Prophylactic Response Research Articles

Protective Effect of Ca- Folinate and Ginseng in Male Rats Treated with Methotrexate

The objective of this study was to assess the prevalence of neuron and hepatotoxicity of Methotrexate (MTX) and prophylactic response to Ca- Folinate (Ca-F) and Ginseng (G). Forty two of male albino rat were divided to seven groups six rats for each. 1 st control group received 1ml saline i.p daily for 4weeks (C), 2 nd group treated with Ca-F (5 mg /kg b.wt i.p.) for 4 weeks. 3 rd group treated with G (25 mg /kg b.wt orally) for 4 weeks. 4 th group treated with MTX (0.45 mg /kg b.wt i.p.) for 4 weeks. 5 th group treated with MTX + Ca-F (0.45 mg/kg and 5 mg/ kg i.p.) for 4 weeks, respectively. 6 th group treated with MTX + G (0.45 mg/kg and 25 mg/ kg i.p.) for 4 weeks, respectively. 7 th group treated with MTX + Ca-F + G (0.45 mg/kg, 5 mg/kg and 25 mg/ kg i.p) for 4 weeks, respectively. In this study, aspartic acid (ASP), glutamic acid (GLU), ALT, AST, γ-GT, MDA, GSSG and NO were increase (P< 0.05) in MTX group comparing with control group in rat brain. Glycine (GLY), γ amino butyric acid (GABA), Norepinephrine (NE), Dopamine (DA), serotonin (5TH) and GSH were decrease (P< 0.05) in MTX group comparing with control group in rat brain. All these parameters were improved with G, F and there combination comparing with MTX group. Histopathological examination showed ameliorates effect for all treatments against MTX pathogenesety. It could be concluded that F and G influences and regeneration of neurons amino acids and catecholamine's activity and decrease liver enzymes and oxidative stress markers.

Oral administration of synthetic selenium nanoparticles induced robust Th1 cytokine pattern after HBs antigen vaccination in mouse model.

The present study proposed that the administration of SeNPs with a conventional HBs antigen vaccine induces a better immune response with a Th1 bias.

Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages.

Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future.

Whole cell vaccination using immunogenic cell death by an oncolytic adenovirus is effective against a colorectal cancer model

Cancer vaccine application is limited to specific cancer types because few cancer-associated antigens are known to induce tumor rejection. Accordingly, we assessed the utility of Ad881, an oncolytic adenovirus in which viral replication was strictly regulated by the cancer-specific midkine promoter, as a cancer vaccine in a murine colorectal cancer model lacking specific cancer-associated antigens. In CT26 and CMT93 cells, Ad881 (multiplicity of infection: 100 or 1,000) showed stronger cytotoxicity and oncolysis in vitro than its equivalent replication-defective adenovirus, Ad884. CT26 cells (1 × 104) infected with Ad881 (multiplicity of infection: 1,000) for 24 hours were suitable as vaccine antigens without tumor formation in our model. Repeated vaccinations, but not single vaccination, induced a greater prophylactic immune response. The percentage of mice that rejected the tumor challenge was 0, 4, and 38% after no vaccination, single vaccination, and repeated vaccinations, respectively. Immunogenic cell death marker high-mobility group box 1 protein (HMGB1) and adenosine triphosphate in culture medium were higher after Ad881 infection (24.3 ng/ml and 48.2 nmol/l, respectively) than after Ad884 infection (8.6 ng/ml and 15.4 nmol/l, respectively) or oxaliplatin treatment (3.7 ng/ml and 1.8 nmol/l, respectively). These results indicate that repeated whole cell vaccination using an oncolytic adenovirus may be a potent approach to evoke immunogenic cell death.

Sulodexide. Prophylactic and therapy response to endothelial dysfunction

Endothelial dysfunction plays the key role in the development of cardiovascular system disorders. Sulodexide, decreasing oxidative stress and stabilizing endothelial cells, has protective properties on endothelial dysfunction. The article describes the role of sulodexide both in prophylaxis and therapy of venous and arterial diseases, underlining its clinical efficacy as demonstrated in clinical trials. Besides, the article describes its role in the management of some other diseases, like diabetic nephropathy, diabetic foot, tinnitus, or hemorrhoids.

