[Comorbidity in 207 cannabis users in a specific outpatient setting]. / Comorbidités chez 207 usagers de cannabis en consultation jeunes consommateurs.

BACKGROUND: Health care seeking for a problematic use of cannabis is in progress in France. OBJECTIVES: The aim is to assess the addictive and psychiatric comorbidity in cannabis users seen in the specific setting at the Lariboisière hospital. METHOD: Two hundred and seven cannabis users were included from January 2004 to December 2009. Twelve-month and lifetime diagnosis of abuse and dependence (cannabis, alcohol, cocaine/crack) (DSM-IV), current and lifetime mood disorders, anxiety disorders, eating disorders and psychotic disorders were assessed (Mini-International Neuropsychiatric Interview). Logistic regression analyses identified adjusted odds ratios associated with the gender and the health care seeking (P=0.01). RESULTS: One hundred and forty-seven men (71%) and 60 women (29%), 29.3±8.6 years (15.2-51.6 years). Most of the outpatients ask for health care themselves (59.7%), whereas 19.4% are asked to seek health care by relatives (19.4%) or because of an academic, health or justice injunction (20.4%). In total, 49.3% of the outpatients are single, 35.7% are cohabitating, 9.3% are married and 6.3% are separated/divorced. About 20.4% of the outpatients are students, 35.7% have a professional activity, 19% are jobless, 2.4% are impaired, 0.5% are retired, at home and 12.1% do not have an official income. Twelve-month and lifetime prevalence of abuse/dependence are: cannabis (10.1/82.1% and 8.7/88.4%), alcohol (9.7/8.7% and 19.3/18.8%), cocaine/crack (2.4/3.4% and 4.8/11.6%). The mean duration of cannabis dependence for the current dependent users is 8.4±5.8 years. The mean number of "joints" during the last 6 months is 6±4.3, the mean amount of cannabis per week is 12.5±11.3g. About 51.3% of the dependent users report externalized and/or internalized disorders at school during childhood and adolescence. In total, 19.4% of the dependent users have a suicide attempt history and 18.9% have a psychiatric hospitalisation history, more frequently women (P<0.01 and P=0.02). About 73.8% have a psychologist or psychiatrist care history. In total, 38.1% of users have at least one current mood disorder, females more frequently than males (P<0.001). Current and lifetime prevalence of mood disorders are: major depressive disorder (MDD) (29.1% and 57.1%); current dysthymia (20.3%); hypomania (1.9 and 6.7%); mania (2.9 and 12.8%). Females have more frequently than males current and lifetime MDD (P<0.001). About 53.2% of users have at least one current anxiety disorder, females more frequently than males (P<0.001). Current and lifetime prevalence of anxiety disorders are: panic disorder (10 and 16.4%); agoraphobia (13.9 and 17.4%); social phobia (26.9 and 32.8%); obsessive-compulsive disorder (9.5 and 12.9%); post-traumatic stress disorder (PTSD) (6.5 and 16.4%); current generalized anxiety disorder (26.8%). Females have more frequently current and lifetime: agoraphobia (P=0.01 and P<0.001); PTSD (P<0.001); current social phobia (P=0.049). Current and lifetime eating disorders prevalence are: anorexia (0 and 1.5%); bulimia (4 and 8%); females more frequently have bulimia (P=0.02 and P<0.001). In total, 4.8% have a psychotic disorder. Adjusted odds ratios of associated variables to gender (women/men) are lifetime MDD OR=4.71 [2.1-10.61] (P<0.001) and later age of onset of cannabis abuse OR=1.1 [1.04-1.17] (P=0.002). Adjusted odds ratios associated with personal health care seeking compared to a non personal motivated health care seeking are the numbers of criteria of 12-month cannabis dependence OR=1.26 [1.06-1.51] (P=0.009) and age OR=1.07 [1.03-1.12] (P=0.002). CONCLUSION: Our survey confirms the high mood and anxiety disorders comorbidity in cannabis dependent users seen in a specific setting and underlines the need to evaluate those disorders.

