Prostate cancer: Autologous immunotherapy optimized by indoleamine-2,3-dioxygenase (IDO)-inhibitor as immune-tolerance breaker

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12509-12509
Author(s):  
E. M. Lasalvia-Prisco ◽  
E. Garcia-Giralt ◽  
S. Cucchi ◽  
J. Larrañaga ◽  
D. Wagner

12509 Background: In several peer review publications (Cancer Biol Ther 2003) our team has reported a procedure of cancer immunotherapy using an autologous thermostable hemoderivative vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors including prostate cancer. Last year (ASCO Meeting 2005) we have reported that the tolerance break for tumor associated antigens through the interference with CD4+CD25+ regulatory cells is a component of the mechanism of action of the ATHV antitumoral effect. Therefore, we have intended to optimize this autologous immunotherapy adding to the procedure different steps of immune-tolerance blockage selected due to their proven efficacy in pre-clinical models and their feasibility in the frame of ATHV technology. In this study we report the results in prostate cancer when the adjuvant step added was the translational knowledge the tolerance blockage by IDO-inhibition through 1-Methyl-Tryptophane or 1-MT (Munn DH et al J Exp Med 1999). Methods: Thirty metastasic prostate cancer patients, hormone and chemotherapy resistant, Performance Status ≤ 2 and PSA progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were randomized in 3 groups submitted to 3 different treatments: I, only sympthomatic; II, the previously reported ATHV and III, ATHV + simultaneous s.c. 1-MT. Tumor size increase (tumor growth) measured according RECIST was registered in each case. Mean difference in the 3 groups was statistically assessed (Student’s t-test). Tryptophane to Kynurenine conversion was tested to assess IDO inhibition. Results: Tumor growth was significantly slower in Group II and III than in Group I (p<0.01 and p<0.005). Tumor growth was also significantly slower in Group III than in Group II (p<0.02). IDO-inhibition was confirmed only in Group III. No relevant toxicities were detected. Conclusions: These results support that additional tolerance break by IDO-inhibition optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine. No significant financial relationships to disclose.

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12515-12515
Author(s):  
E. Garcia-Giralt ◽  
E. Lasalvia-Prisco ◽  
S. Cucchi ◽  
E. Lasalvia-Galante ◽  
J. Vazquez ◽  
...  

12515 Background: Advanced ovarian cancer has been included in several studies about an immunotherapy procedure using an Autologous Thermostable Hemoderivative Vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors (Cancer Biol Ther 2003). Like in most cancer vaccines, the net anti-tumoral effect of ATHV has low intensity despite the addition of several adjuvant steps: immune response enhancement by GM-CSF, immune tolerance break by cyclophosphamide or interference with CD4+CD25+ regulatory cells (E. Lasalvia-Prisco et al. ASCO 2003–2005). The inclusion of another adjuvant immunomodulatory step to ATHV in patients with advanced ovarian cancer was explored in this study. The tested adjuvancy was the local and remote immune-stimulation elicited by a subcutaneous silicate-granuloma (SSG), a phenomenon well proven in preclinical models (RM Fauve et al. Immune Lett 1987; E Fontan et al Proc Nat Acad of Sci 1983). Methods: Twenty four metastasic ovarian cancer patients, chemotherapy resistant, performance status ≤ 2 and CA-125 progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were 3-group randomized, submitted to 3 different treatments: I only sympthomatic; II the previously reported ATHV and III ATHV + SSG. Tumor Growth was assessed in each case by the tumor size increase (RECIST measured). Mean difference in the 3 groups was statistically assessed (Student’s test). Results: Tumor Growth was slower in Group II and III than in Group I (p<0.02, p<0.005). Tumor growth was slower in Group III than in Group II (p<0.02). No relevant toxicities were detected. Conclusions: The results support that in advanced ovarian cancer an additional subcutaneous silicate granuloma as adjuvant agent optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine. The bypass of the immune-ignorance could be discussed as its mechanism of action. No significant financial relationships to disclose.


