Evidence for an overestimated vulnerability of adolescent rats to develop signs of drug addiction

Drug addiction is a multi-etiological disorder to which some individuals are more vulnerable an others. Whereas converging clinical and epidemiological studies report a peak of drug use ring adolescence, many behavioral traits characterizing teenagers have been proposed to contribute to this vulnerability, including a heightened sensation-seeking, an enhanced impulsivity d a larger influence exerted by peers. By many aspects, juvenile rodents display behavioral traits at resemble those of teenagers. However, the concept of increased vulnerability to drug addiction juvenile rats remains in debate. Indeed, only a few studies directly compared juvenile and adult fdents regarding behavioral predictors of drug abuse. Moreover, some key features of drug diction have never been investigated in juvenile rats yet. For this very reason, we conducted a arge-scale behavioral comparison of adult and adolescent rats with the aim of dissecting their espective behavioral traits and vulnerabilities to drug addiction. We first have shown that juvenile rats exhibited an enhanced motor impulsivity, and a loss of control over reward seeking assessed by a persistent reward taking despite adverse consequences mild electric footshocks]. We also report that juvenile rats displayed a higher anxiety profile, ind we discuss why these behaviors might represent key underpinning mechanisms leading to an enhanced vulnerability to drug abuse. Meanwhile, we collected clear cut observations that do not support such an interpretation. In Articular, juvenile and adult rats displayed identical novelty-induced habituation and preference at are considered to represent two potent predictors of cocaine initiation and compulsive intake, "pre strikingly, juvenile rats were less attracted by cues predicting reward in a Pavlovian utoshaping task, suggesting a lower propensity for cues or context to trigger the reinstatement of a^previously extinguished reward seeking behavior. Finally, using a paradigm assessing schedule- ciuced polydipsia, juvenile and adult rats exhibited similar compulsive drinking, under control conditions and following a chronic cocaine treatment as well. Hence, these observations call for a cautious interpretation of adolescent vulnerability to drug use. In particular, we underlined that even the most compulsive young rats did not consume ärger amounts of cocaine than adults, nor exhibited larger efforts in a cue-induced relapse aradigm, despite a transient increased motivation for lever-pressing. And further, despite a higher ensitivity to the behavioral effects of cocaine, juvenile rats did not differ from adults in their ropensity to constantly prefer saccharin over cocaine in a discrete-choice procedure, even after a ?'Id chronic stress procedure. Altogether, our results shape an objective overview of the juvenile rats' behavior in relation to oth drug and non-drug rewards, suggesting a heterogeneous and task-specific profile. Despite elements potentially underlying a real risk for substance use, adolescent rats do not exhibit a ehavioral repertoire suggesting increased vulnerability for compulsive drug abuse. Our conclusions strongly encourage deeper neurobiological investigations of the developing brain, and also open a debate on a possible overestimation of juvenile rats' and teenager's risk to develop aladaptive behaviors and drug addiction. - L'addiction aux drogues est une pathologie d'origine multifactorielle, à laquelle certains individus sont plus vulnérables que d'autres. De nombreuses études cliniques et épidémiologiques suggèrent une consommation excessive de drogues pendant l'adolescence, et plusieurs explications ont été avancées pour justifier cette tendance, parmi lesquelles on note une augmentation de la recherche de sensation, une impulsivité plus marquée et une plus forte influence de l'entourage. Le rat juvénile présente de nombreuses caractéristiques développementales similaires à l'adolescence humaine. En revanche, la vulnérabilité des rats juvéniles à l'abus de drogue est encore sujette à caution. En effet, peu d'études ont directement comparé des traits de comportements pouvant refléter un accroissement du risque d'abus chez les rats juvéniles par comparaison aux rats adultes. En outre, certaines caractéristiques fondamentales de l'addiction chez l'homme n'ont pas encore été étudiées chez le rat adolescent. Ce travail de thèse s'est donc donné pour objectif de comparer le comportement de rats adultes vis-à-vis de celui de rats adolescents, afin d'évaluer dans quelle mesure ces derniers seraient plus vulnérables à l'abus de drogues. Nos résultats indiquent que les rats juvéniles présentent une augmentation des comportements impulsifs, ainsi qu'une plus grande persistance à rechercher de manière compulsive une récompense en dépit de légers chocs électriques. Les rats juvéniles présentent également un profil anxieux plus élevé, ce qui peut constituer une autre source de vulnérabilité. Cependant, certaines caractéristiques comportementales ne suggèrent pas de vulnérabilité chez les rats juvéniles. Aucune différence entre rats adultes et adolescents n'a été trouvée pour l'habituation et la préférence pour la nouveauté, deux traits prédisant l'initiation et la prise compulsive de drogue. De plus, nous avons montré que les rats adolescents attribuent moins d'intérêt à des stimuli prédisant la disponibilité d'une récompense, suggérant une vulnérabilité plus faible à la rechute induite par les stimuli associés à la prise de drogue. Une étude complémentaire des comportements compulsifs indique une absence de différence entre rats adultes et adolescents, à la fois en condition basale ou après un traitement chronique à la cocaïne. L'étude des comportements de prise de drogue ne va pas non plus dans le sens d'une vulnérabilité des rats adolescents. Bien que les rats compulsifs sélectionnés pendant la période juvénile présentent une plus grande motivation à prendre de la cocaïne, ils ne diffèrent ni dans la quantité de cocaïne consommée, ni dans la rechute induite par les stimuli environnementaux. En dépit d'une sensibilisation comportementale plus importante, les rats adolescents présentent la même préférence que les adultes face à un choix entre une drogue et une récompense alternative, suggérant une résilience à la cocaïne comparable à celle des adultes. Enfin, cette résilience pour la cocaïne n'est pas affectée par un stress chronique lors de l'adolescence. En résumé, cette étude dresse un regard objectif sur les comportements en lien avec une vulnérabilité à l'abus de drogues chez le rat juvénile, suggérant que celle-ci est hétérogène et spécifique au protocole utilisé. En dépit de certains éléments de vulnérabilité, les rats adolescents ne présentent pas d'attirance excessive pour la cocaïne, ni de prédisposition à la consommation compulsive de cette drogue. L'ensemble de ces éléments pourra constituer une base solide pour l'investigation neurobiologique du cerveau en développement, et ouvre un débat sur une possible surestimation de la vulnérabilité des rats juvéniles et de leurs homologues humains aux pathologies psychiatriques telles que l'addiction aux drogues.