Refining perception-based farmer typologies with the analysis of past census data.

Perception-based typologies have been used to explore the decision making process of farmers and to inform policy design. These typologies have been criticised, however, for not fully capturing true farmer behaviour, and are consequently limited for supporting policy formulation. We present a method that develops a typology, using a social survey approach based on how farmers perceive their environment (e.g. birds and agri-environmental schemes). We then apply time-series census data on past farm strategies (i.e. land use allocation, management style and participation into agri-environmental schemes) to refine these typologies. Consequently, this offers an approach to improving the profiling of farmer types, and strengthens the validity of input into future agricultural policies. While the social survey highlights a certain degree of awareness towards birds with respect to farmer types, the analysis of past farm strategies indicated that farmers did not entirely follow their stated objectives. External factors such as input and output price signals and subsidy levels had a stronger influence on their strategies rather than stated environmental and social issues. Consequently, the refining of farmer types using this approach would aid the design of policy instruments, which integrate ecological issues within planning.

[Cannabis withdrawal syndrome in patients with cannabis dependence only, and in patients with cannabis and opioid dependence]. / Syndrome de sevrage au cannabis dans une population de patients mono- et polydépendants (cannabis et opiacés).

BACKGROUND: The cannabis withdrawal syndrome occurs after cannabis cessation in more than 50% of dependent smokers. But although opioid-dependent patients are more frequently cannabis users and cannabis-dependent than the general population, the frequency and phenomenology of cannabis withdrawal symptoms in this specific population is unknown. Our hypothesis was that cannabis-dependent patients with current opioid dependence would experience the same withdrawal syndrome after cannabis cessation. OBJECTIVE: To describe cannabis withdrawal symptoms in cannabis-only dependent patients and in cannabis-dependent patients with current opioid dependence. METHODS: Using retrospective interviews, we evaluated the number and duration of six cannabis withdrawal symptoms in two groups: 56 cannabis-dependent patients without and 43 cannabis dependent patients with current opioid dependence. Cannabis and opioid dependence diagnoses were defined with DSM IV criteria using the MINI structured interview. RESULTS: The two groups were not different in terms of age of onset of cannabis use, and number of cannabis joints smoked at the time of the cannabis cessation attempt. The frequency of a cannabis withdrawal syndrome (defined as at least two different symptoms) did not differ in the two groups (65%). Neither was the proportion of subjects with the following symptoms: appetite or weight loss (30.8%), irritability (45.1%), anxiety (56%), aggression (36.3%) and restlessness (45.1%). Patients with cannabis dependence and current opioid dependence were more likely to report sleep disturbances (79.1 vs. 53.6%, chi(2)=6.91, P=0.007). The median duration of this cannabis withdrawal syndrome was 20 days post-cessation. CONCLUSION: This is, to our knowledge, the first study describing cannabis withdrawal syndrome in cannabis-dependent patients with current opioid dependence. These patients experience a cannabis withdrawal syndrome as often as cannabis-only dependent subjects, but describe more frequently sleep disturbances. This high rate of sleep disturbances may cause relapse to cannabis use.

[Sociodemographic profiles, addictive and mental comorbidity in cannabis users in an outpatient specific setting]. / Facteurs sociodémographiques, conduites addictives et comorbidité psychiatrique des usagers de cannabis vus en consultation spécialisée.