2013 ◽  
Author(s):  
Παναγιώτης Σιδεράς

Aim: The consecutive administration of two different bone seeking radio-pharmaceuticals such as 186Re-HEDP and 89Sr-Cl was compared with 89Sr-Cl plus chemotherapy and 186Re-HEDP alone were investigated to determine the effectiveness and toxicity in pain palliation of bone metastases in patients with prostate, breast and lung cancer.Material and Methods: The effect of treatment with consecutive infusions with 186Re-HEDP and 89Sr-Cl was compared with 89Sr-Cl plus chemotherapy and 186Re-HEDP alone on pain symptoms, quality of life and bone marrow function. In total, we treated 32 patients of which 11 (Group I) were treated (5 men with prostate cancer and 6 women with breast cancer) with consecutive infusions with 186Re-HEDP and 89Sr-Cl, 12(Group II) were mostly men with prostate cancer that received 89Sr-Cl plus chemotherapy and 9 patients (Group III) 6 women with stage IV breast cancer, 1 man with lung cancer and 2 men with hepatocellular cancer with 186Re-HEDP alone. The follow up period was 16 weeks. In Group I the patients received an infusion of 186Re-HEDP [(dose of 1200MBq (32.4 mCi) ±96.21 MBq (2.6mCi)] followed by bi-weekly blood counts until 8 weeks to measure myelotoxicity. At the end of this period 89Sr-Cl was infused at a dose of 137 MBq (3.7mCi) ± 3.63MBq (0.098mCi) followed in the same manner with bi-weekly measurement in blood counts to estimate overall patient responsiveness to therapy, increase in performance and toxicity. In Group II all patients received a standard dose of 89Sr-Cl [148MBq(4 mCi) ± 2.2 MBq (0.06 mCi). In Group III all patients received a standard 186Re-HEDP dose of 1480 MBq (40 mCi) ± 3.7MBq (0.01 mCi) and Zolendronate. All patients were interviewed using standardized form of questions before and after therapy weekly for 16 weeks.Results: In Group I 91%(10/11) of the patients reported pain relief after the end of 16 weeks whereas 18% (2/11) reported discontinuation of their analgesics and remained pain-free. Pain showed a decrease from 7.8±1.7 to a value of 2.8±1.2 on a visual analogue scale (p<0.0001). Patients also described an improvement on Karnofsky performance scale from 68±6 to 79±4 (p<0.005), 16 after completion of therapy. Myelotoxicity was observed in 2 patients (18%) manifesting as thrombocytopenia grade III, 4(36%) stage II and 5(45%) as stage I. The maximum nadir of platelets and leukocyte counts were observed at the end of 4 weeks of each therapy and was completely reversible at the end of each therapy. In Group II which was comprised mainly from prostate cancer patients 67%(8/12) reported pain relief at the end of 16 weeks with only 1 patient (8%) discontinued all analgesics. Pain score on VAS decreased from 8.3±1.8 to 3.7±1.7 (p<0.0001), improvement on Karnofsky performance scale was from 75 to 80. Myelotoxicity was seen in 4/12 (33%) of the patients and this could be attributed likely to the combined affect of chemotherapy and radioisotope treatment manifesting as grade III thrombocytopenia, grade II in 6/12 (50%) and only in 2/12 (16%) as grade I. In group III, which appeared a slightly more heterogenous than the other two groups, 1 lung cancer patient expired within the 16 weeks of follow up likely secondary to type I respiratory failure and 1 patient with hepatocellular carcinoma was lost to follow up. All other patients mainly breast cancer showed adequate analgesia with decrease of pain on VAS from 8.2±1.3 to 4.1±1.9 (p<0.008) with none discontinuing all analgesics. Improvement on Karnofsky scale was recorded as 75-80(p>0.2). Myelotoxicity was seen in 2/9 (22%) manifesting as grade III thrombocytopenia, 4/9 (44) as grade II and 3/9 (33%) as grade I.Conclusion: All radiopharmaceuticals used either consecutively or in combination with chemotherapy or alone were effective in metastatic bone pain palliation. There was no significant induction of Myelotoxicity except with a percentage of 33% seen in 89Sr-Cl plus chemotherapy group. In this small prospective study we achieved bone pain palliation with consecutive administration of 2 different radiopharmaceuticals. We modified slightly the dose of 186Re-HEDP such as to avoid serious and potentially lethal myelotoxicity. We achieved a greater and longer analgesic response as compared to the other two groups based on the fact that faster induction of analgesia was attained with the relatively low beta emitter 186Re-HEDP and greater pain relief with a longer duration of pain control the high beta emitter 89Sr-Cl.