MDR1 C3435T polymorphism predicts anti-epileptic prophylactic therapy response in Turkish migraine patients

MDR1 C3435T polymorphism predicts anti-epileptic prophylactic therapy response in Turkish migraine patients

Highlights of This Issue

T-cell based immunotherapy seems to be a promising approach as a new treatment for multiple myeloma. Fichtner and colleagues evaluated an impact of immunosuppression and antigen-expression on the development of specific CD8+ T-cell responses against CTA in patients with plasmacell-dyscrasias. The antigen-specific immunoresponses correlated with the expression of the antigen and an early stage of disease. In conclusion, T-cell-based immunotherapy might be performed in an early stage of disease, where the tumor-associated immunosuppression is low and a prophylactic immune response against antigens that were not yet expressed might be possible to establish.Oxidative stress rescue mechanisms have the potential to increase cancer susceptibility, cause chemoresistance, and affect outcome. Despite being a regulator of the main mediator of the redox stress response, NRF2, the Kelch-like ECH-associated protein 1 (KEAP1) has not been extensively studied in breast cancer. Hartikainen and colleagues report associations of KEAP1 gene SNPs with breast cancer risk and survival. In addition to being associated with increased breast cancer risk, the investigated polymorphisms modified the effects of radiotherapy and tamoxifen treatment on patient survival. The knowledge of the involvement of NRF2 pathway in BC lays ground to its translation in clinical use.Natural killer cell lymphomas (NKCLs) are rare but aggressive neoplasms, and little is known concerning the pathogenesis. Küçük and colleagues performed a global analysis of DNA methylation and identified a set of genes recurrently transcriptionally silenced through aberrant promoter hypermethylation. The list is enriched in previously reported tumor-suppressor genes. Many of these genes may contribute to neoplastic transformation by deregulating critical functions such as NK-cell activation/homeostasis and apoptosis. For example, BIM is frequently silenced and its reactivation leads to cell death and increased chemosensitivity in NKCLs. Another interesting finding is the frequent promoter methylation of asparagine synthetase that may predict sensitivity to asparaginase treatment, suggesting the possibility of adjustment in asparaginase containing chemotherapeutic regimens.HGF/MET signaling is frequently activated in human colorectal cancer (CRC) and the mechanism by which the activation of this pathway is not fully elucidated. By using immunohistochemistry, Liu and colleagues found that decreased BATF2 correlates with tumor progression and poor CRC patient prognosis as well as MET expression. In vitro, BATF2 downregulates MET expression through its interaction with c-Jun/AP-1. MET inhibitors in combination with IFN-β produce a synergistic cytotoxicity both in vitro and in vivo. This study suggests that IFNs, as an adjuvant in combination with MET inhibitors, may serve as a novel therapeutic strategy for CRC patients.