CONTEXT: In the 1990s, cannabis consumption in France increased considerably. So, in 10 years, the number of adolescents reporting regular cannabis use (10 or more times during the last 12 months) tripled. In 2004, an official program to address problems related to cannabis addiction was implemented. As part of this program, specific outpatient settings for cannabis use disorders were created. OBJECTIVE: We present the sociodemographic characteristics, the prevalence of cannabis, alcohol and others psychoactive substances and the prevalence of mental disorders in 90 cannabis users seen at an outpatient specific setting for cannabis use disorders in the Lariboisière hospital (a university hospital in Paris). MEASURES: Twelve months prevalence of substance abuse and dependence, psychiatric diagnoses based on the DSM-IV and the Mini-International Neuropsychiatric Interview (MINI) results are described. RESULTS: The study population had the following characteristics: 67% male, mean age 27.5 (S.D.=8.4) years and 59% single or divorced. Approximately, two-thirds of the users (67%) were students or currently working and 32% were unemployed. Twenty-two percent of the cannabis users received unemployment, welfare or disability benefits and 11% declared no source of revenue. Most of the users (63%) decided on their own to seek care at the setting. Seventy-three percent of the subjects had seen a psychologist or a psychiatrist in the past, with or without relation to cannabis use. By far, most of the users were cannabis dependent (82%) and 9% cannabis abusers in the last 12 months according to DSM-IV criteria prior to their visit. Seven percent of the cannabis users had alcohol dependence and 7% were abusers. The 12 months prevalence of cocaine or ecstasy dependence was 2% and the prevalence of benzodiazepines, heroin or stimulants dependence 1%. The main substances used over lifetime were tobacco (99%); alcohol (96%); cocaine (41%); benzodiazepines and hypnotics (41%); ecstasy (40%) and heroin (23%). Four percent of cannabis users had a history of intravenous drug use. The main consumption mode of cannabis in France is the blunt. About three-quarters of the consumption is in the form of resin (hashish) and one-quarter as marijuana (grass). The average consumption of cannabis in the last six months was equivalent to 5.8 blunts per day (S.D.=4.4) and 12 g per week (S.D.=10.5), and the average monthly cost was 159 euro (S.D.=133) (234 USD, S.D.=196). The prevalence of psychiatric disorders according to DSM-IV criteria in the sample is high. A current mood disorder was present in 48% and an anxiety disorder in 55% of the cannabis users in the last 12 months. The prevalence of affective disorders in the last 12 months was major depressive disorder (38%), dysthymia (19%), hypomania (3%) and mania (1%). The prevalence of anxiety disorders in the last 12 months was social phobia (29%); generalised anxiety disorder (17%); panic disorder with or without agoraphobia (16%); obsessive compulsive disorder (12%); agoraphobia without panic disorder (9%) and post-traumatic stress disorder (5%). The prevalence of schizophrenia was 4%. The prevalence of bulimia was 4% and no anorexia. Women are more likely to report an affective disorder (64% versus 41%; p=0.04) or a post-traumatic stress disorder (17% versus 0%; p<0.001) in the last 12 months. The prevalence of family history for psychiatric disorders was 52% and for addiction, 59%. CONCLUSIONS: The cannabis users seen in our specific setting are a fairly homogeneous group and for the most part addicted to cannabis only, but with very high rates of dependence. Indeed, other than tobacco dependence, 80% of the users were only dependent on, or abused on cannabis in the last 12 months. In comparison with the cohort of French cannabis users (n=4202) seen at specific outpatient settings for marijuana users in 2005, cannabis users seen in Lariboisière Hospital are older, the percentage of females is greater, they are more dependent on marijuana and have a high prevalence of affective and anxiety disorders.

Smoking ban in a psychiatry department: are nonsmoking employees less exposed to environmental tobacco smoke?

Staff members of psychiatric facilities are at high risk of secondhand smoking. Smoking exposure was assessed in 41 nonsmoking employees of a psychiatry department before and after a ban. Subjective exposure measures decreased in 76% of the subjects. Salivary cotinine decreased in the subsample of seven subjects with high pre-ban levels (32+/-8 vs 40+/-17 ng/ml, p=.045).

[Does addiction to antidepressants exist? About a case of one addiction to tianeptine]. / La toxicomanie aux antidépresseurs existe-t-elle? A propos d'un cas de dépendance à la tianeptine.

