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Over the past few years, data have suggested that severe peripheral arterial occlusive disease (PAOD) is associated with nilotinib exposure. However, the characteristics of this adverse drug reaction are poorly described since its frequency is low. As far as we know, no study using a spontaneous adverse drug reactions reporting system was performed to describe the characteristics of cases of PAOD related to nilotinib. We performed a study to describe the cardiovascular risk profile of cases of PAOD in patients treated with nilotinib spontaneously reported to the French Pharmacovigilance Database (FPVD). We selected all cases of “vascular disorders,” as the System Organ Class in MedDRA®, in which nilotinib was “suspected” and recorded in the French Pharmacovigilance Database between 2007 and 21 October 2014. We then identified cases of PAOD with a Low Level Term and through a detailed summary of the clinical description. We identified 25 cases of POAD. Most of the patients were older than 60 years (84 %) or had another cardiovascular risk factor such as hypercholesterolemia, arterial hypertension, overweight/obesity, smoking, or diabetes mellitus (72 %). Females (13 cases) and males (12 cases) were equally represented, but the presence of cardiovascular risk factors was more frequent in females than in males. The mean time from initiation of nilotinib to PAOD onset was 24 months and was significantly longer in patients aged less than 60 years compared with those aged over 60 years (33.8 ± 24.6 months vs. 22.6 ± 17.5 months, p = 0.002). Pre-existing cardiovascular risk factors, especially diabetes mellitus, also seem to accelerate its occurrence. The FPVD is a useful tool in describing the cardiovascular risk profile of patients with PAOD during nilotinib exposure. Physicians have to be particularly vigilant in patients older than 60 years of age; in patients younger than 60 years of age, long-term surveillance has to be maintained.

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

Les dernieres RPC sur le traitement neoadjuvant du cancer du rectum dataient de 2005. Elles ont ete mises a jour en integrant les dernieres publications. Pour les tumeurs T3 ou T4, une IRM est recommandee pour preciser la marge circonferentielle. Aucun des examens d’imagerie ne peut predire avec precision le statut ganglionnaire. La RT preoperatoire diminue le taux de recidive locale mais altere le resultat fonctionnel digestif et la fonction sexuelle apres chirurgie conservatrice. Les cancers du haut rectum resecables d’emblee ne doivent pas beneficier d’un traitement neoadjuvant. Pour les tumeurs du tiers moyen et du tiers inferieur du rectum, l’indication depend de l’evaluation en imagerie. Certaines tumeurs avec une bonne marge circonferentielle peuvent etre traitees par chirurgie d’emblee. Les tumeurs mrT3d et T4 doivent beneficier d’une radiochimiotherapie. La CT associee a la RT repose sur le 5FU oral (capecitabine). L’utilisation du FU IV est une alternative possible. Il n’y a pas d’interet a ajouter une autre molecule de chimiotherapie. Apres RT courte, la chirurgie doit etre realisee au maximum 7 jours suivants l’irradiation. Apres CTRT, il ne semble pas necessaire de prolonger le delai d’attente au dela de 6-8 semaines.

At the time of diagnosis, around 20% of patients with pancreatic cancer present at a resectable stage, 50% have metastatic disease and 30% have locally advanced tumour, non-metastatic but unresectable because of superior mesenteric artery or coeliac encasement. Despite advances in chemoradiotherapy and improved systemic chemotherapeutic agents, patients with locally advanced pancreatic cancer suffer from high rates of distant metastatic failure and from local progression, with a median survival time ranging from 5 to 11 months. In the past 30 years, modest improvements in median survival have been attained for these patients treated by chemoradiotherapy or chemotherapy protocols. The optimal therapy for patients with locally advanced pancreatic carcinoma remains controversial. This review aims to evaluate the role of radiotherapy for these patients.