Putative Prophylaxes of Aloe vera Latex and Inner Gel as Immunomodulator

Some of the phytochemicals present in Aloe vera can provide relief to rheumatoid arthritis (RA) patients through promoting wound healing as well as reducing inflammation and relieving pain, which are common symptoms of RA patients. Emodin in Aloe vera latex inhibited various inflammation kinases and signaling pathways in vitro and in vivo models of pancreatitis, arthritis and atherosclerosis. Novel molecular targets of emodin have been revealed in therapeutic uses based on animal studies, but only limited data related to the bioavailability, pharmacokinetics and metabolism of emodin are available till now. Western blot and quantitative PCR confirmed aloe emodin in Aloe vera latex up-regulating galectin-3 expression; recombinant galectin-3 augmented expression of antiviral genes IFN-β/r, PKR and 2’,5’-oligoadenylate synthase in infected cells, agreeing with expression pattern of those treated with aloe emodin. Galectin-3 which is a β-galactoside-binding animal protein, is evolutionarily highly conserved and it has been demonstrated in RA patients to advance the transformation of synovial fluid into fibrotic tissue, in addition to activating osteoclasts, producing severe debilitation in patients. More work of emodin and aloe emodin needs to done to fully translate the observed preclinical findings in RA and related complications. Aloe pectins obtained from Aloe vera inner leaf gel were distinguished by size: the room temperature extraction generated a high molecular weight (HMW), whereas extraction with heating produced a low molecular weight pectin. The HMW aloe pectin calcium gel is highly efficient encapsulating agent suitable for controlled release of pharmacological substance, such as protein, antibodies and vaccines. Inhibition of galectin-3 mediated cellular interaction by pectin from dietary sources, such as citrus pectin, was revealed through haemagglutination significantly. The up-regulation of galectin-3 expression by potential therapeutics, such as emodin, aloe emodin, aloe pectin was focused in present review. In addition, protein and/or lectin having anti-inflammatory, radical scavenging and anti-oxidant enzymes’ activity in Aloe vera gel were fully expected as putative prophylactic and biological response modifiers in the treatment of a broad range of inflammatory diseases such as RA.

Factors associated with lithium efficacy in bipolar disorder.

About one-third of lithium-treated, bipolar patients are excellent lithium responders; that is, lithium monotherapy totally prevents further episodes of bipolar disorder for ten years and more. These patients are clinically characterized by an episodic clinical course with complete remission, a bipolar family history, low psychiatric comorbidity, mania-depression episode sequences, a moderate number of episodes, and a low number of hospitalizations in the pre-lithium period. Recently, it has been found that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. Lithium exerts a neuroprotective effect, in which increased expression of brain-derived neurotrophic factor (BDNF) and inhibition of the glycogen synthase kinase-3 (GSK-3) play an important role. The response to lithium has been connected with the genotype of the BDNF gene and serum BDNF levels. A better response to lithium is connected with the Met allele of the BDNF Val/Met polymorphism, as is a hyperthymic temperament. Excellent lithium responders have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. The preservation of cognitive functions in long-term lithium-treated patients may be connected with the stimulation of the BDNF system, with the resulting prevention of affective episodes exerting deleterious cognitive effects, and possibly also with lithium's antiviral effects. A number of candidate genes that are related to neurotransmitters, intracellular signaling, neuroprotection, circadian rhythms, and other pathogenic mechanisms of bipolar disorder were found to be associated with the lithium prophylactic response. The Consortium on Lithium Genetics (ConLiGen) has recently performed the first genome-wide association study on the lithium response in bipolar disorder.

Recontextualizing the behavioral immune system within psychoneuroimmunology.

We believe that the concept of the behavioral immune system (BIS) picks out an important set of phenomena, namely, the relationships between the immune system and disease-avoidant psychology. However, our enthusiasm is tempered by the recognition that (a) there are unresolved ambiguities in the BIS concept, which has been used in a variety of (sometimes inconsistent) ways; (b) many types of phenomena it has been used to identify are already well characterized in other disciplines that have received inadequate attention by BIS researchers; and that (c) these disciplines offer a broader contextualization of the phenomena. We argue that the BIS concept should be recontextualized within and integrated with such research programs. More specifically, we believe that the BIS should be set within the framework of psychoneuroimmunology. We consider several ways in which the BIS might be differentiated from psychoneuroimmunology, arguing that none of these clearly sets the BIS apart. These include (a) the notion of the BIS a purely defensive, prophylactic response to disease threats; (b) the BIS as concerned primarily with disgust-related responses; (c) the BIS’s role in generating large-scale effects of pathogens on social structure; (d) the BIS as a primarily psychological, rather than a mechanistic, account of psycho-immune interactions; and (e) the BIS as a specifically evolutionary, rather than descriptive, approach to disease-avoidant psychology and behavior. We believe that centering BIS research within psychoneuroimmunology will better capture the value and novelty of BIS research, more accurately reflect the intentions of BIS researchers, and better advance their aims.