2005 ◽  
Vol 15 (1) ◽  
pp. 26-31 ◽  
Author(s):  
V. Loizzi ◽  
C. Rossi ◽  
G. Cormio ◽  
A. Cazzolla ◽  
D. Altomare ◽  
...  

The purpose of this study was to investigate the clinical features of hepatic metastasis in patients with epithelial ovarian cancer. From 1998 to 2002, all women with hepatic metastasis from ovarian cancer were identified at the University of Bari. Twenty-nine patients identified included one having stage IIC, one stage IIIA, two stage IIIB, 17 stage IIIC, and eight stage IVB. Eight women had hepatic metastasis at the time of the diagnosis of ovarian cancer (group I), 10 patients had hepatic metastasis as first recurrence (group II), and 11 (group III) as a second relapse. The median survival from the time of liver metastasis diagnosis was 19 months in group I patients, 24 months in group II patients, and 10 months in group III patients. No statistical differences in survival were seen among the three groups (P = 0.7). Cell type, performance status at the time of the primary tumor diagnosis, number of hepatic lesions, the presence of other sites of disease at the time of hepatic metastasis, and platinum-based chemotherapy were significantly related to survival. Better performance status, serous cell-type tumor, single hepatic lesion, the absence of other sites of disease, and platinum-based chemotherapy are good prognostic factors.


Author(s):  
K.K. SEKHRI ◽  
C.S. ALEXANDER ◽  
H.T. NAGASAWA

C57BL male mice (Jackson Lab., Bar Harbor, Maine) weighing about 18 gms were randomly divided into three groups: group I was fed sweetened liquid alcohol diet (modified Schenkl) in which 36% of the calories were derived from alcohol; group II was maintained on a similar diet but alcohol was isocalorically substituted by sucrose; group III was fed regular mouse chow ad lib for five months. Liver and heart tissues were fixed in 2.5% cacodylate buffered glutaraldehyde, post-fixed in 2% osmium tetroxide and embedded in Epon-araldite.


1998 ◽  
Vol 80 (09) ◽  
pp. 393-398 ◽  
Author(s):  
V. Regnault ◽  
E. Hachulla ◽  
L. Darnige ◽  
B. Roussel ◽  
J. C. Bensa ◽  
...  

SummaryMost anticardiolipin antibodies (ACA) associated with antiphospholipid syndrome (APS) are directed against epitopes expressed on β2-glycoprotein I (β2GPI). Despite a good correlation between standard ACA assays and those using purified human β2GPI as the sole antigen, some sera from APS patients only react in the latter. This is indicative of heterogeneity in anti-β2GPI antibodies. To characterize their reactivity profiles, human and bovine β2GPI were immobilized on γ-irradiated plates (β2GPI-ELISA), plain polystyrene precoated with increasing cardiolipin concentrations (CL/β2GPI-ELISA), and affinity columns. Fluid-phase inhibition experiments were also carried out with both proteins. Of 56 selected sera, restricted recognition of bovine or human β2GPI occurred respectively in 10/29 IgA-positive and 9/22 IgM-positive samples, and most of the latter (8/9) were missed by the standard ACA assay, as expected from a previous study. Based on species specificity and ACA results, IgG-positive samples (53/56) were categorized into three groups: antibodies reactive to bovine β2GPI only (group I) or to bovine and human β2GPI, group II being ACA-negative, and group III being ACA-positive. The most important group, group III (n = 33) was characterized by (i) binding when β2GPI was immobilized on γ-irradiated polystyrene or cardiolipin at sufficient concentration (regardless of β2GPI density, as assessed using 125I-β2GPI); (ii) and low avidity binding to fluid-phase β2GPI (Kd in the range 10–5 M). In contrast, all six group II samples showed (i) ability to bind human and bovine β2GPI immobilized on non-irradiated plates; (ii) concentration-dependent blockade of binding by cardiolipin, suggesting epitope location in the vicinity of the phospholipid binding site on native β2GPI; (iii) and relative avidities approximately 100-fold higher than in group III. Group I patients were heterogeneous with respect to CL/β2GPI-ELISA and ACA results (6/14 scored negative), possibly reflecting antibody differences in terms of avidity and epitope specificity. Affinity fractionation of 23 sera showed the existence, in individual patients, of various combinations of antibody subsets solely reactive to human or bovine β2GPI, together with cross-species reactive subsets present in all samples with dual reactivity namely groups III and II, although the latter antibodies were poorly purified on either column. Therefore, the mode of presentation of β2GPI greatly influences its recognition by anti-β2GPI antibodies with marked inter-individual heterogeneity, in relation to ACA quantitation and, possibly, disease presentation and pathogenesis.