Resume Propos La prevalence des anticorps antiphospholipides (APL) au cours du purpura thrombopenique immunologique (PTI) varie entre 25 et 75 % selon les etudes. Le risque de thrombose dans ce sous-groupe est discute. En parallele, 22 a 42 % des syndromes des antiphospholipides (SAPL) s’accompagnent de thrombopenie. Patients et methodes L’objectif principal etait de comparer au diagnostic le profil d’anticoagulant circulant (ACC), d’anticorps anticardiolipines (ACL) et anti-β2GP-I entre une cohorte de 93 patients atteints de PTI chronique et une cohorte de 27 patients atteints de SAPL primaire. Les objectifs secondaires etaient : evaluer le risque de thrombose chez les patients atteints de PTI selon la presence d’APL (suivi median : 36 mois) ; comparer le profil d’APL chez les patients atteints de SAPL avec ou sans thrombopenie ; evaluer la survenue de lupus chez les patients atteints de SAPL en fonction de la presence de thrombopenie (suivi median : 48 mois). Resultats Dans la cohorte de PTI, la prevalence d’APL etait de 25 % ; une association de plusieurs APL (ACC, ACL, anti-β2GP-I) etait moins frequente que dans le groupe de SAPL ; deux phlebites spontanees sont survenues, sans particularite de profil d’APL. Une thrombopenie etait presente chez 26 % des SAPL, moderee, asymptomatique, parfois labile et sans particularite de profil d’APL ; une patiente thrombopenique a developpe un lupus. Conclusion Les patients atteints de PTI et ayant des APL ont moins frequemment une association d’APL que dans le SAPL ; le risque thrombotique semble modere.

To study potential role of smoking and alcohol in lymphoid neoplasms (LN). A case–control study that included 824 cases and 752 hospital controls aged 18–75 years was conducted. Cases were newly diagnosed with non-Hodgkin’s or Hodgkin’s lymphoma, multiple myeloma, or lymphoproliferative syndrome (LPS). Controls were matched with the cases by gender, age, and center. Overall, smoking was not related to LN. However, average tobacco consumption tended to be inversely related to non-Hodgkin’s lymphoma (NHL), LPS, and the hairy cell leukemia (HCL) subtype, with a significant negative trend for the latter (OR of 0.4, 0.2, 0.1 for consumptions of ≤10, 11–20, >20 cig/day). An inverse association between ‘ever drinking’ and Hodgkin’s lymphoma (HL: OR = 0.5 [0.3–0.8]) and NHL (OR = 0.7 [0.5–1.0]) was evidenced and restricted to the diffuse large B-cell lymphoma subtype, with significant negative trends. The controls’ smoking and drinking habits were similar to those of French population. The results remained unchanged after adjustment for potential confounding factors and when smoking and drinking were both included in the models. Results are consistent with those of several previous studies and suggest a direct or indirect protective effect of smoking with respect to HCL although based on small numbers. The negative relationship between alcohol consumption and Hodgkin’s and NHL, also previously reported, needs further investigations.

Summary What is known and objective Peripheral vascular adverse events have been reported with ponatinib treatment in chronic myeloid leukaemia (CML) after failure of dasatinib or nilotinib. We here report peripheral arterial occlusive disease (PAOD) in a patient who had previously received only imatinib as tyrosine kinase inhibitor. Case description The patient was a 70-year-old man with no history of cardiovascular disease. He developed arterial hypertension 5 months after the initiation of ponatinib and PAOD 41 months later. What is new and conclusion Peripheral arterial occlusive disease can occur several years after the initiation of ponatinib in patients who had previously received only imatinib. Long-term surveillance is required for preventing the complications of ponatinib-associated PAOD.

Purpose: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries. Patients and Methods: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients. Results: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin’s lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine–based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years. Conclusion: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II–targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.

