by introducing sodium bisulfite groups to the C11/C11'-positions of the parent bis-imine. The prodrug form is highly water soluble, stable in aqueous conditions, and the rate of DNA cross-link formation is much slower compared to the parent bis-imine.

An asymmetric C8/C8'-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs.

A novel sequence-selective extended PBD dimer 4 has been synthesized that binds with high affinity to an interstrand cross-linking site spanning 11 DNA base pairs. Despite its molecular weight (984.07) and length, the molecule has significant DNA interstrand cross-linking potency (approximately 100-fold greater than the clinically used agent melphalan) and sub-micromolar cytotoxicity in a number of tumour cell lines, suggesting that it readily penetrates cellular and nuclear membranes to reach its DNA target.

Do new therapeutic approaches (autotransplants, thalidomide, dexamethasone) improve the survival of patients with multiple myeloma followed in a rheumatology department?

Survival of patients with multiple myeloma (MM) showed no improvement between the 1960s and 1990s. During the last decade, new therapeutic approaches seemed likely to offer hope of prolonging survival. The aim of this study was to examine if this survival increased with the usage of new treatments. The method involves a retrospective study of 123 patients with MM, diagnosed between 1975 and 1999, all receiving treatment. They were divided into two groups: group 1 included 55 patients given the so-called "old treatments" [melphalan-prednisone, cyclophosphamide-prednisone, polychemotherapy (vincristine, melphalan, cyclophosphamide, prednisone (VMCP), VMCP-VBAP)], and group 2 included 68 patients receiving at least one of the so-called "new treatments" (dexamethasone, thalidomide, high-dose chemotherapy followed by autotransplants, bisphosphonates, interferon). The two groups were similar in terms of age, sex ratio and renal impairment, and the percentage of light-chain MM was identical in both groups. Patients who had been given a "new" treatment (group 2) had longer median survival than the patients in group 1 (54 vs 42 months). Independent analysis of each treatment modality showed increased median survival in MM patients treated using autotransplantation compared with untreated patients (125 vs 45 months). Survival was also longer in MM patients treated with thalidomide than in untreated patients (72 vs 42 months). On the other hand, neither bisphosphonates, interferon-alpha nor dexamethasone result in improved survival. Our findings emphasize the increased survival of the MM patients treated with new therapeutic approaches.