We report on a tianeptine dependence lasting for eighteen months in a 42 year old patient. The patient had a previous history of addiction to opiates, amineptine, cocaïne and alcohol. He also had a family history of addiction to alcohol and opiates. Tianeptine was prescribed for a major depressive disorder. The patient alleged a "flash sensation" like with heroin since the very first doses with a physical and psychological well-being sensation, better psychomotor performances and transient mood elation. His addiction to tianeptine was immediate and heavy. The positive reinforcement faded away after one month and a total dependance took over, with physical and psychological withdrawal symptoms when doses were not renewed. After two months of treatment, the daily consumption of tianeptine was of 90 tablets. The patient was hospitalised to treat both the addiction to tianeptine and the ongoing major depressive disorder. He was taking 240 tablets daily. In the literature, reports of addictions to antidepressants are scarce and most of them involve agents with amphetamine-like properties, including amineptine and tranylcypromine. Other reports involving other antidepressant agents, including amitriptyline, fluoxetine and tianeptine remain exceptional. Addictions to antidepressants almost exclusively concern patients with a diagnosis of personality disorder and a previous history of drug or alcohol abuse and who are treated for a depressive disorder. Tianeptine, which is devoid of any psychostimulating effect in human, does not seem to have addictive properties apart from the reports of scarce cases.

[Catatonia de novo, report on a case: immediate vital prognosis and psychiatric prognosis in longer term]. / Catatonie de novo, à propos d'un cas: pronostic vital immédiat et pronostic psychiatrique à plus long terme.

We report on the case of a 20 year old woman with no previous psychiatric history, who displayed a first episode of catatonia with acute onset. Symptoms started plainly with sudden general impairment, intense asthenia, headache, abdominal pain and confusion. After 48 hours, the patient was first admitted to an emergency unit and transferred to an internal medicine ward afterwards. She kept confused. Her behaviour was bizarre with permanent swinging of pelvis, mannerism, answers off the point and increasingly poor. The general clinical examination was normal, except for the presence of a regular tachycardia (120 bpm). The paraclinical investigations also showed normal: biology, EEG, CT Scan, lumbar puncture. Confusion persisted. The patient remained stuporous, with fixed gazing and listening-like attitudes. She managed to eat and move with the help of nurses but remained bedridden. The neurological examination showed hypokinaesia, extended hypotonia, sweating, urinary incontinence, bilateral sharp reflexes with no Babinski's sign and an inexhaustible nasoorbicular reflex. The patient was mute and contrary, actively closed her eyes, but responded occasionally to simple instructions. For short moments, she suddenly engaged in inappropriate behaviors (wandering around) while connecting back to her environment answering the telephone and talking to her parents. The patient's temperature rose twice in the first days but with no specific etiology found. During the first 8 days of hospitalization, an antipsychotic treatment was administered: haloperidol 10 mg per os daily and cyamemazine 37.5 mg i.m. daily. Despite these medications, the patient worsened and was transferred to our psychiatric unit in order to manage this catatonic picture with rapid onset for which no organic etiology was found. On admission, the patient was stuporous, immobile, unresponsive to any instruction, with catalepsy, maintenance of postures, severe negativism and refusal to eat. A first treatment by benzodiazepine (clorazepate 20 mg i.v.) did not lead to any improvement. The organic investigations were completed with cerebral MRI and the ruling out of a Wilson's disease. Convulsive therapy was then decided. It proved dramatically effective from the first attempt; 4 shocks were carried out before the patient's relatives ask for her discharge from hospital. The patient revealed she had experienced low delirium during her catatonic state. The clinical picture that followed showed retardation with anxiety. She was scared with fear both for the other patients and the nursing team. She kept distant and expressed few affects. The treatment at the time of discharge was olanzapine 10 mg per os. She was discharged with a diagnosis of catatonia but with no specific psychiatric etiological diagnosis associated. She discontinued her follow-up a few weeks later. After one year, we had no information about her. Catatonia has now become rare but remains a problem for clinicians. We reviewed data concerning short term vital prognosis and psychiatric long term prognosis in catatonia. Lethal catatonia is associated with acute onset, both marked psychomotor and neurovegetative symptoms. In the light of literature, there is no proband clinical criterion during the episode that is of relevant diagnostic value to ascertain the psychiatric etiology.

IgG-recognizing shed tumor-associated antigens can promote tumor invasion and metastasis.