Our previous work on rat hippocampus showed that a loss of docosahexaenoic acid (DHA) occurs in the fatty acid composition of phosphatidylethanolamine (PE), plasmenylethanolamine (PmE) and phosphatidylserine (PS) with increasing age. The present study investigated whether a DHA-enriched phospholipid dietary supplement could restore DHA levels and cholinergic activity. Male rats were fed a balanced diet containing both linoleic and alpha-linolenic acids until the age of 2, 18 and 21 months. From 18 to 21 months, one subgroup received a diet supplemented with DHA-enriched phospholipids from egg yolk (E-PL), and another a diet with DHA-enriched phospholipids from pig brain (B-PL). Compared to the control diet, the E-PL diet restored the proportion of polyunsaturated fatty acids (PUFAs: 22:6n-3 and 20:4n-6) in PE and PmE, while enhancing spontaneous and evoked-acetylcholine (Ach) release. The B-PL diet had no effect on PUFAs, but increased basal extracellular levels of Ach in 21-month-old rats as compared to the age-matched control. Our results show that supplementation with DHA-enriched egg PL can enhance Ach release and correct PUFA composition.

An ultrastructural study of rat hippocampus was performed on young (group 1) and old (group 4) rats receiving daily subcutaneous injections of aluminum l -glutamate and on old untreated rats (group 5). Young controls were treated with sodium l -glutamate (group 2) and physiological saline (group 3). Group 1 showed vacuolated astrocytes with numerous lipofuscin deposits, mitochondrial swelling, a thinning of the myelin sheath, and many multivesicular bodies invading the cytoplasm. Cellular structure did not appear to be affected in groups 2 and 3. Group 4 showed swollen mitochondria, a demyelination process in axonal regions, sizable perivascular oedema with vessel retraction and gliofilament bundles. In this group, lipofuscin deposits in astrocytes were associated with multivesicular bodies that thinned the myelin sheath to the breaking point; however, no excitotoxic glutamate-induced effects were observed. In group 5, extreme cytoplasmic vacuolation was observed, with massive mitochondrial swelling, considerable thinning of the myelin sheath (at times to the breaking point), sizable vacuolar degeneration and gliofilament bundles. These results indicate that ultrastructural alterations in the hippocampus, such as cell vacuolization, massive mitochondrial swelling and the demyelination process, occur with aging and independently of aluminum intoxication. Similar alterations were observed in aluminum l -glutamate-intoxicated young rats, but not in controls. These results are consistent with aluminum-induced acceleration of the aging process.

Parmi les agents anti-cancereux, ceux qui interagissent directement avec l'ADN sont les plus toxiques pour les cellules de la lignee germinale. L'atteinte de ces cellules est essentiellement le fait des agents alkylants dont la toxicite est dose-dependante. La rapidite et la qualite de recuperation de la spermatogenese est essentiellement fonction de la severite de l'atteinte des spermatogonies souches. Les etudes experimentales conduites chez la souris et le rat ont permis de progresser dans la connaissance des mecanismes de la toxicite germinale des agents cytotoxiques, mais ces donnees ne sont pas toujours superposables a celles observees en clinique. Les etudes ont essentiellement ete conduites chez les patients porteurs de tumeurs germinales du testicule ou de maladie de Hodgkin. Du fait de leur curabilite potentielle et de leur frequente survenue chez le sujet jeune, elles representent en effet les situations cliniques dans lesquelles il est essentiel d'essayer de preserver la fertilite du sujet. Le choix des protocoles chimiotherapiques les moins toxiques pour la lignee germinale, a resultat therapeutique equivalent, est actuellement un moyen de reduire au maximum le risque d'azoospermie definitive. Ce risque n'est cependant jamais nul justifiant le recours systematique a l'auto-conservation de gametes avant toute chimiotherapie chez un sujet susceptible de developper un projet de paternite.