2015 ◽  
Vol 18 (3) ◽  
pp. 098
Author(s):  
Cem Arıtürk ◽  
Serpil Ustalar Özgen ◽  
Behiç Danışan ◽  
Hasan Karabulut ◽  
Fevzi Toraman

<p class="p1"><span class="s1"><strong>Background:</strong> The inspiratory oxygen fraction (FiO<sub>2</sub>) is usually set between 60% and 100% during conventional extracorporeal circulation (ECC). However, this strategy causes partial oxygen pressure (PaO<sub>2</sub>) to reach hyperoxemic levels (&gt;180 mmHg). During anesthetic management of cardiothoracic surgery it is important to keep PaO<sub>2</sub> levels between 80-180 mmHg. The aim of this study was to assess whether adjusting FiO<sub>2</sub> levels in accordance with body temperature and body surface area (BSA) during ECC is an effective method for maintaining normoxemic PaO<sub>2</sub> during cardiac surgery.</span></p><p class="p1"><span class="s1"><strong>Methods:</strong> After approval from the Ethics Committee of the University of Acıbadem, informed consent was given from 60 patients. FiO<sub>2</sub> adjustment strategies applied to the patients in the groups were as follows: FiO<sub>2</sub> levels were set as 0.21 × BSA during hypothermia and 0.21 × BSA + 10 during rewarming in Group I; 0.18 × BSA during hypothermia and 0.18 × BSA + 15 during rewarming in Group II; and 0.18 × BSA during hypothermia and variable with body temperature during rewarming in Group III. Arterial blood gas values and hemodynamic parameters were recorded before ECC (T1); at the 10th minute of cross clamp (T2); when the esophageal temperature (OT) reached 34°C (T3); when OT reached 36°C (T4); and just before the cessation of ECC (T5).</span></p><p class="p1"><span class="s1"><strong>Results:</strong> Mean PaO<sub>2</sub> was significantly higher in Group I than in Group II at T2 and T3 (<em>P</em> = .0001 and <em>P</em> = .0001, respectively); in Group I than in Group III at T1 (<em>P</em> = .02); and in Group II than in Group III at T2, T3, and T4 <br /> (<em>P</em> = .0001 for all). </span></p><p class="p1"><span class="s1"><strong>Conclusion: </strong>Adjustment of FiO<sub>2</sub> according to BSA rather than keeping it at a constant level is more appropriate for keeping PaO<sub>2</sub> between safe level limits. However, since oxygen consumption of cells vary with body temperature, it would be appropriate to set FiO<sub>2</sub> levels in concordance with the body temperature in the <br /> rewarming period.</span></p>


2016 ◽  
pp. 108-111
Author(s):  
T.F. Tatarchuk ◽  
◽  
D.G. German ◽  

The article presents the comparative analysis of the state of the cervix in women with endometrial polyps and micropolyps. Patients and methods. The study involved 130 patients aged 18-35 years: 70 patients with endometrial polyps (group I), 30 patients with micropolyps (group II) and 30 patients of the control group (group III). Results. According to the anamnesis of women in the I group were significantly more frequent diseases of the cervix, which corrected physical surgery methods, in particular cryodestruction. In group II, the representatives of these indicators were similar to healthy. Normal colposcopic picture met significantly less frequently in patients and I, and II group. The differences in the incidence of HPV high oncogenic risk in all groups were not statistically significant. Conclusion. Destructive methods used in the detection of any changes in the cervix are often overly aggressive, form scars and contributing to inflamaciones process. In the chain of events leading to the formation of PE, cervical pathology and its correction can take the basic place. Key words: endometrial polyp, micropolyps, chronic endometritis, uterine cervix, colposcopy.