Tumors secreting glycoproteins that act as tumor-associated antigens have been described as highly invasive and metastatic. In this study, the consequences of the humoral immune response (HIR) against these antigens were investigated. Using an in vitro model of tumor cell invasion, results indicated that the invasiveness of tumor cells secreting antigenic secreted/shed tumor glycoproteins (STGP) increases in the presence of specific anti-STGP IgG, polymorphonuclear cells and monocytes. This in vitro model showed that the coincidental presence in the matrix of both STGP and specific anti-STGP IgG increases the local release of IL-1beta, IL-6 and vascular endothelial growth factor (VEGF) by stromal cells, but not by tumor cells. Using an in vivo model, the experiments show that immune-competent mice develop an anti-tumor HIR with anti-STGP IgG production. In this model, tumor growth was increased in parallel with the serum concentration of specific anti-STGP IgG. In athymic nude (nu/nu)-beige mice the same trend was observed, suggesting a T-cell-independent tumor-promoting effect induced by anti-STGP IgG. Tumor histology showed intense infiltration of IgG-positive plasma cells and lymphocytes. A severe combined immunodeficient-beige mouse-based in vivo model of tumors, experimentally infiltrated with monoclonal IgG plasmocytoma cells, showed that only specific anti-STGP-IgG-secreting cells could exacerbate tumor invasion, angiogenesis and metastasis. These results suggest that tumors shedding/secreting antigenic STGP can induce a host IgG immune response that can promote invasion and metastasis by inducing tumor infiltrating stromal cells to release proinflammatory cytokines and VEGF.

Tumor cells express FcgammaRI which contributes to tumor cell growth and a metastatic phenotype.

High levels of circulating immune complexes containing tumor-associated antigens are associated with a poor prognosis for individuals with cancer. The ability of B cells, previously exposed to tumor-associated antigens, to promote both in vitro and in vivo tumor growth formed the rationale to evaluate the mechanism by which immune complexes may promote tumor growth. In elucidating this mechanism, FcgammaRI expression by tumor cells was characterized by flow cytometry, polymerase chain reaction, and sequence analysis. Immune complexes containing shed tumor antigen and anti-shed tumor antigen Ab cross-linked FcgammaRI-expressing tumor cells, which resulted in an induction of tumor cell proliferation and of shed tumor antigen production. Use of selective tyrosine kinase inhibitors demonstrated that tumor cell proliferation induced by immune complex cross-linking of FcgammaRI is dependent on the tyrosine kinase signal transduction pathway. A selective inhibitor of phosphatidylinositol-3 kinase also inhibited this induction of tumor cell proliferation. These findings support a role for immune complexes and FcgammaRI expression by tumor cells in augmentation of tumor growth and a metastatic phenotype.

Direct in vivo transfection of antisense Fas-ligand reduces tumor growth and invasion.

The expression of Fas ligand (FasL) by tumor cells has been reported to have multiple, conflicting effects on tumor growth. The majority of the data support the theory that FasL expressing tumor cells evade immune surveillance by killing T cells expressing Fas. However, the role of the humoral immune-blockade by FasL expressing tumor cells has not been assessed. Using immune-competent mice, we observed that FasL expressing tumor cells reduced the antitumor antibody production together with the T and B cell content of the spleen in these mice. Further, to determine if the expression of FasL in the environment of the tumor suppresses the humoral antitumor immune response and influences tumor growth, a mouse model lacking T cells was used. To assess whether a local reduction of FasL could reduce tumor progression, a plasmid encoding antisense FasL cDNA was delivered directly into a growing tumor (SW620 colon carcinoma). Intratumoral delivery of the plasmid was able to transfect tumor cells, stromal cells, and peritumoral muscle cells. This antisense FasL tumor tissue transfection persisted for at least 25 days, produced a systemic decrease in soluble FasL, and resulted in a 50% reduction in the rate of tumor growth when compared with tumor tissue of the control groups. These results suggest that direct transfection of antisense FasL cDNA impairs FasL translation in tumor and stromal cells, and can inhibit tumor progression by impairing the FasL-mediated, stromal cell-assisted, tumor counter-attack.