Ablation of human colon carcinoma in nude mice by 131I-labeled monoclonal anti-carcinoembryonic antigen antibody F(ab')2 fragments.

Pooled F(ab')2 fragments of three MAbs against distinct epitopes of carcinoembryonic antigen (CEA) were used for radioimmunotherapy of nude mice bearing a subcutaneous human colon carcinoma xenograft. 9-10 d after transplantation when tumor nodules were in exponential growth, 36 mice were treated by intravenous injection of different amounts of 131I-labeled MAb F(ab')2. All 14 mice injected with a single dose of 2,200 (n = 10) or 2,800 microCi (n = 4) showed complete tumor remission. 8 of the 10 mice treated with 2,200 microCi survived in good health for 1 yr when they were killed and shown to be tumor free. Four of nine other mice treated with four fractionated doses of 400 microCi showed no tumor relapse for more than 9 mo. In contrast, all 15 mice injected with 1,600-3,000 microCi 131I-control IgG F(ab')2 showed tumor growth retardation of only 1-4 wk, and 15 of 16 mice injected with unlabeled anti-CEA MAb F(ab')2 showed unmodified tumor progression as compared with untreated mice. From tissue radioactivity distributions it was calculated that by an injection of 2,200 microCi 131I-MAb F(ab')2 a mean dose of 8,335 rad was selectively delivered to the tumor, while the tissue-absorbed radiation doses for the normal organs were: peripheral blood, 2,093; stomach, 1,668; kidney, 1,289; lung, 1,185; liver, 617; spleen, 501; small intestine, 427; large intestine, 367; bone, 337; and muscle, 198. These treatments were well tolerated since out of 19 mice with complete tumor remission only 4 required bone marrow transplantation and 17 were in good health for 6-12 mo of observation. The results demonstrate the selective destruction of established human colon carcinoma transplants by intravenous injection of either single or fractionated doses of 131I-MAb F(ab')2.

Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection.

BACKGROUND: Visceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co-infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4(+) T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes. CONCLUSION: Our results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection.

Determinants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study.