Minimal residual disease (MRD) quantification is widely used for therapeutic stratification in pediatric acute lymphoblastic leukemia (ALL). A robust, reproducible, sensitivity of at least 0.01% has been achieved for IG/TCR clonal rearrangements using allele-specific quantitative PCR (IG/TCR-QPCR) within the EuroMRD consortium. Whether multiparameter flow cytometry (MFC) can reach such inter-center performance in ALL MRD monitoring remains unclear. In a multicenter study, MRD was measured prospectively on 598 follow-up bone marrow samples from 102 high-risk children and 136 adult ALL patients, using IG/TCR-QPCR and 4/5 color MFC. At diagnosis, all 238 patients (100%) had at least one suitable MRD marker with 0.01% sensitivity, including 205/238 samples (86%) by using IG/TCR-QPCR and 223/238 samples (94%) by using MFC. QPCR and MFC were evaluable in 495/598 (83%) samples. Qualitative results (

Imatinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML). Indication was based on the STI571 0109 study, in which imatinib favorably compared to historical treatments in patients failing prior therapies. The relevance of these results to currently newly diagnosed AP-CML patients remains unknown. We evaluated the benefit of imatinib in 42 newly diagnosed AP-CML patients. In all, 16 patients had hematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome (ACAs; HEM-AP), 16 solely had ACAs (ACA-AP) and 10 had hematological acceleration plus ACAs (HEM-AP + ACA). Major cytogenetic responses were achieved in 93.7% of HEM-AP patients, 75% of patients with ACA-AP (P=NS) and 40% of patients with HEM-AP + ACA (P=0.0053). The 24-month failure-free survival rate was 87.5% in HEM-AP patients, 43.8% in ACA-AP patients and 15% in HEM-AP + ACA patients (P=0.022). The 24-month estimate of progression-free survival was 100% in HEM-AP patients, 92.8% in ACA-AP patients and 58.3% in HEM-AP + ACA patients (P=0.0052). In conclusion, frontline imatinib allows favorable outcomes in HEM-AP and ACA-AP patients but appears insufficient for patients with HEM-AP + ACA. Broader-target and/or more potent BCR-ABL tyrosine kinase inhibitors alone or in combination may be considered in this setting.

The present study was designed to assess the role of the adrenergic tone in the regulation of carotid arterial compliance during aging. An experimental model of in situ isolated carotid arteries has been used to evaluate the elastic properties of the arterial wall in young (3-mo-old) and older (18-mo-old) Wistar rats. Binding experiments were performed in the same strain of rats to evaluate alpha 1- and beta-adrenoceptor affinity and density. In a third set of experiments, structural parameter of the carotid artery in younger and older rats was evaluated. Arterial distensibility (compliance per unit of volume) was significantly lower in older rats. This was associated with a significant thickness of the media (45.6 +/- 2.8 vs. 57.5 +/- 5.7 microns, P < 0.01) and increased collagen content in older rats (4,420 +/- 310 vs. 7,320 +/- 850 microns 2/mm, P < 0.001). However, carotid arterial compliance was not altered in older rats because of the significant increase in cross-sectional area with aging. Aging did not affect alpha 1-adrenoceptor affinity and density, whereas it decreased beta-density without changing their affinity. Pharmacological stimulation of alpha 1-adrenoceptor with phenylephrine (10(-5) M) decreased compliance in older but not in younger animals. Blockade of these receptors with prazosin or labetalol increased compliance in younger and had no effect on older rats. beta-receptor stimulation with isoproterenol or blockade with propranolol had no effect in any of the studied groups. We suggest that with aging there is an increased vasoconstricting effect of alpha-agonists and a decreased vasodilatative action of alpha-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Over the last 3 decades, progress in the treatment of acute lymphoblastic leukemia (ALL) in children has dramatically improved the outcome of patients, leading to cure rates of more than 80%. In adult ALL, the improvements in outcome have been modest with cure rates approximating 40%. In pediatric trials, patients older than 10 years of age are often considered high-risk patients and are treated more intensively. In adult trials, adolescents and young adults with ALL are considered as standard-risk patients and receive chemotherapy scheduled for patients up to 60 years of age. These divergent treatment approaches in adolescents led many pediatric and adult groups to compare their results in this subgroup of patients and to conclude that adolescents may benefit from treatment with pediatric regimens. In young adults, recent studies have demonstrated that outcome may be improved by pediatric-inspired reinforced chemotherapeutic strategies but also by allogeneic transplantation. In this chapter focusing on ALL in young adults, we summarize the specific biologic characteristics of the disease and the results of recent adult protocols. Therapeutic strategies inspired from pediatric approaches will be emphasized. The development of collaborative trials in optimized psychosocial environments will be required to steadily improve the results in this population of young adults.