B lymphocyte pathology in human colorectal cancer. Experimental and clinical therapeutic effects of partial B cell depletion.

Accumulating data are showing that the humoral immune response against tumors could favor tumor progression. However, no B lymphocyte pathology has been reported in cancer. Using anti-IgM Ab we nonspecifically depleted B cells in tumor-bearing mice, a treatment that resulted in significant reduction of tumor burden. We analyzed the B lymphocyte phenotype of abdominal lymph nodes and peripheral blood from advanced colon cancer patients by flow cytometry, and compared the B cell phenotype with that found in samples from normal donors. In both lymph nodes and peripheral blood of cancer patients, abnormal populations of B lymphocytes appeared that express an increased CD21 and/or sTn antigens on their cell surface. All patients showed a reduction of CD19+ cells. In a limited clinical test, we analyzed the effects of a partial B cell depletion with Rituximab. The treated patients did not develop any side-effects; the CD21-hyperpositive lymphocytes were reduced, but the proportion of sTn-positive lymphocytes remained unaffected. Apparent reduction of the tumor burden was reported in 50% of the patients when the treatment was ended.

[Mental disorders and migraine: epidemiologic studies]. / Troubles mentaux et migraine: données épidémiologiques.

Epidemiologic studies in the general population, taking into account certain bias inherent to the clinical observation have confirmed the clinical impression reporting a higher psychiatric comorbidity with persons suffering from migraine than in persons without migraine. Persons with migraine are at increased risk for affective and anxiety disorders, personality traits disorders (neuroticism), suicide attempts, but not for alcohol or illicit drug abuse. The comorbidity is more important in migraine with aura than in migraine without aura. Concerning affective disorders, the lifetime prevalence of major depression is 34.4% in persons with migraine and 10.4% in persons without migraine. For bipolar I disorder, prevalence is 6.8% in migraine with aura versus 0.9% when no migraine. Compared to no migraine, the lifetime prevalence of anxiety disorders in migraine is significantly increased in: panic disorder (10.9% vs 1.8%); generalized anxiety disorder (10.2% vs 1.9%); obsessive-compulsive disorder (8.6% vs 1.8%); phobic disorder (39.8% vs 20.6%). In addition, no psychopathological, biological or genetic explanation seems to be meaningful for the comprehension of this comorbidity pattern. These results remain primarily descriptive but they justify a clinical investigation of affective and anxiety disorders, and suicide attempts, in all person with migraine, and it also justifies the treatment of pain associated with the treatment of eventual affective or anxiety disorders.

Promotion of tumor invasion by cooperation of granulocytes and macrophages activated by anti-tumor antibodies.

We investigated the potential role of anti-tumor antibodies and tumor antigens in the formation of immune complexes which promote matrix degradation and angiogenesis. B-cell deficient or B-cell depleted mice showed a reduction in tumor invasion and metastasis. In vitro invasion assays and in vivo models of metastasis showed that anti-sTn antibodies and sTn tumor antigens form complexes which induce granulocytes and macrophages together to mediate tumor invasion and metastasis by processes including extracellular matrix degradation and angiogenesis. These results suggest the existence of a tumor promoting role of a B-cell immune response induced by shed tumor associated antigens of solid, nonlymphoid tumors.

Staging of colorectal cancer: biology vs. morphology.