BACKGROUND: Although methicillin-susceptible Staphylococcus aureus (MSSA) native bone and joint infection (BJI) constitutes the more frequent clinical entity of BJI, prognostic studies mostly focused on methicillin-resistant S. aureus prosthetic joint infection. We aimed to assess the determinants of native MSSA BJI outcomes. METHODS: Retrospective cohort study (2001-2011) of patients admitted in a reference hospital centre for native MSSA BJI. Treatment failure determinants were assessed using Kaplan-Meier curves and binary logistic regression. RESULTS: Sixty-six patients (42 males [63.6%]; median age 61.2 years; interquartile range [IQR] 45.9-71.9) presented an acute (n = 38; 57.6%) or chronic (n = 28; 42.4%) native MSSA arthritis (n = 15; 22.7%), osteomyelitis (n = 19; 28.8%) or spondylodiscitis (n = 32; 48.5%), considered as "difficult-to-treat" in 61 cases (92.4%). All received a prolonged (27.1 weeks; IQR, 16.9-36.1) combined antimicrobial therapy, after surgical management in 37 cases (56.1%). Sixteen treatment failures (24.2%) were observed during a median follow-up period of 63.3 weeks (IQR, 44.7-103.1), including 13 persisting infections, 1 relapse after treatment disruption, and 2 super-infections. Independent determinants of treatment failure were the existence of a sinus tract (odds ratio [OR], 5.300; 95% confidence interval [CI], 1.166-24.103) and a prolonged delay to infectious disease specialist referral (OR, 1.134; 95% CI 1.013-1.271). CONCLUSIONS: The important treatment failure rate pinpointed the difficulty of cure encountered in complicated native MSSA BJI. An early infectious disease specialist referral is essential, especially in debilitated patients or in presence of sinus tract.

Intermittent ketoconazole therapy of chronic mucocutaneous candidiasis in childhood.

We report the clinical and laboratory findings in two children with chronic mucocutaneous candidiasis (CMC) treated successfully with intermittent long-term ketoconazole therapy. Both had chronic infection of the nails, skin and mucous membranes with positive cultures for candida. Both were resistant to multiple local and systemic antifungal agents. After institution of ketoconazole therapy there was a dramatic improvement with clearing of the oral (one week), skin (two months) and nail lesions (5 months). After 8 months the drug was stopped and clinical remission persisted for 10 and 7 months respectively. Relapse of oral candidiasis was treated with a short course of ketoconazole (4-16 weeks) leading to complete healing of the lesions. Clinical improvement was not related to an amelioration in lymphocyte transformation. There was no change in the progressive deterioration of the lymphocyte responses to candida antigen which was probably due to persisting candida cell wall components (e.g. mannan).

Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) enrolled in two prospective trials.

The purpose of this study was to assess the outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in 2 prospective, randomized, open-label clinical trials (1994-2005), with or without Five-Factor Score (FFS)-defined poor-prognosis factors, focusing on survival, disease-free survival, relapses, clinical and laboratory findings, therapeutic responses, and factors predictive of relapse. Forty-four patients with FFS ≥ 1 were assigned to receive 6 or 12 cyclophosphamide pulses plus corticosteroids and the seventy-four with FFS = 0 received corticosteroids alone, with immunosuppressant adjunction when corticosteroids failed. Patients were followed (2005-2011) under routine clinical care in an extended study and data were recorded prospectively. Mean ± SD follow-up was 81.3 ± 39.6 months. Among the 118 patients studied, 29% achieved long-term remission and 10% died. Among the 115 patients achieving a first remission, 41% experienced ≥1 relapses, 26.1 ± 26.8 months after treatment onset, with 57% of relapses occurring when corticosteroid-tapering reached <10 mg/day. Treatment achieved new remissions in >90%, but relapses recurred in 38%. Overall survival was good, reaching 90% at 7 years, regardless of baseline severity. Age ≥65 years was the only factor associated with a higher risk of death during follow-up. The risk of relapse was higher for patients with anti-myeloperoxidase antibodies and lower for those with >3000 eosinophils/mm(3). Sequelae remained frequent, usually chronic asthma and peripheral neuropathy. In conclusion, EGPA patients' survival rate is very good when treatment is stratified according to the baseline FFS. Relapses are frequent, especially in patients with anti-myeloperoxidase antibodies and baseline eosinophilia <3000/mm(3).

Autotransplant for Hodgkin lymphoma after failure of upfront BEACOPP escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone).

BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) escalated is the preferred upfront Hodgkin lymphoma (HL) treatment in a number of countries. Upon failure, high-dose chemotherapy with autologous stem cell support (HDT/ASCT) is performed, but its effectiveness has not been verified in this setting. We analyzed all Swiss cases of chemosensitive HL autografted after failure of BEACOPP escalated (n = 22) and compared outcomes with 22 cases of HDT/ASCT following frontline ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) failure. Five-year progression-free survival (PFS) was 76% for ABVD and 42% for BEACOPP escalated (p = 0.029). Two- and 5-year overall survival (OS) was 90% and 71% for ABVD and 72% and 65% for BEACOPP escalated, respectively (p = not significant). Three patients in the ABVD and four in the BEACOPP escalated groups underwent allotransplant for relapse after HDT/ASCT. Grade 3-4 toxicities were comparable in both groups. Three cases of therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML) were recorded in the BEACOPP escalated group. The acceptable PFS and OS of chemosensitive patients with HL autografted after failure of upfront BEACOPP escalated seem to justify this approach.