Summary— Central 5HT1A-receptors have been found with a high density in brainstem and are involved in cardiovascular control. The high-affinity binding of [3H]-8-OH-DPAT, a specific 5HT1A-receptor ligand, was measured in medulla oblongata of normotensive and spontaneously hypertensive rats (SHR). The maximal number of [3H]-8-OH-DPAT binding site (Bmax) was significantly increased in SHR when compared to normotensive rats. Whether central 5HT1A-receptors are involved in the etiology of hypertension or are influenced by other neurochemical events remains to be investigated.

Radioiodinated m-iodobenzylguanidine [( 125I]MIBG) and tritiated norepinephrine [( 3H]NE]) uptake and release were compared, in different regions of the brain of the rat. The classification of the regions according to uptake was the same for both tracers:striatum greater than hypothalamus greater than hippocampus greater than cortex greater than brainstem. Tetrabenazine (TBZ), a granular monoamine uptake inhibitor reduced the uptake in the different regions. The inhibition rate was higher for [3H]NE uptake than for [125I]MIBG. The spontaneous release was the same for [125I]MIBG and [3H]NE and was the lowest in the striatum. The K+ stimulated release of [3H]NE was more complete than the release of [125I]MIBG and was the most important in the striatum. From these results, it is inferred that MIBG enters the brain tissue via NE uptake mechanisms. It appears that MIBG is stored in the chromaffin granules, as NE, but also in the cytoplasm. A modified molecule derived from MIBG which would cross the blood-brain barrier, would then appear as a potential scintigraphic marker of monoamine uptake, storage and release.

Fifty-four percent of adults with acute lymphoblastic leukemia (ALL) who entered the LALA-94 trial experienced a first relapse. We examined the outcome of these 421 adult patients. One hundred and eighty-seven patients (44%) achieved a second complete remission (CR). The median disease-free survival (DFS) was 5.2 months with a 5-year DFS at 12%. Factors predicting a better outcome after relapse were any transplant performed in second CR (P0.0001), a first CR duration1 year (P=0.04) and platelet level100 x 10(9)/l at relapse (P=0.04). Risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse. The best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation (SCT). Geno-identical allogeneic SCT was performed in 55 patients, and 3 patients received donor lymphocyte infusions. Forty-four transplantations were performed from an unrelated donor (of which four were cord blood). We conclude that most adult patients with recurring ALL could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option.

Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.

Summary The authors report five cases of Agrobacterium radiobacter infections in immunocompromised patients (four hematologic malignancies undergoing chemotherapy and one AIDS patient). In all cases, bacteremia developped often associated with an intravascular catheter. Antimicrobial sensitivity was variable and treatment was based on sensitivity data for each individual isolate.

Infection of immunosuppressed patients by human cytomegalovirus (CMV) may be responsible for a wide range of symptoms, depending on the affected organ. Iatrogenic immunosuppression is an important contributing factor secondary to organ transplantation or to treatment for haematological malignancies. In these conditions appropriate diagnosis of infection by CMV has practical relevance for the management of the patients.1 Detection of CMV in bone marrow by the pathologist has been reported as a rare event, although pancytopenia may be indicative of such infection.2–5 The purpose of this report is to present a case of a patient who had been treated for a B-cell prolymphocytic leukaemia five years before the onset of a relapse of the disease accompanied by CMV infection of bone marrow. It is intended to stress the possibility of this rare feature that can be missed by the histopathologist at routine diagnosis. We report the case of a woman in her 70s in whom a B-cell prolymphocytic leukaemia had been diagnosed. She was successfully treated with fludarabine and Endoxan (cyclophosphamide). In 2005, five years …

In order to assess the eventual prognostic significance of early response to chemotherapy in adult acute lymphoblastic leukemia (ALL), we recommended to perform a bone marrow aspiration at day 15 after the beginning of the induction, in the last two French multicentric trials: AALL85 and AALL87.

