Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study

OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.     

Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation

The clinical activity of rituximab, a chimeric monoclonal antibodywhich binds to the CD20 antigen, was evaluated as a single first-linetherapy for patients with follicular non-Hodgkin lymphoma (NHL). Fiftypatients with follicular CD20⁺ NHL and a low tumor burdenwere analyzed for clinical and molecular responses. They received 4 weekly infusions of rituximab at a dose of 375 mg/m². Theresponse rate a month after treatment (day 50) was 36 of 49 (73%),with 10 patients in complete remission, 3 patients in completeremission/unconfirmed, and 23 patients in partial remission. Tenpatients had stable disease, and the disease progressed in 3 patients. One of 13 (8%) patients in complete remission, 9 of 23 (39%) patients in partial remission, and 5 of 10 (50%) patients withstable disease exhibited disease progression during the first year.Within the study population, 32 patients were initially informative forpolymerase chain reaction (PCR) data on bcl-2-J_H rearrangement. On day 50, 17 of 30 patients (57%) were negative forbcl-2-J_H rearrangement in peripheral blood, and 9 of 29 (31%) were negative in bone marrow; a significant association wasobserved between molecular and clinical responses(P < .0001). At month 12, 16 of 26 patients (62%) werePCR negative in peripheral blood. These results indicate that earlymolecular responses can be sustained for up to 12 months and that thisresponse is highly correlated with progression-free survival. Rituximabhas a high clinical activity and a low toxicity and induces a highcomplete molecular response rate in patients with follicular lymphomaand a low tumor burden.     

AIDS-related cholangiopathy

Several types of biliary tract abnormality of undertermined origin have been described among AIDS patients. The aims of this study are (1) to evaluate whether biliary tree involvement is in fact one or several homogeneous morphological entities, (2) to specify the role of CMV orCryptosporidium sp. infection, and (3) to evaluate the possible efficacy of treatment. Since ultrasound had revealed abnormality in the biliary tree, 26 consecutive AIDS patients underwent cholangiography. Cholangiograms enabled us to distinguish between two types of biliary tract involvement: (1) gradual and regular stenosis of the terminal portion of the common bile duct associated with dilation but without irregularity of the intrahepatic biliary ducts was present in 27% of our cases, and (2) distal stenosis of the extrahepatic biliary ducts combined with diffuse irregularity of the caliber of the intrahepatic bile ducts was present in 73% of our cases. Concomitant infection by CMV orCryptosporidium sp. was significantly more frequent when intrahepatic duct irregularities were present (94%) than when absent (14%,P<0.001). Anti-CMV treatment and sphincterotomy were unsuccessful in treating anomalies of the intrahepatic biliary tract. Conversely, sphincterotomy caused rapid and lasting disappearance of pain in all our patients. In conclusion, biliary tract involvement in AIDS patients is of two types. CMV infection and infection byCryptosporidium sp. are most frequent when the large intrahepatic ducts are implicated.     

Flavopiridol Induces Apoptosis in Chronic Lymphocytic Leukemia Cells Via Activation of Caspase-3 Without Evidence of bcl-2 Modulation or Dependence on Functional p53

Flavopiridol has been reported to induce apoptosis in lymphoid celllines via downregulation of bcl-2. The in vitro activity offlavopiridol against human chronic lymphocytic leukemia (CLL) cells andpotential mechanisms of action for inducing cytotoxicity were studied.The in vitro viability of mononuclear cells from CLL patients (n = 11) was reduced by 50% at 4 hours, 24 hours, and 4 days at aflavopiridol concentration of 1.15 µmol/L (95% confidence interval[CI] ±0.31), 0.18 µmol/L (95% CI±0.04), and 0.16 µmol/L (95% CI ±0.04), respectively. Loss ofviability in human CLL cells correlated with early induction ofapoptosis. Exposure of CLL cells to 0.18 µmol/L of flavopiridolresulted in both decreased expression of p53 protein and cleavage ofthe caspase-3 zymogen 32-kD protein with the appearance of its 20-kD subunit. Contrasting observations of others in tumor cell lines, flavopiridol cytotoxicity in CLL cells did not correlate with changesin bcl-2 protein expression alterations. We evaluated flavopiridol'sdependence on intact p53 by exposing splenocytes from wild-type(p53^+/+) and p53 null (p53^/) micethat demonstrated no preferential cytotoxicity as compared with amarked differential with F-ara-a and radiation. Incubation of CLL cellswith antiapoptotic cytokine interleukin-4 (IL-4) did not alter theLC₅₀ of flavopiridol, as compared with a marked elevationnoted with F-ara-a in the majority of patients tested. These datademonstrate that flavopiridol has significant in vitro activity againsthuman CLL cells through activation of caspase-3, which appears to occurindependently of bcl-2 modulation, the presence of IL-4, or p53 status.Such findings strongly support the early introduction of flavopiridolinto clinical trials for patients with B-CLL.     