Author(s):  
Г.В. ШИРЯЕВ ◽  
Ю.Г. ТУРЛОВА ◽  
Г.С. НИКИТИН

Изучено влияние кормовой добавки в форме индивидуальных болюсов Метраболь на возможность снижения негативного влияния субклинического кетоза (СКК) и результативность искусственного осеменения высокопродуктивных молочных коров в посттранзитный период. Животные были подобраны по принципу условных аналогов и разделены на 3 группы в зависимости от концентрации β-оксимасляной кислоты в их крови. В I группе (n=18) у коров не было СКК, концентрация кислоты составляла <1,0 ммоль/л, во II группе (n=21) у животных зарегистрирован СКК, концентрация кислоты — 1,0…1,4 ммоль/л. С целью поиска решения по снижению негативного влияния СКК на репродуктивные показатели была сформирована III группа коров, переболевших СКК (n=24) с концентрацией β-оксимасляной кислоты в крови 1,0…1,4 ммоль/л, но с использованием болюсов, применяемых для ускоренного восстановления репродуктивной функции коров после отела. Важной составляющей опыта явилось то, что к моменту гормональной синхронизации у коров всех 3 групп фиксировалось отсутствие СКК (снижение β-оксимасляной кислоты до уровня <1,0 ммоль/л). Для синхронизации полового цикла выбрана схема Пресинх-овсинх. Установлено, что гормональная синхронизация животных, перенесших СКК, в сравнении со здоровыми, не позволяет снизить негативное влияние данного нарушения обмена веществ. Во II группе у животных зафиксированы самые низкие репродуктивные показатели (количество использованных доз; индекс осеменения, сервис-период; время от первого до успешного осеменения; результат первичного осеменения; количество животных, осемененных 3 и более раз). В III группе применение болюсов позволило, в сравнении с животными II группы, не только избежать отрицательного воздействия СКК, но и превзойти по изучаемым параметрам животных из I группы. The effect of the feed additive in the form of individual boluses Metrabol on the possibility of reducing the negative effect of subclinical ketosis (CCK) and the effectiveness of artificial insemination of highly productive dairy cows in the post-transit period was studied. The animals were selected according to the principle of conditional analogs and divided into 3 groups depending on the concentration of β-hydroxybutyric acid in their blood. In group I (n=18), the cows did not have SSC, the acid concentration was <1.0 mmol/L, in group II (n=21), SSC was registered in animals — 1.0...1.4 mmol / L. In order to find a solution to reduce the negative effect of CCB on reproductive indices, a group III of cows was formed who had CCB (n = 24) with a concentration of β-hydroxybutyric acid in their blood of 1.0...1.4 mmol/L, but using boluses, used to accelerate the restoration of the reproductive function of cows after calving. An important component of the experiment was that by the time of hormonal synchronization, cows of all 3 groups had no SSC (decrease in β-hydroxybutyric acid to a level of <1.0 mmol/L). To synchronize the sexual cycle, the Pressinh-ovsinh scheme was chosen. It was found that hormonal synchronization of animals that underwent SSC, in comparison with healthy ones, does not allow reducing the negative effect of this metabolic disorder. In group II, animals had the lowest reproductive indices (number of doses used; insemination index, service period; time from first to successful insemination; result of primary insemination; number of animals inseminated 3 or more times). In group III, the use of boluses made it possible, in comparison with animals of group II, not only to avoid the negative effect of SSC, but also to surpass the animals from group I in terms of the studied parameters.