The accumulation of [3H]spiperone and [3H]dopamine was measured in striatum and pituitary gland slices of rat. Contrary to [3H]dopamine, [3H]spiperone storage was similar in striatum and pituitary gland. In addition, [3H]spiperone accumulation was not diminished by reserpine and tetrabenazine. These data show that spiperone is not subject to the granular uptake/storage mechanism and suggest that spiperone and its derivatives are specific ligands for dopamine receptors only.

Iodobenzamide is a promising agent to investigate D2 receptors by SPECT in living human brain. In this work, we have evaluated this radiolabeled compound in two animal models of D2 receptors supersensitivity. In the first model, rats were treated chronically with haloperidol during three weeks (S.C. injection of 0.5 mg/kg/day). One week after the last day of treatment, they were I.V. injected with 125I-IBZM. In vivo specific binding study showed a 45 percent increase of 125I-IBZM fixation in the striatum of treated rats. In a second step of experiments, animals were unilaterally lesioned by a stereotaxic injection of 6-OHDA in the substantia nigra, 23 days before receiving 125I-IBZM. Autoradiographic analysis of coronal brain sections showed a 38 percent enhancement of 125I-IBZM in vivo binding in the striatum on the lesioned side as compared to the contralateral intact side; this increase occurred in striatal lateral area. These data demonstrate that 125I-IBZM is convenient to detect alterations of dopamine D2 receptors in vivo in the rat. Thus IBZM labelled with 123I can be a very useful imaging agent for the exploration of D2 receptors in pathological situations.

Purpose: Major initial prognostic factors predicting chronic myeloid leukaemia (CML) response to imatinib mesylate (IM) therapy are represented by hema-tological status, Sokal score and duration of disease before IM. Before the era of IM, CML patients harbouring der(9) deletion classically had a worse outcome when compared to non deleted pts, but some preliminary studies suggest that this adverse factor might be reversed by IM. Additionally der(9) deletion seems to be more frequent in Variant Ph chromosome (vPh) patients (up to 30%) whereas its frequency is about 10% in classical Ph pts. We evaluated in this retrospective multicentric study the response to IM in vPh population and the possible impact of der(9) deletion on this response. 92 vPh patients treated by IM were selected from 11 hematology departments within the country. vPh chromosome was assessed by conventional karyotyping analysis and der(9) deletion by FISH. IM resistant patients were screened for ABL kinase site mutation by direct sequencing. Statistical analysis of survival and descriptive parameters were performed according to Kaplan Meyer method, log-rank test, Chi-2 and non parametric Kruskal Wallis tests. Results: among the vPh population 75% pts had a simple translocation and 25% had a more complex one (chromosomes 9, 22 and at least two other break-points). Initially 95% pts were in chronic phase (CP), 2.5% in accelerated phase (AP) and 2.5% in blastic crisis (BC).19 pts (33.3%) were scored in each Sokal score category (low, intermediate and high). At IM initiation: 83% were in CP (>35% Ph+ ), 8% were in major cytogenetic response (after interferon) and 9% were either in AP or in BC. 74 pts were screened for der(9) deletion, which was present in 16.2% of them. IM response and survival data were available for 53 pts with CP (with > 35% Ph+ ) at IM initiation. Median age of this CP population at diagnosis was 50.8 (19.5–79.4), median disease duration before IM initiation : 2 Mo (0–92.4), median follow-up after IM initiation : 24.8 Mo (6.1–69.9). 71.7% achieved RcyM including 67.9% in RcyC. 19 pts presented IM failure or suboptimal response (European LeukemiaNet consensus). 1 pt stopped IM for liver intolerance. We observed 9 (16.9%) primary resistance and 10 (18.9%) loss of response. 12% pts progressed towards AP/BC. 12 resistant pts were screened for ABL kinase site mutations : 3 of them harboured mutations. We found no difference for the overall survival between the populations with (n=9) and without (n=33) der(9q) deletions (median of survival not reached ). Respectively 1 pt (11%) and 3 pts (9%) died in these two cohorts. We found a trend for an increased rate of resistance in the der(9) deletion cohort (55.6% vs 30.3%) but the difference was not significative (p=0.16). We only found significant differences in the repartition of the Sokal score between these two cohorts with more frequent high scores for vPh patients (p=0.03). Resistance in vPh IM treated pts is high (35.8%) but the disease duration before IM was heterogenous. Der(9) deletions slightly increases the rate of IM resistance but we found no difference of survival between the two cohorts.