L'éthylglucuronide: un marquer de la consommation d'alcool [Ethyl glucuronide: a biomarker of alcohol consumption]

Excessive alcohol consumption represents a major risk factor for morbidity and mortality. It is therefore indispensable to be able to detect at-risk drinking. Ethyl glucuronide (EtG) is a specific marker of alcohol consumption. The determination of ethyl glucuronide in urine or blood can be used to prove recent driving under the influence of alcohol, even if ethanol is no longer detectable. The commercialization of an EtG specific immunological assay now allows to obtain preliminary results rapidly and easily with satisfying sensitivity. Moreover, the detection of ethyl glucuronide in hair offers the opportunity to evaluate an alcohol consumption over a long period. The EtG concentration in hair is in correlation with the amount of ingested alcohol. Thus, the analysis of ethyl glucuronide can be used to monitor abstinence, to detect alcohol relapse and to identify at-risk drinkers. However, a cut off allowing to detect chronic alcohol abuser reliably still does not exist. Therefore, it is recommended to perform the analysis of ethyl glucuronide in complement to the existing blood markers. A study financed by the Swiss Foundation for Alcohol Research is actually conducted by the West Switzerland University Center of Legal Medicine in order to establish an objective cut-off.

Feasibility and efficacy of accelerated weekly concomitant boost postoperative radiation therapy combined with concomitant chemotherapy in patients with locally advanced head and neck cancer.

BACKGROUND: The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. RESULTS AND DISCUSSION: Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. CONCLUSION: Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting.

No association between herpes simplex virus 1 and cardiac myxoma.

PRINCIPLES: Cardiac myxoma is the most commonly diagnosed cardiac tumour. Infection of herpes simplex virus 1 (HSV1) has been postulated to be a factor for this pathologic entity. The aim of the current study was to evaluate the association between HSV 1 and myxoma occurrence.METHODS: Between 1965 and 2005, 70 patients (36 female, mean age: 52.6 years) underwent a resection of myxoma. Selected variables such as hospital mortality and morbidity were studied. A follow-up (FU; mean FU time: 138 +/- 83 months) was obtained (76% complete). Immunohistological studies with monoclonal antibodies against HSV type 1 were performed on tumour biopsies of 40 patients.RESULTS: The mean age was 53 +/- 16 years (range 23 to 84 years, 51% female). Of the investigated population, 31 (44%) were in New York Heart Association (NYHA) class III-IV. Mitral valve stenosis was identified in 14 patients (20%), and in 25 (36%) patients mitral valve was insufficient. During hospitalisation 3 patients suffered from a transient neurological disorder, and in addition to myxoma resection 18 (25.7%) patients had to undergo an additional intervention. The overall survival rate was 91% at 40 years. There was no early postoperative mortality in follow-up, although 4 patients died and 2 patients had been re-operated on for recurrent myxomas after 2 and 9 years. Immunohistology revealed no positive signals for HSV-1 antigens among the 40 analysed cases.CONCLUSION: Complete surgical resection, septum included, was the treatment of choice and mandatory to prevent relapse. Peri-operative morbidity and mortality over 40 years remained low, and no association between HSV infection and occurrence of cardiac myxoma was found.

Non-classical karyotypic features in relapsed childhood B-cell precursor acute lymphoblastic leukemia.

Karyotype analysis of acute lymphoblastic leukemia (ALL) at diagnosis has provided valuable prognostic markers for treatment stratification. However, reports of cytogenetic studies of relapsed ALL samples are limited. We compared the karyotypes from 436 nonselected B-cell precursor ALL patients at initial diagnosis and of 76 patients at first relapse. We noticed a relative increase of karyotypes that did not fall into the classic ALL cytogenetic subgroups (high hyperdiploidy, t(12;21), t(9;22), 11q23, t(1;19), <45 chromosomes) in a group of 29 patients at relapse (38%) compared to 130 patients at presentation (30%). Non-classical cytogenetic aberrations in these 29 patients were mostly found on chromosomes 1, 2, 7, 9, 13, 14, and 17. We also describe six rare reciprocal translocations, three of which involved 14q32. The most frequent abnormalities were found in 9p (12/29 cases) and were associated with a marked decrease in the duration of the second remission, but not of the probability of 10-year event-free survival after relapse treatment. From 29 patients with non-classical cytogenetic aberrations, only 8 (28%) had been stratified to a high risk-arm on the first treatment protocol, suggesting that this subgroup might benefit from the identification of new prognostic markers in future studies.