AAV–sBTLA facilitates HSP70 vaccine-triggered prophylactic antitumor immunity against a murine melanoma pulmonary metastasis model in vivo

Activation of the BTLA–HVEM co-inhibitory signaling pathway impairs antitumor immunity. Our previous study demonstrated that the extracellular domain of murine BTLA (the soluble form of BTLA) can facilitate HSP70 vaccine-triggered antitumor immunity by blocking BTLA–HVEM interactions in a murine TC-1 non-metastatic tumor model. However, it is unknown whether this strategy has beneficial effects on highly malignant metastatic tumors, such as melanoma. To address this question, we expressed the soluble form of BTLA (sBTLA) in combination with HSP70 vaccine and examined the resulting antitumor activity in a melanoma pulmonary metastasis model. A recombinant adeno-associated virus (AAV) vector was used for the sBTLA gene delivery because of its high transfection efficiency and low toxicity. In vitro expression of AAV–sBTLA enhanced lymphocyte activation and induced specific cytotoxicity against B16F1 murine melanoma cells, while in vivo administration of AAV–sBTLA plus HSP70 vaccine by tail vein injection exerted a limited, late-stage antitumor effect against the existing B16F1 cells. However, the combination treatment generated a potent prophylactic antitumor response in the melanoma lung metastasis model in B6 mice. In this case, most of the metastatic foci were inhibited, and mouse survival was prolonged. Furthermore, the Th1 cytokines IL-2 and IFN-γ were up-regulated, while the negative regulatory molecules IL-10 and TGF-β were down-regulated. The number of regulatory T cells also decreased in the tumor environment. Therefore, AAV–sBTLA plus HSP70 vaccine may have therapeutic potential for the prevention of metastatic melanoma.

Induction of IFN-γ cytokine response against hepatitis B surface antigen using melittin.

In this study we co-administered melittin along with HBsAg/alum vaccine to investigate if it helps elicitation of Th1/Th2 response. Hepatitis B virus (HBV) infection is a life-threatening liver infection, which can lead to chronic liver disease. Vigorous T cell responses are stimulated at acute, self-limiting HBV infection, while chronic HBV infection elicits very weak T cell responses. The prevalence of HBV infection has been decreased by the approved vaccination approach using recombinant HBs antigen (HBsAg) and alum i.e. HBV vaccine. Alum, a strong Th2 stimulator, is usually used as adjuvant to increase HBsAg immunogenicity. The present vaccine does not induce protective and/or prophylactic immune response in some groups. Melittin, major active component in the venom of honeybee, induces Th1 development. Experimental mice were immunized with melittin plus hepatitis B vaccine on day 0 following by two booster doses with the same injections. Lymphocyte proliferation, IFN-γ, and IL-4 level, total antibody and isotyping of IgG1, IgG2a IgG2b, and IgM were measured using ELISA. Administration of melittin and HBV vaccine had no effect on lymphoproliferation and total antibody responses, but increased IFN-γ response and induced Th1 response. The present study proposed that administration of melittin along with conventional vaccine shifts T cell responses towards Th1/Th2 dominated with Th1 response. The resultant immune response leads to activation of both cell-mediated and humoral immune responses, both of which required for clearance of HBV infection.