Twelve cases of primary pulmonary lymphoma are presented. Most of them were localized to the lung, and had histologic features of low degree malignancy and B phenotype. Complete or partial response was obtained in most cases with chemotherapy alone or combined with surgery.

Surface markers were studied in a series of follicular lymphomas with immunofluorescence on frozen sections (39 cases) and on cell suspensions (21 cases), and with immunoperoxidase on frozen sections using a panel of 15 monoclonal antibodies (17 cases). With immunofluorescence on frozen sections, 22/39 cases showed monotypic sIg (IgMK: 14 cases, IgML: 7 cases, M: 1 case). In the remaining 17 cases the neoplastic follicles were negative. Nevertheless, even if sIg is not detected, the absence of an extracellular immunoglobulin network is indicative of the neoplastic, and not of the reactive nature of lymphoid follicles. The results obtained with immunofluorescence on frozen sections and on cell suspensions were identical in about half of the cases. In 9/21 cases monotypic sIg were detected by only one of these two methods. All the 17 cases studied with immunoperoxidase on frozen sections using monoclonal antibodies demonstrated monotypic sIg. On low magnification 6/17 sIg+ exhibited a nodular staining pattern while 7/17 cases this staining was diffuse. In 4/17 cases the staining pattern for heavy and light chains was different. A thin mantle zone, with sIgM plus sIgD cells, was observed in only 4 cases. Anti-HLA-DR and Leu-10 were positive in all cases. T cells positive for OKT3 were mainly distributed in the interfollicular areas; OKT4 + cells outnumbered OKT8 + cells. Within the neoplastic follicles, T cells stained mainly for OKT4 and OKT8 + cells were scarce. Leu-7 + cells predominated within the neoplastic nodules in 5 cases. With the anti-dendritic reticulum cell monoclonal antibody, all 17 cases showed a network, usually more loosely arranged than in reactive follicles. In 4 cases, of follicular and diffuse lymphoma, this network was extremely dissociated and in some areas these cells were scanty or lacking. We concluded that immunoperoxidase on frozen sections, using monoclonal antibodies, appears to be the most reliable method for the immunological phenotyping of follicular lymphomas.

A partir de 100 arteriographies, les auteurs etudient l'anatomie radiologique de l'artere honteuse interne chez l'homme, son trajet, sa projection par rapport au cadre osseux et ses principales branches collaterales. Les auteurs insistent sur les variations d'origine de l'artere perineale qu'ils classent en quatre types. Ils proposent de considerer l'artere perineale comme une branche de bifurcation terminale de l'artere honteuse interne pour le perinee, l'autre branche etant destinee au penis. Ils precisent les anomalies d'origine de l'artere du bulbe du penis qu'ils regroupent en cinq types. Une artere honteuse interne accessoire est retrouvee dans 6% des cas. Enfin, les auteurs montrent l'existence de nombreuses anastomoses arterielles au niveau de l'artere honteuse interne, en particulier avec l'artere controlaterale.