Author(s):  
M. M. Chaudhary ◽  
C. T. Khasatiya ◽  
S. B. Patel ◽  
S. S. Chaudhary ◽  
V. B. Atara ◽  
...  

The serum progesterone and estradiol profiles during synchronization of estrus by buck effect and PGF2α treatments were monitored in Surti does. Total eighteen non-pregnant does selected were evenly divided into 3 groups, 6 does in each group. The does of Group I were teased with a sexuallyactive- apronized buck; and those of Group II were treated with PGF2α, i.e., Inj. Lutalyse® @ 7.5 mg/doe IM twice 11 days apart, while the Group III served as untreated control. Blood samples were collected from all the animals on day 0 (before 1st PGF2α injection), 3rd day (during treatment), 11th day (before 2nd PGF2α injection), 14th day (after treatment) and 40th day (post-service) by jugular vein puncture. The serum separated was stored at -20°C till further analysis. In all the three groups, 83.33% does, conceived at first service in the sampling cycle. The overall mean serum progesterone concentration of Group I does (5.82±0.72 ng/ml) was significantly higher (p less than 0.01) as compared to Group II (2.93±0.38 ng/ml) and III (2.88±0.30 ng/ml). Similarly, the overall mean serum progesterone concentration of Surti does on day 0 (2.65±0.46 ng/ml), 3rd (2.56±0.80 ng/ml), 11th (4.45±0.84 ng/ml) and 14th (3.40±0.63 ng/ml) did not differ significantly, but the overall mean level at day 40 (6.31±0.45 ng/ml) was significantly (p less than 0.01) higher, because most of animals became pregnant at that time. The overall mean serum oestradiol-17β levels of Group I (24.40±2.98 pg/ ml) was significantly higher (p less than 0.01) than in Group II (15.77±1.77 pg/ml) and III (12.21±1.45 pg/ ml). On the other hand, the overall mean serum oestradiol-17β levels of Surti does on day 0 (12.89±1.21 pg/ml), 3rd (15.84±1.74 pg/ml), 11th (14.81±1.96 pg/ml), 14th (22.15±2.97 pg/ml) and 40th (21.64±5.16 pg/ml) did not differ significantly (p>0.05) and the slightly higher overall mean level found at 40th day might be the influence of the non-pregnant does at first service in the cumulative animals. The hormonal profile reflected the initiation of cyclicity and establishment of pregnancy in treated and control animals.


2020 ◽  
Author(s):  
Jan Niclas Mumm ◽  
Lucas Bohn ◽  
Lennert Eismann ◽  
Alexander Buchner ◽  
Theresa Vilsmaier ◽  
...  

BACKGROUND Pelvic floor training (PFT) is the gold standard for conservative treatment of male stress urinary incontinence. OBJECTIVE To evaluate patients´ perspective at risk of incontinence on PFT and application of digital technologies for PFT. METHODS Patients undergoing transurethral surgery of the prostate (group I), radical prostatectomy (group II) or treatment at a specialized incontinence outpatient clinic (group III) were surveyed anonymously. Chi-Square test and Kruskal-Wallis-analysis were used for statistical analysis. RESULTS 180 patients were included in the final analysis. In group I (n=35) no patient underwent PFT prior to transurethral surgery. 23.5% of patients in group II (n=51) and 95.7% of patients in group III (n=94) performed PFT. 11.4% in group I, 80.4% in group II and 91.5% in group III have been advised to perform PFT by their urologist. Regarding the information level on PFT, patients from group I (median 1, range 0-5) are less satisfied than patients from group II (median 3, 0-9) or group III (median 5, range 0-10, p<0.001). 88.6% of patients from group I are willing to perform PFT as preventive treatment or to avoid incontinence surgery, 100% from group II and 68.4% from group III (p<0.001). The likelihood to use digital PFT is higher in group I (median: 9, range 0-10) and II (median: 9, range 0-10) than in group III (median: 4, range 0-10, p<0.001). CONCLUSIONS Patients at risk of incontinence currently have limited access to PFT, although they are willing to perform PFT. Digital PFT is highly accepted by patients preoperatively and might be a valuable tool to increase PFT participation.


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