Polymorphism of circadian clock genes and prophylactic lithium response

The therapeutic action of lithium in bipolar mood disorder may be connected with its effect on biological rhythms. In the present study, an attempt was made to investigate an association between multiple single nucleotide polymorphisms (SNPs) and their haplotypes pertaining to four genes involved in regulation of biological rhythms [circadian locomotor output cycle kaput (CLOCK), aryl hydrocarbon receptor nuclear translocator-like (ARNTL), timeless circadian clock (TIMELESS), period circadian clock 3 (PER 3)], and the efficacy of lithium prophylaxis. The study was performed on 115 patients with bipolar mood disorder (45 males, 70 females) with a mean age of 52 ± 12 years, with lithium prophylaxis for 22 ± 8 years, recruited from the outpatients in the Department of Psychiatry, Poznan University of Medical Sciences. The assessment of the lithium prophylactic response was made retrospectively using the Alda scale. Genotyping was done for nine SNPs of the CLOCK gene, 18 SNPs of the ARNTL gene, six SNPs of the timeless circadian clock (TIM) gene, and nine SNPs of the PER3 gene. An association with the degree of lithium prophylaxis was found for six SNPs and three haplotype blocks of the ARNTL gene, and two SNPs and one haplotype block of the TIM gene. No association with SNPs or haplotypes of the CLOCK and PER3 genes was observed. The results suggest that the ARNTL and TIM genes may be associated with the lithium prophylactic response in bipolar illness. This association may be related to the role of these genes in the predisposition to bipolar mood disorder. Of special interest may be polymorphisms of these genes involved both in the predisposition to bipolar mood disorder and the lithium response.

High larval density does not induce a prophylactic immune response in a butterfly

Immune function is greatly affected by biotic and abiotic factors, arguably owing to resource allocation trade‐offs. While starvation typically exerts negative effects on immune function, there are two competing hypotheses regarding the impact of population density: a high population density may decrease or increase immune competence, either as a result of reduced energy stores or of augmented resource allocation to minimise infection risk (density‐dependent prophylaxis). Against this background, the effects of population (= larval rearing) density and transient food stress on adult immune function and life‐history traits in the temperate‐zone butterfly Pieris napi (Linnaeus) have been examined. Both a period of larval starvation and high larval rearing density prolonged the development time and reduced the body mass. All immune parameters measured (pro‐phenoloxidase and phenoloxidase activity, haemocyte number, encapsulation rate) were also negatively affected by high density, whereas starvation had no effect. We thus found no evidence for density‐dependent prophylaxis, but a diminished performance at a high density probably caused by reduced energy stores. The present study reinforces that the maintenance and deployment of an efficient immune system is costly, which may prohibit prophylactic responses to high population densities.

A Conserved Region of Leptospiral Immunoglobulin-Like A and B Proteins as a DNA Vaccine Elicits a Prophylactic Immune Response against Leptospirosis

The leptospiral immunoglobulin-like (Lig) proteins LigA and LigB possess immunoglobulin-like domains with 90-amino-acid repeats and are adhesion molecules involved in pathogenicity. They are conserved in pathogenic Leptospira spp. and thus are of interest for use as serodiagnostic antigens and in recombinant vaccine formulations. The N-terminal amino acid sequences of the LigA and LigB proteins are identical, but the C-terminal sequences vary. In this study, we evaluated the protective potential of five truncated forms of LigA and LigB proteins from Leptospira interrogans serovar Canicola as DNA vaccines using the pTARGET mammalian expression vector. Hamsters immunized with the DNA vaccines were subjected to a heterologous challenge with L. interrogans serovar Copenhageni strain Spool via the intraperitoneal route. Immunization with a DNA vaccine encoding LigBrep resulted in the survival of 5/8 (62.5%) hamsters against lethal infection (P < 0.05). None of the control hamsters or animals immunized with the other vaccine preparations survived. The vaccine induced an IgG antibody response and, additionally, conferred sterilizing immunity in 80% of the surviving animals. Our results indicate that the LigBrep DNA vaccine is a promising candidate for inclusion in a protective leptospiral vaccine.