PURPOSE: An accurate determination of the extent or staging of a disease is critical, because it provides the basis for making therapeutic decisions. Staging is a collaborative effort by the surgeon and the pathologist. Radioimmunoguided surgery has been evaluated for its ability to help surgeons determine the extent of disease during surgery, when management decisions have the most impact on patient care. This study was done to compare radioimmunoguided surgery "biostaging" with traditional pathologic staging (TNM) as predictors of survival in patients undergoing curative resections for colorectal cancer. METHODS: Ninety-seven patients with colorectal cancer were prospectively enrolled in radioimmunoguided surgery protocols. Evaluation of follow-up survival data was performed. All patients underwent exploratory laparotomy and radioimmunoguided surgery with resection of their primary colorectal tumor. Survival data were analyzed with the Kaplan-Meier method with log-rank comparisons. RESULTS: Of 97 patients enrolled in the study, 59 were evaluable and completely resectable by radioimmunoguided surgery. Mean follow-up was 62 months, with a range of 34 to 89 months. By traditional staging 13 patients were pStage I, 18 patients were pStage II, and 28 patients were pStage III. By radioimmunoguided surgery biostaging, 24 patients were radioimmunoguided surgery-negative whereas 35 patients were radioimmunoguided surgery-positive. Survival rates by pathologic stage approached a significant difference, but did not, as of the conclusion of the study period, reach it (P = 0.12). Survival rates based on radioimmunoguided surgery status demonstrated a highly significant difference (P = 0.0002). CONCLUSIONS: Radioimmunoguided surgery biostaging provides new information intraoperatively on cancer staging that has not been available before. This may lead to new strategies for therapy that can be individualized and optimized for each patient with cancer.

First results for resetting the antitumor immune response by immune corrective surgery in colon cancer.

BACKGROUND: A critical step for cancer recurrence is the failure of the cellular immune response. It is suspected that chronic humoral immune responses against some tumor-associated antigens (TAA) can contribute to that failure. METHODS: In this study, we tested the ability of an immune corrective surgical procedure to prevent recurrences of colon cancer in stages I, II, and III. Radiolabeled anti-TAG antibodies injected intravenously become concentrated on TAG-72 immune complexes presented by follicular dendritic cells, which are responsible for the persistent humoral response against TAG-72 TAA. Using a hand-held gamma probe, we can intraoperatively detect and remove lymph nodes involved in TAG-72 presentation. By removing these lymph nodes, together with the tumor tissue, presentation and source of TAG-72 are drastically reduced. RESULTS: The impact of this TAA suppression on the tumor recurrence process is analyzed in a sample of 24 patients. The immune corrective surgical procedure did not increase morbidity. Five years after surgery the following were disease free: 5 of 5 stage I, 6 of 6 stage II, and 10 of 13 stage III. The global survival of this group was 87.5%. Compared with the standard surgical treatment of colon cancer (58% survival for the same stages), this surgical immune corrective procedure introduces a statistically significant improvement of 29% (P <0.001). CONCLUSIONS: The surgical removal of lymph nodes involved in the persistent humoral immune response against TAA has an important beneficial impact on colon cancer treatment.

[Lymphadenectomy in colorectal carcinoma]. / Lymphadenektomie beim colorectalen Carcinom.

Recurrence of colorectal carcinomas occurs in about 50% of the cases with localized neoplasia. It is understood that the tumor recurrence is due to residual micrometastases not found during surgery or extraregional (peripheral blood or bone marrow). We developed a procedure to detect non-visible, abdominal metastases using a radiolabeled anti-tumor cell antibody injected before the operation (radioimmunoguided surgery RIGS). However, even with the best technique, it is not possible to remove all micrometastasis if a hematogenic dissemination happens. Based on the knowledge of disturbing humoral immune reaction is mounted against shed tumor associated antigens (TAA), we developed a new method to reduce and correct the B cell response and B cell recruitment due to chronic TAA immun complex presentation on follicular dendritic cells (immune corrective surgery, ICS). This method is based on a selective lymphadenectomy. The target lymph nodes were those loaded with TAA-immune complex. The detection method used was the injection of radiolabeled antibody able to recognize the immune complex. From 20 patients (stage I, II and III) treated with ICS, 17 survived more than 5 years 'showing a statistically significant increase of survival compared to patients treated with standard procedures. In conclusion, these data show that surgery of colorectal cancer should be selectively extended to specific anatomical regions in order to remove hidden micrometastases, and more importantly, correct postoperative immune processes that could suppress the T cell response against residual tumor cells.