Intracerebroventricular (i.c.v.) injections of dihydropyridine derivatives calcium channel agonist (BAY K8644) and antagonist (nifedipine, nicardipine, PN 200-110) induced opposite long-lasting changes in blood pressure (BP) in pentobarbital anesthetized spontaneously hypertensive rats (SMR). I.c.v. nifedipine (NIF), nicardipine (NIC), and PN 200-110 decreased mean blood pressure dose-dependently and stereoselectively, (+) NIC and (+) PN being 8 and 3 times more potent than their (-) isomers, respectively. The decrease in BP was due to a withdrawal of the sympathetic tone, since NIF- and NIC-induced falls in BP were suppressed after either hexamethonium (HXM), 6 OHDA or bilateral adrenalectomy. I.c.v. BAY K8644 increased BP dose-dependently. The i.c.v. BAY K8644-induced hypertensive effect was inhibited: a), by NIF and (+) PN but not by (-) PN, therefore probably occurring at central DHP sites; b), by HXM and reserpine, thus probably mediated by an increase in sympathetic tone; c) by i.c.v. methylatropine (MA) while i.v. MA and i.c.v. HXM had no inhibitory effect, thus probably involving central muscarinic sites. In SHR, NIC did not after the K(+)-evoked ACh release but suppressed the BAY K8644-induced increase in ACh release. In anesthetized normotensive control rats (WKY), neither i.c.v. NIF, NIC or BAY increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data suggest that central DHP sites may be involved in the cholinergic transmission and may participate in genetic hypertension via sympathetic tone.

Based on the study of 400 opacification procedures of the testicular vein performed in the course of exploration of male infertility, the authors describe certain hitherto poorly recognized radio-anatomical features. The normal radiological anatomy and numerous anatomical variations of the testicular venous system are presented.

In order to investigate the mechanism of uptake of meta-iodobenzylguanidine (mIBG) by the adrenal glands, autoradiographic and pharmacologic studies were performed in mice and dogs receiving radioiodinated mIBG. In mice, on macroautoradiography of whole body sections 48 h after 125I-mIBG, most of the radioactivity was focused in the adrenal glands. On microautoradiography, silver grains were exclusively located in the adrenal medulla. Tissue counting after phenoxybenzamine, cocaine, and desipramine treatment resulted in 45%, 35%, and 0% inhibition of mIBG uptake, respectively. Tissue counting and scintigraphic studies demonstrated a more than 50% mIBG release from the adrenal glands after reserpine. These data indicate the high affinity of mIBG for adrenal medulla and suggest that the mIBG and catecholamine uptake mechanisms are only partially the same.

Au terme de cette etude, il apparait donc que la veine spermatique connait de nombreuses variations anatomiques. Elle a egalement des connexions multiples et variees. Ces elements sont importants a connaitre; ils interviennent dans le bilan pre-operatoire d'une cure de varicocele, evitant le risque de recidive (Huguet, Bensussan et coll., 1980); ils expliquent les possibilites de suppleance par cette veine dans certains cas pathologiques (Chatel, Bigot et coll., 1978) (fig. 38).

Primary nonHodgkin’s lymphoma of the testis is a localized disease in 50 per cent of the cases. Clinical records and pathological material from 9 stage IE cancer patients treated at our institutions were reviewed. All but 1 patient had B cell type lymphomas of intermediate (6) or high (3) grade according to the Working Formulation. Mean survival was 49 months and actuarial survival was 74 per cent at 5 years. Chemotherapy differed with time and frequently was associated with subdiaphragmatic involved field and prophylactic contralateral testis radiotherapy. In view of the good prognosis of patients receiving doxorubicin-based chemotherapy and recent reports on low stage nonHodgkin’s lymphoma we recommend an aggressive brief therapy for stage IE lymphoma of the testis after orchiectomy.

The uptake and release of mIBG, a tracer of the monoamine uptake and storage function, were studied on superfused rat cerebral cortex sections. mIBG was taken up and released by a mechanism comparable to that of norepinephrine (NE), but this storage appeared to be less specific for mIBG than for NE. This implies that when mIBG is used as a scintigraphic tracer of monoaminergic synaptic vesicles, imaging should be delayed long enough to ensure release of the molecule from its nonspecific binding sites.

This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. Biodistribution demonstrated an early and preferential uptake by both adrenal glands and heart and then storage in the adrenal gland of both agents, however I-CPP is less stable in vivo than mIBG. Reserpine depletion study in rat indicated that the I-CPP and mIBG uptake mechanisms are not similar.