Complexities of Short-Term Mobility for Sex Work and Migration among Sex Workers: Violence and Sexual Risks,Barriers to Care,and Enhanced Social and Economic Opportunities

Despite research on the health and safety of mobile and migrant populations in the formal and informal sectors globally, limited information is available regarding the working conditions, health, and safety of sex workers who engage in short-term mobility and migration. The objective of this study was to longitudinally examine work environment, health, and safety experiences linked to short-term mobility/migration (i.e., worked or lived in another city, province, or country) among sex workers in Vancouver, Canada, over a 2.5-year study period (2010–2012). We examined longitudinal correlates of short-term mobility/migration (i.e., worked or lived in another city, province, or country over the 3-year follow-up period) among 646 street and off-street sex workers in a longitudinal community-based study (AESHA). Of 646 sex workers, 10.84 % (n = 70) worked or lived in another city, province, or country during the study. In a multivariate generalized estimating equations (GEE) model, short-term mobility/migration was independently correlated with older age (adjusted odds ratio (AOR) 0.95, 95 % confidence interval (CI) 0.92–0.98), soliciting clients in indoor (in-call) establishments (AOR 2.25, 95 % CI 1.27–3.96), intimate partner condom refusal (AOR 3.00, 1.02–8.84), and barriers to health care (AOR 1.77, 95 % CI 1.08–2.89). In a second multivariate GEE model, short-term mobility for sex work (i.e., worked in another city, province, or country) was correlated with client physical/sexual violence (AOR 1.92, 95 % CI 1.02–3.61). In this study, mobile/migrant sex workers were more likely to be younger, work in indoor sex work establishments, and earn higher income, suggesting that short-term mobility for sex work and migration increase social and economic opportunities. However, mobility and migration also correlated with reduced control over sexual negotiation with intimate partners and reduced health care access, and mobility for sex work was associated with enhanced workplace sexual/physical violence, suggesting that mobility/migration may confer risks through less control over work environment and isolation from health services. Structural and community-led interventions, including policy support to allow for more formal organizing of sex work collectives and access to workplace safety standards, remain critical to supporting health, safety, and access to care for mobile and migrant sex workers.     

Neisseria gonorrhoeae Strain with Reduced Susceptibilities to Extended-Spectrum Cephalosporins

The spread of Neisseria gonorrhoeae strains with reduced susceptibility to extended-spectrum cephalosporins is an increasing public health threat. Using Etest and multiantigen sequence typing, we detected sequence type 1407, which is associated with reduced susceptibilities to extended-spectrum cephalosporins, in 4 major populated regions in California, USA, in 2012.     

Severe Malaria Not Responsive to Artemisinin Derivatives in Man Returning from Angola to Vietnam

Resistance to artemisinin derivatives, the most potent antimalarial drugs currently used, has emerged in Southeast Asia and threatens to spread to Africa. We report a case of malaria in a man who returned to Vietnam after 3 years in Angola that did not respond to intravenous artesunate and clindamycin or an oral artemisinin-based combination.     

Identification of Possible Virulence Marker from Campylobacter jejuni Isolates

A novel protein translocation system, the type-6 secretion system (T6SS), may play a role in virulence of Campylobacter jejuni. We investigated 181 C. jejuni isolates from humans, chickens, and environmental sources in Vietnam, Thailand, Pakistan, and the United Kingdom for T6SS. The marker was most prevalent in human and chicken isolates from Vietnam.     

A revised method for determination of dialkylphosphate levels in human urine by solid-phase extraction and liquid chromatography with tandem mass spectrometry: application to human urine samples from Japanese children

Objectives

Biological monitoring of organophosphorus insecticide (OP) metabolites, specifically dialkylphosphates (DAP) in urine, plays a key role in low-level exposure assessment of OP in individuals. The aims of this study are to develop a simple and sensitive method for determining four urinary DAPs using high-performance liquid chromatography with tandem mass spectrometry (LC–MS/MS), and to assess the concentration range of urinary DAP in Japanese children.

Methods

Deuterium-labeled DAPs were used as internal standards. Urinary dimethylphosphate (DMP) and diethylphosphate (DEP), which passed through the solid-phase extraction (SPE) column, and dimethylthiophosphate (DMTP) and diethylthiophosphate (DETP), which were extracted from a SPE column using 2.5 % NH₃ water including 50 % acetonitrile, were prepared for separation analysis. The samples were then injected into LC–MS/MS. The optimized method was applied to spot urine samples from 3-year-old children (109 males and 116 females) living in Aichi Prefecture in Japan.

Results

Results from the validation study demonstrated good within- and between-run precisions (<10.7 %) with low detection limits (0.4 for DMP and DMTP, 0.2 for DEP and 0.1 μg/L for DETP). The geometric mean values and detection rates of the urinary DAPs in Japanese children were 14.4 μg/L and 100 % for DMP, 5.3 μg/L and 98 % for DMTP, 5.5 μg/L and 99 % for DEP, and 0.6 μg/L and 80 % for DETP, respectively.

Conclusions

The present high-throughput method is simple and reliable, and can thereby further contribute to development of an exposure assessment of OP. The present study is the first to reveal the DAP concentrations in young Japanese children.