P.4.010 Association of personality features with lithium prophylactic response

Schizotypy is a multidimensional construct indexing psychometric risk for schizophrenia. This study investigated the factor structure and clinical associations of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) short scales, assessed at follow-up in an originally help-seeking sample identified as ultra-high risk for psychosis.Participants were 228 help-seeking individuals identified as ultra-high risk for psychosis between 2 and 14 years previously (mean, 7.09; SD, 3.17; median, 6.41). The 43-item O-LIFE short scales (Unusual Experiences, Introvertive Anhedonia, Cognitive Disorganization, Impulsive Nonconformity) and indices of depression, anxiety, positive and negative psychotic symptoms, functioning, and quality of life were administered at follow-up. Structural equation modeling was used.Impulsive Nonconformity was shown to be an unstable factor and was excluded. A 3-factor model of Unusual Experiences, Cognitive Disorganization, and Introvertive Anhedonia was found to be the best description of the data, compared with a 1-factor model. Unusual Experiences factor was associated with positive psychotic symptoms; Cognitive Disorganization was associated with depression and anxiety; and Introvertive Anhedonia was associated with positive and negative psychotic symptoms, quality of life, and functioning.The Impulsive Nonconformity factor of the O-LIFE short scales should be interpreted with caution. A well-fitting 3-factor model provides support for a dimensional structure in schizotypy that is similar to that of schizophrenia. Separate dimensions were differentially associated with psychopathology, functioning, and quality of life. The interpersonal dimension of schizotypy was the only dimension associated with poorer functioning and quality of life and may be a sensitive indicator of need for care.

1732 – Characteristics associated with lithium response in bipolar I and II disorders

Lithium remains the gold standard of prophylactic treatment in bipolar disorder. However 10–40% of patients are not responder to lithium and there is still no operational predictive markers of lithium response. Moreover, previous studies relate some conflicting results due to the absence of an unanimous definition and evaluation of prophylactic lithium response. Our objective was to identify clinical factors associated with prophylactic lithium response assessed by Alda questionnaire that includes 6 categories of prophylactic response from no response for at least two years of treatment to no relapse for three years. To study characteristics associated with lithium response. All 516 participants met the DSM-IV criteria for bipolar disorder. They all received at least once in their life lithium (for at least two years) and all completed the Alda questionnaire. They were compared on several sociodemographic and clinical factors which were collected using the DIGS. Psychological dimensions were assessed with the ALS and AIS (for affective lability and instability), the BIS (for impulsivity) and the WURS (for ADHD screening) and history of childhood trauma. Among the 516 subjects, 132 (25,6%) were lithium responders with no relapse during at least two years of treatment; 106 (20,5%) were poor lithium responders. These groups were compared for clinical, dimensional and childhood trauma characteristics, using both univariate and multivariate analyses. Characteristics associated with lithium response may help to define personalized strategies.

Association of ABCB1 Polymorphisms with the Antiemetic Efficacy of Granisetron plus Dexamethasone in Breast Cancer Patients

Resistance to antiemetic treatment with 5-hydroxytryptamine 3 receptor antagonists is a problem, with 20-30% of patients showing unsatisfactory responses. Efflux transport by P-glycoprotein, encoded by the ATP-binding cassette ABCB1 gene in the blood-brain barrier, has been the suggested resistance mechanism. We evaluated the association between the antiemetic efficacy of granisetron plus dexamethasone and ABCB1 polymorphisms 3435C>T and 2677G>T/A. Sixty-four breast cancer patients treated with doxorubicin plus cyclophosphamide were evaluated for their responses to antiemetic therapy. Genotyping of patient DNA samples for ABCB1 single nucleotide polymorphisms was performed; the genotypes were then investigated for their association with the efficacy of prophylactic antiemetics. The acute phase complete response rate was 83% in GG subjects (n = 12), and 69% (n = 35) and 41% (n = 17) in heterozygous and homozygous carriers of the 2677T/A allele, respectively (p = 0.047). The ABCB1 2677 TT genotype group showed significantly lower rates of complete control of acute emesis than the group with GG genotypes (p = 0.045). No significant association with complete response was found for 3435C>T (p = 0.190). ABCB1 polymorphisms may influence the extent of acute emesis control in granisetron-treated patients, making the ABCB1 genotype a predictor of prophylactic antiemetic response.