Extramedullary hematopoiesis in the adult mouse liver is associated with specific hepatic sinusoidal endothelial cells.

In previous work, two anatomically distinct-liver sinusoid endothelial cells (LEC): LEC-1 and LEC-2, have been described. We also reported that extramedullary hepatic hematopoiesis occurs only in close contact with LEC-1, suggesting that these cells may provide the microenvironment necessary for the maintenance and growth of hematopoietic cells. In the present work, we studied the capacity of LEC-1 and LEC-2 to maintain in vitro hematopoiesis. LEC-1 and LEC-2 were isolated and cloned from livers of adult mice. Bone marrow cells (BM) enriched with primitive hematopoietic progenitors were isolated from day-2, post-5-FU-treated mice (5-FUBMC). LEC-1 supported the maintenance and differentiation of hematopoietic progenitors for more than 6 weeks in vitro. In contrast, LEC-2 cells poorly supported the proliferation of hematopoietic cells for only two weeks of the co-culture. LEC-1 and 5-FUBMC cocultures showed cobblestone-area formation and the presence of hematopoietic progenitors that are able to form colonies (CFC) in the adhering fraction after six weeks of coculture. LEC-1 co-cultures treated with a cocktail of cytokines (stem cell factor, interleukin [IL]1alpha, IL-3, and Epo) showed that megakaryocyte (CFU-Mk) and erythrocyte progenitors (BFU-e) were present during the entire period of the culture. Granulocyte-macrophage progenitors (CFU-GM) were present only during the first three weeks of the culture. These results suggest that LEC-1, but not LEC-2, provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of primitive hematopoietic cells. This could explain the anatomical restriction of hematopoietic cells for growing in LEC-1 domains during liver extramedullary hematopoiesis.

[Toxic habits in relation to cancer of the larynx]. / Hábitos tóxicos en relación con el cáncer de laringe.

Various modifiable toxic risk factors for cancer of the larynx were evaluated in our geographic area in a retrospective epidemiological study of a sample of 373 patients diagnosed as cancer of the larynx chosen randomly at the La Fe Hospital of Valencia Spain over a 5-year period. A "z" test of the contrast of proportions of the laryngeal cancer series studied and the results of a National Health Survey showed significant differences between the two study populations (p < 0.05). Compared with the National Health Survey, smoking had an odds ratio (OR) of 72.21 (33.10 < OR < 166.31) (p < 0.05, Mantel-Haenszel test). The association between smoking and cancer of the larynx increased with the dose. Alcohol consumption had an OR: 1.52 (1.09 < OR < 2.11) (p < 0.05, Mantel-Haenszel test). Smoking carried a risk of 71.21 and had an etiological fraction of 98.61% (IC 95%: 65.17-100%), thus representing 98.61% of all etiological factors. Control of smoking could have prevented 65.17-100% of cases of cancer of the larynx (243 cases in our series). Alcohol consumption had a risk of 0.52 and etiological fraction of 34.21% (IC 95%: 2.38-100%). Control of alcohol use could have prevented cancer of the larynx in 2.38-100% of cases (9 cases in our series).

Radioimmunoguided Surgery for Gastrointestinal Malignancies: An Analysis of 14 Years of Clinical Experience.

BACKGROUND: The identification of all sites of intra-abdominal adenocarcinoma is key to optimal surgical resection and tumor staging. Conventional imaging methods and direct visualization and palpation have limited sensitivity and specificity. Radioimmunoguided surgery (RIGS) has a potential to improve these parameters. METHODS: The development of the RIGS concept is presented, and the studies of tumor localization, detection of disseminated disease, staging, and survival are correlated with the tumor biopsy of gastrointestinal carcinoma, particularly colorectal carcinoma. RESULTS: RIGS can detect clinically and histologically occult neoplasm. Also, by providing immediate intraoperative information, the RIGS approach improves surgical staging, impacts on surgical and medical care, and affects patient prognosis. CONCLUSIONS: RIGS may become the standard of care for the surgical staging and treatment of colorectal cancer and other gastrointestinal malignancies.