Optic perineuritis: clinical and radiographic features.

BACKGROUND: Optic perineuritis is an uncommon variety of orbital inflammatory disease that is distinct from demyelinating optic neuritis. OBJECTIVE: To describe the clinical and radiographic features of idiopathic optic perineuritis, with particular emphasis on those features that help to distinguish this condition from optic neuritis. METHODS: We reviewed the medical records of 14 patients with optic perineuritis who were seen in 2 neuro-ophthalmology clinics. RESULTS: Patients ranged in age from 24 to 60 years; 5 were older than 50 years. All patients had visual loss, eye pain, or both. The visual acuity was 20/20 or better in 8 of the 15 eyes. The results of visual field testing were normal in 2 eyes, and a paracentral scotoma or an arcuate defect was seen in 7. Magnetic resonance imaging scans demonstrated circumferential enhancement around the optic nerve, sometimes with intraorbital extension. Response to corticosteroids was dramatic; however, 4 patients had a relapse with lowering of the dose. CONCLUSIONS: In contrast to those with optic neuritis, patients with optic perineuritis are often older at onset and are more likely to show sparing of central vision. Magnetic resonance imaging scans demonstrate enhancement around, rather than within, the optic nerve. Response to corticosteroids is more dramatic than in patients with optic neuritis, and patients are more likely to experience recurrence after stopping treatment.

Minor salivary gland tumors: a clinicopathological study of 18 cases

Introduction: Minor salivary gland tumors (MSGTs) are infrequent, representing 10-15% of all salivary neoplasms. Despite this low frequency, MSGTs conform a heterogeneous group of neoplasms characterized by a broad range of histological types. Patients and method: We identified cases of MSGT in a retrospective study of the biopsies made in the period 1997-2007 in the Service of Oral Surgery (Dental Clinic of the University of Barcelona, Spain). The data collected comprised patient age and sex, the clinical characteristics and location of the tumor, the duration of the lesion, its size, the treatment provided, and the histopathological findings. Results: Of the 18 cases of MSGT studied, 12 corresponded to women (66.7%) and 6 to men (33.3%). The great majority (94.4%) were benign tumors. The preferential location was the posterior third of the hard palate (33.2%), followed by the soft palate (16.7%) and the mucosa of the upper lip (16.7%). The histopathological diagnoses of our MSGTs comprised 10 pleomorphic adenomas (55.3%), 2 cystadenomas (11.1%), 1 myoepithelioma (5.6%), 1 sialadenoma papilliferum (5.6%), 1 basal cell adenoma (5.6%), 1 Warthin"s tumor (5.6%), 1 canalicular adenoma (5.6%), and 1 low-grade polymorphic adenocarcinoma (5.6%). Discussion and conclusions: Coinciding with our own results, the literature describes a high recurrence rate for MSGTs (5-30%) when surgical removal is incomplete. Six percent of all benign minor salivary gland tumors are considered to relapse, versus 65% of all malignant lesions. Periodic clinical controls are required, since the possibility of malignant transformation must be taken into account

Tissue homing and persistence of defined antigen-specific CD8+ tumor-reactive T-cell clones in long-term melanoma survivors.

Tumor antigen-specific cytotoxic T cells (CTLs) play a major role in the adaptive immune response to cancers. This CTL response is often insufficient because of functional impairment, tumor escape mechanisms, or inhibitory tumor microenvironment. However, little is known about the fate of given tumor-specific CTL clones in cancer patients. Studies in patients with favorable outcomes may be very informative. In this longitudinal study, we tracked, quantified, and characterized functionally defined antigen-specific T-cell clones ex vivo, in peripheral blood and at tumor sites, in two long-term melanoma survivors. MAGE-A10-specific CD8+ T-cell clones with high avidity to antigenic peptide and tumor lytic capabilities persisted in peripheral blood over more than 10 years, with quantitative variations correlating with the clinical course. These clones were also found in emerging metastases, and, in one patient, circulating clonal T cells displayed a fully differentiated effector phenotype at the time of relapse. Longevity, tumor homing, differentiation phenotype, and quantitative adaptation to the disease phases suggest the contribution of the tracked tumor-reactive clones in the tumor control of these long-term metastatic survivor patients. Focusing research on patients with favorable outcomes may help to identify parameters that are crucial for an efficient antitumor response and to optimize cancer immunotherapy.