TEMPS-A and long-term lithium response: Positive correlation with hyperthymic temperament

BackgroundLithium is still regarded as a cornerstone for the long-term treatment of bipolar disorder. The best response to lithium is associated with clinical features of episodic clinical course, complete remission, bipolar family history and low psychiatric comorbidity. However, a specific personality profile for the best lithium response was not estimated so far. Such a possibility occurred with an advent of temperament scale for bipolar disorder and of an ability to quantitatively assess lithium prophylactic response. MethodsThe study was performed on 71 patients with bipolar mood disorder (21 males, 50 females), aged 31–82 (59±12) years, which have been treated with lithium carbonate for at least 5 years (5–37 years, mean 15 years). In all patients, the assessment of five temperaments of TEMPS-A scale (depressive, cyclothymic, hyperthymic, irritable and anxious) was done, and correlated with the quality of lithium prophylaxis according to Alda scale. ResultsThe mean scores for five temperaments of TEMPS-A were not significantly different in male and female patients. The response to lithium correlated significantly positively with hyperthymic temperament score (r=0.31, p=0.009), and negatively with anxiety (r=−0.27, p=0.022), cyclothymic (r=−0.26, p=0.032), and depressive (r=−0.23, p=0.052) temperaments scores. LimitationsRelatively small number of patients. ConclusionsThe main finding of the study is an association of lithium response with hyperthymic temperament. This positive correlation as well as other negative correlations between lithium response and TEMPS-A temperaments are discussed in view of clinical and genetic findings in bipolar patients.

Phase II trial of huKS-IL2 with cyclophosphamide (CTX) in patients with extensive disease small-cell lung cancer (ED-SCLC).

7090 Background: huKS-IL2 immunocytokine is a humanized antibody specific for EpCAM, fused at its Fc end to two molecules of IL2. Results of a phase 1b study of huKS-IL2 plus low-dose CTX, and preclinical data, provided a rationale to evaluate this combination in SCLC, which is often EpCAM-positive. Methods: Patients (pts) with ED-SCLC responding (PR/CR) to 4 cycles of first-line Pt-based chemotherapy were randomized 1,5:1 to receive huKS-IL2/CTX or best supportive care (BSC). Pts in the huKS-IL2/CTX arm received six 21-day cycles of CTX 300 mg/m2 on day (d) 1, and 1.5 mg/m2/d huKS-IL2 on d2–4, followed by 21-d cycles of CTX on d1 and huKS-IL2 on d2 until progression. Pts were stratified for prophylactic cranial irradiation (PCI) and response to chemotherapy. Primary endpoint was PFS rate at 6 months (mo). Secondary endpoints included OS rates at 12 and 18 mo from start of Pt-based chemotherapy, median PFS and OS, safety, and immunogenicity. Results: 108 pts (64 huKS-IL2/CTX arm, 44 BSC arm) were randomized and treated. Baseline characteristics were balanced between arms; however, higher % of males (75 vs 61.4%) and of ECOG PS 0 (45.3 vs 38.6%) were observed in the active arm. Median age was 61.7 (32; 81) and 59.2 (45; 74) years in the active and BSC arm, respectively. Most pts were in PR at randomization (2 pts – 1 in each arm – had CR). PCI was used in 15 (23.4%) and 11 (25%) pts in the active and BSC arm, respectively. No significant differences in PFS or OS were observed in the active vs BSC arm: PFS rate was 6.4 vs 12.2%; median PFS was 1.5 vs 1.4 mo; OS rates at 12 and 18 mo were 52 vs 61% and 24 vs 29%, respectively; median OS was 12.3 vs 14.1 mo. One PR (45% reduction vs randomization baseline) was observed in the active arm. In a subset of pts who received PCI, median PFS was 1.7 vs 1.5 mo, median OS 21.5 vs 14.3 mo in the active vs BSC arm, respectively. AEs observed more frequently in the active arm were flu-like symptoms, rash, hypotension, lymphopenia, LFT and creatinine elevations; all Grade 3/4 AEs related to huKS-IL2 were reversible/manageable. Conclusions: HuKS-IL2/CTX was well tolerated, but showed no benefit in pts with ED-SCLC in PR/CR after chemotherapy. A trend for improved PFS and OS was observed in pts who received prior PCI.